Indolyl-pyridinones and related compounds and their use in therapy

Abstract

The invention provides indolyl-pyridinones and related compounds, pharmaceutical compositions, their use for inhibiting signal transducer and activator of transcription 6 (STAT6), and their use in the treatment of a disease or condition, such as an inflammatory disorder, allergic condition, or proliferative disorder.

Description

INDOLYL-PYRIDINONES AND RELATED COMPOUNDS AND THEIR USE IN THERAPYCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 779,570, filed March 28, 2025, and United States Provisional Patent Application serial number 63 / 721,053, filed November 15, 2024; the contents of each of which are hereby incorporated by reference.FIELD OF THE INVENTION

[0002] The invention provides indolyl-pyridinones and related compounds, pharmaceutical compositions, their use for inhibiting signal transducer and activator of transcription 6 (STAT6), and their use in the treatment of a disease or condition, such as an inflammatory disorder, allergic condition, or proliferative disorder.BACKGROUND

[0003] Inflammatory disorders impact a substantial number of patients and often involve situations where the patient’s biological response to a stimulus results in the immune system attacking the body’s own cells or tissues. This can lead to abnormal inflammation and result in chronic pain, redness, swelling, stiffness, and / or damage to normal tissues. Current treatment options for these inflammatory disorders are not effective for all patients and / or can have substantial adverse side effects.

[0004] Signal transducer and activator of transcription 6 (STAT6) is a protein that transmits signals from receptor complexes to the nucleus in order to activate gene expression. STAT6 is implicated in regulation of genes that control cell proliferation and immune cell function, polarization of the immune system, various allergic conditions, and the development of tumors.

[0005] New compounds that inhibit STAT6 are needed to treat STAT6-mediated diseases and conditions. The present invention addresses the foregoing needs and provides other related advantages.SUMMARY

[0006] The invention provides indolyl-pyridinones and related compounds, pharmaceutical compositions, their use for inhibiting signal transducer and activator of transcription 6 (STAT6), and their use in the treatment of a disease or condition, such as an inflammatory disorder, allergic condition, or proliferative disorder. In particular, one aspect of the invention provides a collection of indolyl-pyridinones 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 indolyl-pyridinones and related compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0007] Another aspect of the invention provides a collection of indolyl-pyridinones, such as a compound represented by Formula II:(II)or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of indolyl-pyridinones and relatedcompounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.Another aspect of the invention provides a collection of indolyl-pyridinones, such as a compound represented by Formula A-I:(A-I)or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of indolyl-pyridinones and related compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0008] Another aspect of the invention provides a collection of indolyl-pyridinones, such as a compound represented by Formula A-II:or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of indolyl-pyridinones and related compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0009] Another aspect of the invention provides a method of treating a disease or condition mediated by STAT6 in a subject. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II, A-I, or A-II, to a subject in need thereof to treat the disease or condition, as further described in the detailed description.

[0010] Another aspect of the invention provides a method of treating a disease or condition selected from an inflammatory disorder, allergic condition, or proliferative disorder. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II, A-I, or A-II, to treat the disease or condition.

[0011] Another aspect of the invention provides a method of inhibiting the activity of STAT6. The method comprises contacting a STAT6 with an effective amount of a compound described herein, such as a compound of Formula I, II, A-I, or A-II, to inhibit the activity of said STAT6, as further described in the detailed description.DETAILED DESCRIPTION

[0012] The invention provides indolyl-pyridinones and related compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma translocation protein 1 (STAT6), and their use in the treatment of a disease or condition, such as an inflammatory disorder, allergic condition, or proliferative disorder. 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. Blackwell, eds.); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987, and periodic updates); and Current Protocols in Immunology’’’ (J. E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.

[0013] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.Definitions

[0014] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March ’s Advanced Organic Chemistry, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0015] The term “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. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In certain embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, 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 certain embodiments, “cycloaliphatic” refers to a monocyclic C3-C6hydrocarbon 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.

[0016] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” 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. In certain embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain 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). In certain embodiments, 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. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups.Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

[0017] Exemplary bridged bicyclics include:H

[0018] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0019] The term “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0020] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in A-substituted pyrrolidinyl)).

[0021] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0022] As used herein, the term “bivalent Ci-s (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0023] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n– wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0024] The term “-(Co alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-” encompasses a bond (i.e., Co) and a -(C1.3 alkylene)- group.

[0025] The term “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.

[0026] The term “halogen” or “halo” means F, Cl, Br, or I.

[0027] The term “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. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more nonaromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “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 (.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.

[0028] The terms “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 n electrons shared in a cyclic array; and having, in additionto carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / / quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0029] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it. The term “pyridinylene” refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it. For example, “pyridinylene” is a bivalent pyridine radical when it has twogroups attached to it (e.g., ); “pyridinylene” is a trivalent pyridine radical when ithas three groups attached to it (e.g., ). The term “pyridazinylene” refers to a multivalent pyridazine radical having the appropriate number of open valences to account for groups attached to it. For example, “pyridazinylene” is a bivalent pyridazine radical when it hasN-N1 _ / / \\ _ |two groups attached to it (e.g., \= / ). The term “pyrimidinylene” refers to a multivalent pyrimidine radical having the appropriate number of open valences to account for groups attached to it. For example, “pyrimidinylene” is a bivalent pyrimidine radical when it has two N—.groups attached toit (e.g.,NI ).

[0030] 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. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, 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-dihydro-2 / / pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in A substituted pyrrolidinyl).

[0031] 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. Examples of such 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. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3A-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by an oxo group. The term “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 ithas two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.

[0032] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0033] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “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. Unless otherwise indicated, 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. The term “stable,” as used herein, 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.

[0034] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(CH2)o 4R0; -(CH2)o 4OR0; -0(CH2)o-4R°, -0-(CH2)O 4C(O)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O4SRO; -(CH2)O4Ph, which may be substituted with R°; -(CH2)o 40(CH2)O iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O4N(RO)2; -(CH2)O4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O 4N(R°)C(O)NR°2;-N(R°)C(S)NRO2; -(CH2)O^N(R°)C(0)OR°; -N(R°)N(R°)C(0)R°; -N(R°)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)o4C(O)OR°; -(CH2)o4C(O)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)O4OC(O)R°; -OC(0)(CH2)O-ISR-, SC(S)SR°; -(CH2)o4SC(O)R°; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O ^OC(O)NRO2;-C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)o4SSR°; -(CH2)o4S(O)2R°; -(CH2)O4S(O)2ORO; -(CH2)O4OS(O)2R°; -S(0)2NRO2; -S(O)(NR°)R°; -S(O)2N=C(NR°2)2; -(CH2)O 4S(0)RO; -N(R°)S(O)2NRO2; -N(R°)S(0)2RO; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -0P(0)(0RO)2; SiR°3; -(Ci^ straight or branched alkylene)O-N(R°)2; or-(Ci-4 straight or branched alkylene)C(O)O-N(R°)2.

[0035] Each R° is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono-or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =0 and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, -(CH2)o2R*, -(haloR*), -(CH2)o-2OH, -(CH2)o2OR*, -(CH2)0 2CH(OR*)2; -O(haloR*), -CN, -N3, -(CH2)0 2C(O)R*, -(CH2)o2C(O)OH, -(CH2)02C(O)OR*, -(CH2)O 2SR*, -(CH2)O2SH, -(CH2)O 2NH2, -(CH2)O 2NHR’, -(CH2)O 2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR*.

[0036] Each R* is independently selected from Ci-4aliphatic, -CH2Ph, -0(CH2)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; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2 3O-, or -S(C(R*2))2-3S-, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] When R* is Ci-6 aliphatic, R* is optionally substituted with halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is independently selected from Ci4aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0038] An optional substituent on a substitutable nitrogen is independently R, -NR^, -C(O)Rf, -C(O)ORf, -QO / CCC Rt, -C(O)CH2C(O)Rt, -S(O)2R+, -S(O)2NRf2, -C(S)NRt2, -C(NH)NR^2, or -N(R^)S(O)2Rt; wherein each R:is independently hydrogen, Ci-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 Ci-6 aliphatic,:is optionally substituted with halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is independently selected from Ci-4 aliphatic, -CH2Ph, -0(CH2)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.

[0039] As used herein, 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. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate,cyclopentanepropionate, digluconate, dodecyl sulfate, 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, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0040] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977, 66(1), 1-19; P. Gould, International J. of Pharmaceutics 1986, 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference.

[0041] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci 4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0042] Unless otherwise stated, 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 A conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are withinthe 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.

[0043] 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. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) 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.

[0044] 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 an atropisomer e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.

[0045] 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.

[0046] Unless specified otherwise, the term “about” refers to within ±10% of the stated value. The invention encompasses embodiments where the value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0047] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0048] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and Ci-Ce alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0049] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0050] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group.

[0051] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0052] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, / c / V-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. The term “hydroxyalkoxyl” refers to an alkoxyl group that is substituted with at least one hydroxyl.Exemplary hydroxyalkoxyl groups include -OCH2CH2OH. -OC^CTH OH C^CFEOH, and the like. The term “alkoxylene” refers to a bivalent alkoxyl group.

[0053] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0054] The symbol “ ” indicates a point of attachment.

[0055] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0056] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0057] As used herein, 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, include humans.

[0058] As used herein, the term “compound” refers to a quantity of molecules that is sufficient to be weighed, tested for its structural identity, and to have a demonstrable use (e.g., a quantity that can be shown to be active in an assay, an in vitro test, or in vivo test, or a quantity that can be administered to a patient and provide a therapeutic benefit).

[0059] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.

[0060] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations,applications, or dosages and is not intended to be limited to a particular formulation or administration route.

[0061] As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0062] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0063] As used herein, 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 oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remingto ’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] ,

[0064] Throughout the description, where 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.

[0065] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.I. Indolyl-pyridinones and Related Compounds

[0066] The invention provides indolyl-pyridinones 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.

[0067] Part A

[0068] One aspect of the invention provides a compound represented by Formula I:(I)or a pharmaceutically acceptable salt thereof; wherein:R2is Ci-6 alkyl, Ci-6 hydroxyalkyl, C3-7 cycloalkyl, halo, -C(O)-(Ci-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(triazolonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7;R3is hydrogen, C1-4 alkyl, Ci-4haloalkoxyl, or C3-7 cycloalkyl;R4is Ci-4alkyl, C1.4 hydroxyalkyl, C3-7 cycloalkyl, Ci-4alkoxyl, Ci-4haloalkoxyl, -(C1-4 alkylene)-(Ci-4alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -N(RA)-C(O)-R8, -C(O)-N(RA)-R8, -N(RA)C(O)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C0-6 alkylene)-R9;R6represents independently for each occurrence halogen, C1-4 alkyl, C3-7 cycloalkyl, -N(RA)(RB), -(C0-6alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogenatoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence Ci-4 alkyl or C3-7 cycloalkyl;R8is C1-4alkoxyl, -C(O)-OH, -C(O)-(Ci-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is Ci-4alkoxyl, -C(O)-OH, C3-7cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci-4 haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;X1is -(C 1-6 alkylene)-;A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12;R11and R12each represents independently for each occurrence halo, C1-4 alkyl, C1.4 haloalkyl, C1.4 alkoxyl, C1.4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

[0069] The definitions of 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 ofa 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).

[0070] In certain embodiments, the compound is a compound of Formula I.

[0071] As defined generally above, R1is hydrogen or halo. In certain embodiments, R1is hydrogen. In certain embodiments, R1is halo. In certain embodiments, R1is chloro. In certain embodiments, R1is bromo. In certain embodiments, R1is fluoro. In certain embodiments, R1is iodo. In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1 below.

[0072] As defined generally above, R2is Ci-6 alkyl, Ci-6 hydroxyalkyl, C3-7 cycloalkyl, halo, -C(O)-(C i-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(triazolonyl substituted with x occurrences of R6), -(Co-6 alkyl ene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7. In certain embodiments, R2is C1-6 alkyl, Ci-6 hydroxyalkyl, C3-7 cycloalkyl, halo, -C(O)-(Ci-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7.

[0073] In certain embodiments, R2is Ci-6 alkyl, Ci-6 hydroxyalkyl, C3-7 cycloalkyl, halo, or -C(O)-(Ci-4 alkyl). In certain embodiments, R2is Ci-6 alkyl. In certain embodiments, R2is C1.4 alkyl. In certain embodiments, R2is methyl. In certain embodiments, R2is ethyl. In certain embodiments, R2is C3 alkyl. In certain embodiments, R2is C4 alkyl. In certain embodiments,R2is C5 alkyl. In certain embodiments, R2is C6alkyl. In certain embodiments, R2is C1-6 hydroxyalkyl. In certain embodiments, R2is C1-4 hydroxyalkyl. In certain embodiments, R2is C3-7 cycloalkyl. In certain embodiments, R2is C3-5 cycloalkyl. In certain embodiments, R2is cyclopropyl. In certain embodiments, R2is halo. In certain embodiments, R2is chloro. In certain embodiments, R2is bromo. In certain embodiments, R2is fluoro. In certain embodiments, R2is iodo. In certain embodiments, R2is -C(O)-(Ci-4 alkyl). In certain embodiments, R2is -C(O)-CH3.

[0074] In certain embodiments, R2is -(pyri dinonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7.

[0075] In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6) or a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is -(pyridin-2-on-5-yl substituted with x occurrences of R6) or a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7.

[0076] In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), or -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is pyridinonyl substituted with x occurrences of R6. In certain embodiments, R2is pyridin-2-on-5-yl substituted with x occurrences of R6. In certain embodiments, R2is -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is -(Ci-3alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen andoxygen). In certain embodiments, R2is -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is -(cyclopropylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen).

[0077] In certain embodiments, R2is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein each heteroaryl is substituted with x occurrences of R7.

[0078] In certain embodiments, R2is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 5-membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 6-membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms that are nitrogen, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 9-membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 10-membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with x occurrences of R7.

[0079] In certain embodiments, R2is selected from tert-butyl,

[0081] In certain embodiments, R2is tert-butyl. In certain embodiments,R2is Ocertain embodiments,R2is In certain embodiments, R2is. In certainembodiments,R2is. In certain embodiments, R2is. In certainN;embodiments, R2is. In certain embodiments, R2is. In certainOembodiments, R2is. In certain embodiments, R2is. In certain embodiments,OR2i In certain embodiments, R2is. In certain embodiments, R2isN; O. In certain embodiments, R2is. In certain embodiments,. In certain embodiments, R2is. In certain embodiments, R2isIn certain embodiments, R2isIn certain embodiments, R2isIn certain embodiments,R2is In certain embodiments,R2is

[0082] In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1 below.

[0083] As defined generally above, R3is hydrogen, C1.4 alkyl, C1-4 haloalkoxyl, or C3-7 cycloalkyl. In certain embodiments, R3is hydrogen, C1-4 alkyl, or C3-7 cycloalkyl. In certain embodiments, R3is C1-4 alkyl or C3-7 cycloalkyl. In certain embodiments, R3is methyl or cyclopropyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is methyl or n-propyl. In certain embodiments, R3is methyl. In certain embodiments, R3is ethyl. In certain embodiments, R3is w-propyl. In certain embodiments, R3is C3-7 cycloalkyl. In certain embodiments, R3is cyclopropyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1 below.

[0084] As defined generally above, R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 alkoxyl, C1.4 haloalkoxyl, -(Ci-4alkylene)-(Ci-4alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(CO-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -N(RA)-C(O)-R8, -C(O)-N(RA)-R8, -N(RA)C(O)N(RA)(RB), or -(Co-ealkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -(Ci-4alkylene)-(C 1.4 alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -N(RA)-C(O)-R8, -C(O)-N(RA)-R8, or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo).

[0085] In certain embodiments, R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -(Ci-4alkylene)-(Ci-4 alkoxyl), -C(O)-OH, hydroxyl, or -(Co-6 alkylene)-N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -N(RA)-C(O)-R8, -C(O)-N(RA)-R8, or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo).

[0086] In certain embodiments, R4is -(Co-6 alkylene)-N(RA)(RB), -N(RA)-(Co-6 alkylene)-R8, or -N(RA)-C(O)-R8

[0087] In certain embodiments, R4is C1-4 alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is C3 alkyl. In certainembodiments, R4is C4 alkyl. In certain embodiments, R4is n-propyl. In certain embodiments, R4is C1-4 hydroxyalkyl. In certain embodiments, R4is C3-7 cycloalkyl. In certain embodiments, R4is C3-5 cycloalkyl. In certain embodiments, R4is cyclopropyl. In certain embodiments, R4is cyclobutyl. In certain embodiments, R4is C1-4 alkoxyl. In certain embodiments, R4is methoxy. In certain embodiments, R4is Ci.4haloalkoxyl. In certain embodiments, R4is Ci haloalkoxyl. In certain embodiments, R4is -(Ci-4alkylene)-(Ci-4 alkoxyl). In certain embodiments, R4is -C(O)-OH. In certain embodiments, R4is hydroxyl.

[0088] In certain embodiments, R4is -(Co-6 alkylene)-N(RA)(RB). In certain embodiments, R4is -N(RA)(RB). In certain embodiments, R4is -NH2, -N(H)CH3. In certain embodiments, R4is -N(CH3)2. In certain embodiments, R4is -NH2. In certain embodiments, R4is -N(H)CH3. In certain embodiments, R4is -N(CH3)2. In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R4is -(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R4is -(C1-4 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen).

[0089] In certain embodiments, R4is -N(RA)-(Co-6 alkylene)-R8. In certain embodiments, R4is -N(H)-(Co-6 alkylene)-R8. In certain embodiments, R4is -N(RA)-R8. In certain embodiments, R4is -N(H)-R8. In certain embodiments, R4is -N(RA)-(C1-3alkylene)-R8. In certain embodiments, R4is -N(H)-(C1-3alkylene)-R8. In certain embodiments, R4is -N(RA)-C(O)-R8. In certain embodiments, R4is -N(H)-C(O)-R8.

[0090] In certain embodiments, R4is -C(O)-N(RA)-R8. In certain embodiments, R4is -C(O)-N(H)-R8. In certain embodiments, R4is -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is -(C0-6alkylene)-N(H)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is -(C1-3 alkylene)-N(H)-(6-membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo).

[0091] In certain embodiments, R4is selected from -NH2, -N(CH3)2, -N(H)CH3, hydroxy,

[0092] In certain embodiments, R4is -NH2, -N(CH3)2, -N(H)CH3,In certain embodiments, R4is -NH2, -N(CH3)2, -N(H)CH3, or [image]. In certain embodiments, R4is —J, ’, or

[0093] In certain embodiments, R4is

[0094] In certain embodiments, R4is

[0095] In certain embodiments, R4isIn certain embodiments, R4isIn certain embodiments, R4isIn certain embodiments, R4isIn certain embodiments, R4isN / \In certain embodiments, R4is In certain embodiments, R4isIn certain embodiments, R4is’. In certain embodiments, R4is*. In certainembodiments, R4is. In certainembodiments, R4isIn certain embodiments, R4isembodiments, R4isIn certain embodiments, R4isIn certain.0embodiments, R4is0. In certain embodiments, R4is' —?. In certain O Oembodiments, R4is. In certain embodiments, R4is. In certaini / embodiments, R4isIn certain embodiments, R4isF F. In certainembodiments, R4is In certain embodiments, R4is In certain embodiments,In certain embodiments, R4is / . In certain embodiments, R4isIn certain embodiments, R4isIn certain embodiments, R4iscertain embodiments, R4isIn certain embodiments, R4is selected from the groups depicted in the compounds in Table 1 below.

[0096] As defined generally above, R5is Ci-4 alkyl, Ci-4 hydroxyalkyl, Ci-4 haloalkyl, or -(Co-6 alkylene)-R9. In certain embodiments, R5is Ci-4 alkyl. In certain embodiments, R5is methyl. In certain embodiments, R5is Ci-4 hydroxyalkyl. In certain embodiments, R5is C2-4 hydroxyalkyl. In certain embodiments, R5is C1-4 haloalkyl. In certain embodiments, R5is Ci haloalkyl. Incertain embodiments, R5is C2 haloalkyl. In certain embodiments, R5is -(Co-6 alkylene)-R9. In certain embodiments, R5is -R9. In certain embodiments, R5is -(C1-3 alkylene)-R9.

[0097] In certain embodiments, R5is C1-4 alkyl or C1-4 haloalkyl. In certain embodiments, R5is - (Co-6 alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is -(Co-2alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is -(Co-6 alkylene)- (6-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms).

[0098] In certain embodiments, R5is selected from methyl,certain embodiments, R5is methyl,

[0099] In certain embodiments, R5isIn certain embodiments, R5isFIn certain embodiments, R3isIn certain embodiments, R5is. In certainembodiments, R5is. In certain embodiments, R5is. In certainembodiments, R5isIn certain embodiments, R5is. In certainFembodiments, R5is. In certain embodiments, R5is. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1 below.

[0100] As defined generally above, R6represents independently for each occurrence halogen, Ci- 4 alkyl, C3-7 cycloalkyl, -N(RA)(RB), -(Co-6alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R6represents independently for each occurrence C1-4 alkyl, C3-7 cycloalkyl, -N(RA)(RB), -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen.

[0101] In certain embodiments, R6represents independently for each occurrence C1-4 alkyl. In certain embodiments, R6is methyl. In certain embodiments, R6represents independently for each occurrence C3-7 cycloalkyl. In certain embodiments, R6is cyclopropyl. In certain embodiments, R6represents independently for each occurrence -N(RA)(RB). In certain embodiments, R6represents independently for each occurrence -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7). In certain embodiments, R6represents independently for each occurrence a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen.

[0102] In certain embodiments, one instance of R6occurs on the pyridinone nitrogen atom and is Ci-4alkyl, and any additional instances of R6are each independently C1-4 alkyl or -N(RA)(RB). In certain embodiments, one instance of R6occurs on the pyridinone nitrogen atom and is methyl, and any additional instances of R6are each independently methyl, -NH2, -N(H)CH3, -N(CH3)2, -(Co-i alkylene)-(pyrazolyl substituted with 0 or 1 occurrences of methyl), cyclopropyl, or morpholinyl. In certain embodiments, one instance of R6occurs on the pyridinone nitrogen atom and is methyl, and any additional instances of R6are each independently methyl, -NH2, -N(H)CH₃, or -N(CH3)2.

[0103] In certain embodiments, R6represents independently for each occurrence methyl, -NH2, -N(H)CH3, -N(CHS)2, -(CO-I alkylene)-(pyrazolyl substituted with 0 or 1 occurrences of methyl), cyclopropyl, or morpholinyl. In certain embodiments, R6is -NH2. In certain embodiments, R6is -N(H)CH3. In certain embodiments, R6is -N(CH3)2. In certain embodiments, R6is -(Co-i alkylene)-(pyrazolyl substituted with 0 or 1 occurrences of methyl). In certain embodiments, R6is morpholinyl. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1 below.

[0104] In certain embodiments, R6represents independently for each occurrence methyl, -NH2, -N(H)CH3, -N(CH3)2, -(CO-I alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl; and R7represents independently for each occurrence methyl or cyclopropyl.

[0105] As defined generally above, R7represents independently for each occurrence C1-4 alkyl or C3-7 cycloalkyl. In certain embodiments, R7represents independently for each occurrence C1-4 alkyl. In certain embodiments, R7is methyl. In certain embodiments, R7represents independently for each occurrence C3-7 cycloalkyl. In certain embodiments, R7is cyclopropyl. In certain embodiments, R7represents independently for each occurrence methyl or cyclopropyl. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1 below.

[0106] As defined generally above, R8is Ci-4alkoxyl, -C(O)-OH, -C(O)-(C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7.

[0107] In certain embodiments, R8is Ci-4alkoxyl. In certain embodiments, R8is methoxy. In certain embodiments, R8is -C(O)-OH. In certain embodiments, R8is -C(O)-(C1-4 alkyl). In certain embodiments, R8is hydroxyl. In certain embodiments, R8is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In certain embodiments, R8is a 5-memberedmonocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In certain embodiments, R8is a 5-membered monocyclic heteroaryl containing 2 or 3 nitrogen atoms. In certain embodiments, R8is a 6-membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In certain embodiments, R8is a 6-membered monocyclic heteroaryl containing 1 or 2 nitrogen atoms.

[0108] In certain embodiments, R8is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 4-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 5-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7.

[0109] In certain embodiments, R8is tetrahydropyranyl, pyrazolyl, methoxy, pyridinyl, morpholinyl, acetyl, oxetanyl, pyrrolidinyl substituted with w occurrences of R7, tetrazolyl, or tetrahydro-2H-thiopyranyl 1,1-dioxide. In certain embodiments, R8is tetrahydropyranyl, pyrazolyl, pyridinyl, morpholinyl, oxetanyl, pyrrolidinyl substituted with w occurrences of R7, tetrazolyl, or tetrahydro-2H-thiopyranyl 1,1-dioxide. In certain embodiments, R8is tetrahydropyranyl, morpholinyl, oxetanyl, pyrrolidinyl substituted with w occurrences of R7, or tetrahydro-2H-thiopyranyl 1,1-dioxide. In certain embodiments, R8is pyrazolyl, pyridinyl, or tetrazolyl.

[0110] In certain embodiments, R8is tetrahydropyranyl. In certain embodiments, R8is pyrazolyl. In certain embodiments, R8is pyridinyl. In certain embodiments, R8is morpholinyl. In certain embodiments, R8is acetyl. In certain embodiments, R8is oxetanyl. In certain embodiments, R8is pyrrolidinyl substituted with w occurrences of R7. In certain embodiments, R8is tetrazolyl. In certain embodiments, R8is tetrahydro-2H-thiopyranyl 1,1-dioxide. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1 below.

[0111] As defined generally above, R9is Ci-4 alkoxyl, -C(O)-OH, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclicheteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrences of halo. In certain embodiments, R9is Ci-4 alkoxyl. In certain embodiments, R9is methoxy. In certain embodiments, R9is -C(O)-OH. In certain embodiments, R9is C3-7 cycloalkyl. In certain embodiments, R9is cyclopropyl. In certain embodiments, R9is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrences of halo. In certain embodiments, R9is a 5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrences of halo. In certain embodiments, R9is pyrazolyl, imidazolyl, or triazolyl. In certain embodiments, R9is a 6-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrences of halo. In certain embodiments, R9is a 4-6 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is tetrahydropyranyl.

[0112] In certain embodiments, R9is pyrazolyl, cyclopropyl, tetrahydropyranyl, or triazolyl, or R9is pyridinyl substituted with w occurrences of halo. In certain embodiments, R9is pyrazolyl. In certain embodiments, R9is cyclopropyl. In certain embodiments, R9is tetrahydropyranyl. In certain embodiments, R9is triazolyl. In certain embodiments, R9is pyridinyl substituted with w occurrences of halo. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1 below.

[0113] As defined generally above, RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci-4haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAand RBeach represent independently for each occurrence hydrogen and C1-4 alkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10.

[0114] In certain embodiments, RAis hydrogen. In certain embodiments, RArepresents independently for each occurrence C1-4 alkyl. In certain embodiments, RAis methyl. In certainembodiments, RBis hydrogen. In certain embodiments, RBrepresents independently for each occurrence C1-4 alkyl. In certain embodiments, RBis methyl.

[0115] In certain embodiments, RAand RBeach represent independently for each occurrence hydrogen or methyl. In certain embodiments, RAand RBare hydrogen. In certain embodiments, RAand RBare methyl. In certain embodiments, RAis hydrogen, and RBis methyl. In certain embodiments, RAis methyl, and RBis hydrogen.

[0116] In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 4-6 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form an azetidine or pyrrolidine ring, each of which is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form an azetidine ring which is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a pyrrolidine ring which is substituted with 0 or 1 occurrences of R10. In certain embodiments, RAis selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, RBis selected from the groups depicted in the compounds in Table 1 below.

[0117] As defined generally above, R10represents independently for each occurrence Ci-4 alkyl, hydroxyl, or Ci-4 alkoxyl. In certain embodiments, R10represents independently for each occurrence Ci-4 alkyl. In certain embodiments, R10is methyl. In certain embodiments, R10is hydroxyl. In certain embodiments, R10represents independently for each occurrence Ci-4 alkoxyl. In certain embodiments, R10is methoxy. In certain embodiments, R10represents independently for each occurrence hydroxyl or methoxy. In certain embodiments, R10is selected from the groups depicted in the compounds in Table 1 below.

[0118] As defined generally above, X1is -(Ci-6 alkylene)-. In certain embodiments, X1is -(C1-3 alkylene)-. In certain embodiments, X1is -(C2-3 alkylene)-. In certain embodiments, X1is -CH2-.In certain embodiments, X1is -CH2CH2-. In certain embodiments, X1is -CH2CH2CH2-. In certain embodiments, X1is selected from the groups depicted in the compounds in Table 1 below.

[0119] As defined generally above, A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is phenyl substituted with q occurrences of R11. In certain embodiments, A1is phenyl substituted with q occurrences of halo. In certain embodiments, A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 6-membered monocyclic heteroaryl containing 1 or 2 heteroatoms that are nitrogen, wherein the heteroaryl is substituted with z occurrences of R12.Br

[0120] In certain embodiments, A1is selected fromF. In certain embodiments, A1is selected fromFFIn certain embodiments, A1is

[0123] In certain embodiments, A1isIn certain embodiments, A1isIn certain embodiments,A1is In certain embodiments,A1is Cl embodiments, A1isembodiments, A1isembodiments, A1isembodiments, A1isembodiments, A1isBrembodiments,A1is In certain embodiments, A1isembodiments,A1is In certain embodiments, A1is3. In certainembodiments, A1isIn certain embodiments,A1isembodiments,A1is In certain embodiments, A1is. In certainembodiments, A1is In certain embodiments, A1is V In certainBrembodiments, A i i-s' — '. In certai •n embodi •ments, A i i-s HQNM. In certainembodiments,A1is In certain embodiments, A1isIn certainembodiments, A1isIn certain embodiments, A1is selected from the groups depicted in the compounds in Table 1 below.

[0124] As defined generally above, R11and R12each represents independently for each occurrence halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxyl, Ci-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13.

[0125] In certain embodiments, R11represents independently for each occurrence halo, C1-4 alkoxyl, C3-7 cycloalkyl, C2-3 alkynyl, or a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heteroaryl is substituted with z occurrences of R13.

[0126] In certain embodiments, R11represents independently for each occurrence halo. In certain embodiments, R11represents independently for each occurrence C1-4 alkyl. In certain embodiments, R11represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R11represents independently for each occurrence C1-4 alkoxyl. In certain embodiments, R11represents independently for each occurrence C1-4 haloalkoxyl. In certain embodiments, R11represents independently for each occurrence C3-7 cycloalkyl. In certain embodiments, R11represents independently for each occurrence C2-3 alkynyl.

[0127] In certain embodiments, one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13.

[0128] In certain embodiments, R11represents independently for each occurrence halo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, or acetylenyl; or one occurrence of R11is oxazolyl substituted with q occurrences of R13. In certain embodiments, R11represents independently for each occurrence methoxy, fluoro, chloro, bromo, iodo, cyclopropyl, or acetylenyl; or one occurrence of R11is oxazolyl substituted with z occurrences of R13. In certain embodiments, R11represents independently for each occurrence chloro, bromo, or fluoro. In certain embodiments, R11is methyl. In certain embodiments, R11is trifluoromethyl. In certain embodiments, R11is difluoromethyl. In certain embodiments, R11is methoxy. In certain embodiments, R11is trifluoromethoxy. In certain embodiments, R11is fluoro. In certain embodiments, R11is chloro. In certain embodiments, R11is bromo. In certain embodiments, R11is iodo. In certain embodiments, R11is cyclopropyl. In certain embodiments, R11is acetylenyl. In certain embodiments, one occurrence of R11is oxazolyl substituted with q occurrences of R13. In certain embodiments, R11is selected from the groups depicted in the compounds in Table 1 below.

[0129] In certain embodiments, R12represents independently for each occurrence halo, C1-4 alkyl, Ci-4 alkoxyl, Ci-4 haloalkyl, C1-4 haloalkoxyl, or C2-3 alkynyl. In certain embodiments, R12represents independently for each occurrence halo. In certain embodiments, R12represents independently for each occurrence C1-4 alkyl. In certain embodiments, R12represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R12represents independently for each occurrence C1-4 alkoxyl. In certain embodiments, R12represents independently for each occurrence C1-4 haloalkoxyl. In certain embodiments, R12represents independently for each occurrence C3-7 cycloalkyl. In certain embodiments, R12represents independently for each occurrence C2-3 alkynyl.

[0130] In certain embodiments, R12represents independently for each occurrence halo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, or acetylenyl. In certain embodiments, R12represents independently for each occurrence methyl, chloro, bromo, fluoro, tri fluoromethyl, acetylenyl, or difluoromethyl. In certain embodiments, R11represents independently for each occurrence chloro, bromo, or fluoro. In certain embodiments, R12is methyl. In certain embodiments, R12is trifluoromethyl. In certain embodiments, R12is difluoromethyl. In certain embodiments, R12is methoxy. In certain embodiments, R12is trifluorom ethoxy. In certain embodiments, R12is chloro. In certain embodiments, R12is bromo. In certain embodiments, R12is fluoro. In certain embodiments, R12is cyclopropyl. In certain embodiments, R12is acetylenyl. In certain embodiments, R12is selected from the groups depicted in the compounds in Table 1 below.

[0131] As defined generally above, R13represents independently for each occurrence C1-4 alkyl or halo. In certain embodiments, R13represents independently for each occurrence C1-4 alkyl. In certain embodiments, R13is methyl. In certain embodiments, R13represents independently for each occurrence halo. In certain embodiments, R13is fluoro. In certain embodiments, R13is chloro. In certain embodiments, R13is bromo. In certain embodiments, R13is iodo. In certain embodiments, R13is selected from the groups depicted in the compounds in Table 1 below.

[0132] As defined generally above, q represents independently for each occurrence 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the groups depicted in the compounds in Table 1 below.

[0133] As defined generally above, w represents independently for each occurrence 0 or 1. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is selected from the groups depicted in the compounds in Table 1 below.

[0134] As defined generally above, x is 1, 2, or 3. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is selected from the groups depicted in the compounds in Table 1 below.

[0135] As defined generally above, z represents independently for each occurrence 0, 1, or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z represents independently for each occurrence 0 or 1. In certain embodiments, z represents independently for each occurrence 1 or 2. In certain embodiments, z is selected from the groups depicted in the compounds in Table 1 below.

[0136] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments.

[0137] Another aspect of the invention provides a compound represented by Formula I-1:or a pharmaceutically acceptable salt thereof; wherein:R1is hydrogen or halo;R2is Ci-6 alkyl, Ci-6 hydroxyalkyl, C3-7 cycloalkyl, halo, -C(O)-(Ci-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7;R3is hydrogen, C1-4 alkyl, or C3-7 cycloalkyl;R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -C(O)-OH, hydroxyl, -(C0-6 alkylene)-N(RA)(RB), -(C0-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(C0-6 alkylene)-R8, -N(RA)-C(O)-R8, -C(O)-N(RA)-R8, or -(C0-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C0-6 alkylene)-R9;R6represents independently for each occurrence C1-4 alkyl, C3-7 cycloalkyl, -N(RA)(RB), -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence C1.4 alkyl or C3-7 cycloalkyl;R8is C1-4 alkoxyl, -C(O)-OH, -C(O)-(C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is C1.4 alkoxyl, -C(O)-OH, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen and C1-4 alkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, or C1-4 alkoxyl; X1is -(C1-6 alkylene)-;A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12;R11and R12each represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

[0138] The definitions of variables in Formula I-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).

[0139] In certain embodiments, the compound is a compound of Formula I-1.

[0140] As defined generally above, R1is hydrogen or halo. In certain embodiments, R1is hydrogen. In certain embodiments, R1is halo. In certain embodiments, R1is chloro. In certain embodiments, R1is bromo. In certain embodiments, R1is fluoro. In certain embodiments, R1is iodo. In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1 below.

[0141] As defined generally above, R2is Ci-6 alkyl, Ci-6 hydroxyalkyl, C3-7 cycloalkyl, halo, -C(O)-(C i-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7.

[0142] In certain embodiments, R2is Ci-6 alkyl, Ci-6 hydroxyalkyl, C3-7 cycloalkyl, halo, or -C(O)-(Ci-4 alkyl). In certain embodiments, R2is Ci-6 alkyl. In certain embodiments, R2is C1-4 alkyl. In certain embodiments, R2is methyl. In certain embodiments, R2is ethyl. In certainembodiments, R2is C3 alkyl. In certain embodiments, R2is C4 alkyl. In certain embodiments, R2is C5 alkyl. In certain embodiments, R2is Ce alkyl. In certain embodiments, R2is C1-6 hydroxyalkyl. In certain embodiments, R2is C1-4 hydroxyalkyl. In certain embodiments, R2is C3-7 cycloalkyl. In certain embodiments, R2is C3-5 cycloalkyl. In certain embodiments, R2is cyclopropyl. In certain embodiments, R2is halo. In certain embodiments, R2is chloro. In certain embodiments, R2is bromo. In certain embodiments, R2is fluoro. In certain embodiments, R2is iodo. In certain embodiments, R2is -C(O)-(Ci-4 alkyl). In certain embodiments, R2is -C(O)-CH3.

[0143] In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6), -(C0-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7.

[0144] In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6) or a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is -(pyridin-2-on-5-yl substituted with x occurrences of R6) or a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7.

[0145] In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), or -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is pyridinonyl substituted with x occurrences of R6. In certain embodiments, R2is pyridin-2-on-5-yl substituted with x occurrences of R6. In certain embodiments, R2is -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is -(Ci-3alkylene)-(6-memberedsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is -(cyclopropylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen).

[0146] In certain embodiments, R2is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein each heteroaryl is substituted with x occurrences of R7.

[0147] In certain embodiments, R2is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 5-membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 6-membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms that are nitrogen, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 9-membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 10-membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with x occurrences of R7.O

[0148] In certain embodiments, R2is selected from tert-butyl,. In

[0150] In certain embodiments, R2is terZ-butyl. In certain embodiments,R2iscertain embodiments,R2is In certain embodiments, R2isIn certain embodiments, R2isembodiments, R2is In certain embodiments, R2isembodiments,R2is In certain embodiments, R2isIn certain embodiments,In certain embodiments, R2isIn certain embodiments, R2is In certain embodiments,In certain embodiments, R2isIn certain embodiments, R2isIn certain embodiments,R2is In certain embodiments,R2is

[0151] In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1 below.

[0152] As defined generally above, R3is hydrogen, C1-4 alkyl, or C3-7 cycloalkyl. In certain embodiments, R3is C1-4 alkyl or C3-7 cycloalkyl. In certain embodiments, R3is methyl or cyclopropyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is methyl or / / -propyl. In certain embodiments, R3is methyl. In certain embodiments, R3is ethyl. In certain embodiments, R3is / / -propyl. In certain embodiments, R3is C3-7 cycloalkyl. In certain embodiments, R3is cyclopropyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1 below.

[0153] As defined generally above, R4is C1-4 alkyl, Ci.4hydroxyalkyl, C3-7 cycloalkyl, C1-4 alkoxyl, Ci.4haloalkoxyl, -(Ci-4alkylene)-(Ci-4alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(CO-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -N(RA)-C(O)-R8, -C(O)-N(RA)-R8, or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo).

[0154] In certain embodiments, R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -C(O)-OH, hydroxyl, or -(Co-6 alkylene)-N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -N(RA)-C(O)-R8, -C(O)-N(RA)-R8, or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo).

[0155] In certain embodiments, R4is -(Co-6 alkylene)-N(RA)(RB), -N(RA)-(C0-6alkylene)-R8, or -N(RA)-C(O)-R8.

[0156] In certain embodiments, R4is Ci-4 alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is C3 alkyl. In certain embodiments, R4is C4 alkyl. In certain embodiments, R4is n-propyl. In certain embodiments, R4is C1-4 hydroxyalkyl. In certain embodiments, R4is C3-7 cycloalkyl. In certain embodiments, R4is C3-5 cycloalkyl. In certain embodiments, R4is cyclopropyl. In certain embodiments, R4is cyclobutyl. In certain embodiments, R4is C1-4 alkoxyl. In certain embodiments, R4is methoxy. In certain embodiments, R4is Ci.4haloalkoxyl. In certain embodiments, R4is Ci haloalkoxyl. In certain embodiments, R4is -(Ci-4alkylene)-(Ci-4 alkoxyl). In certain embodiments, R4is -C(O)-OH. In certain embodiments, R4is hydroxyl.

[0157] In certain embodiments, R4is -(Co-6 alkylene)-N(RA)(RB). In certain embodiments, R4is -N(RA)(RB). In certain embodiments, R4is -NH2, -N(H)CH3. In certain embodiments, R4is -N(CH3)2. In certain embodiments, R4is -NH2. In certain embodiments, R4is -N(H)CH3. In certain embodiments, R4is -N(CH3)2. In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R4is -(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R4is -(C1-4 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen).

[0158] In certain embodiments, R4is -N(RA)-(Co-6 alkylene)-R8. In certain embodiments, R4is -N(H)-(CO-6 alkylene)-R8. In certain embodiments, R4is -N(RA)-R8. In certain embodiments, R4is -N(H)-R8. In certain embodiments, R4is -N(RA)-(CI-3 alkylene)-R8. In certain embodiments, R4is -N(H)-(CI-3 alkylene)-R8. In certain embodiments, R4is -N(RA)-C(O)-R8. In certain embodiments, R4is -N(H)-C(O)-R8.

[0159] In certain embodiments, R4is -C(O)-N(RA)-R8. In certain embodiments, R4is -C(O)-N(H)-R8. In certain embodiments, R4is -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is -(Co-6 alkylene)-N(H)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is -(C1-3 alkylene)-N(H)-(6-membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo).

[0160] In certain embodiments, R4is selected from -NH2, -N(CH3)2, -N(H)CH3, hydroxy,— N / I —

[0161] In certain embodiments, R4is -NH2, -N(CH3)2, -N(H)CH3,J,In certain embodiments, R4is -NH2, -N(CH3)2, - H\NI \ '"1 — N ] I— N y I— NZ\— OH N(H)CHS, or I. In certain embodiments, R4is1, or

[0162] In certain embodiments, R4is

[0163] In certain embodiments, R4is

[0164] In certain embodiments, R4isIn certain embodiments, R4isIn certain embodiments, R4isIn certain embodiments, R4isIn certain embodiments, R4isN / \In certain embodiments, R4is In certain embodiments, R4isIn certain embodiments, R4is’. In certain embodiments, R4is*. In certainembodiments, R4is. In certainembodiments, R4isIn certain embodiments, R4isembodiments, R4isIn certain embodiments, R4isIn certain.0embodiments, R4is0. In certain embodiments, R4is' —?. In certain O Oembodiments, R4is. In certain embodiments, R4is. In certaini / embodiments, R4isIn certain embodiments, R4isF F. In certainembodiments, R4is In certain embodiments, R4is In certain embodiments,In certain embodiments, R4is / . In certain embodiments, R4isIn certain embodiments, R4isIn certain embodiments, R4iscertain embodiments, R4isIn certain embodiments, R4is selected from the groups depicted in the compounds in Table 1 below.

[0165] As defined generally above, R5is Ci-4 alkyl, Ci-4 hydroxyalkyl, Ci-4 haloalkyl, or -(Co-6 alkylene)-R9. In certain embodiments, R5is Ci-4 alkyl. In certain embodiments, R5is methyl. In certain embodiments, R5is Ci-4 hydroxyalkyl. In certain embodiments, R5is C2-4 hydroxyalkyl. In certain embodiments, R5is C1-4 haloalkyl. In certain embodiments, R5is Ci haloalkyl. Incertain embodiments, R5is C2 haloalkyl. In certain embodiments, R5is -(Co-6 alkylene)-R9. In certain embodiments, R5is -R9. In certain embodiments, R5is -(C1-3 alkylene)-R9.

[0166] In certain embodiments, R5is C1-4 alkyl or C1-4 haloalkyl. In certain embodiments, R5is - (Co-6 alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is -(Co-2alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is -(Co-6 alkylene)- (6-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms).

[0167] In certain embodiments, R5is selected from methyl,certain embodiments, R5is methyl,

[0168] In certain embodiments, R5isIn certain embodiments, R5isIn certain embodiments, R5isIn certain embodiments, R5is. In certainembodiments, R5is. In certain embodiments, R5is. In certainembodiments, R5isIn certain embodiments, R5is. In certainFembodiments, R5is. In certain embodiments, R is. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1 below.

[0169] As defined generally above, R6represents independently for each occurrence Ci-4 alkyl, C3-7 cycloalkyl, -N(RA)(RB), -(Co-6alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen.

[0170] In certain embodiments, R6represents independently for each occurrence C1-4 alkyl. In certain embodiments, R6is methyl. In certain embodiments, R6represents independently for each occurrence C3-7 cycloalkyl. In certain embodiments, R6is cyclopropyl. In certain embodiments, R6represents independently for each occurrence -N(RA)(RB). In certain embodiments, R6represents independently for each occurrence -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7). In certain embodiments, R6represents independently for each occurrence a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen.

[0171] In certain embodiments, one instance of R6occurs on the pyridinone nitrogen atom and is C1-4 alkyl, and any additional instances of R6are each independently C1-4 alkyl or -N(RA)(RB). In certain embodiments, one instance of R6occurs on the pyridinone nitrogen atom and is methyl, and any additional instances of R6are each independently methyl, -NH2, -N(H)CH3, -N(CH3)2, -(C0-1 alkylene)-(pyrazolyl substituted with 0 or 1 occurrences of methyl), cyclopropyl, or morpholinyl. In certain embodiments, one instance of R6occurs on the pyridinone nitrogen atom and is methyl, and any additional instances of R6are each independently methyl, -NH2, -N(H)CH₃, or -N(CH3)2.

[0172] In certain embodiments, R6represents independently for each occurrence methyl, -NH2, -N(H)CH3, -N(CH3)2, -(Co-i alkylene)-(pyrazolyl substituted with 0 or 1 occurrences of methyl), cyclopropyl, or morpholinyl. In certain embodiments, R6is -NH2. In certain embodiments, R6is -N(H)CH3. In certain embodiments, R6is -N(CH3)2. In certain embodiments, R6is -(C0-1 alkylene)-(pyrazolyl substituted with 0 or 1 occurrences of methyl). In certain embodiments, R6is morpholinyl. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1 below.

[0173] In certain embodiments, R6represents independently for each occurrence methyl, -NH2, -N(H)CH₃, -N(CH3)2, -(CO-I alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl; and R7represents independently for each occurrence methyl or cyclopropyl.

[0174] As defined generally above, R7represents independently for each occurrence C1-4 alkyl or C3-7 cycloalkyl. In certain embodiments, R7represents independently for each occurrence C1-4 alkyl. In certain embodiments, R7is methyl. In certain embodiments, R7represents independently for each occurrence C3-7 cycloalkyl. In certain embodiments, R7is cyclopropyl. In certain embodiments, R7represents independently for each occurrence methyl or cyclopropyl. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1 below.

[0175] As defined generally above, R8is Ci-4alkoxyl, -C(O)-OH, -C(O)-(C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7.

[0176] In certain embodiments, R8is Ci-4alkoxyl. In certain embodiments, R8is methoxy. In certain embodiments, R8is -C(O)-OH. In certain embodiments, R8is -C(O)-(C1-4 alkyl). In certain embodiments, R8is hydroxyl. In certain embodiments, R8is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In certain embodiments, R8is a 5-membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In certain embodiments, R8is a 5-membered monocyclic heteroaryl containing 2 or 3 nitrogen atoms. In certain embodiments, R8is a 6-membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In certain embodiments, R8is a 6-membered monocyclic heteroaryl containing 1 or 2 nitrogen atoms.

[0177] In certain embodiments, R8is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 4-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 5-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7.

[0178] In certain embodiments, R8is tetrahydropyranyl, pyrazolyl, methoxy, pyridinyl, morpholinyl, acetyl, oxetanyl, pyrrolidinyl substituted with w occurrences of R7, tetrazolyl, or tetrahydro-2H-thiopyranyl 1,1-dioxide. In certain embodiments, R8is tetrahydropyranyl, pyrazolyl, pyridinyl, morpholinyl, oxetanyl, pyrrolidinyl substituted with w occurrences of R7, tetrazolyl, or tetrahydro-2H-thiopyranyl 1,1-dioxide. In certain embodiments, R8is tetrahydropyranyl, morpholinyl, oxetanyl, pyrrolidinyl substituted with w occurrences of R7, or tetrahydro-2H-thiopyranyl 1,1-dioxide. In certain embodiments, R8is pyrazolyl, pyridinyl, or tetrazolyl.

[0179] In certain embodiments, R8is tetrahydropyranyl. In certain embodiments, R8is pyrazolyl. In certain embodiments, R8is pyridinyl. In certain embodiments, R8is morpholinyl. In certain embodiments, R8is acetyl. In certain embodiments, R8is oxetanyl. In certain embodiments, R8is pyrrolidinyl substituted with w occurrences of R7. In certain embodiments, R8is tetrazolyl. In certain embodiments, R8is tetrahydro-2H-thiopyranyl 1,1-dioxide. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1 below.

[0180] As defined generally above, R9is Ci- 4 alkoxyl, -C(O)-OH, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrences of halo. In certain embodiments, R9is C1-4 alkoxyl. In certain embodiments, R9is methoxy. In certain embodiments, R9is -C(O)-OH. In certain embodiments, R9is C3-7 cycloalkyl. In certain embodiments, R9is cyclopropyl. In certain embodiments, R9is a 5-6membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrences of halo. In certain embodiments, R9is a 5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrences of halo. In certain embodiments, R9is pyrazolyl, imidazolyl, or triazolyl. In certain embodiments, R9is a 6-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrences of halo. In certain embodiments, R9is a 4-6 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is tetrahydropyranyl.

[0181] In certain embodiments, R9is pyrazolyl, cyclopropyl, tetrahydropyranyl, or triazolyl, or R9is pyridinyl substituted with w occurrences of halo. In certain embodiments, R9is pyrazolyl. In certain embodiments, R9is cyclopropyl. In certain embodiments, R9is tetrahydropyranyl. In certain embodiments, R9is triazolyl. In certain embodiments, R9is pyridinyl substituted with w occurrences of halo. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1 below.

[0182] As defined generally above, RAand RBeach represent independently for each occurrence hydrogen and Ci-4 alkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10.

[0183] In certain embodiments, RAis hydrogen. In certain embodiments, RArepresents independently for each occurrence Ci-4 alkyl. In certain embodiments, RAis methyl. In certain embodiments, RBis hydrogen. In certain embodiments, RBrepresents independently for each occurrence Ci-4 alkyl. In certain embodiments, RBis methyl.

[0184] In certain embodiments, RAand RBeach represent independently for each occurrence hydrogen or methyl. In certain embodiments, RAand RBare hydrogen. In certain embodiments, R and RBare methyl. In certain embodiments, RAis hydrogen, and RBis methyl. In certain embodiments, RAis methyl, and RBis hydrogen.

[0185] In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are takentogether with said nitrogen atom to form a 4-6 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form an azetidine or pyrrolidine ring, each of which is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form an azetidine ring which is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a pyrrolidine ring which is substituted with 0 or 1 occurrences of R10. In certain embodiments, RAis selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, RBis selected from the groups depicted in the compounds in Table 1 below.

[0186] As defined generally above, R10represents independently for each occurrence Ci-4 alkyl, hydroxyl, or Ci-4 alkoxyl. In certain embodiments, R10represents independently for each occurrence Ci-4 alkyl. In certain embodiments, R10is methyl. In certain embodiments, R10is hydroxyl. In certain embodiments, R10represents independently for each occurrence Ci-4 alkoxyl. In certain embodiments, R10is methoxy. In certain embodiments, R10represents independently for each occurrence hydroxyl or methoxy. In certain embodiments, R10is selected from the groups depicted in the compounds in Table 1 below.

[0187] As defined generally above, X1is -(Ci-6 alkylene)-. In certain embodiments, X1is -(C1-3 alkylene)-. In certain embodiments, X1is -(C2-3 alkylene)-. In certain embodiments, X1is -CH2-. In certain embodiments, X1is -CH2CH2-. In certain embodiments, X1is -CH2CH2CH2-. In certain embodiments, X1is selected from the groups depicted in the compounds in Table 1 below.

[0188] As defined generally above, A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is phenyl substituted with q occurrences of R11. In certain embodiments, A1is phenyl substituted with q occurrences of halo. In certain embodiments, A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences ofR12. In certain embodiments, A1is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 6-membered monocyclic heteroaryl containing 1 or 2 heteroatoms that are nitrogen, wherein the heteroaryl is substituted with z occurrences of R12.Br

[0189] In certain embodiments, A1is selected fromFFBr Cl

[0190] In certain embodiments, A1is selected from

[0191] In certain embodiments, A1isIn certain embodiments, A1is selected fromF F FF

[0192] In certain embodiments, A1isIn certain embodiments, A1isIn certain embodiments,A1is In certain embodiments,A1isembodiments, A1isIn certain embodiments,A1isFembodiments,A1is In certain embodiments,A1is1. In certainembodiments, A1isembodiments, A1isembodiments, A1isembodiments,A1is In certain embodiments, A1isembodiments,A1is In certain embodiments, A1is3. In certainembodiments, A1isIn certain embodiments,A1isembodiments,A1is In certain embodiments, A1is. In certainembodiments, A1isIn certain embodiments, A1is \. In certainembodiments, A1isIn certain embodiments, A1is. In certainF OCF3embodiments,A1isr. In certain embodiments, A1is. In certainembodiments, A1is. In certain embodiments, A1is selected from the groups depicted in the compounds in Table 1 below.

[0193] As defined generally above, R11and R12each represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13.

[0194] In certain embodiments, R11represents independently for each occurrence halo, C1-4 alkoxyl, C3-7 cycloalkyl, C2-3 alkynyl, or a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heteroaryl is substituted with z occurrences of R13.

[0195] In certain embodiments, R11represents independently for each occurrence halo. In certain embodiments, R11represents independently for each occurrence C1-4 alkyl. In certainembodiments, R11represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R11represents independently for each occurrence C1-4 alkoxyl. In certain embodiments, R11represents independently for each occurrence C1-4 haloalkoxyl. In certain embodiments, R11represents independently for each occurrence C3-7 cycloalkyl. In certain embodiments, R11represents independently for each occurrence C2-3 alkynyl.

[0196] In certain embodiments, one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13.

[0197] In certain embodiments, R11represents independently for each occurrence halo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, or acetylenyl; or one occurrence of R11is oxazolyl substituted with q occurrences of R13. In certain embodiments, R11represents independently for each occurrence methoxy, fluoro, chloro, bromo, iodo, cyclopropyl, or acetylenyl; or one occurrence of R11is oxazolyl substituted with z occurrences of R13. In certain embodiments, R11represents independently for each occurrence chloro, bromo, or fluoro. In certain embodiments, R11is methyl. In certain embodiments, R11is trifluoromethyl. In certain embodiments, R11is difluorom ethyl. In certain embodiments, R11is methoxy. In certain embodiments, R11is trifluoromethoxy. In certain embodiments, R11is fluoro. In certain embodiments, R11is chloro. In certain embodiments, R11is bromo. In certain embodiments, R11is iodo. In certain embodiments, R11is cyclopropyl. In certain embodiments, R11is acetylenyl. In certain embodiments, one occurrence of R11is oxazolyl substituted with q occurrences of R13. In certain embodiments, R11is selected from the groups depicted in the compounds in Table 1 below.

[0198] In certain embodiments, R12represents independently for each occurrence halo, C1-4 alkyl, C1-4 alkoxyl, C1.4 haloalkyl, C1-4 haloalkoxyl, or C2-3 alkynyl. In certain embodiments, R12represents independently for each occurrence halo. In certain embodiments, R12represents independently for each occurrence C1-4 alkyl. In certain embodiments, R12represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R12represents independently for each occurrence C1-4 alkoxyl. In certain embodiments, R12represents independently for each occurrence C1-4 haloalkoxyl. In certain embodiments, R12representsindependently for each occurrence C3-7 cycloalkyl. In certain embodiments, R12represents independently for each occurrence C2-3 alkynyl.

[0199] In certain embodiments, R12represents independently for each occurrence halo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, or acetylenyl. In certain embodiments, R12represents independently for each occurrence methyl, chloro, bromo, fluoro, trifluoromethyl, acetylenyl, or difluoromethyl. In certain embodiments, R11represents independently for each occurrence chloro, bromo, or fluoro. In certain embodiments, R12is methyl. In certain embodiments, R12is trifluoromethyl. In certain embodiments, R12is difluoromethyl. In certain embodiments, R12is methoxy. In certain embodiments, R12is trifluoromethoxy. In certain embodiments, R12is chloro. In certain embodiments, R12is bromo. In certain embodiments, R12is fluoro. In certain embodiments, R12is cyclopropyl. In certain embodiments, R12is acetylenyl. In certain embodiments, R12is selected from the groups depicted in the compounds in Table 1 below.

[0200] As defined generally above, R13represents independently for each occurrence C1-4 alkyl or halo. In certain embodiments, R13represents independently for each occurrence C1.4 alkyl. In certain embodiments, R13is methyl. In certain embodiments, R13represents independently for each occurrence halo. In certain embodiments, R13is fluoro. In certain embodiments, R13is chloro. In certain embodiments, R13is bromo. In certain embodiments, R13is iodo. In certain embodiments, R13is selected from the groups depicted in the compounds in Table 1 below.

[0201] As defined generally above, q represents independently for each occurrence 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the groups depicted in the compounds in Table 1 below.

[0202] As defined generally above, w represents independently for each occurrence 0 or 1. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is selected from the groups depicted in the compounds in Table 1 below.

[0203] As defined generally above, x is 1, 2, or 3. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is selected from the groups depicted in the compounds in Table 1 below.

[0204] As defined generally above, z represents independently for each occurrence 0, 1, or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z represents independently for each occurrence 0 or 1. In certain embodiments, z represents independently for each occurrence 1 or 2. In certain embodiments, z is selected from the groups depicted in the compounds in Table 1 below.

[0205] The description above describes multiple embodiments relating to compounds of Formula I-1. The patent application specifically contemplates all combinations of the embodiments.

[0206] In certain embodiments, the compound of Formula I is further defined by Formula I-A, or a pharmaceutically acceptable salt thereof:(I-A)In certain embodiments, the compound is a compound of Formula I-A. In certain embodiments, the definition of each of the variables in Formula I-A is one of the embodiments described above in connection with Formula I. The description above describes multiple embodiments relating to compounds of Formula I-A. The patent application specifically contemplates all combinations of the embodiments.

[0207] In certain embodiments, the compound of Formula I is further defined by Formula la or lb, or a pharmaceutically acceptable salt thereof:la lbIn certain embodiments, the definition of each of the variables in Formula la and lb is one of the embodiments described above in connection with Formula I. In certain embodiments, the compound of Formula I is further defined by Formula Ia or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula la. In certain embodiments, the compound of Formula I is further defined by Formula lb or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula lb. The description above describes multiple embodiments relating to compounds of Formulae la and lb. The patent application specifically contemplates all combinations of the embodiments.

[0208] In certain embodiments, the compound of Formula I is further defined by Formula Ic or Id, or a pharmaceutically acceptable salt thereof:Ic IdIn certain embodiments, the definition of each of the variables in Formula Ic and Id is one of the embodiments described above in connection with Formula I. In certain embodiments, the compound of Formula I is further defined by Formula Ic or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula Ic. In certain embodiments, the compound of Formula I is further defined by Formula Id or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula Id. The description above describes multiple embodiments relating to compounds of Formulae Ic and Id. The patent application specifically contemplates all combinations of the embodiments.

[0209] In certain embodiments, the compound of Formula I is further defined by Formula Ie, If, or Ig, or a pharmaceutically acceptable salt thereof:le If IgIn certain embodiments, the definition of each of the variables in Formula le, If, and Ig is one of the embodiments described above in connection with Formula I. In certain embodiments, the compound of Formula I is further defined by Formula le or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula le. In certain embodiments, the compound of Formula I is further defined by Formula If or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula If. In certain embodiments, the compound of Formula I is further defined by Formula Ig or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula Ig. The description above describes multiple embodiments relating to compounds of Formulae le, If, and Ig. The patent application specifically contemplates all combinations of the embodiments.

[0210] In certain embodiments, the compound of Formula I is further defined by Formula Ih, li, Ij, Ik, II, or Im, or a pharmaceutically acceptable salt thereof:Ih li IjIk II ImIn certain embodiments, the definition of each of the variables in each of Formula Ih, li, Ij, Ik, II, and Im is one of the embodiments described above in connection with Formula I. In certain embodiments, the compound of Formula I is further defined by Formula Ih or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula li or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula Ij or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula Ik or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula Im or a pharmaceutically acceptable salt thereof.

[0211] In certain embodiments, the compound is a compound of Formula Ih. In certain embodiments, the compound is a compound of Formula li. In certain embodiments, the compound is a compound of Formula Ij. In certain embodiments, the compound is a compound of Formula Ik. In certain embodiments, the compound is a compound of Formula II. In certain embodiments, the compound is a compound of Formula Im. The description above describes multiple embodiments relating to compounds of Formulae Ih, li, Ij, Ik, II, and Im. The patent application specifically contemplates all combinations of the embodiments.

[0212] Another aspect of the invention provides a compound represented by Formula II:(II)or a pharmaceutically acceptable salt thereof; wherein:R1is halo, hydroxyl, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 cycloalkyl, C1-6alkoxyl, -C(O)-(C1-8aliphatic), -(Co-6 alkylene)-CN, -C(O)-O-(C1-8aliphatic), -OC(O)-(C1-8aliphatic), -0C(0)N(RA)(RB), -N(RA)C(O)2-(C 1-8 aliphatic), -S(O)2-(Ci-8aliphatic), or S(O)2N(RA)(RB);R2is C1-6 alkyl, C2-6 alkenyl, C1-6 hydroxyalkyl, C1-6 haloalkoxyl, C1-6 alkoxyl, C3-7 cycloalkyl, halo, -C(O)-(Ci-4 alkyl), -OR14, -N(R13)(R16), -(pyridinonyl substituted with x occurrences of R6), -(C2-4 alkynylene)-(pyri dinonyl substituted with x occurrences of R6), -(triazol onyl substituted with x occurrences of R6), -(Co-6 alkylene)-(C3-7 cycloalkyl substituted with z occurrences of R17), -(Co-6alkylene)-(phenyl substituted with t occurrences of R18), -(Co-6 alkylene)-(6-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with z occurrences of R17), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7;R3is hydrogen, C1-4 alkyl, C 1.4 haloalkoxyl, or C3-7 cycloalkyl;R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -(C1.4 alkylene)-(C 1-4 alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(Co-6 alkylene)-C(O)-R8, -N(RA)-(Co-6 alkylene)-R8, -N(RA)-(Co-6 alkylene)-C(O)-R8, -C(O)-N(RA)-R8, -N(RA)C(0)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4alkyl, Ci-4 hydroxyalkyl, Ci-4 haloalkyl, or -(Co-6 alkylene)-R9;R6represents independently for each occurrence halogen, Ci-4 alkyl, C3-7 cycloalkyl, -N(RA)(RB), -(C0-6alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, Ci-4alkoxyl, or C3-7 cycloalkyl;R8is C1-4 alkoxyl, -C(O)-OH, -C(O)-(C1-4alkyl), C1-4 haloalkyl, -N(RA)(RB), C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl), -(pyridinonyl substituted with x occurrences of C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is C1-4alkoxyl, -C(O)-OH, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci-4 haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -N(RA)-(C1-4haloalkyl), or -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of C1-4 alkyl);X1is a covalent bond or -(C1-6alkylene)-, wherein 0 or 1 methylene group is replaced with -N(RA)-, O, or -C(O)-;A1is (i) phenyl substituted with q occurrences of R11, (ii) a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12, (iii) a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclicheteroaryl is substituted with z occurrences of R12, (iv) a 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10, (v) C3-6 cycloalkyl substituted with 0 or 1 occurrence of R10, or (vi) C1-6 alkyl, C1-4haloalkyl, -C(O)-R7, or C1-4alkoxyl;A2is an oxo-substituted 5-6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5;R11and R12each represents independently for each occurrence halo, hydroxyl, -C(O)-(Ci-4alkoxyl), C1-4 alkyl, C1.4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, -SF5, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;R14is C3-7 cycloalkyl, a 5-6 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with z occurrences of R7, phenyl substituted with z occurrences of R7, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7;R15and R16are independently hydrogen, C1.4 alkyl, C1-4 haloalkyl, or 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7; or an instance of R15and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R17is C1-4 alkyl, C1-4 haloalkyl, cyano, or 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R18is halo, hydroxyl, or C1.4 alkyl;t is 0, 1, 2 or 3;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

[0213] The definitions of variables in Formula II above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable isa 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).

[0214] In certain embodiments, the compound is a compound of Formula II.

[0215] As defined generally above, R1is halo, hydroxyl, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 cycloalkyl, Ci-6alkoxyl, -C(O)-(Ci-8 aliphatic), -(Co-6 alkylene)-CN, -C(O)-O-(Ci-8 aliphatic), -OC(O)-(Ci-8 aliphatic), -0C(0)N(RA)(RB), -N(RA)C(O)2-(Ci-8 aliphatic), -S(O)2-(Ci-8aliphatic), or S(O)2N(RA)(RB). In certain embodiments, R1is halo. In certain embodiments, R1is fluoro. In certain embodiments, R1is chloro. In certain embodiments, R1is bromo. In certain embodiments, R1is hydroxyl. In certain embodiments, R1is C1-6 alkyl. In certain embodiments, R1is methyl. In certain embodiments, R1is C2alkyl. In certain embodiments, R1is C3 alkyl. In certain embodiments, R1is C4 alkyl. In certain embodiments, R1is C5 alkyl. In certain embodiments, R1is C>, alkyl. In certain embodiments, R1is C1-6 haloalkyl. In certain embodiments, R1is Ci haloalkyl. In certain embodiments, R1is -CF3. In certain embodiments, R1is C2haloalkyl. In certain embodiments, R1is C3 haloalkyl. In certain embodiments, R1is C4 haloalkyl. In certain embodiments, R1is C5 haloalkyl. In certain embodiments, R1is C& haloalkyl. In certain embodiments, R1is C3-7 cycloalkyl. In certain embodiments, R1is C3 cycloalkyl. In certain embodiments, R1is C4 cycloalkyl. In certain embodiments, R1is C5 cycloalkyl. In certain embodiments, R1is Ce cycloalkyl. In certain embodiments, R1is C7 cycloalkyl. In certain embodiments, R1is C1-6 alkoxyl. In certain embodiments, R1is Ci alkoxyl. In certain embodiments, R1is C2alkoxyl. In certain embodiments, R1is C3 alkoxyl. In certain embodiments, R1is C4 alkoxyl. In certain embodiments, R1is C5 alkoxyl. In certain embodiments, R1is Ce alkoxyl. In certain embodiments, R1is -C(O)-(Ci-8 aliphatic). In certain embodiments, R1is -(Co-6 alkylene)-CN. In certain embodiments, R1is -CN. In certain embodiments, R1is -C(O)-O-(Ci-8 aliphatic). In certain embodiments, R1is -OC(O)-(Ci-8 aliphatic). In certain embodiments, R1is -OC(O)N(RA)(RB). In certain embodiments, R1is -N(RA)C(O)2-(CI-8 aliphatic). In certain embodiments, R1is -S(O)2-(Ci-8 aliphatic). In certain embodiments, R1is S(O)2N(RA)(RB). In certain embodiments, R1is selected from the groups depicted in the compounds in Table 2 below.

[0216] As defined generally above, R2is Ci-6 alkyl, C2-6 alkenyl, Ci-6 hydroxyalkyl, C1-6haloalkoxyl, Ci-6 alkoxyl, C3-7 cycloalkyl, halo, -C(O)-(Ci-4 alkyl), -OR14, -N(R15)(R16), -(pyridinonyl substituted with x occurrences of R6), -(C2-4 alkynylene)-(pyri dinonyl substituted with x occurrences of R6), -(triazolonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(C3-7 cycloalkyl substituted with z occurrences of R17), -(Co-6 alkylene)-(phenyl substituted with t occurrences of R18), -(Co-6 alkylene)-(6-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with z occurrences of R17), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7. In certain embodiments, R2is C1-6 alkyl. In certain embodiments, R2is methyl. In certain embodiments, R2is C2 alkyl. In certain embodiments, R2is C3 alkyl. In certain embodiments, R2is C4 alkyl. In certain embodiments, R2is C5 alkyl. In certain embodiments, R2is Ce alkyl. In certain embodiments, R2is C2-6 alkenyl. In certain embodiments, R2is C2 alkenyl. In certain embodiments, R2is C3alkenyl. In certain embodiments, R2is C4 alkenyl. In certain embodiments, R2is C5 alkenyl. In certain embodiments, R2is Ce alkenyl. In certain embodiments, R2is Cue hydroxyalkyl. In certain embodiments, R2is C1hydroxyalkyl. In certain embodiments, R2is C2 hydroxyalkyl. In certain embodiments, R2is C3hydroxyalkyl. In certain embodiments, R2is C4 hydroxyalkyl. In certain embodiments, R2is C5 hydroxyalkyl. In certain embodiments, R2is Ce hydroxyalkyl. In certain embodiments, R2is C1-6 haloalkoxyl. In certain embodiments, R2is Ci haloalkoxyl. In certain embodiments, R2is C2 haloalkoxyl. In certain embodiments, R2is C3 haloalkoxyl. In certain embodiments, R2is C4 haloalkoxyl. In certain embodiments, R2is C5 haloalkoxyl. In certain embodiments, R2is Ce haloalkoxyl. In certain embodiments, R2is C1-6 alkoxyl. In certain embodiments, R2is Ci alkoxyl. In certain embodiments, R2is C2 alkoxyl. In certain embodiments, R2is C3 alkoxyl. In certain embodiments, R2is C4 alkoxyl. In certain embodiments, R2is C5 alkoxyl. In certain embodiments, R2is Ce alkoxyl. In certain embodiments, R2is C3-7 cycloalkyl. In certain embodiments, R2is C3 cycloalkyl. In certain embodiments, R2is C4 cycloalkyl. In certain embodiments, R2is C5 cycloalkyl. In certainembodiments, R2is C6cycloalkyl. In certain embodiments, R2is C7cycloalkyl. In certain embodiments, R2is halo. In certain embodiments, R2is fluoro. In certain embodiments, R2is chloro. In certain embodiments, R2is bromo. In certain embodiments, R2is -C(O)-(Ci-4 alkyl). In certain embodiments, R2is -OR14. In certain embodiments, R2is -N(R15)(R16). In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6). In certain embodiments, R2is -(C2-4 alkynylene)-(pyridinonyl substituted with x occurrences of R6). In certain embodiments, R2is -(triazolonyl substituted with x occurrences of R6). In certain embodiments, R2is -(Co-6 alkylene)-(C3-7 cycloalkyl substituted with z occurrences of R17). In certain embodiments, R2is -(Co-6 alkylene)-(phenyl substituted with t occurrences of R18). In certain embodiments, R2is -(Co-6 alkylene)-(6-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with z occurrences of R17). In certain embodiments, R2is -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 5 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 9 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is selected from the groups depicted in the compounds in Table 2 below.

[0217] As defined generally above, R3is hydrogen, C1.4 alkyl, C1-4 haloalkoxyl, or C3-7 cycloalkyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is Ci alkyl. In certain embodiments, R3is C2 alkyl. In certainembodiments, R3is C3alkyl. In certain embodiments, R3is C4alkyl. In certain embodiments, R3is Ci-4haloalkoxyl. In certain embodiments, R3is Ci haloalkoxyl. In certain embodiments, R3is C2 haloalkoxyl. In certain embodiments, R3is C3 haloalkoxyl. In certain embodiments, R3is C4 haloalkoxyl. In certain embodiments, R3is C3-7 cycloalkyl. In certain embodiments, R3is C3 cycloalkyl. In certain embodiments, R3is C4 cycloalkyl. In certain embodiments, R3is C5 cycloalkyl. In certain embodiments, R3is Ce cycloalkyl. In certain embodiments, R3is C7 cycloalkyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 2 below.

[0218] As defined generally above, R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 alkoxyl, C1.4 haloalkoxyl, -(Ci-4alkylene)-(Ci-4alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(C0-6alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C0-6alkylene)-C(O)-R8, -N(RA)-(Co-6 alkylene)-R8, -N(RA)-(C0-6alkylene)-C(O)-R8, -C(O)-N(RA)-R8, -N(RA)C(0)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is C1-4 alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is C2 alkyl. In certain embodiments, R4is C3 alkyl. In certain embodiments, R4is C4 alkyl. In certain embodiments, R4is C1-4 hydroxyalkyl. In certain embodiments, R4is Ci hydroxyalkyl. In certain embodiments, R4is C2 hydroxyalkyl. In certain embodiments, R4is C3 hydroxyalkyl. In certain embodiments, R4is C4 hydroxyalkyl. In certain embodiments, R4is C3-7 cycloalkyl. In certain embodiments, R4is C3 cycloalkyl. In certain embodiments, R4is C4 cycloalkyl. In certain embodiments, R4is C5 cycloalkyl. In certain embodiments, R4is Ce cycloalkyl. In certain embodiments, R4is C7 cycloalkyl. In certain embodiments, R4is C1-4 alkoxyl. In certain embodiments, R4is Ci alkoxyl. In certain embodiments, R4is C2 alkoxyl. In certain embodiments, R4is C3 alkoxyl. In certain embodiments, R4is C4 alkoxyl. In certain embodiments, R4is C1-4 haloalkoxyl. In certain embodiments, R4is Ci haloalkoxyl. In certain embodiments, R4is C2 haloalkoxyl. In certain embodiments, R4is C3 haloalkoxyl. In certain embodiments, R4is C4 haloalkoxyl. In certain embodiments, R4is -(Ci-4alkylene)-(Ci-4 alkoxyl). In certain embodiments, R4is -C(O)-OH. In certain embodiments, R4is hydroxyl. In certain embodiments, R4is -(Co-6 alkylene)-N(RA)(RB). In certain embodiments, R4is -N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected fromnitrogen and oxygen). In certain embodiments, R4is -(Co-6 alkylene)-C(O)-R8. In certain embodiments, R4is -N(RA)-(Co-6 alkylene)-R8. In certain embodiments, R4is -N(RA)-(Co-6 alkylene)-C(O)-R8. In certain embodiments, R4is -C(O)-N(RA)-R8. In certain embodiments, R4is -N(RA)C(O)N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is selected from the groups depicted in the compounds in Table 2 below.

[0219] As defined generally above, R5is Ci-4 alkyl, Ci-4 hydroxyalkyl, Ci-4 haloalkyl, or -(Co-6 alkylene)-R9. In certain embodiments, R5is Ci-4 alkyl. In certain embodiments, R5is methyl. In certain embodiments, R3is C2 alkyl. In certain embodiments, R3is C3 alkyl. In certain embodiments, R5is C4 alkyl. In certain embodiments, R5is C1-4 hydroxyalkyl. In certain embodiments, R3is Ci hydroxyalkyl. In certain embodiments, R5is C2 hydroxyalkyl. In certain embodiments, R5is C3 hydroxyalkyl. In certain embodiments, R5is C4 hydroxyalkyl. In certain embodiments, R5is C1-4 haloalkyl. In certain embodiments, R5is Ci haloalkyl. In certain embodiments, R3is C2 haloalkyl. In certain embodiments, R5is C3 haloalkyl. In certain embodiments, R5is C4 haloalkyl. In certain embodiments, R5is -(Co-6 alkylene)-R9. In certain embodiments, R5is -R9. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 2 below.

[0220] As defined generally above, R6represents independently for each occurrence halogen, Ci-4 alkyl, C3-7 cycloalkyl, -N(RA)(RB), -(Co-6alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R6is halogen. In certain embodiments, R6is fluoro. In certain embodiments, R6is chloro. In certain embodiments, R6is bromo. In certain embodiments, R6is C1-4 alkyl. In certain embodiments, R6is methyl. In certain embodiments, R6is C2 alkyl. In certain embodiments, R6is C3 alkyl. In certain embodiments, R6is C4 alkyl. In certain embodiments, R6is C3-7 cycloalkyl. In certain embodiments, R6is C3 cycloalkyl. In certain embodiments, R6is C4 cycloalkyl. In certain embodiments, R6is C5 cycloalkyl. In certain embodiments, R6is Ce cycloalkyl. In certain embodiments, R6is C7 cycloalkyl. In certain embodiments, R6is -N(RA)(RB). In certainembodiments, R6is -(Co-6alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7). In certain embodiments, R6is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 2 below.

[0221] As defined generally above, R7represents independently for each occurrence Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxyl, or C3-7 cycloalkyl. In certain embodiments, R7is C1-4 alkyl. In certain embodiments, R7is methyl. In certain embodiments, R7is C2 alkyl. In certain embodiments, R7is C3 alkyl. In certain embodiments, R7is C4 alkyl. In certain embodiments, R7is C1-4 haloalkyl. In certain embodiments, R7is Ci haloalkyl. In certain embodiments, R7is -CF3. In certain embodiments, R7is C2 haloalkyl. In certain embodiments, R7is C3 haloalkyl. In certain embodiments, R7is C4 haloalkyl. In certain embodiments, R7is C1-4 alkoxyl. In certain embodiments, R7is Ci alkoxyl. In certain embodiments, R7is C2 alkoxyl. In certain embodiments, R7is C3 alkoxyl. In certain embodiments, R7is C4 alkoxyl. In certain embodiments, R7is C3-7 cycloalkyl. In certain embodiments, R7is C3 cycloalkyl. In certain embodiments, R7is C4 cycloalkyl. In certain embodiments, R7is C5 cycloalkyl. In certain embodiments, R7is C > cycloalkyl. In certain embodiments, R7is C7 cycloalkyl. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 2 below.

[0222] As defined generally above, R8is C1.4 alkoxyl, -C(O)-OH, -C(O)-(C1-4 alkyl), C1.4 haloalkyl, -N(RA)(RB), C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl), -(pyridinonyl substituted with x occurrences of C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is C1.4 alkoxyl. In certain embodiments, R8is Ci alkoxyl. In certain embodiments, R8is C2 alkoxyl. In certain embodiments, R8is C3 alkoxyl. In certain embodiments, R8is C4 alkoxyl. In certain embodiments, R8is -C(O)-OH. In certain embodiments, R8is -C(O)-(Ci-4 alkyl). In certain embodiments, R8is C 1.4 haloalkyl. In certain embodiments, R8is Ci haloalkyl. In certain embodiments, R8is C2 haloalkyl. In certain embodiments, R8is C3 haloalkyl. In certain embodiments, R8is C4 haloalkyl. In certainembodiments, R8is -N(RA)(RB). Tn certain embodiments, R8is C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl). In certain embodiments, R8is C3 cycloalkyl substituted with w occurrences of -(phenyl )-(C 1.4 alkoxyl). In certain embodiments, R8is C4 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl). In certain embodiments, R8is C5 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl). In certain embodiments, R8is Ce cycloalkyl substituted with w occurrences of -(phenyl )-(C 1-4 alkoxyl). In certain embodiments, R8is C7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl). In certain embodiments, R8is C3-7 cycloalkyl. In certain embodiments, R8is -(pyridinonyl substituted with x occurrences of Ci-4 alkyl). In certain embodiments, R8is hydroxyl. In certain embodiments, R8is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R8is a 5 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R8is a 6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R8is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is a 6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 2 below.

[0223] As defined generally above, R9is C1.4 alkoxyl, -C(O)-OH, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrence of halo. In certain embodiments, R9is C1.4 alkoxyl. In certain embodiments, R9is Ci alkoxyl. In certain embodiments, R9is C2 alkoxyl. In certain embodiments, R9is C3 alkoxyl. In certain embodiments, R9is C4 alkoxyl. In certain embodiments, R9is -C(O)-OH. In certainembodiments, R9is C3-7 cycloalkyl. In certain embodiments, R9is C3 cycloalkyl. In certain embodiments, R9is C4 cycloalkyl. In certain embodiments, R9is C5 cycloalkyl. In certain embodiments, R9is Ce cycloalkyl. In certain embodiments, R9is C7 cycloalkyl. In certain embodiments, R9is a 4-6 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is a 4 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is a 5 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is a 6 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrence of halo. In certain embodiments, R9is a 5 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrence of halo. In certain embodiments, R9is a 6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with w occurrence of halo. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 2 below.

[0224] As defined generally above, RAand RBeach represent independently for each occurrence hydrogen, C 1-4 alkyl, and Ci-4haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis hydrogen. In certain embodiments, RAis C1-4 alkyl. In certain embodiments, RAis methyl. In certain embodiments, RAis C2 alkyl. In certain embodiments, RAis C3 alkyl. In certain embodiments, RAis C4 alkyl. In certain embodiments, RAis C1-4 haloalkyl. In certain embodiments, RAis Ci haloalkyl. In certain embodiments, RAis -CF3. In certain embodiments, RAis C2 haloalkyl. In certain embodiments, RAis C3 haloalkyl. In certain embodiments, RAis C4 haloalkyl. In certain embodiments, RBis hydrogen. In certain embodiments, RBis C1-4 alkyl. In certain embodiments, RBis methyl. In certain embodiments, RBis C2 alkyl. In certain embodiments, RBis C3 alkyl. In certain embodiments, RBis C4 alkyl. In certain embodiments, RBis C1.4 haloalkyl. In certain embodiments, RBis Ci haloalkyl. In certain embodiments, RBis -CF3. In certain embodiments, RBis C2 haloalkyl. In certain embodiments, RBis C3 haloalkyl. In certain embodiments, RBis C4 haloalkyl. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom,wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 4 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 5 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 6 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis selected from the groups depicted in the compounds in Table 2 below. In certain embodiments, RBis selected from the groups depicted in the compounds in Table 2 below.

[0225] As defined generally above, R10represents independently for each occurrence Ci-4 alkyl, hydroxyl, Ci-4 alkoxyl, Ci-4 haloalkoxyl, -N(RA)-(C1-4haloalkyl), or -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of Ci-4 alkyl). In certain embodiments, R10is Ci-4 alkyl. In certain embodiments, R10is methyl. In certain embodiments, R10is C2 alkyl. In certain embodiments, R10is C3 alkyl. In certain embodiments, R10is C4 alkyl. In certain embodiments, R10is hydroxyl. In certain embodiments, R10is C1-4 alkoxyl. In certain embodiments, R10is Ci alkoxyl. In certain embodiments, R10is C2 alkoxyl. In certain embodiments, R10is C3 alkoxyl. In certain embodiments, R10is C4 alkoxyl. In certain embodiments, R10is C1-4 haloalkoxyl. In certain embodiments, R10is Ci haloalkoxyl. In certain embodiments, R10is C2 haloalkoxyl. In certain embodiments, R10is C3 haloalkoxyl. In certain embodiments, R10is C4 haloalkoxyl. In certain embodiments, R10is -N(RA)-(Ci-4 haloalkyl). In certain embodiments, R10is -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of Ci-4 alkyl). In certain embodiments, R10is selected from the groups depicted in the compounds in Table 2 below.

[0226] As defined generally above, X1is a covalent bond or -(C1-6alkylene)-, wherein 0 or 1 methylene group is replaced with -N(RA)-, O, or -C(O)-. In certain embodiments, X1is a covalent bond. In certain embodiments, X1is -(Ci-6 alkylene)-, wherein 0 or 1 methylene group is replaced with -N(RA)-, O, or-C(O)-. In certain embodiments, X1is -(Ci-6 alkylene)-. In certain embodiments, X1is -(Ci-6 alkylene)-, wherein 1 methylene group is replaced with -N(RA)-, O, or — C(O)-. In certain embodiments, X1is -(Ci alkylene)-. In certain embodiments, X1is -(C2 alkylene)-. In certain embodiments, X1is -(C3 alkylene)-. In certain embodiments, X1is -(C4 alkylene)-. In certain embodiments, X1is -(C5 alkylene)-. In certain embodiments, X1is -(Ce alkylene)-. In certain embodiments, X1is selected from the groups depicted in the compounds in Table 2 below.

[0227] As defined generally above, A1is (i) phenyl substituted with q occurrences of R11, (ii) a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12, (iii) a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with z occurrences of R12, (iv) a 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10, (v) C3-6 cycloalkyl substituted with 0 or 1 occurrence of R10, or (vi) Ci-6 alkyl, Ci.4haloalkyl, -C(O)-R7, or C1-4 alkoxyl. In certain embodiments, A1is phenyl substituted with q occurrences of R11. In certain embodiments, A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 5 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substitutedwith z occurrences of R12. In certain embodiments, A1is a 9 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is a 3 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is a 4 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is a 5 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is a 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is a 7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is C3-6 cycloalkyl substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is C3 cycloalkyl substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is C4 cycloalkyl substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is C5 cycloalkyl substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is Cr, cycloalkyl substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is C1-6 alkyl, Ci-4haloalkyl, -C(O)-R7, or Ci-4alkoxyl. In certain embodiments, A1is Ci-6 alkyl. In certain embodiments, A1is methyl. In certain embodiments, A1is C2 alkyl. In certain embodiments, A1is C3 alkyl. In certain embodiments, A1is C4 alkyl. In certain embodiments, A1is C5 alkyl. In certain embodiments, A1is C>, alkyl. In certain embodiments, A1is Ci-4haloalkyl. In certain embodiments, A1is Ci haloalkyl. In certain embodiments, A1is -CF3. In certain embodiments, A1is C2 haloalkyl. In certain embodiments, A1is C3 haloalkyl. In certain embodiments, A1is C4 haloalkyl. In certain embodiments, A1is -C(O)-R7. In certain embodiments, A1is Ci-4alkoxyl. In certain embodiments, A1is Ci alkoxyl. In certainembodiments, A1is C2 alkoxyl. In certain embodiments, A1is C3 alkoxyl. In certain embodiments, A1is C4 alkoxyl. In certain embodiments, A1is selected from the groups depicted in the compounds in Table 2 below.

[0228] As defined generally above, A2is an oxo-substituted 5-6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5. In certain embodiments, A2is an oxo-substituted 5 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5. In certain embodiments, A2is an oxo-substituted 6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5. In certain embodiments, A2is one of the following:In certain embodiments, A2isIn certain embodiments,A2In certain embodiments, A2isIn certain embodiments,A2is In certain embodiments, A2is selected from the groups depicted in the compounds in Table 2 below.

[0229] As defined generally above, R11and R12each represents independently for each occurrence halo, hydroxyl, -C(O)-(C 1-4 alkoxyl), C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, -SF5, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13. In certain embodiments, R11is halo. In certain embodiments, R11is fluoro. In certain embodiments, R11is chloro. In certain embodiments, R11is bromo. In certain embodiments, R11is hydroxyl. In certain embodiments, R11is -C(O)-(Ci-4 alkoxyl). In certain embodiments, R11is C1.4 alkyl. In certain embodiments, R11is methyl. In certain embodiments, R11is C2 alkyl. In certain embodiments, R11is C3 alkyl. In certain embodiments, R11is C4 alkyl. In certain embodiments,R11is Ci-4 haloalkyl. In certain embodiments, R11is Ci haloalkyl. In certain embodiments, R11is -CF3. In certain embodiments, R11is C2 haloalkyl. In certain embodiments, R11is C3 haloalkyl. In certain embodiments, R11is C4 haloalkyl. In certain embodiments, R11is C1-4 alkoxyl. In certain embodiments, R11is Ci alkoxyl. In certain embodiments, R11is C2 alkoxyl. In certain embodiments, R11is C3 alkoxyl. In certain embodiments, R11is C4 alkoxyl. In certain embodiments, R11is C1-4 haloalkoxyl. In certain embodiments, R11is Ci haloalkoxyl. In certain embodiments, R11is C2 haloalkoxyl. In certain embodiments, R11is C3 haloalkoxyl. In certain embodiments, R11is C4 haloalkoxyl. In certain embodiments, R11is C3-7 cycloalkyl. In certain embodiments, R11is C3 cycloalkyl. In certain embodiments, R11is C4 cycloalkyl. In certain embodiments, R11is C5 cycloalkyl. In certain embodiments, R11is Ce cycloalkyl. In certain embodiments, R11is C7 cycloalkyl. In certain embodiments, R11is -SF5. In certain embodiments, R11is C2-3 alkynyl. In certain embodiments, R11is C2 alkynyl. In certain embodiments, R11is C3 alkynyl. In certain embodiments, one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13. In certain embodiments, R12is halo. In certain embodiments, R12is fluoro. In certain embodiments, R12is chloro. In certain embodiments, R12is bromo. In certain embodiments, R12is hydroxyl. In certain embodiments, R12is -C(O)-(Ci-4 alkoxyl). In certain embodiments, R12is C1.4 alkyl. In certain embodiments, R12is methyl. In certain embodiments, R12is C2 alkyl. In certain embodiments, R12is C3 alkyl. In certain embodiments, R12is C4 alkyl. In certain embodiments, R12is C1-4 haloalkyl. In certain embodiments, R12is Ci haloalkyl. In certain embodiments, R12is -CF3. In certain embodiments, R12is C2 haloalkyl. In certain embodiments, R12is C3 haloalkyl. In certain embodiments, R12is C4 haloalkyl. In certain embodiments, R12is C1-4 alkoxyl. In certain embodiments, R12is Ci alkoxyl. In certain embodiments, R12is C2 alkoxyl. In certain embodiments, R12is C3 alkoxyl. In certain embodiments, R12is C4 alkoxyl. In certain embodiments, R12is C1-4 haloalkoxyl. In certain embodiments, R12is Ci haloalkoxyl. In certain embodiments, R12is C2 haloalkoxyl. In certain embodiments, R12is C3 haloalkoxyl. In certain embodiments, R12is C4 haloalkoxyl. In certain embodiments, R12is C3-7 cycloalkyl. In certain embodiments, R12is C3 cycloalkyl. In certain embodiments, R12is C4 cycloalkyl. In certain embodiments, R12is C5 cycloalkyl. In certain embodiments, R12is Ce cycloalkyl. In certain embodiments, R12is C7 cycloalkyl. In certain embodiments, R12is -SF5. In certainembodiments, R12is C2-3 alkynyl. In certain embodiments, R12is C2 alkynyl. In certain embodiments, R12is C3 alkynyl. In certain embodiments, R11is selected from the groups depicted in the compounds in Table 2 below. In certain embodiments, R12is selected from the groups depicted in the compounds in Table 2 below.

[0230] As defined generally above, R13represents independently for each occurrence C1-4 alkyl or halo. In certain embodiments, R13is C1-4 alkyl. In certain embodiments, R13is methyl. In certain embodiments, R13is C2 alkyl. In certain embodiments, R13is C3 alkyl. In certain embodiments, R13is C4 alkyl. In certain embodiments, R13is halo. In certain embodiments, R13is fluoro. In certain embodiments, R13is chloro. In certain embodiments, R13is bromo. In certain embodiments, R13is selected from the groups depicted in the compounds in Table 2 below.

[0231] As defined generally above, R14is C3-7 cycloalkyl, a 5-6 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with z occurrences of R7, phenyl substituted with z occurrences of R7, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R14is C3-7 cycloalkyl. In certain embodiments, R14is C3 cycloalkyl. In certain embodiments, R14is C4 cycloalkyl. In certain embodiments, R14is C5 cycloalkyl. In certain embodiments, R14is Ce cycloalkyl. In certain embodiments, R14is C7 cycloalkyl. In certain embodiments, R14is a 5-6 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with z occurrences of R7. In certain embodiments, R14is a 5 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with z occurrences of R7. In certain embodiments, R14is a 6 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with z occurrences of R7. In certain embodiments, R14is phenyl substituted with z occurrences of R7. In certain embodiments, R14is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R14is a 5 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R14is a 6 membered monocyclic heteroaryl containing 1, 2, or 3nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R14is selected from the groups depicted in the compounds in Table 2 below.

[0232] As defined generally above, R15and R16are independently hydrogen, Ci-4 alkyl, Ci-4 haloalkyl, or 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7; or an instance of R15and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, R13is hydrogen. In certain embodiments, R15is Ci-4 alkyl. In certain embodiments, R15is Ci alkyl. In certain embodiments, R15is C2 alkyl. In certain embodiments, R15is C3alkyl. In certain embodiments, R15is C4alkyl. In certain embodiments, R15is C 1-4 haloalkyl. In certain embodiments, R15is Ci haloalkyl. In certain embodiments, R15is C2 haloalkyl. In certain embodiments, R15is C3 haloalkyl. In certain embodiments, R15is C4haloalkyl. In certain embodiments, R15is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R15is a 5 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R15is a 6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R16is hydrogen. In certain embodiments, R16is C1-4 alkyl. In certain embodiments, R16is Ci alkyl. In certain embodiments, R16is C2 alkyl. In certain embodiments, R16is C3 alkyl. In certain embodiments, R16is C4 alkyl. In certain embodiments, R16is C1-4 haloalkyl. In certain embodiments, R16is Ci haloalkyl. In certain embodiments, R16is C2 haloalkyl. In certain embodiments, R16is C3 haloalkyl. In certain embodiments, R16is C4 haloalkyl. In certain embodiments, R16is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R16is a 5 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R16is a 6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, an instance of R13and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring issubstituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of R13and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 3 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of R13and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 4 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of R13and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 5 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of R15and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 6 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, an instance of R15and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, R15is selected from the groups depicted in the compounds in Table 2 below. In certain embodiments, R16is selected from the groups depicted in the compounds in Table 2 below.

[0233] As defined generally above, R17is Ci-4 alkyl, Ci-4 haloalkyl, cyano, or 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R17is Ci-4 alkyl. In certain embodiments, R17is Ci alkyl. In certain embodiments, R17is C2 alkyl. In certain embodiments, R17is C3 alkyl. In certain embodiments, R17is C4 alkyl. In certain embodiments, R17is C1-4 haloalkyl. In certain embodiments, R17is Ci haloalkyl. In certain embodiments, R17is C2 haloalkyl. In certain embodiments, R17is C3 haloalkyl. In certain embodiments, R17is C4 haloalkyl. In certain embodiments, R17is cyano. In certain embodiments, R17is 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R17is selected from the groups depicted in the compounds in Table 2 below.

[0234] As defined generally above, R18is halo. In certain embodiments, R18is fluoro. In certain embodiments, R18is chloro. In certain embodiments, R18is bromo. In certain embodiments, R18is hydroxyl. In certain embodiments, R18is C1-4 alkyl. In certain embodiments, R18is C1alkyl. In certain embodiments, R18is C2 alkyl. In certain embodiments, R18is C3 alkyl. In certain embodiments, R18is C4 alkyl. In certain embodiments, R18is selected from the groups depicted in the compounds in Table 2 below.

[0235] As defined generally above, t is 0, 1, 2 or 3. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is selected from the corresponding values in the groups depicted in the compounds in Table 2 below.

[0236] As defined generally above, q represents independently for each occurrence 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the corresponding values in the groups depicted in the compounds in Table 2 below.

[0237] As defined generally above, w represents independently for each occurrence 0 or 1. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is selected from the corresponding values in the groups depicted in the compounds in Table 2 below.

[0238] As defined generally above, x is 1, 2, or 3. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is selected from the corresponding values in the groups depicted in the compounds in Table 2 below.

[0239] As defined generally above, z represents independently for each occurrence 0, 1, or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is selected from the corresponding values in the groups depicted in the compounds in Table 2 below.

[0240] Part B

[0241] One aspect of the invention provides a compound represented by Formula A-I:(A-I)or a pharmaceutically acceptable salt thereof; wherein:R1is hydrogen or halo;R2is C1-6 hydroxyalkyl, -C(O)-(Ci-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(triazolonyl substituted with x occurrences of R6), -(Ci-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7;R3is hydrogen, C1-4 alkyl, Ci.4haloalkoxyl, or C3-7 cycloalkyl;R4is C1.4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(C0-6alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(O)N(RA)(RB), or -(Co-6 alkyl ene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C0-6 alkylene)-R9;R6represents independently for each occurrence halogen, C1-4 alkyl, C3-7 cycloalkyl, -N(C1-4 alkyl)2, -(C0-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogenatoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence Ci-4 alkyl or C3-7 cycloalkyl;R8is C1-4alkoxyl, -C(O)-OH, -C(O)-(Ci-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is Ci-4alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci-4 haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, or C1-4 alkoxyl; X1is -(C 1-6 alkylene)-;A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12;R11and R12each represents independently for each occurrence halo, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

[0242] The definitions of variables in Formula A-I above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable isa 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).

[0243] In certain embodiments, the compound is a compound of Formula A-I.

[0244] As defined generally above, R1is hydrogen or halo. In certain embodiments, R1is hydrogen. In certain embodiments, R1is halo. In certain embodiments, R1is chloro. In certain embodiments, R1is bromo. In certain embodiments, R1is fluoro. In certain embodiments, R1is iodo. In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1 below.

[0245] As defined generally above, R2is C1-6 hydroxyalkyl, -C(O)-(C1-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(triazolonyl substituted with x occurrences of R6), -(C1-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7. In certain embodiments, R2is C1-6 hydroxyalkyl. In certain embodiments, R2is -C(O)-(C1-4 alkyl). In certain embodiments, R2is -(pyridinonyl substitutedwith x occurrences of R6). In certain embodiments,R2is0substituted with x occurrences of R6. In certain embodiments, R2is -(triazolonyl substituted with x occurrences of R6). In certain embodiments, R2is -(Ci-6alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is -(pyridin-2-on-5-yl substituted with x occurrences of R6) or a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substitutedwith x occurrences of R7. In certain embodiments, R2is selected from / er / -butyl,O. In certainembodiments, R2is selected from, and. In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1 below.

[0246] As defined generally above, R3is hydrogen, Ci-4 alkyl, Ci-4 haloalkoxyl, or C3-7 cycloalkyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is methyl or n-propyl. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is C1-4 haloalkoxyl. In certain embodiments, R3is or C3-7 cycloalkyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1 below.

[0247] As defined generally above, R4is C1.4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(Ci-4alkylene)-(Ci-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(C0-6alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(O)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is Ci-4 alkyl. In certain embodiments, R4is Ci.4hydroxyalkyl. In certain embodiments, R4is C3-7 cycloalkyl. In certain embodiments, R4is Ci.4haloalkoxyl. In certain embodiments, R4is -(Ci-4alkylene)-(Ci-4alkoxyl). In certain embodiments, R4is hydroxyl. In certain embodiments, R4is -(Co-6 alkylene)-N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R4is -N(RA)-(Co-6alkylene)-R8. In certain embodiments, R4is -C(O)-N(RA)-R8. In certain embodiments, R4is -N(RA)C(O)N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is C1-4 alkyl, C1-4 hydroxyalkyl, or -(Co-6 alkylene)-N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-C(O)-R8, -N(RA)-(C0-6alkylene)-R8, -C(O)-N(RA)-R8, or -N(RA)C(O)N(RA)(RB). In certain embodiments, R4is -N(RA)(RB). In certain embodiments, R4is -NH2, -N(H)CH3, or -N(CH3)2. In certain embodiments, R4is selected from -NH2, -N(CH3)2, -N(H)CH3, hydroxy,embodiments, R4is selected from the groups depicted in the compounds in Table 1 below.

[0248] As defined generally above, R5is Ci-4 alkyl, Ci-4 hydroxyalkyl, C1-4 haloalkyl, or -(Co-6 alkylene)-R9. In certain embodiments, R5is Ci-4 alkyl. In certain embodiments, R5is Ci-4 hydroxyalkyl. In certain embodiments, R5is C1-4 haloalkyl. In certain embodiments, R5is -(Co-6 alkylene)-R9. In certain embodiments, R5is C1-4 alkyl or C1-4 haloalkyl. In certain embodiments, R5is -(C0-6alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is -(C0-2alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is selected from methyl,FIn certain embodiments, R5is selected from the groups depicted in the compounds in Table 1 below.

[0249] As defined generally above, R6represents independently for each occurrence halogen, Ci- 4 alkyl, C3-7 cycloalkyl, -N(Ci-4alkyl)2, -(Co-6 alkyl ene)-(5 -membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R6is halogen. In certain embodiments, R6is C1-4alkyl. In certain embodiments, R6is C3-7 cycloalkyl. In certain embodiments, R6is -N(C1-4alkyl)2. In certain embodiments, R6is -(Co-6 alkylene)-(5 -membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7). In certain embodiments, R6is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R6represents independently for each occurrence C1-4alkyl or -N(C1-4alkyl)2. In certain embodiments, R6represents independently for each occurrence methyl, -N(CH3)2, -(C0-1 alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl.In certain embodiments, R6represents independently for each occurrence methyl, -N(CH3)2, -(Co-i alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl; and R7represents independently for each occurrence methyl or cyclopropyl. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1 below.

[0250] As defined generally above, R7represents independently for each occurrence Ci-4 alkyl or C3-7 cycloalkyl. In certain embodiments, R7is C1.4 alkyl. In certain embodiments, R7is C3-7 cycloalkyl. In certain embodiments, R7represents independently for each occurrence methyl or cyclopropyl. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1 below.

[0251] As defined generally above, R8is Ci-4alkoxyl, -C(O)-OH, -C(O)-(C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is Ci-4alkoxyl. In certain embodiments, R8is -C(O)-OH. In certain embodiments, R8is -C(O)-(Ci-4 alkyl). In certain embodiments, R8is hydroxyl. In certain embodiments, R8is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In certain embodiments, R8is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1 below.

[0252] As defined generally above, R9is Ci.4alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo. In certain embodiments, R9is Ci-4alkoxyl. In certain embodiments, R9is C3-7 cycloalkyl. In certain embodiments, R9is a 4-6 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1 below.

[0253] As defined generally above, RAand RBeach represent independently for each occurrence hydrogen, C alkyl, and Ci-4haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis hydrogen. In certain embodiments, RAis Ci-4 alkyl. In certain embodiments, RAis C haloalkyl. In certain embodiments, RBis hydrogen. In certain embodiments, RBis Ci-4 alkyl. In certain embodiments, RBis Ci-4haloalkyl. In certain embodiments, RAand RBeach represent independently for each occurrence hydrogen or methyl. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, RBis selected from the groups depicted in the compounds in Table 1 below.

[0254] As defined generally above, R10represents independently for each occurrence Ci-4 alkyl, hydroxyl, or Ci-4 alkoxyl. In certain embodiments, R10is Ci-4 alkyl. In certain embodiments, R10is hydroxyl. In certain embodiments, R10is C alkoxyl. In certain embodiments, R10is selected from the groups depicted in the compounds in Table 1 below.

[0255] As defined generally above, X1is -(Ci.6 alkylene)-. In certain embodiments, X1is -CH2-. In certain embodiments, X1is selected from the groups depicted in the compounds in Table 1 below.

[0256] As defined generally above, A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is phenyl substituted with q occurrences of R11. In certain embodiments, A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substitutedwith z occurrences of R12. In certain embodiments, A1is selected from. In certain embodiments, A1is selected from the groups depicted in the compounds in Table 1 below.

[0257] As defined generally above, R11and R12each represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13. In certain embodiments, R11is halo. In certain embodiments, R11is C1-4 alkyl. In certain embodiments, R11is C1.4 haloalkyl. In certain embodiments, R11is C1-4 alkoxyl. In certain embodiments, R11is C1-4 haloalkoxyl. In certain embodiments, R11is C3-7 cycloalkyl. In certain embodiments, R11is C2-3 alkynyl. In certain embodiments, R11represents independently for each occurrence halo, C1-4 alkyl, or C1-4haloalkyl. In certain embodiments, R11represents independently for each occurrence methoxy, fluoro, chloro, bromo, iodo, cyclopropyl, or acetylenyl; or one occurrence of R11is oxazolyl substituted with z occurrences of R13. In certain embodiments, R11represents independently for each occurrence chloro, bromo, or fluoro. In certain embodiments, one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13. In certain embodiments, R12is halo. In certain embodiments, R12is Ci-4 alkyl. In certain embodiments, R12is Ci-4 haloalkyl. In certain embodiments, R12is Ci-4 alkoxyl. In certain embodiments, R12is Ci-4 haloalkoxyl. In certain embodiments, R12is C3-7 cycloalkyl. In certain embodiments, R12is C2-3 alkynyl. In certain embodiments, R12represents independently for each occurrence methyl, chloro, bromo, fluoro, trifluoromethyl, acetylenyl, or difluoromethyl. In certain embodiments, R11is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R12is selected from the groups depicted in the compounds in Table 1 below.

[0258] As defined generally above, R13represents independently for each occurrence C1-4 alkyl or halo. In certain embodiments, R13is C1-4 alkyl. In certain embodiments, R13is halo. In certain embodiments, R13is selected from the groups depicted in the compounds in Table 1 below.

[0259] As defined generally above, q represents independently for each occurrence 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the groups depicted in the compounds in Table 1 below.

[0260] As defined generally above, w represents independently for each occurrence 0 or 1. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is selected from the groups depicted in the compounds in Table 1 below.

[0261] As defined generally above, x is 1, 2, or 3. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is selected from the groups depicted in the compounds in Table 1 below.

[0262] As defined generally above, z represents independently for each occurrence 0, 1, or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is selected from the groups depicted in the compounds in Table 1 below.

[0263] The description above describes multiple embodiments relating to compounds of Formula A-I. The patent application specifically contemplates all combinations of the embodiments.

[0264] Another aspect of the invention provides a compound represented by Formula A-I-1:(A-l-1)or a pharmaceutically acceptable salt thereof; wherein:R1is hydrogen or halo;R2is C1-6 hydroxyalkyl, -C(O)-(Ci-4 alkyl), -(pyridinonyl substituted with x occurrences ofR6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7;R3is hydrogen, C1-4 alkyl, or C3-7 cycloalkyl;R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -C(O)-N(RA)-R8, or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C0-6 alkylene)-R9;R6represents independently for each occurrence C1-4 alkyl, C3-7 cycloalkyl, -N(Ci-4alkyl)2, -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms,wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence Ci-4 alkyl or C3-7 cycloalkyl;R8is C1-4alkoxyl, -C(O)-OH, -C(O)-(Ci-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is Ci-4alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen and C1-4 alkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, or C1-4 alkoxyl; X1is -(C 1-6 alkylene)-;A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12;R11and R12each represents independently for each occurrence halo, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

[0265] The definitions of variables in Formula A-I-l above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of avariable 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).

[0266] In certain embodiments, the compound is a compound of Formula A-I-l.

[0267] As defined generally above, R1is hydrogen or halo. In certain embodiments, R1is hydrogen. In certain embodiments, R1is halo. In certain embodiments, R1is chloro. In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1 below.

[0268] As defined generally above, R2is C1-6 hydroxyalkyl, -C(O)-(Ci-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7. In certain embodiments, R2is C1-6 hydroxyalkyl. In certain embodiments, R2is -C(O)-(Ci-4 alkyl). In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6). In certain embodiments, R2is -(Co-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with x occurrences of R7.. In certain embodiments, R2is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the bicyclic heteroaryl is substituted with x occurrences of R7. In certain embodiments, R2is -(pyridin-2-on-5-yl substituted with x occurrences of R6) or a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7. In certain embodiments,R2is selected from fer / -butyl,In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1 below.

[0269] As defined generally above, R3is hydrogen, Ci-4 alkyl, or C3-7 cycloalkyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is methyl or / / -propyl. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is C3-7 cycloalkyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1 below.

[0270] As defined generally above, R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(Ci-4alkylene)-(Ci-4 alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -C(O)-N(RA)-R8, or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is C1-4 alkyl. In certain embodiments, R4is Ci-4hydroxyalkyl. In certain embodiments, R4is C3-7 cycloalkyl. In certain embodiments, R4is C1-4 haloalkoxyl. In certain embodiments, R4is -(C1-4 alkylene)-(Ci-4alkoxyl). In certain embodiments, R4is -C(O)-OH. In certain embodiments, R4is hydroxyl. In certain embodiments, R4is -(Co-6alkylene)-N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R4is -N(RA)-(C0-6alkylene)-R8. In certain embodiments, R4is -C(O)-N(RA)-R8. In certain embodiments, R4is -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is -N(RA)(RB). In certain embodiments, R4is -NH2, -N(H)CH3, or -N(CH3)2. In certain embodiments, R4is selected from -NH2, -N(CH3)2, -In certain embodiments, R4is selected from the groups depicted in the compounds in Table 1 below.

[0271] As defined generally above, R5is C1.4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(Co-6 alkylene)-R9. In certain embodiments, R5is C1-4 alkyl. In certain embodiments, R5is C1-4 hydroxyalkyl. In certain embodiments, R5is C1-4 haloalkyl. In certain embodiments, R5is -(Co-6 alkylene)-R9. In certain embodiments, R5is C1-4 alkyl or C1-4 haloalkyl. In certain embodiments, R5is -(Co-6alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogenatoms). In certain embodiments, R5is -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms). In certain embodiments, R5is selected from methyl,F, and. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1 below.

[0272] As defined generally above, R6represents independently for each occurrence C1.4 alkyl, C3-7 cycloalkyl, -N(C1-4 alkyl)2, -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R6is C1.4 alkyl. In certain embodiments, R6is C3-7 cycloalkyl. In certain embodiments, R6is -N(Ci-4alkyl2. In certain embodiments, R6is -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7). In certain embodiments, R6is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R6represents independently for each occurrence methyl, -N(CH3)2, -(Co-i alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl. In certain embodiments, R6represents independently for each occurrence methyl, -N(CH3)2, -(C0-1 alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl; and R7represents independently for each occurrence methyl or cyclopropyl. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1 below.

[0273] As defined generally above, R7represents independently for each occurrence C1-4 alkyl or C3-7 cycloalkyl. In certain embodiments, R7is C1-4 alkyl. In certain embodiments, R7is C3-7 cycloalkyl. In certain embodiments, R7represents independently for each occurrence methyl or cyclopropyl. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1 below.

[0274] As defined generally above, R8is C1-4alkoxyl, -C(O)-OH, -C(O)-(C1-4alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is C1-4alkoxyl. In certain embodiments, R8is -C(O)-OH. In certain embodiments, R8is -C(O)-(Ci-4 alkyl). In certain embodiments, R8is hydroxyl. In certain embodiments, R8is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In certain embodiments, R8is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1 below.

[0275] As defined generally above, R9is Ci.4alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo. In certain embodiments, R9is Ci-4alkoxyl. In certain embodiments, R9is C3-7 cycloalkyl. In certain embodiments, R9is a 4-6 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1 below.

[0276] As defined generally above, RAand RBeach represent independently for each occurrence hydrogen and C1.4 alkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis hydrogen. In certain embodiments, RAis C1-4 alkyl. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RBis hydrogen. In certain embodiments, RBis C1-4 alkyl. In certain embodiments, RAand RBeach represent independently for each occurrence hydrogen or methyl. In certain embodiments, RAis selected from the groups depicted in the compounds in Table 1below. In certain embodiments, RBis selected from the groups depicted in the compounds in Table 1 below.

[0277] As defined generally above, R10represents independently for each occurrence C1-4 alkyl, hydroxyl, or C1-4 alkoxyl. In certain embodiments, R10is C1.4 alkyl. In certain embodiments, R10is hydroxyl. In certain embodiments, R10is C1-4 alkoxyl. In certain embodiments, R10is selected from the groups depicted in the compounds in Table 1 below.

[0278] As defined generally above, X1is -(Ci-6 alkylene)-. In certain embodiments, X1is -CH2-. In certain embodiments, X1is selected from the groups depicted in the compounds in Table 1 below.

[0279] As defined generally above, A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is phenyl substituted with q occurrences of R11. In certain embodiments, A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted Clwith z occurrences of R12. In certain embodiments, A1is selected fromIn certain embodiments, A1is selected from the groups depicted in the compounds in Table 1 below.

[0280] As defined generally above, R11and R12each represents independently for each occurrence halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxyl, Ci-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13. In certain embodiments, R11is halo. In certain embodiments, R11is C1-4 alkyl. In certain embodiments, R11is C1.4 haloalkyl. In certain embodiments, R11is C1-4 alkoxyl. In certain embodiments, R11is C1-4 haloalkoxyl. In certain embodiments, R11is C3-7 cycloalkyl. In certain embodiments, R11is C2-3 alkynyl. In certain embodiments, one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13. In certain embodiments, R11represents independently for each occurrence methoxy, fluoro, chloro, bromo, iodo, cyclopropyl, or acetylenyl; or one occurrence of R11is oxazolyl substituted with z occurrences of R13. In certain embodiments, R11represents independently for each occurrence chloro, bromo, or fluoro. In certain embodiments, R12is halo. In certain embodiments, R12is C1.4 alkyl. In certain embodiments, R12is C1-4 haloalkyl. In certain embodiments, R12is C1-4 alkoxyl. In certain embodiments, R12is C1-4 haloalkoxyl. In certain embodiments, R12is C3-7 cycloalkyl. In certain embodiments, R12is C2-3 alkynyl. In certain embodiments, R12represents independently for each occurrence methyl, chloro, bromo, fluoro, trifluoromethyl, acetylenyl, or difluoromethyl. In certain embodiments,IllR11is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R12is selected from the groups depicted in the compounds in Table 1 below.

[0281] As defined generally above, R13represents independently for each occurrence Ci-4 alkyl or halo. In certain embodiments, R13is Ci-4 alkyl. In certain embodiments, R13is halo. In certain embodiments, R13is selected from the groups depicted in the compounds in Table 1 below.

[0282] As defined generally above, q represents independently for each occurrence 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the groups depicted in the compounds in Table 1 below.

[0283] As defined generally above, w represents independently for each occurrence 0 or 1. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is selected from the groups depicted in the compounds in Table 1 below.

[0284] As defined generally above, x is 1, 2, or 3. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is selected from the groups depicted in the compounds in Table 1 below.

[0285] As defined generally above, z represents independently for each occurrence 0, 1, or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is selected from the groups depicted in the compounds in Table 1 below.

[0286] The description above describes multiple embodiments relating to compounds of Formula A-I-l. The patent application specifically contemplates all combinations of the embodiments.

[0287] Another aspect of the invention provides a compound represented by Formula A-II:or a pharmaceutically acceptable salt thereof; wherein:R1is halo, hydroxyl, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 cycloalkyl, Ci-6 alkoxyl, -C(O)-(Ci-s aliphatic), -(Co-6 alkylene)-CN, -C(O)-O-(Ci-s aliphatic), -OC(O)-(Ci-8aliphatic), -0C(0)N(RA)(RB), -N(RA)C(O)2-(CI-8aliphatic), -S(O)2-(Ci-8aliphatic), or S(0)2N(RA)(RB);R2is C2-6 alkenyl, C1-6 hydroxyalkyl, -C(O)-(C1-4 alkyl), -N(R15)(R16), -(pyridinonyl substituted with x occurrences of R6), -(C2-4 alkynylene)-(pyridinonyl substituted with x occurrences ofR6), -(triazolonyl substituted with x occurrences ofR6), -(Co-ealkylene)-(C3-7 cycloalkyl substituted with z occurrences ofR17), -(Ci-6 alkylene)-(6-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with z occurrences ofR17), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences ofR7;R3is hydrogen, C1-4 alkyl, Ci-4haloalkoxyl, or C3-7 cycloalkyl;R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(Co-6 alkylene)-C(O)-R8, -N(RA)-(Co-6 alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(0)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C0-6 alkylene)-R9;R6represents independently for each occurrence halogen, C1-4 alkyl, C3-7 cycloalkyl, -N(Ci-4alkyl)2, -(Co-6alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences ofR7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-7 cycloalkyl;R8is C1-4 alkoxyl, -C(O)-OH, -C(O)-(C1-4alkyl), C1-4 haloalkyl, -N(RA)(RB), C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl), -(pyridinonyl substituted with x occurrences of C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1,2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is Ci-4alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci-4 haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -N(RA)-(C1-4haloalkyl), or -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of C1-4 alkyl);X1is a covalent bond or -(C1-6 alkylene)-, wherein 0 or 1 methylene group is replaced with -N(RA)-, O, or -C(O)-;A1is (i) phenyl substituted with q occurrences of R11, (ii) a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12, (iii) a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with z occurrences of R12, (iv) a 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10, (v) C3-6 cycloalkyl substituted with 0 or 1 occurrence of R10, or (vi) C1-6 alkyl, C1-4 haloalkyl, -C(O)-R7, or C1-4 alkoxyl;A2is an oxo-substituted 5-6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5;R11and R12each represents independently for each occurrence halo, hydroxyl, -C(O)-(Ci-4 alkoxyl), C1-4 alkyl, C1.4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, -SF5, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;R14is C3-7 cycloalkyl, a 5-6 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with z occurrences of R7, phenyl substituted with z occurrences of R7, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7;R15and R16are independently hydrogen, C1.4 alkyl, Ci-4haloalkyl, or 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7; or an instance of R15and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R17is Ci-4 alkyl, C1-4 haloalkyl, cyano, or 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R18is halo, hydroxyl, or C1.4 alkyl;t is 0, 1, 2 or 3;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

[0288] The definitions of variables in Formula A-II above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[0289] In certain embodiments, the compound is a compound of Formula A-II.

[0290] As defined generally above, R1is halo, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, Ci-ealkoxyl, -C(O)-(Ci-8aliphatic), -(Co-6 alkylene)-CN, -C(O)-O-(Ci-8aliphatic), -OC(O)-(Ci-8 aliphatic), -OC(O)N(RA)(RB), -N(RA)C(O)2-(CI-8aliphatic), -S(O)2-(Ci-8aliphatic), or S(O)2N(RA)(RB). In certain embodiments, R1is halo. In certain embodiments, R1is hydroxyl. In certain embodiments, R1is Ci-6 alkyl. In certain embodiments, R1is C1-6 haloalkyl. In certain embodiments, R1is C3-7 cycloalkyl. In certain embodiments, R1is Ci-6 alkoxyl. In certainembodiments, R1is -C(O)-(Ci.8 aliphatic). In certain embodiments, R1is -(Co-6 alkylene)-CN. In certain embodiments, R1is -C(0)-0-(Ci-8 aliphatic). In certain embodiments, R1is -0C(0)-(Ci-8 aliphatic). In certain embodiments, R1is -OC(O)N(RA)(RB). In certain embodiments, R1is -N(RA)C(O)2-(CI-8aliphatic). In certain embodiments, R1is -S(0)2-(Ci-s aliphatic). In certain embodiments, R1is S(O)2N(RA)(RB). In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1 below.

[0291] As defined generally above, R2is C2-6 alkenyl, Ci-6 hydroxyalkyl, -C(O)-(Ci-4 alkyl), -N(R15)(R16), -(pyridinonyl substituted with x occurrences of R6), -(C2-4 alkynylene)-(pyri dinonyl substituted with x occurrences of R6), -(triazolonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(C3-7 cycloalkyl substituted with z occurrences of R17), -(Ci-6alkylene)-(6-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with z occurrences of R17), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7. In certain embodiments, R2is C2-6 alkenyl. In certain embodiments, R2is C1-6 hydroxyalkyl. In certain embodiments, R2is -C(O)-(Ci-4 alkyl). In certain embodiments, R2is -N(R15)(R16). In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6). In certain embodiments, R2is -(C2-4 alkynylene)-(pyridinonyl substituted with x occurrences of R6). In certain embodiments, R2is -(triazolonyl substituted with x occurrences of R6). In certain embodiments, R2is -(Co-6 alkylene)-(C3-7 cycloalkyl substituted with z occurrences of R17). In certain embodiments, R2is -(Ci-6alkylene)-(6-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with z occurrences of R17). In certain embodiments, R2is -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R2is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R2is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and thebicyclic heteroaryl are substituted with x occurrences of R7. In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1 below.

[0292] As defined generally above, R3is hydrogen, Ci-4 alkyl, Ci-4 haloalkoxyl, or C3-7 cycloalkyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is C1-4 haloalkoxyl. In certain embodiments, R3is C3-7 cycloalkyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1 below.

[0293] As defined generally above, R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(Ci-4alkylene)-(Ci-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C0-6 alkylene)-C(O)-R8, -N(RA)-(Co-6 alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(O)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is C1-4 alkyl. In certain embodiments, R4is Ci-4hydroxyalkyl. In certain embodiments, R4is C3-7 cycloalkyl. In certain embodiments, R4is C 1-4 haloalkoxyl. In certain embodiments, R4is -(Ci-4alkylene)-(Ci-4 alkoxyl). In certain embodiments, R4is hydroxyl. In certain embodiments, R4is -(Co-6alkylene)-N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R4is -(Co-6alkylene)-C(0)-R8. In certain embodiments, R4is -N(RA)-(Co-6 alkylene)-R8. In certain embodiments, R4is -C(O)-N(RA)-R8. In certain embodiments, R4is -N(RA)C(O)N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is selected from the groups depicted in the compounds in Table 1 below.

[0294] As defined generally above, R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(Co-6 alkylene)-R9. In certain embodiments, R5is C1-4 alkyl. In certain embodiments, R is C1-4 hydroxyalkyl. In certain embodiments, R5is C1-4 haloalkyl. In certain embodiments, R5is -(Co-6 alkylene)-R9. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1 below.

[0295] As defined generally above, R6represents independently for each occurrence halogen, Ci.4 alkyl, C3-7 cycloalkyl, -N(CI-4 alkyl)2, -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R6is halogen. In certain embodiments, R6is C1-4 alkyl. In certain embodiments, R6is C3-7 cycloalkyl. In certain embodiments, R6is -N(CI-4 alkyl)2. In certain embodiments, R6is -(Co-6 alkylene)-(5 -membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7). In certain embodiments, R6is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1 below.

[0296] As defined generally above, R7represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-7 cycloalkyl. In certain embodiments, R7is C1-4 alkyl. In certain embodiments, R7is C1-4 haloalkyl. In certain embodiments, R7is C1-4 alkoxyl. In certain embodiments, R7is C3-7 cycloalkyl. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1 below.

[0297] As defined generally above, R8is C1.4 alkoxyl, -C(O)-OH, -C(O)-(C1-4 alkyl), C1-4 haloalkyl, -N(RA)(RB), C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl), -(pyridinonyl substituted with x occurrences of C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is C1-4 alkoxyl. In certain embodiments, R8is -C(O)-OH. In certain embodiments, R8is -C(O)-(Ci-4 alkyl). In certain embodiments, R8is C1-4 haloalkyl. In certain embodiments, R8is -N(RA)(RB). In certain embodiments, R8is C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl). In certain embodiments, R8is -(pyridinonyl substituted with x occurrences of C1-4 alkyl). In certain embodiments, R8is hydroxyl. In certain embodiments, R8is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R8is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independentlyselected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1 below.

[0298] As defined generally above, R9is Ci-4 alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo. In certain embodiments, R9is C1-4 alkoxyl. In certain embodiments, R9is C3-7 cycloalkyl. In certain embodiments, R9is a 4-6 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1 below.

[0299] As defined generally above, RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci.4haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis hydrogen. In certain embodiments, RAis Ci -4 alkyl. In certain embodiments, RAis Ci-4haloalkyl. In certain embodiments, RBis hydrogen. In certain embodiments, RBis C1-4 alkyl. In certain embodiments, RBis C1-4 haloalkyl. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, RBis selected from the groups depicted in the compounds in Table 1 below.

[0300] As defined generally above, R10represents independently for each occurrence C1-4 alkyl, hydroxyl, C1.4 alkoxyl, C1-4 haloalkoxyl, -N(RA)-(Ci-4 haloalkyl), or -C(O)-N(RA)-(Cs-7 cycloalkyl substituted with 0 or 1 occurrences of C1-4 alkyl). In certain embodiments, R10is C1.4 alkyl. In certain embodiments, R10is hydroxyl. In certain embodiments, R10is C1.4 alkoxyl. In certain embodiments, R10is C1-4 haloalkoxyl. In certain embodiments, R10is -N(RA)-(Ci-4 haloalkyl). In certain embodiments, R10is -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1occurrences of C1-4 alkyl). In certain embodiments, R10is selected from the groups depicted in the compounds in Table 1 below.

[0301] As defined generally above, X1is a covalent bond or -(C1-6 alkylene)-, wherein 0 or 1 methylene group is replaced with -N(RA)-, O, or -C(O)-. In certain embodiments, X1is a covalent bond. In certain embodiments, X1is -(C1-6 alkylene)-, wherein 0 or 1 methylene group is replaced with -N(RA)-, O, or -C(O)-. In certain embodiments, X1is selected from the groups depicted in the compounds in Table 1 below.

[0302] As defined generally above, A1is (i) phenyl substituted with q occurrences of R11, (ii) a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12, (iii) a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with z occurrences of R12, (iv) a 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10, (v) C3-6 cycloalkyl substituted with 0 or 1 occurrence of R10, or (vi) C1-6 alkyl, Ci-4haloalkyl, -C(O)-R7, or Ci-4alkoxyl. In certain embodiments, A1is phenyl substituted with q occurrences of R11. In certain embodiments, A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is a 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is C3-6 cycloalkyl substituted with 0 or 1 occurrence of R10. In certain embodiments, A1is C1-6 alkyl, C1.4 haloalkyl, -C(O)-R7, or Ci-4alkoxyl. In certain embodiments, A1is selected from the groups depicted in the compounds in Table 1 below.

[0303] As defined generally above, A2is an oxo- substituted 5-6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5. In certainR3JVR4e b d m n s A i o e5 U m o i e t,2s n of the following:RRA'. In certain embodiments, A2is selected from the groups depicted in the compounds in Table 1 below.

[0304] As defined generally above, R11and R12each represents independently for each occurrence halo, hydroxyl, -C(O)-(Ci-4alkoxyl), Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxyl, Ci-4 haloalkoxyl, C3-7 cycloalkyl, -SF5, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13. In certain embodiments, R11is halo. In certain embodiments, R11is hydroxyl. In certain embodiments, R11is -C(O)-(Ci-4 alkoxyl). In certain embodiments, R11is C1-4 alkyl. In certain embodiments, R11is C1-4 haloalkyl. In certain embodiments, R11is C1.4 alkoxyl. In certain embodiments, R11is C1-4 haloalkoxyl. In certain embodiments, R11is C3-7 cycloalkyl. In certain embodiments, R11is -SF5. In certain embodiments, R11is C2-3 alkynyl. In certain embodiments, one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13. In certain embodiments, R12is halo. In certain embodiments, R12is hydroxyl. In certain embodiments, R12is -C(O)-(Ci-4 alkoxyl). In certain embodiments, R12is C1.4 alkyl. In certain embodiments, R12is C1-4 haloalkyl. In certain embodiments, R12is C1-4 alkoxyl. In certain embodiments, R12is C1-4 haloalkoxyl. In certain embodiments, R12is C3-7 cycloalkyl. In certain embodiments, R12is -SF5. In certain embodiments, R12is C2-3 alkynyl. In certain embodiments, R11is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R12is selected from the groups depicted in the compounds in Table 1 below.

[0305] As defined generally above, R13represents independently for each occurrence C1-4 alkyl or halo. In certain embodiments, R13is C1-4 alkyl. In certain embodiments, R13is halo. In certain embodiments, R13is selected from the groups depicted in the compounds in Table 1 below.

[0306] As defined generally above, R14is C3-7 cycloalkyl, a 5-6 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with zoccurrences of R7, phenyl substituted with z occurrences of R7, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R14is C3-7 cycloalkyl. In certain embodiments, R14is a 5-6 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with z occurrences of R7. In certain embodiments, R14is phenyl substituted with z occurrences of R7. In certain embodiments, R14is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R14is selected from the groups depicted in the compounds in Table 1 below.

[0307] As defined generally above, R15and R16are independently hydrogen, C1-4 alkyl, C1.4 haloalkyl, or 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7; or an instance of R15and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, R15is hydrogen. In certain embodiments, R15is C1-4 alkyl. In certain embodiments, R15is C1-4 haloalkyl. In certain embodiments, R15is 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, R16is hydrogen. In certain embodiments, R16is C1-4 alkyl. In certain embodiments, R16is C1-4 haloalkyl. In certain embodiments, R16is 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7. In certain embodiments, an instance of R15and R16attached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, R15is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R16is selected from the groups depicted in the compounds in Table 1 below.

[0308] As defined generally above, R17is C1-4 alkyl, C1-4 haloalkyl, cyano, or 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R17is C1-4 alkyl. In certain embodiments, R17is C1-4 haloalkyl. In certain embodiments, R17is cyano. In certain embodiments, R17is 6-membered saturatedheterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R17is selected from the groups depicted in the compounds in Table 1 below.

[0309] As defined generally above, R18is halo, hydroxyl, or Ci-4 alkyl. In certain embodiments, R18is halo. In certain embodiments, R18is hydroxyl. In certain embodiments, R18is Ci-4 alkyl. In certain embodiments, R18is selected from the groups depicted in the compounds in Table 1 below.

[0310] As defined generally above, t is 0, 1, 2 or 3. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is selected from the groups depicted in the compounds in Table 1 below.

[0311] As defined generally above, q represents independently for each occurrence 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the groups depicted in the compounds in Table 1 below.

[0312] As defined generally above, w represents independently for each occurrence 0 or 1. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is selected from the groups depicted in the compounds in Table 1 below.

[0313] As defined generally above, x is 1, 2, or 3. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is selected from the groups depicted in the compounds in Table 1 below.

[0314] As defined generally above, z represents independently for each occurrence 0, 1, or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is selected from the groups depicted in the compounds in Table 1 below.

[0315] The description above describes multiple embodiments relating to compounds of Formula A-II. The patent application specifically contemplates all combinations of the embodiments.

[0316] Another aspect of the invention provides a compound represented by Formula A-II-a:(A-II-a)or a pharmaceutically acceptable salt thereof; wherein:R1is halo;R2is -(pyridinonyl substituted with x occurrences of R6) or -(triazolonyl substituted with x occurrences of R6);R3is hydrogen or C1-4 alkyl;R4is Ci-4 alkyl, C1.4 hydroxyalkyl, C3-7 cycloalkyl, Ci.4haloalkoxyl, -(Ci-4alkylene)-(Ci-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(Co-6 alkylene)-C(O)-R8, -N(RA)-(C0-6 alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(0)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C0-6 alkylene)-R9;R6represents independently for each occurrence halogen, C1-4 alkyl, C3-7 cycloalkyl, or -N(C1-4alkyl)2;R7represents independently for each occurrence C1-4 alkyl;R8is C1-4 alkoxyl, C1-4 haloalkyl, -N(RA)(RB), C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is C1-4 alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci.4 haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -N(RA)-(Ci-4 haloalkyl), or -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of C1-4 alkyl);X1is a -(C1-6 alkylene)-;A1is (i) phenyl substituted with q occurrences of R11or (ii) a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12;A2is an oxo-substituted 5-6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5;R11and R12each represents independently for each occurrence halo, hydroxyl, -C(O)-(Ci-4 alkoxyl), C1-4 alkyl, C1.4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, or C2-3 alkynyl;t is 0, 1, 2 or 3;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

[0317] The definitions of variables in Formula A-II-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).

[0318] In certain embodiments, the compound is a compound of Formula A-II-a.

[0319] As defined generally above, R1is halo. In certain embodiments, R1is selected from the groups depicted in the compounds in Table 1 below.

[0320] As defined generally above, R2is -(pyridinonyl substituted with x occurrences of R6) or -(triazolonyl substituted with x occurrences of R6). In certain embodiments, R2is -(pyridinonyl substituted with x occurrences of R6). In certain embodiments, R2is -(triazolonyl substituted with x occurrences of R6). In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1 below.

[0321] As defined generally above, R3is hydrogen or Ci-4 alkyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is Ci-4 alkyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1 below.

[0322] As defined generally above, R4is Ci-4 alkyl, Ci-4hydroxyalkyl, C3-7 cycloalkyl, Ci-4 haloalkoxyl, -(Ci-4alkylene)-(Ci-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(Co-6 alkylene)-C(O)-R8, -N(RA)-(Co-6 alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(O)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is C1-4 alkyl. In certain embodiments, R4is Ci-4hydroxyalkyl. In certain embodiments, R4is C3-7 cycloalkyl. In certain embodiments, R4is C 1.4 haloalkoxyl. In certain embodiments, R4is -(Ci-4alkylene)-(Ci-4 alkoxyl). In certain embodiments, R4is hydroxyl. In certain embodiments, R4is -(Co-6alkylene)-N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen). In certain embodiments, R4is -(C0-6 alkylene)-C(O)-R8. In certain embodiments, R4is -N(RA)-(Co-6 alkylene)-R8. In certain embodiments, R4is -C(O)-N(RA)-R8. In certain embodiments, R4is -N(RA)C(O)N(RA)(RB). In certain embodiments, R4is -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo). In certain embodiments, R4is selected from the groups depicted in the compounds in Table 1 below.

[0323] As defined generally above, R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(Co-6 alkylene)-R9. In certain embodiments, R5is C1-4 alkyl. In certain embodiments, R5is C1-4 hydroxyalkyl. In certain embodiments, R3is C1-4 haloalkyl. In certain embodiments, R5is -(Co-6 alkylene)-R9. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1 below.

[0324] As defined generally above, R6represents independently for each occurrence halogen, Ci.4 alkyl, C3-7 cycloalkyl, or -N(Ci-4alkyl)2. In certain embodiments, R6is halogen. In certain embodiments, R6is C1-4 alkyl. In certain embodiments, R6is C3-7 cycloalkyl. In certain embodiments, R6is -N(CI-4 alkyl)2. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1 below.

[0325] As defined generally above, R7represents independently for each occurrence C1.4 alkyl. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1 below.

[0326] As defined generally above, R8is Ci-4alkoxyl, C 1 -4 haloalky 1, -N(RA)(RB), C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is C1.4 alkoxyl. In certain embodiments, R8is C1-4 haloalkyl. In certain embodiments, R8is -N(RA)(RB). In certain embodiments, R8is C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl). In certain embodiments, R8is hydroxyl. In certain embodiments, R8is a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, R8is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7. In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1 below.

[0327] As defined generally above, R9is C1.4 alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo. In certain embodiments, R9is C1-4 alkoxyl. In certain embodiments, R9is C3-7 cycloalkyl. In certain embodiments, R9is a 4-6 membered saturated heterocyclyl containing 1 oxygen atom. In certain embodiments, R9is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo. In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1 below.

[0328] As defined generally above, RAand RBeach represent independently for each occurrence hydrogen, Ci-4 alkyl, and Ci-4haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis hydrogen. In certain embodiments, RAis Ci-4 alkyl. In certain embodiments, RAis Ci-4haloalkyl. In certain embodiments, RBis hydrogen. In certain embodiments, RBis Ci-4 alkyl. In certain embodiments, RBis Ci-4 haloalkyl. In certain embodiments, an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10. In certain embodiments, RAis selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, RBis selected from the groups depicted in the compounds in Table 1 below.

[0329] As defined generally above, R10represents independently for each occurrence Ci-4 alkyl, hydroxyl, Ci-4 alkoxyl, Ci-4 haloalkoxyl, -N(RA)-(Ci-4 haloalkyl), or -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of Ci-4 alkyl). In certain embodiments, R10is Ci-4 alkyl. In certain embodiments, R10is hydroxyl. In certain embodiments, R10is C1-4 alkoxyl. In certain embodiments, R10is Ci-4 haloalkoxyl. In certain embodiments, R10is -N(RA)-(Ci-4 haloalkyl). In certain embodiments, R10is -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of C1-4 alkyl). In certain embodiments, R10is selected from the groups depicted in the compounds in Table 1 below.

[0330] As defined generally above, X1is a -(Ci-6 alkylene)-. In certain embodiments, X1is selected from the groups depicted in the compounds in Table 1 below.

[0331] As defined generally above, A1is (i) phenyl substituted with q occurrences of R11or (ii) a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12. In certain embodiments, A1is phenyl substituted with q occurrences of R11. In certain embodiments, A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl issubstituted with z occurrences of R12. In certain embodiments, A1is selected from the groups depicted in the compounds in Table 1 below.

[0332] As defined generally above, A2is an oxo- substituted 5-6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5. In certain embodiments, A2is selected from the groups depicted in the compounds in Table 1 below.

[0333] As defined generally above, R11and R12each represents independently for each occurrence halo, hydroxyl, -C(O)-(Ci-4alkoxyl), Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxyl, Ci-4 haloalkoxyl, or C2-3 alkynyl. In certain embodiments, R11is halo. In certain embodiments, R11is hydroxyl. In certain embodiments, R11is -C(O)-(C1-4 alkoxyl). In certain embodiments, R11is C1-4 alkyl. In certain embodiments, R11is C1-4 haloalkyl. In certain embodiments, R11is C1-4 alkoxyl. In certain embodiments, R11is C1-4 haloalkoxyl. In certain embodiments, R11is C2-3 alkynyl. In certain embodiments, R12is halo. In certain embodiments, R12is hydroxyl. In certain embodiments, R12is -C(O)-(Ci-4 alkoxyl). In certain embodiments, R12is C1.4 alkyl. In certain embodiments, R12is C1-4 haloalkyl. In certain embodiments, R12is C1-4 alkoxyl. In certain embodiments, R12is C1-4 haloalkoxyl. In certain embodiments, R12is C2-3 alkynyl. In certain embodiments, R11is selected from the groups depicted in the compounds in Table 1 below. In certain embodiments, R12is selected from the groups depicted in the compounds in Table 1 below.

[0334] As defined generally above, t is 0, 1, 2 or 3. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is selected from the groups depicted in the compounds in Table 1 below.

[0335] As defined generally above, q represents independently for each occurrence 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is selected from the groups depicted in the compounds in Table 1 below.

[0336] As defined generally above, w represents independently for each occurrence 0 or 1. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is selected from the groups depicted in the compounds in Table 1 below.

[0337] As defined generally above, x is 1, 2, or 3. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is selected from the groups depicted in the compounds in Table 1 below.

[0338] As defined generally above, z represents independently for each occurrence 0, 1, or 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is selected from the groups depicted in the compounds in Table 1 below.

[0339] The description above describes multiple embodiments relating to compounds of Formula A-II-a. The patent application specifically contemplates all combinations of the embodiments.

[0340] In certain embodiments, the compound of Formula I is further defined by Formula I-A, or a pharmaceutically acceptable salt thereof:(I-A).

[0341] In certain embodiments, the compound is a compound of Formula I-A. In certain embodiments, the definition of each of the variables in Formula I-A is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula I-A. The patent application specifically contemplates all combinations of the embodiments.

[0342] In certain embodiments, the compound of Formula I is further defined by Formula la or lb, or a pharmaceutically acceptable salt thereof:la lb

[0343] In certain embodiments, the compound is a compound of Formula la. In certain embodiments, the definition of each of the variables in Formula la is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula la. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is a compound of Formula lb. In certain embodiments, the definition of each of the variables in Formula lb is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula lb. The patent application specifically contemplates all combinations of the embodiments.

[0344] In certain embodiments, the compound of Formula I is further defined by Formula Ic or Id, or a pharmaceutically acceptable salt thereof:

[0345] In certain embodiments, the compound is a compound of Formula Ic. In certain embodiments, the definition of each of the variables in Formula Ic is one of the embodimentsdescribed above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula Ic. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is a compound of Formula Id. In certain embodiments, the definition of each of the variables in Formula Id is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula Id. The patent application specifically contemplates all combinations of the embodiments.

[0346] In certain embodiments, the compound of Formula I is further defined by Formula le, If, or Ig, or a pharmaceutically acceptable salt thereofle If Ig

[0347] In certain embodiments, the compound is a compound of Formula le. In certain embodiments, the definition of each of the variables in Formula le is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula le. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is a compound of Formula If. In certain embodiments, the definition of each of the variables in Formula If is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula If. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is a compound of Formula Ig. In certain embodiments, the definition of each of the variables in Formula Ig is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compoundsof Formula Ig. The patent application specifically contemplates all combinations of the embodiments.

[0348] In certain embodiments, the compound of Formula I is further defined by Formula Ih, li, Ij, Ik, II, or Im, or a pharmaceutically acceptable salt thereof:

[0349] In certain embodiments, the compound is a compound of Formula Ih. In certain embodiments, the definition of each of the variables in Formula Ih is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula Ih. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is a compound of Formula li. In certain embodiments, the definition of each of the variables in Formula li is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula li. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is acompound of Formula Ij. In certain embodiments, the definition of each of the variables in Formula Ij is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula Ij. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is a compound of Formula Ik. In certain embodiments, the definition of each of the variables in Formula Ik is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula Ik. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is a compound of Formula II. In certain embodiments, the definition of each of the variables in Formula II is one of the embodiments described above in connection with Formula A-I, A-I-l, A-II, and A-II-a. The description above describes multiple embodiments relating to compounds of Formula II. The patent application specifically contemplates all combinations of the embodiments. In certain embodiments, the compound is a compound of Formula Im. In certain embodiments, the definition of each of the variables in Formula Im is one of the embodiments described above in connection with Formula A-I, A-I-l, A-ll, and A-ll-a. The description above describes multiple embodiments relating to compounds of Formula Im. The patent application specifically contemplates all combinations of the embodiments.

[0350] In certain embodiments, the compound of Formula I is further defined by Formula A-II-b or a pharmaceutically acceptable salt thereofJ A1x1AlR2(A-II-b)

[0351] In certain embodiments, the compound is a compound of Formula A-II-b. In certain embodiments, the definition of each of the variables in Formula A-II-b is one of theembodiments described above in connection with Formula A-I, A-I-1, A-II, and A-II-a. Incertain embodiments, A2in FormulaA-II-b isR. The description above describes multiple embodiments relating to compounds of Formula A-II-b. The patent application specifically contemplates all combinations of the embodiments, or a pharmaceutically acceptable salt thereof.

[0352] Part C

[0353] Another aspect of the invention provides 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 1.0 ill-100 533'XXN / zby<Nv\ X ^ICI-101 uQ 5230 - CKo o-104 504iv1-105 yO 488z~A \N'-106 539-124 582 / O z o z — —'z Z~ — \ \~-125 516T c ' IZlQ z j _ TZ / / ° if,-126 516 / 0'A^Hvk-127 553HF-128 487C / 'NH2

[0354] Another aspect of the invention provides a compound in Table 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 2 below.Table 2.Compound LC-MS (ES)StructureNo. m / z of [M+H]+ClII-1 489Z HClN JL KJ - - / II-2 648 7" N V.H bClII-3 659y iiII-4 580

[0355] Another aspect of the invention provides a compound in Table 3 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 3 below.Table 3.Compound LC-MS (ES)StructureNo. m / z of [M+HJ+III-2 485III-29III-30III-78 583III-79 569

[0356] Methods for preparing compounds described herein are illustrated in the following synthetic schemes. The schemes are provided for the purpose of illustrating the invention and are not intended to limit the scope or spirit of the invention. Starting materials shown in the schemes can be obtained from commercial sources or can be prepared based on procedures described in the literature.

[0357] In the schemes, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will beapparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known in the art, for example, as described in detail in Protecting Groups in Organic Synthesis, 3rdEdition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1999 and Greene's Protective Groups in Organic Synthesis, 5th Ed., (Peter G. M. Wuts, John Wiley & Sons: 2014), the entire contents of both of which are hereby incorporated by reference.

[0358] The synthetic route illustrated in Scheme l is a general method for preparing substituted indolylpyridin-2(l / / )-ones 1J. To obtain compound 1J, the synthesis begins with the A-alkylation of optionally substituted 6-bromo or iodo) indole 1A, followed by a Pd-catalyzed coupling with bis(pinacolato)diboron to yield compound 1C. This compound can then undergo Suzuki cross-coupling to introduce aryl / heterocyclyl groups, producing intermediate ID.Reacting these intermediates with NBS or NIS forms building block IE. Separately,bromofluoropyridone IF is N-alkylated, subjected to nucleophilic substitution with a suitable amine, and converted to a pinacol boronic ester, yielding building block II. Finally, IE and II are coupled via Pd-catalysis to afford compound 1 J.SCHEME 1.

[0359] The synthetic route illustrated in Scheme 2 is a general method for preparing indolylpyridin-2(l / 7)-one 2G and the monoalkylated (2F) or acylated (2H) derivative. Amino-bromopyridone 2A reacted with Boc anhydride and then reacted with bis(pinacolato)diboron to yield compound 2C, which may be coupled with a IE-type compound (Scheme 1) to produce key building block 2D. From 2D, monoalkylated derivative 2F can be obtained by alkylationfollowed by Boc deprotection. Alternatively, it can be deprotected first, and the resulting amine can undergo acylation to afford compound 2H.SCHEME 2.2H 2G 2F

[0360] The synthetic route illustrated in Scheme 3 is a general method for preparing indolylpyridone 3J. Optionally substituted nitroindole 3A is A'-alkylated and subsequently halogenated to yield building block 3C. Separately, an alkyl group may be introduced at the nitrogen of a bromopyridone-3 -carboxylic ester, followed by boronation under Miyaura conditions to obtain building block 3F. Pd-catalyzed coupling of 3C and 3F produces key intermediate 3H, suitable for synthesizing triazole compound 31. In the final step, carboxylic ester cleavage yields acid 3J.SCHEME 3.

[0361] The synthetic route illustrated in Scheme 4 is a general method for preparing indolyl-pyridinones 4I. As shown in Scheme 4, bromo-fluoro pyridinone 4A is A -alkylated to provide alkylated pyridinone 4B, which undergoes substitution by BOC-protected cyclic amine 4C to form BOC-protected bromo pyridinone compound 4D. Miyaura borylation of BOC-protected bromo pyridinone compound 4D with bis(pinacolato)diboron (B₂pin₂) provides boronic ester 4E, which then undergoes Suzuki coupling with bromo-indole compound 4F to provide BOC-protected indolyl-pyridinone 4G.. V-Alkylation of the BOC-protected indolyl-pyridinone 4G provides alkylated BOC-protected indolyl-pyridinone 4H, which is then deprotected (e.g., with trifluoroacetic acid) to form indolyl-pyridinone 4I.SCHEME 4.4H

[0362] The synthetic route illustrated in Scheme 5 is a general method for preparing amide-containing indolyl-pyridinones 5J. As shown in Scheme 5, bromo-fluoro pyridinone 5A is N-alkylated to provide alkylated pyridinone 5B, which undergoes substitution by methyl estersubstituted cyclic amine 5C to form pyridinone methyl ester compound 5D. Miyaura borylation of pyridinone methyl ester compound 5D with bis(pinacolato)diboron (B₂pin₂) provides boronic ester 5E, which undergoes Suzuki coupling with indole compound 5F to provide methyl ester indolyl-pyridinone 5G. Hydrolysis of methyl ester indolyl-pyridinone 5G provides carboxylic acid indolyl-pyridinone compound 5H, which is then reacted with amine 51 to provide amide-containing indolyl-pyridinone 5J.SCHEME 5.

[0363] The synthetic route illustrated in Scheme 6 is a general method for preparing indolyl-pyridinones 6G. As shown in Scheme 6, amino-bromo pyridinone 6A is reacted with di-tert-butyl dicarbonate (BOC anhydride) to provide BOC-protected pyridinone 6B. The BOC-protected pyridinone 6B is A-alkylated to form alkylated BOC-protected pyridinone 6C.Miyaura borylation of alkylated BOC-protected pyridinone 6C with bis(pinacolato)diboron (B₂pin₂) provides boronic ester 6D, which undergoes Suzuki coupling with indole compound 6E to provide BOC-protected indolyl-pyridinone 6F. Deprotection of BOC-protected indolyl-pyridinone 6F (e.g., trifluoroacetic acid) generates indolyl pyridinone 6G.SCHEME 6.6A

[0364] The synthetic route illustrated in Scheme 7 is a general method for preparing indolyl-pyridinones 8H. As shown in Scheme 8, bromo indole 8A is coupled with boronic ester 8B under Suzuki conditions to form alkylated indole 8C. The alkylated indole 8C is coupled with BOC-protected bromo pyridinone 8D (e.g., in the presence of Cui) to form BOC-protected indolyl pyridinone 8E. Condensation of the BOC-protected indolyl pyridinone 8E with an aldehyde 8F (e.g., I₂, triethylsilane, hexafluoroisopropanol) forms BOC-protected alkylated indolyl-pyridinone 8G, which is then deprotected (e.g., trifluoroacetic acid) to form indolyl-pyridinone 8H.SCHEME 7

[0365] The synthetic route illustrated in Scheme 8 is a general method for preparing indolyl-pyridazones 9G. As shown in Scheme 9, bromo-chloro pyridazone 9A is reacted with benzophenone imine 9B, an ammonia equivalent, to provide benzophenone imine adduct 9C.Cleavage of the benzophenone imine adduct 9C (e.g., HC1, water) gives primary amino pyridazone 9D. Miyaura borylation of primary amino pyridazone 9D with bis(pinacolato)diboron (B₂pin₂) provides boronic ester 9E, which undergoes Suzuki coupling with indole compound 9F to give indolyl-pyridazone 9G.SCHEME 8.O9A 9CO

[0366] The synthetic route illustrated in Scheme 9 is a general method for preparing indolyl-pyrimidones 10D. As shown in Scheme 10, Miyaura borylation of bromo-hydroxy pyrimidone 10A with bis(pinacolato)diboron (B₂pin₂) provides boronic ester 10B, which undergoes Suzuki coupling with indole compound 10C to give indolyl-pyrimidone 10D.SCHEME 9.10B

[0367] The synthetic route illustrated in Scheme 10 is a general method for preparing indolyl-pyridinones 11F. As shown in Scheme 11, dibromo pyridinone 11A is coupled with amino compound 11B to form amino-bromo pyridinone 11C. Miyaura borylation of amino-bromo pyridinone 11C with bis(pinacolato)diboron (B₂pin₂) provides boronic ester 11D, which undergoes Suzuki coupling with indole compound 11E to give indolyl-pyridinone 11F.SCHEME 10.

[0368] The modular synthetic routes illustrated in the schemes above can be adjusted to provide additional indolyl-pyridinones and related compounds by conducting functional group transformations on the intermediate and final compounds. Such functional group transformations are well known in the art, as described in, for example, Comprehensive Organic Synthesis (B. M. Trost & I. Fleming, eds., 1991-1992); Organic Synthesis, 3rdEd. (Michael B. Smith, Wavefunction, Inc., Irvine: 2010); Modern Methods of Organic Synthesis, 4thEd.(William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004); March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8thEd., (Michael B.Smith, John Wiley & Sons, New York: 2020); and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018).II. Therapeutic Applications

[0369] Compounds described herein are useful for treating a disease or condition mediated by STAT6. Exemplary diseases or conditions mediated by STAT6 include inflammatory disorders (e.g, chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), allergic conditions (e.g., chronic sinusitis and allergic rhinitis), and proliferative disorders (e.g., cancer).

[0370] Accordingly, one aspect of the invention provides a method of treating a disease or condition mediated by STAT6 in a subject. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, or other compounds in Section I, to treat the disease or condition. In certain embodiments, the compound is a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, lg, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I, or defined by one of the embodiments described above. In certain embodiments, the compound is a compound of Formula A-I or A-II. Further description of exemplary diseases or conditions mediated by STAT6 is provided herein below.

[0371] Another aspect of the invention provides a method of treating a disease or condition selected from an inflammatory disorder, allergic condition, or proliferative disorder. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, lh, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I, to treat the disease or condition. In certain embodiments, the compound is a compound of Formula I, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I, or defined by one of the embodiments described above. In certain embodiments, the compound is a compound of Formula A-I or A-II.

[0372] Another aspect of the invention provides a method of inhibiting the activity of STAT6. The method comprises contacting a STAT6 with an effective amount of a compound described herein, such as a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, or II, or other compounds in Section I, to inhibit the activity of said STAT6. In certain embodiments, the compound is a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I, or defined by one of the embodiments described above. In certain embodiments, the compound is a compound of Formula A-I or A-II.

[0373] Another aspect of the invention provides a compound described herein (such as a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A- II, A-II- a, or A-II-b, or other compounds in Section I) for use in treating a disease or condition, such as a disease or condition described herein. In certain embodiments, the compound is acompound of Formula I, I-1, I-A, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, II, A-I, A-I-1, A-II, A-II-a, or A-II-b, or other compounds in Section I, or defined by one of the embodiments described above. In certain embodiments, the compound is a compound of Formula A-I or A-II.

[0374] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula 1, 1-1, 1- A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II- a, or A-II-b, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease or condition described herein, such as an inflammatory disorder or an allergic disorder. In certain embodiments, the compound is a compound of Formula I, I-1, I-A, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, II, A-I, A-I-1, A-II, A-II-a, or A-II-b, or other compounds in Section I, or defined by one of the embodiments described above. In certain embodiments, the compound is a compound of Formula A-I or A-II.

[0375] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula 1, 1-1, 1- A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II- a, or A-II-b, or other compounds in Section I) for treating a disease or condition, such as a disease or condition described herein. In certain embodiments, the compound is a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I, or defined by one of the embodiments described above. In certain embodiments, the compound is a compound of Formula A-I or A-II.

[0376] In certain embodiments, 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 geriatric human.Exemplary Diseases or Conditions

[0377] Exemplary diseases or conditions mediated by STAT6 include inflammatory disorders (e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), allergic conditions (e g., chronic sinusitis and allergic rhinitis), and proliferative disorders (c.g., cancer).

[0378] In certain embodiments, the disease or condition is inflammatory disorder. Tn certain embodiments, the disease or condition is an allergic condition. In certain embodiments, the disease or condition is a proliferative disorder.

[0379] In certain embodiments, the disease or condition is selected from chronic inflammatory disorder, acute inflammatory disorder, or auto-inflammatory disorder. In certain embodiments, the disease or condition is an obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, a nasal polyp, chronic sinusitis, allergic rhinitis, eosinoph prurigo, or urticaria. In certain embodiments, the disease or condition is atopic dermatitis, asthma, a nasal polyp, chronic obstructive pulmonary disease, eosinophilic esophagitis, or prurigo nodularis. In certain embodiments, the disease or condition is allergic rhinitis, nasal inflammation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis, atopic dermatitis, asthma, allergic rhinitis, arthritis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, multiple sclerosis, endometriosis, eczema, psoriasis, rosacea, or lupus erythematosus.

[0380] In certain embodiments, the disease or condition is cancer.

[0381] In certain embodiments, the cancer is selected from is non-small cell lung cancer (NSCLC), small cell lung cancer, colorectal cancer, rectal cancer, and pancreatic cancer. In certain embodiments, the cancer is selected from non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer. In certain embodiments, the cancer is selected from non-small cell lung cancer (NSCLC) and pancreatic cancer.

[0382] In certain embodiments, 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.

[0383] In certain embodiments, the cancer is lung cancer, pancreatic cancer, colorectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, a lymphoma, or a leukemia. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is breast cancer. In certainembodiments, the cancer is cervical cancer. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is skin cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is bile duct cancer. In certain embodiments, the cancer is nervous system cancer.

[0384] In certain embodiments, 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. In certain embodiments, the cancer is breast adenocarcinoma. In certain embodiments, the cancer is lung adenocarcinoma. In certain embodiments, the cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is cervical adenocarcinoma. In certain embodiments, the cancer is prostate adenocarcinoma. In certain embodiments, the cancer is gastric adenocarcinoma.

[0385] In certain embodiments, the cancer is melanoma.

[0386] In certain embodiments, 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.

[0387] In certain embodiments, the cancer is glioblastoma or neuroblastoma. In certain embodiments, the cancer is glioblastoma. In certain embodiments, the cancer is neuroblastoma.

[0388] In certain embodiments, the cancer is lung cancer, pancreatic cancer, or colorectal cancer. In certain embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer.

[0389] In certain embodiments, the cancer is a lymphoma or a leukemia. In certain embodiments, the cancer is a B-cell lymphoma or chronic myelocytic leukemia.

[0390] In certain embodiments, 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), polycythemiavera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom’s macroglobulinemia, multiple myeloma, heavy chain disease, or a solid tumor such as a sarcoma or carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm’s tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0391] In certain embodiments, the cancer is STAT6 is Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL), primary mediastinal B-cell lymphoma (PMBL), or activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL).

[0392] In certain embodiments, 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.

[0393] In certain embodiments, 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. In certain embodiments, the canceris a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.

[0394] In certain embodiments, 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, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0395] In certain embodiments, 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, orbrain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.

[0396] In certain embodiments, 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.

[0397] In certain embodiments, 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 ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST);Waldenstrom’s macroglobulinemia; and medulloblastoma.

[0398] In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is a leukemia. In certain embodiments, the cancer is Hodgkin’s lymphoma. In certain embodiments, the cancer is non-Hodgkin’s lymphoma. In certain embodiments, the cancer is Burkitt’s lymphoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the cancer is MALT lymphoma. In certain embodiments, the cancer is germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) or primary mediastinal B-cell lymphoma (PMBL). In certain embodiments, the cancer is activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). In certain embodiments, the cancer is a hematological cancer.Additional Methods

[0399] Another aspect of the invention provides methods of inhibiting cell proliferation in a subject by administering to the subject a compound described herein (e.g., a compound ofFormula I, I-1, I-A, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, II, A-I, A-I-1, A-II, A-II-a, or A-II-b, or other compounds in Section I), or inhibiting cell proliferation in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-1, I-A, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, II, A-I, A-I-1, A-II, A-II-a, or A-II-b, or other compounds in Section I). In certain embodiments, the compound is a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I, or defined by one of the embodiments described above. In certain embodiments, the compound is a compound of Formula A-I or A-II. In certain embodiments, cell proliferation is inhibited for T-cells. In certain embodiments, cell proliferation is inhibited for B-cells. In certain embodiments, cell proliferation is inhibited for T-cells and B-cells.III. Combination Therapy

[0400] Another aspect of the invention provides for combination therapy. Compounds described herein (e.g., a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II- a, or A-II-b, or other compounds in Section I) or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat diseases or conditions, such as an inflammatory disorder. In certain embodiments, the compound is a compound of Formula A-I or A-II.

[0401] Accordingly, in certain embodiments, 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 and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In certain embodiments, the method includes co-administering one additional therapeutic agent. In certain embodiments, the method includes co-administering two additional therapeutic agents. In certain embodiments, the method includes co-administering three additional therapeutic agents. In certain embodiments, the method includes co-administering four additional therapeutic agents.

[0402] 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. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with acompound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another.

[0403] In certain embodiments, the compounds of the disclosure can be administered with one or more of a second therapeutic agent, sequentially or concurrently, either by the same route or by different routes of administration. When administered sequentially, the time between administrations is selected to benefit, among others, the therapeutic efficacy and / or safety of the combination treatment. In certain embodiments, the compound of the disclosure can be administered first followed by a second therapeutic agent, or alternatively, the second therapeutic agent administered first followed by the compound of the disclosure. In certain embodiments, the compound of the disclosure can be administered for the same duration as the second therapeutic agent, or alternatively, for a longer or shorter duration as the second therapeutic compound.

[0404] When administered concurrently, the compounds of the disclosure can be administered separately at the same time as the second therapeutic agent, by the same or different routes, or administered in a single composition by the same route. In certain embodiments, the compound of the disclosure is prepared as a first pharmaceutical composition, and the second therapeutic agent prepared as a second pharmaceutical composition, where the first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously, sequentially, or separately. In certain embodiments, the amount and frequency of administration of the second therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent. See, c.., Physicians ’ Desk Reference, 70th Ed, PDR Network, 2015; incorporated herein by reference.

[0405] In certain embodiments, the additional therapeutic agent is a leukotriene inhibitor, nonsteroidal anti-inflammatory drug (NSAID), steroid, tyrosine kinase inhibitor, receptor kinase inhibitor, modulator of nuclear receptor family of transcription factor, HSP90 inhibitor, adenosine receptor (A2A) agonist, disease modifying antirheumatic drugs (DMARDS), phosphodiesterase (PDE) inhibitor, neutrophil elastase inhibitor, modulator of Axl kinase, an anti-cancer agent, anti-allergic agent, anti-nausea agent (or anti-emetic), pain reliever, cytoprotective agent, or a combination thereof. In certain embodiments, the additionaltherapeutic agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof.

[0406] In certain embodiments, the second therapeutic agent is a an NSAID. Examples of NSAIDs considered for use in combination therapies of the invention include but are not limited to acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naioxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, or combinations thereof.

[0407] In certain embodiments, the second therapeutic agent is a steroid. Examples of steroids considered for use in combination therapies of the invention include but are not limited to prednisone, prednisolone, methylprednisone, triacmcinolone, betamethasone, dexamethasone, and prodrugs thereof.

[0408] The doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician. In certain embodiments, the compound described herein (e.g., a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II- a, or A-II-b, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disease or condition. In other embodiments, the compound described herein (e.g., a compound of Formula I, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disease or condition. In certain embodiments, the compound described herein (e.g., a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration. In certain embodiments, the compound is a compound of Formula A-I or A-II.

[0409] In certain embodiments, the compound described herein (e.g., a compound of Formula I, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, orother compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and / or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy. In certain embodiments, the compound is a compound of Formula A-I or A-II.IV. Pharmaceutical Compositions and Dosing Considerations

[0410] As indicated above, the invention provides pharmaceutical compositions, which comprise a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula 1, 1-1, 1-A, la, lb, Ic, Id, le, If, Ig, Ih, li, Ij, Ik, II, Im, II, A-I, A-I-l, A-II, A-II-a, or A-II-b, or other compounds in Section I) and a pharmaceutically acceptable carrier. In certain embodiments, the compound is a compound of Formula A-I or A-II.

[0411] The phrase “therapeutically effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment.

[0412] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritati...

Claims

Claims:

1. A compound represented by Formula A-I:(A-I)or a pharmaceutically acceptable salt thereof; wherein:R1is hydrogen or halo;R2is C1-6 hydroxyalkyl, -C(0)-(Ci-4alkyl), -(pyridinonyl substituted with x occurrences of R6), -(triazolonyl substituted with x occurrences of R6), -(Ci-6 alkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7;R3is hydrogen, C1-4 alkyl, C1-4 haloalkoxyl, or C3-7 cycloalkyl;R4is C1-4 alkyl, Ci-4hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(C0-6 alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(0)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C0-6 alkylene)-R9;R6represents independently for each occurrence halogen, C1-4 alkyl, C3-7 cycloalkyl, -N(C1-4 alkyl)2, -(C0-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogenatoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence Ci-4 alkyl or C3-7 cycloalkyl;R8is Ci-4alkoxyl, -C(O)-OH, -C(O)-(Ci-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is Ci-4alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci-4 haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, or C1-4 alkoxyl; X1is -(C 1-6 alkylene)-;A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12;R11and R12each represents independently for each occurrence halo, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

2. The compound of claim 1, wherein the compound is a compound of Formula A-I.

3. The compound of claim 1, wherein the compound is a compound of Formula A-I-1:(A-I-1)or a pharmaceutically acceptable salt thereof; wherein:R1is hydrogen or halo;R2is C1-6 hydroxyalkyl, -C(O)-(Ci-4 alkyl), -(pyridinonyl substituted with x occurrences of R6), -(Co-6 alkyl ene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7;R3is hydrogen, C1-4 alkyl, or C3-7 cycloalkyl;R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -C(O)-OH, hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -N(RA)-(Co-6 alkylene)-R8, -C(O)-N(RA)-R8, or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R3is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(Co-6 alkylene)-R9;R6represents independently for each occurrence C1-4 alkyl, C3-7 cycloalkyl, -N(Ci-4alkyl)2, -(Co-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence C1-4 alkyl or C3-7 cycloalkyl;R8is C1-4 alkoxyl, -C(O)-OH, -C(O)-(C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is Ci-4alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen and C1-4 alkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, or C1-4 alkoxyl; X1is -(C 1-6 alkylene)-;A1is phenyl substituted with q occurrences of R11, or A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12;R11and R12each represents independently for each occurrence halo, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

4. The compound of claim 1, wherein the compound is a compound of Formula A-I-1.

5. The compound of any one of claims 1-3, wherein X1is -CH2-.

6. The compound of claim 1, wherein the compound is a compound of Formula I-A, or a pharmaceutically acceptable salt thereof:

7. The compound of claim 1, wherein the compound is a compound of Formula la or lb, or a pharmaceutically acceptable salt thereof:la lb8. The compound of any one of claims 1-7, wherein R4is -N(RA)(RB).

9. The compound of any one of claims 1-7, wherein R4is -NH2, -N(H)CH3, or -N(CH3)2.

10. The compound of any one of claims 1-7, wherein R4is selected from -NH2, -N(CH3)2, -N(H)CH3, hydroxy, methoxy, methyl, / / -propyl,11. The compound of any one of claims 1-10, wherein R5is C1-4alkyl or Ci-4 haloalkyl.

12. The compound of any one of claims 1-10, wherein R? is -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms).

14. The compound of any one of claims 1-13, wherein R6represents independently for each occurrence methyl, -N(CH3)2, -(Co-i alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl.

15. The compound of any one of claims 1-13, wherein R7represents independently for each occurrence methyl or cyclopropyl.

16. The compound of claim 1, wherein the compound is a compound of Formula Ic or Id, or a pharmaceutically acceptable salt thereof:Ic Id17. The compound of claim 16, wherein R5is C1-4alkyl or Ci-4 haloalkyl.

18. The compound of claim 16, wherein R5is -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms).

20. The compound of claim 1, wherein the compound is a compound of Formula le, If, or Ig, or a pharmaceutically acceptable salt thereof:

21. The compound of claim 20, wherein R4is -N(RA)(RB).

22. The compound of claim 20, wherein R4is -NH2, -N(H)CH3, or -N(CH3)2.

23. The compound of claim 20, wherein R4is selected from -NH2, -N(CH3)2, -N(H)CH3,hydroxy, methoxy, methyl, n-propyl.,,,,,,24. The compound of any one of claims 1-6 or 16-23, wherein R2is -(pyridin-2-on-5-yl substituted with x occurrences of R6) or a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7.

25. The compound of any one of claims 1-6 or 16-24, wherein R6represents independently for each occurrence methyl, -N(CH3)2, -(Co-i alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl; and R7represents independently for each occurrence methyl or cyclopropyl.

26. The compound of any one of claims 1-6 or 16-23, wherein R2is selected from tert-butyl,O27. The compound of any one of claims 1-6 or 16-23, wherein R2is selected from28. The compound of any one of claims 1-27, wherein A1is phenyl substituted with q occurrences of R11.

29. The compound of any one of claims 1-27, wherein A1is a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R12.

30. The compound of any one of claims 1-27, wherein A1is selected from31. The compound of any one of claims 1-27, wherein A1is selected fromFBr 32. The compound of any one of claims 1-27, wherein A1is selected from33. The compound of claim 1, wherein the compound is a compound of Formula Ih, li, Ij, Ik, II, or Im, or a pharmaceutically acceptable salt thereof:

34. The compound of claim 33, wherein R2is -(pyridin-2-on-5-yl substituted with x occurrences of R6) or a 5-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with x occurrences of R7.

35. The compound of claim 33 or 34, wherein R6represents independently for each occurrence methyl, -N(CH3)2, -(Co-i alkylene)-(pyrazolyl substituted with 0 or 1 occurrence of methyl), cyclopropyl, or morpholinyl; and R7represents independently for each occurrence methyl or cyclopropyl.O36. The compound of claim 33, wherein R2is selected from / e / 7-butyl., and37. The compound of claim 33, wherein R2is selected from, and38. The compound of any one of claims 33-37, wherein R4is -N(RA)(RB).

39. The compound of any one of claims 33-37, wherein R4is -NH2, -N(H)CH₃, or -N(CH3)2.

40. The compound of any one of claims 33-37, wherein R4is selected from -NH2, -N(CH3)2, -41. The compound of any one of claims 33-40, wherein R5is C1.4 alkyl or C1.4 haloalkyl.

42. The compound of any one of claims 33-40, wherein R5is -(Co-6 alkylene)-(5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms).

43. The compound of any one of claims 33-40, wherein R5is selected from methyl,F44. The compound of any one of claims 1-28 or 33-43, wherein R11represents independently for each occurrence methoxy, fluoro, chloro, bromo, iodo, cyclopropyl, or acetylenyl; or one occurrence of R11is oxazolyl substituted with z occurrences of R13.

45. The compound of any one of claims 1-28 or 33-43, wherein R11represents independently for each occurrence chloro, bromo, or fluoro.

46. The compound of any one of claims 1-27, 29, or 33-43, wherein R12represents independently for each occurrence methyl, chloro, bromo, fluoro, trifluoromethyl, acetylenyl, or difluoromethyl.

47. The compound of any one of claims 1-46, wherein R1is hydrogen.

48. The compound of any one of claims 1-46, wherein R1is chloro.

49. The compound of any one of claims 1-48, wherein R3is hydrogen.

50. The compound of any one of claims 1-48, wherein R3is methyl or / / -propyl.

51. The compound of any one of claims 1-50, wherein RAand RBeach represent independently for each occurrence hydrogen or methyl.

52. The compound of any one of claims 1-51, wherein RAis hydrogen.

53. A compound represented by Formula A-II:(A-II)or a pharmaceutically acceptable salt thereof; wherein:R1is halo, hydroxyl, Ci-6 alkyl, Ci-6 haloalkyl, C3-7 cycloalkyl, Ci-ealkoxyl, -C(O)-(Ci-s aliphatic), -(Co-6 alkylene)-CN, -C(O)-O-(Ci-s aliphatic), -OC(O)-(Ci-s aliphatic), -OC(O)N(RA)(RB), -N(RA)C(O)2-(C 1-8 aliphatic), -S(O)2-(Ci-s aliphatic), or S(O)2N(RA)(RB);R2is C2-6 alkenyl, C1-6 hydroxyalkyl, -C(O)-(Ci-4 alkyl), -N(R15)(R16), -(pyridinonyl substituted with x occurrences of R6), -(C2-4 alkynylene)-(pyridinonyl substituted with x occurrences of R6), -(triazolonyl substituted with x occurrences of R6), -(Co-6 alkylene)-(C3-7 cycloalkyl substituted with z occurrences of R17), -(C1-6 alkylene)-(6-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected fromnitrogen and oxygen, wherein the heterocyclyl is substituted with z occurrences of R17), -(C3-6 cycloalkylene)-(6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms; wherein the monocyclic heteroaryl and the bicyclic heteroaryl are substituted with x occurrences of R7;R3is hydrogen, C1-4 alkyl, Ci.4haloalkoxyl, or C3-7 cycloalkyl;R4is C1-4 alkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, C1-4 haloalkoxyl, -(C1-4 alkylene)-(C1-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(Co-6 alkylene)-C(O)-R8, -N(RA)-(Co-6 alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(0)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C0-6 alkylene)-R9;R6represents independently for each occurrence halogen, C1-4 alkyl, C3-7 cycloalkyl, -N(C1-4 alkyl)2, -(C0-6 alkylene)-(5-membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7), or a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R7represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-7 cycloalkyl;R8is C1-4 alkoxyl, -C(O)-OH, -C(O)-(C1-4alkyl), C1-4 haloalkyl, -N(RA)(RB), C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl), -(pyridinonyl substituted with x occurrences of C1-4 alkyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is C1-4 alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci-4 haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken togetherwith said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence Ci-4 alkyl, hydroxyl, Ci-4 alkoxyl, Ci-4 haloalkoxyl, -N(RA)-(C1-4haloalkyl), or -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of Ci-4 alkyl);X1is a covalent bond or -(C1-6alkylene)-, wherein 0 or 1 methylene group is replaced with -N(RA)-, O, or -C(O)-;A1is (i) phenyl substituted with q occurrences of R11, (ii) a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12, (iii) a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with z occurrences of R12, (iv) a 3-7 membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrence of R10, (v) C3-6 cycloalkyl substituted with 0 or 1 occurrence of R10, or (vi) C1-6 alkyl, C1-4 haloalkyl, -C(O)-R7, or C1-4 alkoxyl;A2is an oxo-substituted 5-6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5;R11and R12each represents independently for each occurrence halo, hydroxyl, -C(O)-(Ci-4 alkoxyl), C1-4 alkyl, C1.4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, C3-7 cycloalkyl, -SFs, or C2-3 alkynyl; or one occurrence of R11is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with z occurrences of R13;R13represents independently for each occurrence C1-4 alkyl or halo;R14is C3-7 cycloalkyl, a 5-6 membered monocyclic heterocyclyl containing 1, 2, or 3 nitrogen atoms, wherein the heterocyclyl is substituted with z occurrences of R7, phenyl substituted with z occurrences of R7, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7;R15and R16are independently hydrogen, C1.4 alkyl, C1-4 haloalkyl, or 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R7; or an instance of R15and R16attached to the same nitrogen atom aretaken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R17is Ci-4 alkyl, Ci-4 haloalkyl, cyano, or 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen;R18is halo, hydroxyl, or Ci-4 alkyl;t is 0, 1, 2 or 3;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

54. The compound of claim 53, wherein A2is one of the following:

55. The compound of claim 53, wherein the compound is represented by Formula A-II-a:(A-II-a)or a pharmaceutically acceptable salt thereof; wherein:R1is halo;R2is -(pyridinonyl substituted with x occurrences of R6) or -(triazolonyl substituted with x occurrences of R6);R3is hydrogen or Ci-4 alkyl;R4is Ci-4 alkyl, Ci-4 hydroxyalkyl, C3-7 cycloalkyl, Ci.4haloalkoxyl, -(Ci-4alkylene)-(Ci-4 alkoxyl), hydroxyl, -(Co-6 alkylene)-N(RA)(RB), -(Co-6 alkylene)-(4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen), -(Co-6 alkylene)-C(O)-R8, -N(RA)-(C0-6 alkylene)-R8, -C(O)-N(RA)-R8, -N(RA)C(O)N(RA)(RB), or -(Co-6 alkylene)-N(RA)-(4-6 membered saturated heterocyclyl containing 1 sulfur atom substituted with 0, 1, or 2 occurrences of oxo);R5is Ci-4 alkyl, Ci-4 hydroxyalkyl, Ci-4 haloalkyl, or -(Co-6 alkylene)-R9;R6represents independently for each occurrence halogen, Ci-4 alkyl, C3-7 cycloalkyl, or -N(C1-4alkyl)2;R7represents independently for each occurrence C1-4 alkyl;R8is Ci-4alkoxyl, C1-4 haloalkyl, -N(RA)(RB), C3-7 cycloalkyl substituted with w occurrences of -(phenyl)-(Ci-4 alkoxyl), hydroxyl, a 5-6 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen and oxygen, or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with w occurrence of R7;R9is C1-4 alkoxyl, C3-7 cycloalkyl, a 4-6 membered saturated heterocyclyl containing 1 oxygen atom, or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is substituted with 1 occurrence of halo;RAand RBeach represent independently for each occurrence hydrogen, C1-4 alkyl, and Ci-4 haloalkyl, or an instance of RAand RBattached to the same nitrogen atom are taken together with said nitrogen atom to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the heterocyclic ring is substituted with 0 or 1 occurrence of R10;R10represents independently for each occurrence C1-4 alkyl, hydroxyl, C1-4 alkoxyl, C1-4 haloalkoxyl, -N(RA)-(C1-4haloalkyl), or -C(O)-N(RA)-(C3-7 cycloalkyl substituted with 0 or 1 occurrences of C1-4 alkyl);X1is a -(C1-6 alkylene)-;A1is (i) phenyl substituted with q occurrences of R11or (ii) a 5-6 membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the monocyclic heteroaryl is substituted with z occurrences of R12;A2is an oxo-substituted 5-6 membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms, wherein the ring is substituted by R3, R4, and R5;R11and R12each represents independently for each occurrence halo, hydroxyl, -C(O)-(Ci-4 alkoxyl), C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, or C2-3 alkynyl;t is 0, 1, 2 or 3;q represents independently for each occurrence 1 or 2;w represents independently for each occurrence 0 or 1;x is 1, 2, or 3; andz represents independently for each occurrence 0, 1, or 2.

56. The compound of claim 55, wherein the compound is represented by Formula A-II-b:( A1x'Alhf(A-II-b) or a pharmaceutically acceptable salt thereof.

57. The compound of claim 55 or 56, wherein R2is -(pyridinonyl substituted with x occurrences of R6).

58. The compound of claim 55 or 56, wherein R2is substituted with x occurrences of R659. The compound of any one of claims 55-58, whereinA2is60. The compound of any one of claims 55-59, wherein R3is hydrogen.

61. The compound of any one of claims 55-60, wherein R4is Ci-4 alkyl, Ci-4 hydroxyalkyl, or - (Co-6 alkylene)-N(RA)(RB).

62. The compound of any one of claims 55-60, wherein R4is -(Co-6 alkylene)-C(O)-R8, -N(RA)- (Co-6 alkylene)-R8, -C(O)-N(RA)-R8, or -N(RA)C(O)N(RA)(RB).

63. The compound of any one of claims 55-62, wherein R5is Ci-4 alkyl.

64. The compound of any one of claims 55-63, wherein R6represents independently for each occurrence Ci-4 alkyl or -N(C1-4alkyl)2.

65. The compound of any one of claims 55-64, wherein A1is phenyl substituted with q occurrences of R11.

66. The compound of any one of claims 55-65, wherein R11represents independently for each occurrence halo, Ci-4 alkyl, or Ci-4 haloalkyl.

67. A compound in Table 1, or a pharmaceutically acceptable salt thereof.

68. A compound in Table 2, or a pharmaceutically acceptable salt thereof.

69. A compound in Table 3, or a pharmaceutically acceptable salt thereof.

70. A pharmaceutical composition comprising a compound of any one of claims 1-69 and a pharmaceutically acceptable carrier.

71. A method of treating a disease or condition mediated by STAT6, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-69 to treat the disease or condition.

72. A method of treating a disease or condition selected from an inflammatory disorder, allergic condition, or proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-69 to treat the disease or condition.

73. The method of claim 72, wherein the disease or condition is an obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, a nasal polyp, chronic sinusitis, allergic rhinitis, eosinoph prurigo, urticaria, asthma, eosinophilic esophagitis, or prurigo nodularis.

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