Heteroaryl compounds and their use in treating medical conditions

Abstract

The invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder.

Description

HETEROARYL COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 585,430, filed September 26, 2023, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION

[0002] The invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder. BACKGROUND

[0003] Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. Current treatment options for these cancers are not effective for all patients and / or can have substantial adverse side effects. Moreover, new therapies that achieve an anti- cancer effect through a different mechanism present an opportunity to treat cancers more effectively and / or to treat cancers that have become resistant to currently available medicines.

[0004] 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.

[0005] Nicotinamide adenine dinucleotide (NAD+) is a cofactor that plays an important role in many physiologically essential processes, such as metabolism, energy production, DNA repair, and signaling. Nicotinamide phosphoribosyltransferase (NAmPRTase or NAMPT) is essential for the biosynthesis of NAD+. In mammals, the rate-limiting step in NAD+biosynthesis is the salvage of NAM and conversion to nicotinamide mononucleotide (NMN) catalyzed by NAMPT. Thus, inhibition of NAMPT leads to depletion of NAD+ and a decrease in diseased cell proliferation and even diseased cell death. As a result, NAMPT inhibitors are useful for treating a variety of cancers, metabolic disorders, or inflammatory disorders.

[0006] The need exists for new therapeutic methods and compounds for treating diseases or conditions associated with NAMPT activity. The present invention addresses the foregoing needs and provides other related advantages. SUMMARY

[0007] The invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder. In particular, one aspect of the invention provides a collection of heteroaryl 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 heteroaryl 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 heteroaryl compounds, such as a compound represented by Formula I-1:(I-1) or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heteroaryl compounds are describedin 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 NAMPT. 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, I-1, I-A, I-B, I-C, or I-D, to treat the disease or condition, as further described in the detailed description.

[0010] Another aspect of the invention provides a method of inhibiting the activity of NAMPT. The method comprises contacting a NAMPT with an effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to inhibit the activity of said NAMPT, as further described in the detailed description. DETAILED DESCRIPTION

[0011] The invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic 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.

[0012] 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

[0013] 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.

[0014] 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 some 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 some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0015] 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 some 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 some 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:

[0016] Exemplary bridged bicyclics include:.

[0017] 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.

[0018] The term “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0019] 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 N-substituted pyrrolidinyl)).

[0020] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0021] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0022] 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.

[0023] The term “-(C0alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3alkylene)-” encompasses a bond (i.e., C0) and a -(C1-3 alkylene)- group.

[0024] 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 hydrogenatoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0025] The term “halogen” means F, Cl, Br, or I.

[0026] 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 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 non–aromatic 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 (e.g., “phenylene” is a trivalent phenyl group when it has three groups attached to it (e.g. . The term “arylene” refers to a bivalentaryl group.

[0027] 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 ^ electrons shared in a cyclic array; and having, in addition to 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 quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. 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 ofthe rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. 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.

[0028] 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.

[0029] 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– 2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0030] 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, 3H–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 one or more 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 it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. The term “oxo-heterocyclylene” refers to a multivalent oxo-heterocyclyl group having the appropriate number of open valences to account for groups attached to it.

[0031] 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.

[0032] 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.

[0033] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH2)0–4R ^; –(CH2)0–4OR ^; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR ^)2; –(CH2)0–4SR ^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; – N3; -(CH2)0–4N(R ^)2; –(CH2)0–4N(R ^)C(O)R ^; –N(R ^)C(S)R ^; –(CH2)0–4N(R ^)C(O)NR ^2;-N(R ^)C(S)NR ^2; –(CH2)0–4N(R ^)C(O)OR ^; –N(R ^)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^2; -N(R ^)N(R ^)C(O)OR ^; –(CH2)0–4C(O)R ^; –C(S)R ^; –(CH2)0–4C(O)OR ^; –(CH2)0–4C(O)SR ^; -(CH2)0–4C(O)OSiR ^3; –(CH2)0–4OC(O)R ^; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R ^; –(CH2)0–4C(O)NR ^2; –C(S)NR ^2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH2C(O)R ^; –C(NOR ^)R ^; -(CH2)0–4SSR ^; –(CH2)0–4S(O)2R ^; –(CH2)0–4S(O)2OR ^; –(CH2)0–4OS(O)2R ^; –S(O)2NR ^2; –S(O)(NR ^)R ^; – S(O)2N=C(NR ^2)2; -(CH2)0–4S(O)R ^; -N(R ^)S(O)2NR ^2; –N(R ^)S(O)2R ^; –N(OR ^)R ^; – C(NH)NR ^2; –P(O)2R ^; -P(O)R ^2; -OP(O)R ^2; –OP(O)(OR ^)2; SiR ^3; –(C1–4straight or branched alkylene)O–N(R ^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R ^)2.

[0034] Each R ^ is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -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 =O and =S; or each R ^ is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, – (CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^.

[0035] Each R^is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, 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 =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –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 selectedfrom hydrogen, C1–6aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] When R*is C1–6 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 C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, 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.

[0037] An optional substituent on a substitutable nitrogen is independently –R†, –NR†2, – C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, – C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic, 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 C1–6aliphatic, 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 C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, 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.

[0038] 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, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0039] 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) 33201-217; 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.

[0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0041] 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 E conformational isomers. Therefore, single stereochemical isomers as well asenantiomeric, 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 within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0042] 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.

[0043] 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.

[0044] 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 heteroatomwith 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.

[0045] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0046] 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-C10alkyl, and C1-C6alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0047] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0048] 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.

[0049] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0050] 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.

[0051] 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, tert-butoxy and the like. The term “haloalkoxyl” refers to analkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.

[0052] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane susbstituted with an oxo group is cyclopentanone.

[0053] The symbol “ ” indicates a point of attachment.

[0054] 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.

[0055] 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.

[0056] As used herein, the terms “subject” and “patient” are used interchangeable and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0057] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.

[0058] 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. 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.

[0059] 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.

[0060] 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 an 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, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0061] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0062] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0063] 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.

[0064] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. I. Heteroaryl Compounds

[0065] One aspect of the invention provides heteroaryl 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.

[0066] One aspect of the invention provides a compound represented by Formula I:or a pharmaceutically acceptable salt thereof; wherein: A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A2is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3; A3is phenylene substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4 alkyl; R2represents independently for each occurrence halo, C1-4haloalkyl, C1-4alkoxyl, C1-4alkyl, or C1-4 hydroxyalkyl;R3represents independently for each occurrence halo or C1-4alkyl; Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4alkylene)- N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6alkyl), -C(O)-O-(C1-4alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9);d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)- O-]x-R6, -N(R1A)-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6hydroxyalkyl), -S(O)2-(C1-6alkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- (C3-7 cycloalkyl), -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl), or -S(O)2-N(R1A)- C(O)-N(R1B)(R1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-OH, or -(C1-4alkylene)-C(O)-O-(C1-6alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; or j) hydrogen; R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, andoxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R1A)(R1B), or -(C1-6alkylene)-N(R1A)-C(O)-O-(C1-6alkyl); R6is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R7is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), -(C0-6alkylene)-N(R1B)-C(O)-(C1-4alkyl), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); m and n are independently 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4 alkylene)-R4.

[0067] 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 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).

[0068] In certain embodiments, the compound is a compound of Formula I.

[0069] As defined generally above, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur.

[0070] In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen.

[0071] In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6- membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur.

[0072] In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or. In certain embodiments, A1substituted with p occurrences of R2, wherein B1is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered heteroaryl ring containing 2 heteroatoms that are nitrogen.

[0073] In certain embodiments, A1issubstituted with p occurrences of R2,substituted with 1, 2 or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with p occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with p occurrences of R2orsubstituted with 1, 2 or 3 occurrences of R2.

[0074] In certain embodiments, A1issubstituted with 1, 2 or 3 occurrences of R2,substituted with 1, 2 or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with 1, 2, or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1is substituted with 1, 2 or 3 occurrences of R2,substituted with 1, 2 or 3 occurrences of R2.

[0075] In certain embodiments, A1issubstituted with 0 or 1 occurrences of R2,substituted with 1 or 2 occurrences of R2, orsubstituted with 1 or 2 occurrences of R2. In certain embodiments, A1issubstituted with 0 or 1 occurrence of R2, orsubstituted with 1 or 2.

[0076] In certain embodiments,, each of which is substituted with p occurrences of R2.

[0077] In certain embodiments, A1issubstituted with p occurrences of R2. In certain embodiments,substituted with 2, 3, or 4 occurrences of R2. In certain embodiments,substituted with 1 or 2 occurrences of R2. In certain embodiments, A1issubstituted with 2 occurrences of R2. In certain embodiments, A1substituted with 3 occurrences of R2. In certain embodiments, A1issubstituted with 4 occurrences of R2.

[0078] In certain embodiments, A1issubstituted with p occurrences of R2. In certain embodiments, A1issubstituted with 1, 2, or 3 occurrences of R2. In certain embodiments,substituted with 0 or 1 occurrence of R2. In certainembodiments, A1issubstituted with p occurrences of R2. In certain embodiments,substituted with p occurrences of R2.

[0079] In certain embodiments, A1issubstituted with p occurrences of R2. In certain embodiments, A1issubstituted with 1, 2 or 3 occurrences of R2. In certain embodiments, A1issubstituted with 1 or 2 occurrences of R2. In certain embodiments, A1issubstituted with 1 occurrence of R2.

[0080] In certain embodiments, A1isIn certain emb1odiments, A is

[0081] In certain embodiments, A1isIn certain embodiments,certain embodiments, A1is, , . In certain emb1odiments, A isIn certain embodiments, A1is

[0082] In certain embodiments,certain embodiments, A1is In certain embodiments, A1 1isIn certain embodiments, A In certain embodiments, A1is In certain embodiments,

[0083] In certain embodiments, A1isIn certainembodiments, A25, , , , ,

[0084] In certain embodiments, A1isIn certain e1mbodiments, A is

[0085] In certain embodiments, A1is. In certain embodiments,certain embodiments, A1is . In certain embodiments, A1isIn certain embodiments, A1is26

[0086] In certain embodiments, A1is. In certain embodiments, A1is In cer1 1tain embodiments, A is In certain embodiments, A is In certain embodiments1 1, A isIn certain embodiments, A is In certain embodiments, A1is In certain1embodiments, A is In certain embodiments, A1is1In certain embodiments, A. In certain embodiments, A1is . In c1ertain embodiments, A is In certain1 1embodiments, A isIn certain embodiments, A is selected from the groups depicted in the compounds in Table 1, below.

[0087] As defined generally above, A2is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond; wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3.

[0088] In certain embodiments, A2is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or acovalent bond; wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3.

[0089] In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene.

[0090] In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 6- membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 1 occurrence of R3. In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen.

[0091] In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 1 occurrence of R3. In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene.

[0092] In some embodiments, A2is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R3.

[0093] In some embodiments, A2is a 5-8 membered saturated bicyclic carbocyclylene substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene.

[0094] In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, each of which is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen.

[0095] In certain embodiments, A2is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 1 occurrence of R3. In certain embodiments, A2is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen.

[0096] In some embodiments, A2is a 4-6 membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from oxygen and nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R3; or A2is a covalent bond.

[0097] In certain embodiments, A2is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated bicyclic carbocyclylene, wherein the bicyclic carbocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a covalent bond.

[0098] In certain embodiments,, each of which is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is one of the following:, wherein the nitrogen atom is attached to Z; wherein the saturated carbon is attached to Z; orwherein A2is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is one of the following: , wherein the nitrogen atom is attached to Z;) o wherein the saturated carbon is attached to Z; or.

[0099] In certain embodiments, A2iseach of which is substituted with 0 or 1 occurrences of R3, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2is2wherein the nitrogen atom of A is attached to Z. In certain embodiments, A2iswherein the saturated carbon is attached to Z, wherein A2is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2iswherein the saturated carbon is attached to Z. In certain embodiments, A2is, each of which is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is

[0100] In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3.In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein the saturated carbon of A2is attached to Z.

[0101] In certain embodiments, A2is. In certain embodiments, A2is . In certain embodiments, A2is. In certain embodiments, A2is , wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2is In certain embodiments, A2is. In certain embodiments, A2is. In certain embodiments, A2is, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2is, wherein the saturated carbon of A2is attached to Z.

[0102] In certain embodiments, A2is substituted with 0 occurrences of R3. In certain embodiments, A2is selected from the groups depicted in the compounds in Table 1, below.

[0103] As defined generally above, A3is phenylene substituted with 0 or 1 occurrences of R3. In some embodiments, A3is para-phenylene substituted with 0 or 1 occurrences of R3. In some embodiments, A3is phenylene. In some embodiments, A3is para-phenylene. In certain embodiments, A3is. In some embodiments, A3is selected from the groups depicted in the compounds in Table 1, below.

[0104] As defined generally above, R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R1A, R1B, and R1Care hydrogen. In certain embodiments, R1Aand R1Bare both hydrogen. In certain embodiments, R1Aand R1Bare both methyl. In certain embodiments, R1Ais hydrogen. In certain embodiments, at least one instance of R1Ais hydrogen. In certain embodiments, each R1Ais independently C1-4 alkyl. In certain embodiments, R1Bis hydrogen. In certain embodiments, at least one instance of R1Bis hydrogen. In certain embodiments, each R1Bis independently C1-4alkyl. In certain embodiments, R1Cis hydrogen. In certain embodiments, at least one instance of R1Cis hydrogen. In certain embodiments, each R1Cis independently C1-4 alkyl. In certain embodiments, R1Ais selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R1Bis selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, R1Cis selected from the groups depicted in the compounds in Table 1, below.

[0105] As defined generally above, R2represents independently for each occurrence halo, C1-4haloalkyl, C1-4alkoxyl, C1-4alkyl, or C1-4hydroxyalkyl. In certain embodiments, R2represents independently for each occurrence fluoro, chloro, -CF3, -OCH3, -CH3, or -CH2OH. In certain embodiments, R2represents independently for each occurrence halo. In certain embodiments, each R2is independently fluoro or chloro. In certain embodiments, R2is fluoro. In certain embodiments, R2is chloro. In certain embodiments, R2is selected from the groups depicted in the compounds in Table 1, below.

[0106] As defined generally above, R3represents independently for each occurrence halo or C1-4 alkyl. In certain embodiments, R3represents independently for each occurrence halo. Incertain embodiments, R3represents independently for each occurrence C1-4alkyl. In certain embodiments, R3is fluoro. In certain embodiments, R3is chloro. In certain embodiments, R3is methyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1, below.

[0107] As defined generally above, Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4alkylene)- N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6alkyl), -C(O)-O-(C1-4alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH); f) -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4alkylene)- O-]x-R6, -N(R1A)-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4alkylene)-C(O)-O-(C1-6alkyl), -S(O)2-[(C1-4alkylene)-O-]x-R5, -S(O)2- (C3-7 cycloalkyl), -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)- C(O)-N(R1B)(R1C); h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; or j) hydrogen; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4 alkylene)-R4.

[0108] In certain embodiments, Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one - N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6 alkyl), -C(O)-N(R1A)-(C1-4 haloalkyl), -C(O)- N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1B)-(C1-4alkylene)-[O-(C1-4alkylene)-]x-(C1-6alkoxyl), -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), - C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6hydroxyalkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)- N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), -C(O)- C(O)-N(R1A)-(C1-4alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)- N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))- (C1-4hydroxyalkyl), or -C(O)-O-(C1-4alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl);e) -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6, or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6hydroxyalkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -S(O)2-(C1-4alkylene)-C(O)-O-(C1-6alkyl), -S(O)2-[(C1-4alkylene)-O-]x-R5, -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)- C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C); h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4 alkylene)- R4.

[0109] In certain embodiments, Z is one of the following: a) -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2- (C1-4alkyl), -C(O)-(C1-4alkylene)-O-(C1-4alkyl), or -C(O)-(C1-4alkylene)-[O-(C1-4alkylene)-]y-(C1-6 alkoxyl); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)-N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1B)-(C1-4alkylene)-[O-(C1-4alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, or -C(O)-N(R1A)-(C1-4 alkylene)- N(R1B)-S(O)2-(C1-4alkyl); c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6alkyl), -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)-N(R1A)(R1B), or -C(O)-O-(C1-4alkylene substituted with 1 occurrence of - N(R1A)(R1B))-(C1-4 hydroxyalkyl); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4haloalkyl), or -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6; f) -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), or -N(R1A)-C(O)-O- [(C1-4alkylene)-O-]x-R6; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), - S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-OH, or -(C1-4alkylene)-C(O)-O-(C1-6 alkyl); or i) hydrogen.

[0110] In certain embodiments, Z is one of the following: a) -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or - N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -C(O)- N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl); c) -C(O)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)- C(O)-(C1-4alkyl), -C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), or -C(O)-C(O)-(C1-6hydroxyalkyl); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6alkylene)- N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo); f) -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)-C(O)- (C1-6alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl); or h) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A. In certain embodiments, Z is selected from the groups above, provided that when B1is a 6- membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)-(C1-6hydroxyalkyl). In certain embodiments, Z is selected from the groups above, provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not -C(O)-(C1-6hydroxyalkyl).

[0111] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-OH, -C(O)-O- (C1-6 alkyl), -C(O)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)- O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6alkyl), -S(O)2-(C3-7cycloalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2- N(R1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-N(R1B)(R1C), -S(O)2-[(C1-4 alkylene)-O-]x-R5, - N(R1A)-C(O)-(C1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), - N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl), -N(R1A)-C(O)-O-[(C1-4alkylene)-O-]x-R6, -N(R1A)- C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6, -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R1A)(R1B), -N(R1A)-C(O)-N(R1B)-[(C1-6hydroxyalkyl), -C(O)-(C1-4alkylene)-[O-(C1-4alkylene)-]y-(C1-6alkoxyl), -C(O)N(R1B)-(C1-4alkylene)-[O-(C1-4alkylene)-]y-(C1-6alkoxyl), - C(O)-C(O)-OH, -C(O)-C(O)-N(R1A)(R1B), -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)- N(R1A)-R5, -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -C(O)-N(R1A)-S(O)2-R7, -N(R1A)-S(O)2-R7, -C(O)- C(O)-N(R1A)-S(O)2-(C1-6alkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9), or hydrogen; provided that when B1is a 6- membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)- (C1-4 alkylene)-R4.

[0112] In some embodiments, Z is -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-7cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)), -C(O)-N(R1A)-(C0-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O- (C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9), -N(R1A)-C(O)-N(R1B)- (C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), -N(R1A)-C(O)- (azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one - OH), -S(O)2-(C3-7cycloalkyl), or a 5-membered oxo-heterocyclyl containing 2 ring heteroatomsindependently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A.

[0113] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)- N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)- ]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)- N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)- (C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)- N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-S(O)2-R7, -C(O)-C(O)- N(R1A)(R1B), -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, - C(O)-O-(C1-6 alkyl), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4hydroxyalkyl), -N(R1A)-C(O)- C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)- N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 alkylene)- N(R1C)-S(O)2-(C1-4alkyl), -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4haloalkyl), -N(R1A)- C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)- O-(C1-4 alkylene)-(phenyl), -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-(C1-4 alkylene)- N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), -N(R1A)- S(O)2-R7, -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), - S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-O- (C1-6 alkyl), -S(O)2-N(R1A)-C(O)-N(R1B)(R1C), -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)- N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)- C(O)-OH, or -(C1-4alkylene)-C(O)-O-(C1-6alkyl); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4alkylene)-R4.

[0114] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-(C1-4alkylene)- N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6alkoxyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2- (C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4 alkylene)-R4.

[0115] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)- N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2- (C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4 alkylene)-R4.

[0116] In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)- N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6alkyl)). In certain embodiments, Z is -C(O)-(C1-6hydroxyalkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6alkyl)); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)-(C1-6 hydroxyalkyl).

[0117] In certain embodiments, Z is -C(O)R4or -C(O)-(C1-4 alkylene)-R4. In certain embodiments, Z is -C(O)R4or -C(O)-(C1-4alkylene)-R4; provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2.

[0118] In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)- (C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4alkylene)-O-(C1-4alkyl), -C(O)-(C1-4alkylene)-[O-(C1-4alkylene)-]y-(C1-6alkoxyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or - C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1- 4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or - C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)).

[0119] In some embodiments, Z is -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)- (C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), or -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4. In certain embodiments, Z is -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl) or -C(O)-(C1-4alkylene)- N(R1A)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, - C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), or - C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)). In certain embodiments, Z is -C(O)-(C1-4alkylene)-O-(C1-4alkyl) or -C(O)-(C1-4alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH) or - C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)).

[0120] In some embodiments, Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-6 alkyl), -C(O)-N(R1A)-(C1-4 haloalkyl), -C(O)-N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)- [O-(C1-4alkylene)-]x-(C1-6alkoxyl), -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), - C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl), or -C(O)-N(R1A)-S(O)2-R7.

[0121] In certain embodiments, Z is -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)-N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)- O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), or -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl).

[0122] In certain embodiments, Z is -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), or -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl).

[0123] In certain embodiments, Z is -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), or -C(O)-N(R1A)-(C1-4haloalkyl). In certain embodiments, Z is -C(O)-N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), - C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)- N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), - C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)- [(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)- (C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)-S(O)2-R7.

[0124] In some embodiments, Z is -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)- C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)-O-(C1-4 alkylene)-O- (C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of - N(R1A)(R1B))-(C1-4hydroxyalkyl), or -C(O)-O-(C1-4alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9).

[0125] In some embodiments, Z is -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), - C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)-N(R1A)(R1B), -C(O)- O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4hydroxyalkyl), or -C(O)- O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9).

[0126] In certain embodiments, -C(O)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -C(O)-C(O)- N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), or - C(O)-C(O)-(C1-6 hydroxyalkyl).

[0127] In certain embodiments, Z is -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), - C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-C(O)-N(R1A)- R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl),- C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms).

[0128] In certain embodiments, Z is -C(O)-C(O)-R4or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-OH or -C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -C(O)-O- (C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4hydroxyalkyl), or -C(O)-O-(C1-4alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9).

[0129] In some embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)- C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl). In certain embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)- (C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)- S(O)2-(C1-4 alkyl).

[0130] In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), - N(R1A)-C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)-C(O)- (azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one - OH).

[0131] In certain embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4haloalkyl), or -N(R1A)-C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6. In certain embodiments, Z is - N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)- (morpholinyl), or -N(R1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH).

[0132] In some embodiments, Z is -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), - N(R1A)-C(O)-(C1-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4alkylene)-O-]x-R6, -N(R1A)-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R1A)-S(O)2-R7.

[0133] In some embodiments, Z is -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), -N(R1A)-C(O)-O-[(C1-4alkylene)-O-]x- R6, or -N(R1A)-S(O)2-R7. In certain embodiments, Z is -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)- C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), or -N(R1A)-S(O)2-R7. In certain embodiments, Z is -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-(C1-4alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), or -N(R1A)-C(O)-O-(C1-4 alkylene)-(phenyl).

[0134] In certain embodiments, Z is -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), or-N(R1A)-C(O)-(C1-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)- N(R1B)-S(O)2-(C1-4 alkyl), or -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6. In certain embodiments, Z is -N(R1A)-C(O)-O-[(C1-4alkylene)-O-]x-R6or -N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl).

[0135] In some embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1- 4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O- ]x-R5, -S(O)2-(C3-7cycloalkyl), -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)- N(R1B)(R1C). In some embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1-6alkoxyl), -S(O)2-(C1-4alkylene)-C(O)-O-(C1-6alkyl), -S(O)2-[(C1-4alkylene)-O-]x-R5, -S(O)2- N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2- N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C). In certain embodiments, Z is - S(O)2-(C1-6 alkyl) or -S(O)2-(C3-7 cycloalkyl).

[0136] In certain embodiments, Z is -S(O)2-(C1-6hydroxyalkyl), -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)- (C1-6alkoxyl), -S(O)2-(C1-4alkylene)-C(O)-O-(C1-6alkyl), -S(O)2-[(C1-4alkylene)-O-]x-R5, or - S(O)2-(C3-7 cycloalkyl). In certain embodiments, Z is -S(O)2-N(R1A)-(C1-6 hydroxyalkyl) or - S(O)2-N(R1A)(R1B). In certain embodiments, Z is -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R1A)-C(O)-O-(C1-6alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C).

[0137] In some embodiments, Z is -S(O)2-[(C1-4alkylene)-O-]x-R5, -S(O)2-N(R1A)-C(O)-(C1-6alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl). In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl).

[0138] In some embodiments, Z is -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or - (C1-4alkylene)-C(O)-O-(C1-6alkyl).

[0139] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)- (C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)), -C(O)- N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R1A)-R5, - N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-S(O)2- R7, -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4. In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or - N(R1A)-C(O)-(C1-6 alkyl)), -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -S(O)2-[(C1-4 alkylene)-O-]x-(C1-6 alkyl), - S(O)2-[(C1-4 alkylene)-O-]x-S(O)2-N(R1A)-C(O)-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4.

[0140] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R1A)-R5, and -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl). In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R1A)-R5, and -N(R1A)-C(O)-C(O)- N(R1B)-(C1-6 hydroxyalkyl); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4.

[0141] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)- C(O)-N(R1A)-(C1-6 hydroxyalkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C1-6hydroxyalkyl), -C(O)-C(O)-N(R1A)-(C1-6hydroxyalkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4.

[0142] In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo) or -N(R1A)-C(O)-(C1-6hydroxyalkyl). In some embodiments, Z is - N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl) or -N(R1A)-C(O)-(C1-6 hydroxyalkyl).

[0143] In certain embodiments, Z is -C(O)R4. In certain embodiments, Z is -C(O)R4, provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2. In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2. In certain embodiments, Z is -C(O)-(C1-4alkylene)-R4. In certain embodiments, Z is -C(O)-(C1-4alkylene)-R4, provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2.

[0144] In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl). In some embodiments, Z is - C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4. In some embodiments, Z is -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl). In some embodiments, Z is -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl). In some embodiments, Z is -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with one -OH). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)- C(O)-(C5-8bridged bicyclic cycloalkyl substituted with z occurrence of R9). In some embodiments, Z is -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH). In some embodiments, Z is -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)). In some embodiments, Z is - C(O)-(C3-7cycloalkyl gem-substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)).

[0145] In some embodiments, Z is -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl). In some embodiments, Z is -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R1A)(R1B). In some embodiments, Z is -C(O)-N(R1A)-(C1-6 alkyl). In some embodiments, Z is -C(O)-N(R1A)-(C1-4haloalkyl). In some embodiments, Z is -C(O)-N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl). In some embodiments, Z is -C(O)-N(R1B)- (C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl). In some embodiments, Z is -C(O)-N(R1A)- (C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B). In some embodiments, Z is -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl). In some embodiments, Z is -C(O)- N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6. In some embodiments, Z is -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl). In some embodiments, Z is -C(O)-N(R1A)-S(O)2-R7.

[0146] In some embodiments, Z is -C(O)-C(O)-N(R1A)-R5. In some embodiments, Z is -C(O)- C(O)-N(R1A)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-C(O)-N(R1A)(R1B). In some embodiments, Z is -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl). In some embodiments, Z is -C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl). In some embodiments, Z is -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5-membered heteroaryl containing 1-4 nitrogen atoms). In some embodiments, Z is -C(O)-C(O)-R4. In some embodiments, Z is -C(O)-C(O)-OH.

[0147] In some embodiments, Z is -C(O)-OH. In some embodiments, Z is -C(O)-O-(C1-6 alkyl). In some embodiments, Z is -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B). In some embodiments, Z is -C(O)-O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))- (C1-4hydroxyalkyl). In some embodiments, Z is -C(O)-O-(C1-4alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9).

[0148] In some embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl). In some embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)(R1C). In some embodiments, Z is -N(R1A)-C(O)- C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl). In some embodiments, Z is -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6alkylene)-N(R1C)-S(O)2-(C1-4alkyl).

[0149] In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl). In some embodiments, Z is -N(R1A)-C(O)-N(R1B)(R1C). In some embodiments, Zis -N(R1A)-C(O)-N(R1B)-(C1-4haloalkyl). In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6. In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R1A)-C(O)- (morpholinyl). In some embodiments, Z is-N(R1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH).

[0150] In some embodiments, Z is -N(R1A)-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl). In some embodiments, Z is - N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -N(R1A)- C(O)-O-[(C1-4 alkylene)-O-]x-R6. In some embodiments, Z is -N(R1A)-C(O)-O-(C1-4 alkylene)- (phenyl). In some embodiments, Z is -N(R1A)-C(O)-(C1-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R1A)-S(O)2-R7. In some embodiments, Z is - N(R1A)-S(O)2-(C0-4 alkylene)-N(R1A)(R1B). In some embodiments, Z is -N(R1A)-S(O)2-(C0-6 alkylene)-N(R1B)-C(O)-(C1-4 alkyl). In some embodiments, Z is -N(R1A)-S(O)2-N(R1B)-C(O)-O- R8. In some embodiments, Z is -N(R1A)-S(O)2-N(R1B)-CO2-(C1-4alkylene)-(phenyl).

[0151] In some embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl). In some embodiments, Z is - S(O)2-(C1-6 alkyl). In some embodiments, Z is -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl). In some embodiments, Z is -S(O)2-(C1-4alkylene)-C(O)-O-(C1-6alkyl). In some embodiments, Z is - S(O)2-[(C1-4 alkylene)-O-]x-R5. In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-(C1-6 alkyl). In some embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In some embodiments, Z is -S(O)2- N(R1A)-(C1-6hydroxyalkyl). In some embodiments, Z is -S(O)2-N(R1A)(R1B). In some embodiments, Z is -S(O)2-N(R1A)-C(O)-(C1-6alkyl). In some embodiments, Z is -S(O)2-N(R1A)- C(O)-O-(C1-6 alkyl). In some embodiments, Z is -S(O)2-N(R1A)-C(O)-N(R1B)(R1C).

[0152] In some embodiments, Z is -(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl). In some embodiments, Z is -(C1-4alkylene)-N(R1A)- C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-C(O)-OH. In some embodiments, Z is -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl).

[0153] In some embodiments, Z is a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A. In some embodiments, Z is oxazolidinonyl or imidazolidinonyl substituted with one C1-4alkyl. In certain embodiments, Z is hydrogen.

[0154] In certain embodiments, Z is

[0155] In certain embodiments, Z is51

[0156] In certain embodiments, Z isIn certain embodiments, Z is52, , , , ,provided thatwhen B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not

[0157] In certain embodiments, Z is; provided that when B1is a 6-membered aryl ring53substituted with 0 or 1 occurrences of R2, then Z is not. In certain embodiments, Z is ; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not.

[0158] In certain embodiments,provided that when1B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not. In certain embodiments, Z provided t1hat when B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not. In certain embodiments, Z iscertain embodiments, Z isIn certain embodiments, Z is

[0159] In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is55In certain embodiments,

[0160] In certain embodiments, Z is. In certain embodiments,, , In certain embodiments, Z is

[0161] In certain embodiments, Z is. In certain embodiments, Z is, provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2. In certain embodiments,certain embodiments,certain embodiments, Z is . In certain embodiments,56certain embodiments,In certain embodiments,provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2. In certain embodiments,certain embodiments,certain embodiments,. In certain embodiments,certain embodiments, Z is. In certain embodiments,certain embodiments, Z is. In certain embodiments,. In certain embodiments, Z is . In certain embodiments,. In certain embodiments,In certain embodiments,In certain embodiments,. In certain embodiments, . In certain embodiments,. In certain embodiments, Z isIn certain embodiments, Z iscertain embodiments,certain embodiments, Z i Incertain embodiments, Z isIn certain embodiments, Z is .

[0162] In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is58In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments,embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments,. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is . In certain embodiments, Z is In certain embodiments,certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certainembodiments, Z is . In certain embodiments, Z is . In certainembodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is. In certain embodiments,certain embodiments, Z is . In certain embodiments, Z iscertain embodiments, Z is. In certain embodiments,In certain embodiments, Z i. In certain embodiments, Z iscertain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is . In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is In certain embodiments, Z isIn certain embodiments, Z is 63In certain embodiments, Z isIn certain embodiments, Z is . In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments,. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is

[0163] In certain embodiments above for variable Z that contain -C(O)R4, -C(O)-(C1-4 alkylene)-R4, and / or -C(O)-(C1-6 hydroxyalkyl); it is provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not -C(O)R4, -C(O)-(C1-6 hydroxyalkyl), or -C(O)-(C1-4 alkylene)-R4.

[0164] In certain embodiments, Z is selected from the groups depicted in the compounds in Table 1, below.

[0165] As defined generally above, R4is C1-6hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected fromsulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl.

[0166] In some embodiments, R4is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl.

[0167] In certain embodiments, R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is C1-6hydroxyalkyl. In certain embodiments, R4is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 5 memberedsaturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen. In certain embodiments, R4is selected from the groups depicted in the compounds in Table 1, below.

[0168] As defined generally above, R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R1A)(R1B), or -(C1-6 alkylene)-N(R1A)-C(O)-O-(C1-6 alkyl). In some embodiments, R5is C1-6alkyl, C1-6hydroxyalkyl, -(C1-4alkylene)-(C1-4alkoxyl), or C1-6alkoxyl. In certain embodiments, R5is C1-6alkyl, C1-6hydroxyalkyl, or C1-6alkoxyl. In certain embodiments, R5is C1-6 alkyl. In certain embodiments, R5is -CH3. In certain embodiments, R5is C1-6 hydroxyalkyl. In certain embodiments, R5is C1-6 alkoxyl. In certain embodiments, R5is -(C1-4alkylene)-(C1-4alkoxyl) or -(C1-6alkylene)-N(R1A)(R1B). In certain embodiments, R5is -(C1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R5is -(C1-6 alkylene)-N(R1A)(R1B). In certain embodiments, R5is -(C1-6 alkylene)-N(R1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1, below.

[0169] As defined generally above, R6is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4alkylene)-(C1-4alkoxyl). In certain embodiments, R6is C1-4alkyl, C1-4hydroxyalkyl, or C1-4haloalkyl. In certain embodiments, R6is C1-4alkyl. In certain embodiments, R6is -CH3. In certain embodiments, R6is C1-4 hydroxyalkyl. In certain embodiments, R6is C1-4 haloalkyl. In certain embodiments, R6is -(C1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1, below.

[0170] As defined generally above, R7is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), -(C0-6 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -N(R1B)-C(O)-O-R8. In some embodiments, R7is C1-4alkyl, C1-4alkoxyl or C1-6hydroxyalkyl. In some embodiments, R7is -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)- N(R1A)(R1B), -(C0-6 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -N(R1B)-C(O)-O-R8. In some embodiments, R7is -(C0-4alkylene)-N(R1A)(R1B), -(C0-6alkylene)-N(R1B)-C(O)-(C1-4alkyl), or -N(R1B)-C(O)-O-R8. In some embodiments, R7is -N(R1A)(R1B), -N(R1B)-C(O)-(C1-4alkyl), or - N(R1B)-C(O)-O-R8. In some embodiments, R7is -(C1-4 alkylene)-N(R1A)(R1B) or -(C1-6 alkylene)-N(R1B)-C(O)-(C1-4 alkyl). In some embodiments, R7is C1-4 alkyl, C1-4 alkoxyl, -(C1-4 alkylene)-(C1-4alkoxyl), -(C0-4alkylene)-N(R1A)(R1B), or -N(R1B)-C(O)-O-R8. In certain embodiments, R7is C1-4 alkyl, C1-4 alkoxyl, -(C0-4 alkylene)-N(R1A)(R1B), or -N(R1B)-C(O)-O-R8.

[0171] In certain embodiments, R7is C1-4 alkyl. In certain embodiments, R7is -CH3. In certain embodiments, R7is C1-4alkoxyl. In certain embodiments, R7is C1-6hydroxyalkyl. In certain embodiments, R7is -(C0-4 alkylene)-N(R1A)(R1B). In certain embodiments, R7is - N(R1A)(R1B). In certain embodiments, R7is -(C1-4 alkylene)-N(R1A)(R1B). In certain embodiments, R7is -N(R1B)-C(O)-O-R8. In certain embodiments, R7is -(C1-4alkylene)-(C1-4alkoxyl). In certain embodiments, R7is -(C0-6alkylene)-N(R1B)-C(O)-(C1-4alkyl). In certain embodiments, R7is -N(R1B)-C(O)-(C1-4 alkyl). In certain embodiments, R7is -(C1-6 alkylene)- N(R1B)-C(O)-(C1-4 alkyl). In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1, below.

[0172] As defined generally above, R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl). In certain embodiments, R8is C1-4 alkyl. In certain embodiments, R8is -CH3. In certain embodiments, R8is -(C0-4alkylene)-(phenyl). In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1, below.

[0173] As defined generally above, R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl). In certain embodiments, R9is oxo. In certain embodiments, R9is C1-4alkyl. In certain embodiments, R9is -CH3. In certain embodiments, R9is hydroxyl. In certain embodiments, R9is -C(O)-O-(C1-4 alkyl). In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1, below.

[0174] As defined generally above, m and n are independently 1 or 2. In certain embodiments, m and n are 1. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is selected from the values represented in the compounds in Table 1, below. In certain embodiments, n is selected from the values represented in the compounds in Table 1, below.

[0175] As defined generally above, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. Incertain embodiments, p is 4. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments p is 2 or 3. In certain embodiments p is 3 or 4. In certain embodiments p is 0, 1, or 2. In certain embodiments p is 1, 2, or 3. In certain embodiments, p is 2, 3, or 4. In certain embodiments p is 0, 1, 2, or 3. In certain embodiments p is 1, 2, 3, or 4. In certain embodiments, p is selected from the values represented in the compounds in Table 1, below.

[0176] As defined generally above, x is 1, 2, 3, 4, or 5. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is selected from the values represented in the compounds in Table 1, below.

[0177] As defined generally above, y and z are independently 1, 2, or 3. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, y is selected from the values represented in the compounds in Table 1, below. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is selected from the values represented in the compounds in Table 1, below.

[0178] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments.

[0179] Another aspect of the invention provides a compound represented by Formula I-B:or a pharmaceutically acceptable salt thereof; wherein:substituted with p occurrences of R2,substituted with 1, 2 or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2;A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4 alkyl; R2represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4 hydroxyalkyl; R3is halo or C1-4alkyl; Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4alkylene)-O-(C1-4alkyl), -C(O)-(C1-4alkylene)-[O-(C1-4alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1B)-(C1-4alkylene)-[O-(C1-4alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)- N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7;c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6alkyl), -C(O)-O-(C1-4alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - N(R1A)-C(O)-C(O)-N(R1B)-(C1-4alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6alkylene)-N(R1C)-S(O)2-(C1-4alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH); f) -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4alkylene)- O-]x-R6, -N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- (C3-7cycloalkyl), -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)- C(O)-N(R1B)(R1C); h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl);i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; or j) hydrogen; R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6alkyl, C1-6hydroxyalkyl, -(C1-4alkylene)-(C1-4alkoxyl), C1-6alkoxyl, -(C1-6alkylene)-N(R1A)(R1B), or -(C1-6alkylene)-N(R1A)-C(O)-O-(C1-6alkyl); R6is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R7is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), -(C0-6alkylene)-N(R1B)-C(O)-(C1-4alkyl), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3.

[0180] The definitions of variables in Formula I-B 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).

[0181] In certain embodiments, the compound is a compound of Formula I-B.

[0182] As defined generally above, A1issubstituted with p occurrences of R2,substituted with 1, 2 or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1is substituted with p occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with p occurrences of R2orsubstituted with 1, 2 or 3 occurrences of R2.

[0183] In certain embodiments, A1issubstituted with 1, 2 or 3 occurrences of R2,substituted with 1, 2 or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with 1, 2, or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1substituted with 1, 2 or 3 occurrences of R2,substituted with 1, 2 or 3 occurrences of R2.

[0184] In certain embodiments, A1issubstituted with p occurrences of R2. In certain embodiments, A1issubstituted with 1, 2, or 3 occurrences of R2. In certain embodiments,substituted with 0 or 1 occurrence of R2.

[0185] In certain embodiments, A1issubstituted with 1, 2 or 3 occurrences of R2. In certain embodiments, A1issubstituted with 1 or 2 occurrences of R2. In certain embodiments, A1issubstituted with 1 occurrence of R2.

[0186] In certain embodiments, A1issubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1is2substituted with 2 occurrences of R . In certain embodiments, A1issubstituted with 3 occurrences of R2. In certain embodiments,A is substituted with 4 occurrences of R2.

[0187] In certain embodiments, A1isIn certain embodiments, A1is

[0188] In certain embodiments,certain embodiments,. In certain embodiments,In certain embodiments, A1is

[0189] In certain embodiments,. In certain embodiments, A1is In certain embodiments, A1is In certain embodiments, A1

[0190] In certain embodiments, A1isIn certain emb1odiments, A is

[0191] In certain embodiments,certain embodiments,certain embodiments,In certain embodiments, A1is.

[0192] In certain embodiments, A1is. In certain embodiments, A1is In certain embodiments, A1is1In certain embodiments, A is In certain embodiments, A1i1s. In certain embodiments, A In certain embodiments, A1is . In certain embodiments, A1.

[0193] As generally defined above, A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3.

[0194] In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene.

[0195] In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 6- membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 1 occurrence of R3. In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen.

[0196] In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 1 occurrence of R3. In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene.

[0197] In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene.

[0198] In certain embodiments,, , each of which is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is one of the following: , wherein the nitrogen atom is attached to Z; wherein the saturated carbon is attached to Z; orwherein A2is substituted with 0 or 1 occurrences of R3.

[0199] In certain embodiments, A2is one of the following: , wherein the nitrogen atom is attached to Z;wherein the saturated carbon is attached to Z; or

[0200] In certain embodiments, A2is, each of which is substituted with 0 or 1 occurrences of R3, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2is, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2iswherein the saturated carbon is attached to Z, wherein A2is substituted with 0 or 1 occurrences of R3. In certain embodiments,wherein the saturated carbon is attached to Z. In certain embodiments, A2iseach of which is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is.

[0201] In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2issubstituted with 0 or 1occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2is substituted with 0 or 1 occurrences of R3, wherein the saturated carbon of A2is attached to Z.

[0202] In certain embodiments, A2is. In certain embodiments, A2isIn certain embodiments, A2is. In certain embodiments, A2is, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2is. In certain embodiments, A2is. In certain embodiments, A2iswherein the saturated carbon of A2is attached to Z. In certain embodiments, A2is substituted with 0 occurrences of R3.

[0203] As generally defined above, R3is halo or C1-4alkyl. In some embodiments, R3is halo. In some embodiments, R3is C1-4 alkyl. In some embodiments, R3is methyl.

[0204] In certain embodiments, the definition of each of variables R1A, R1B, R1C, R2, R4, R5, R6, R7, R8, R9, p, x, y, z, and Z is one of the embodiments described above in connection with Formula I.

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

[0206] Another aspect of the invention provides a compound represented by Formula I-C:or a pharmaceutically acceptable salt thereof; wherein:A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen; A2is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bicyclic carbocyclylene and heterocyclylene are substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4alkyl; R2represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4 hydroxyalkyl; R3is halo or C1-4alkyl; Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4alkylene)- N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl ortetrahydropyranyl), -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)-O-(C1-4 alkylene)-O-(C1-4alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)- O-]x-R6, -N(R1A)-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6hydroxyalkyl), -S(O)2-(C1-6alkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- (C3-7 cycloalkyl), -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl), or -S(O)2-N(R1A)- C(O)-N(R1B)(R1C);h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; or j) hydrogen; R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R1A)(R1B), or -(C1-6alkylene)-N(R1A)-C(O)-O-(C1-6alkyl); R6is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R7is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), -(C0-6alkylene)-N(R1B)-C(O)-(C1-4alkyl), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3.

[0207] The definitions of variables in Formula I-C 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).

[0208] In certain embodiments, the compound is a compound of Formula I-C.

[0209] As defined generally above, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen.

[0210] In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered heteroaryl ring containing 2 heteroatoms that are nitrogen.

[0211] In certain embodiments, A1issubstituted with p occurrences of R2,substituted with 1, 2 or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with p occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with p occurrences of R2orsubstituted with 1, 2 or 3 occurrences of R2.

[0212] In certain embodiments, A1issubstituted with 1, 2 or 3 occurrences of R2,substituted with 1, 2 or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with 1, 2, or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments, A1issubstituted with 1, 2 or 3 occurrences of R2,substituted with 1, 2 or 3 occurrences of R2.

[0213] In certain embodiments, A1issubstituted with 0 or 1 occurrences of R2,substituted with 1 or 2 occurrences of R2, orsubstituted with 1 or 2 occurrences of R2. In certain embodiments, A1issubstituted with 0 or 1 occurrence of R2, orsubstituted with 1 or 2.

[0214] In certain embodiments, A1issubstituted with p occurrences of R2. In certain embodiments, A1is orsubstituted with 2, 3, or 4 occurrences of R2. In certain embodiments,substituted with 1 or 2 occurrences of R2. In certain embodiments, A1is orsubstituted with 2 occurrences of R2. In certain embodiments, A1issubstituted with 3 occurrences of R2. In certain embodiments, A1issubstituted with 4 occurrences of R2.

[0215] In certain embodiments, A1issubstituted with p occurrences of R2. In certain embodiments,substituted with 1, 2, or 3 occurrences of R2. In certain embodiments, A1issubstituted with 0 or 1 occurrence of R2.

[0216] In certain embodiments, A1issubstituted with p occurrences of R2. In certain embodiments, A1issubstituted with 1, 2 or 3 occurrences of R2. In certain embodiments, A1issubstituted with 1 or 2 occurrences of R2. In certain embodiments, A1issubstituted with 1 occurrence of R2.

[0217] In certain embodiments, A1is, , , I1n certain embodiments, A is

[0218] In certain embodiments, A1is In certainembodiments,certain embodiments, A1is, , or . In certain embodiments, A1is. In certain embodiments, A1is

[0219] In certain embodiments,certain embodiments, A1is In certain embodiments, A1is I1n certain embodiments, A In certain em1bodiments, A is In certain embodiments,

[0220] In certain embodiments, A1is

[0221] In certain embodiments, A1is, In certain e1mbodiments, A is

[0222] In certain embodiments, A1is. In certain embodiments, A1is In certain embod1iments, A is In certain e1mbodiments, A isor In certain embodiments, A1is

[0223] In certain embodiments, A1is. In certain embodiments, A1is . In certain embodiments, A1is. In certain embodiments, A1is. In certain embodiments,certain embodiments, A1isIn certain embodiments, A1is In certain embodimen1ts, A isIn certain embodiments, A1is In certain em1bodiments, A . In certain embodiments, A1is In cer1tain embodiments, A is

[0224] As defined generally above, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bicyclic carbocyclylene and heterocyclylene are substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen.

[0225] In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R3. In certain embodiments, A2is a 5-8 membered saturated bridged bicyclic carbocyclylene.

[0226] In certain embodiments, A2is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 1 occurrence of R3. In certain embodiments, A2is a5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen.

[0227] In certain embodiments, A2iseach of which is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein the nitrogen atom of A2is attached to Z. In certain embodiments, A2is. In certain embodiments, A2is. In certain embodiments, A2is. In certain embodiments, A2is, wherein the nitrogen atom of A2is attached to Z.

[0228] In certain embodiments, A2is substituted with 0 occurrences of R3.

[0229] As defined generally above, R3is halo or C1-4alkyl. In some embodiments, R3is halo. In some embodiments, R3is C1-4alkyl. In some embodiments, R3is methyl.

[0230] As defined generally above, Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which issubstituted with one C1-4alkyl and one -OH), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4alkylene)- N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6alkyl), -C(O)-O-(C1-4alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6alkylene)-N(R1C)-S(O)2-(C1-4alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH);f) -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)- O-]x-R6, -N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- (C3-7cycloalkyl), -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)- C(O)-N(R1B)(R1C); h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-OH, or -(C1-4alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; or j) hydrogen.

[0231] In certain embodiments, Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one - N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6 alkyl), -C(O)-N(R1A)-(C1-4 haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6alkoxyl), -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), - C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6hydroxyalkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)- N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)- N(R1A)(R1B), -C(O)-O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))- (C1-4hydroxyalkyl), or -C(O)-O-(C1-4alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4alkyl), -N(R1A)-C(O)-O-[(C1-4alkylene)-O-]x-R6, or - N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6alkyl), -S(O)2-[(C1-4alkylene)-O-]x-R5, -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)- C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C);h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A.

[0232] In certain embodiments, Z is one of the following: a) -C(O)-(C1-6hydroxyalkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or - N(R1A)-C(O)-(C1-6alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -C(O)- N(R1A)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl); c) -C(O)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)- C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-(C1-6 hydroxyalkyl); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 alkylene)- N(R1C)-S(O)2-(C1-4alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo); f) -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6hydroxyalkyl), -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)-C(O)- (C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl); or h) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A.

[0233] In certain embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6alkoxyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2- (C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)).

[0234] In certain embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)- N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2- (C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)).

[0235] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)- (C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)), -C(O)- N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R1A)-R5, - N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-S(O)2- R7, -S(O)2-(C1-6hydroxyalkyl), -S(O)2-[(C1-4alkylene)-O-]x-R5, -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A. In some embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-N(R1A)- C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)- N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or - N(R1A)-C(O)-(C1-6 alkyl)), -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-(C1-6hydroxyalkyl), -S(O)2-[(C1-4alkylene)-O-]x-(C1-6alkyl), -S(O)2-[(C1-4alkylene)-O-]x-S(O)2-N(R1A)-C(O)-(C1-6alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl).

[0236] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R1A)-R5, and -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C1-6hydroxyalkyl), - C(O)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl).

[0237] In certain embodiments, the definition of variable Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variable Z is one of the embodiments described below in connection with Formula I-D.

[0238] In certain embodiments, the definition of each of variables R1A, R1B, R1C, R2, R4, R5, R6, R7, R8, R9, p, x, y, and z is one of the embodiments described above in connection with Formula I.

[0239] The description above describes multiple embodiments relating to compounds of Formula I-C. The patent application specifically contemplates all combinations of the embodiments.

[0240] Another aspect of the invention provides a compound represented by Formula I-D:or a pharmaceutically acceptable salt thereof; wherein: A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen; A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturatedmonocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4alkyl; R2represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4hydroxyalkyl; R3is halo or C1-4 alkyl; Z is one of the following: a) -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), - C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH), or -C(O)-(C3-7cycloalkyl substituted with one - N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)- N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms),-C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)- N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))- (C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - N(R1A)-C(O)-C(O)-N(R1B)-(C1-4alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH); f) -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6, or - N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2-N(R1A)- C(O)-O-(C1-6alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; R4is C1-6hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, andoxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R1A)(R1B), or -(C1-6alkylene)-N(R1A)-C(O)-O-(C1-6alkyl); R6is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R7is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), -(C0-6alkylene)-N(R1B)-C(O)-(C1-4alkyl), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and z is 1, 2, or 3; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1is substituted with 0 occurrences of R2, then Z is no4t -C(O)R or -C(O)- (C1-4 alkylene)-R4.

[0241] The definitions of variables in Formula I-D 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).

[0242] In certain embodiments, the compound is a compound of Formula I-D.

[0243] In certain embodiments, the definition of variable A1is one of the embodiments described above in connection with Formula I-C.

[0244] In certain embodiments, the definition of each of variables A2and R3is one of the embodiments described above in connection with Formula I-B.

[0245] As generally defined above, Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one - N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6 alkyl), -C(O)-N(R1A)-(C1-4 haloalkyl), -C(O)- N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1B)-(C1-4alkylene)-[O-(C1-4alkylene)-]x-(C1-6alkoxyl), -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), - C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6hydroxyalkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)- N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), -C(O)- C(O)-N(R1A)-(C1-4alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)- N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))- (C1-4hydroxyalkyl), or -C(O)-O-(C1-4alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl);e) -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6, or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6hydroxyalkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -S(O)2-(C1-4alkylene)-C(O)-O-(C1-6alkyl), -S(O)2-[(C1-4alkylene)-O-]x-R5, -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)- C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C); h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4 alkylene)- R4.

[0246] In certain embodiments, Z is one of the following: a) -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or - N(R1A)-C(O)-(C1-6alkyl));b) -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -C(O)- N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl); c) -C(O)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)- C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-(C1-6 hydroxyalkyl); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 alkylene)- N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo); f) -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)-C(O)- (C1-6alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl); or h) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not -C(O)-(C1-6hydroxyalkyl).

[0247] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)- N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2- (C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4 alkylene)-R4.

[0248] In certain embodiments, Z is -C(O)-(C1-6hydroxyalkyl), -C(O)-(C1-4alkylene)- N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)). In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not - C(O)-(C1-6hydroxyalkyl).

[0249] In certain embodiments, Z is -C(O)R4or -C(O)-(C1-4 alkylene)-R4. In certain embodiments, Z is -C(O)R4or -C(O)-(C1-4 alkylene)-R4; provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2.

[0250] In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)- (C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or - C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)).

[0251] In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)- (C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4alkyl), or -C(O)-(C1-4alkylene)-N(R1A)-C(O)-R4. In certainembodiments, Z is -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl) or -C(O)-(C1-4alkylene)- N(R1A)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4, - C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), or - C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH) or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)).

[0252] In some embodiments, Z is -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)-N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1B)-(C1-4alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4 alkylene)- O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl), or -C(O)-N(R1A)-S(O)2-R7.

[0253] In certain embodiments, Z is -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)-N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1B)-(C1-4alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), - C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4 alkylene)- O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)- N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), or -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl).

[0254] In certain embodiments, Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl).

[0255] In certain embodiments, Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-6 alkyl), or -C(O)-N(R1A)-(C1-4 haloalkyl). In certain embodiments, Z is -C(O)-N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), - C(O)-N(R1B)-(C1-4alkylene)-[O-(C1-4alkylene)-]x-(C1-6alkoxyl), -C(O)-N(R1A)-(C1-4alkylene)- N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), - C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)- [(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6hydroxyalkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)- (C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)-S(O)2-R7.

[0256] In some embodiments, Z is -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), - C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)-N(R1A)(R1B), -C(O)- O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)- O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9).

[0257] In certain embodiments, -C(O)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -C(O)-C(O)- N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), or - C(O)-C(O)-(C1-6 hydroxyalkyl).

[0258] In certain embodiments, Z is -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), - C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-C(O)-N(R1A)- R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl),- C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms).

[0259] In certain embodiments, Z is -C(O)-C(O)-R4or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9).

[0260] In some embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)- C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl). In certain embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)- (C1-4alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6alkylene)-N(R1C)- S(O)2-(C1-4alkyl).

[0261] In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), - N(R1A)-C(O)-N(R1B)-[(C1-4alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)-C(O)- (azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one - OH).

[0262] In certain embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), or -N(R1A)-C(O)-N(R1B)-[(C1-4alkylene)-O-]x-R6. In certain embodiments, Z is - N(R1A)-C(O)-N(R1B)-(C1-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)- (morpholinyl), or -N(R1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH).

[0263] In some embodiments, Z is -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), - N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x- R6, or -N(R1A)-S(O)2-R7. In certain embodiments, Z is -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)- C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), or -N(R1A)-S(O)2-R7. In some embodiments, Z is -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)- C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), or -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6.

[0264] In some embodiments, Z is -S(O)2-(C1-6hydroxyalkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R1A)-C(O)-O-(C1-6alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C). In certain embodiments, Z is - S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R1A)-(C1-6 hydroxyalkyl) or -S(O)2-N(R1A)(R1B). In certain embodiments, Z is -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C). In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), or -S(O)2- N(R1A)-C(O)-O-(C1-6alkyl). In some embodiments, Z is -S(O)2-[(C1-4alkylene)-O-]x-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl).

[0265] In some embodiments, Z is -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or - (C1-4alkylene)-C(O)-O-(C1-6alkyl).

[0266] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R1A)-R5, and -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl). In some embodiments, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R1A)-R5, and -N(R1A)-C(O)-C(O)- N(R1B)-(C1-6hydroxyalkyl); provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not - C(O)R4.

[0267] In some embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)- C(O)-N(R1A)-(C1-6 hydroxyalkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl).In some embodiments, Z is -C(O)R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R1A)-(C1- 6 hydroxyalkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl); provided that when B1is a6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not -C(O)R4.

[0268] In certain embodiments, Z is -C(O)R4. In certain embodiments, Z is -C(O)R4, provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2. In certain embodiments, Z is -C(O)-(C1-6hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2. In certain embodiments, Z is -C(O)-(C1-4alkylene)-R4. In certain embodiments, Z is -C(O)-(C1-4 alkylene)-R4, provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2.

[0269] In some embodiments, Z is -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl). In some embodiments, Z is -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl). In some embodiments, Z is - C(O)-(C1-4 alkylene)-N(R1A)-C(O)-R4. In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)- C(O)-(C3-8cycloalkyl substituted with z occurrence of R9). In some embodiments, Z is -C(O)- (C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with one -OH). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C5-8 bridged bicyclic cycloalkyl substituted with z occurrence of R9). In some embodiments, Z is -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH). In some embodiments, Z is -C(O)- (C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)). In some embodiments, Z is -C(O)-(C3-7 cycloalkyl gem-substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6alkyl)).

[0270] In some embodiments, Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R1A)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 1 occurrence of halo). Insome embodiments, Z is -C(O)-N(R1A)(R1B). In some embodiments, Z is -C(O)-N(R1A)-(C1-6alkyl). In some embodiments, Z is -C(O)-N(R1A)-(C1-4 haloalkyl). In some embodiments, Z is - C(O)-N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R1B)- (C1-4alkylene)-[O-(C1-4alkylene)-]x-(C1-6alkoxyl). In some embodiments, Z is -C(O)-N(R1A)- (C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B). In some embodiments, Z is -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl). In some embodiments, Z is -C(O)- N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6. In some embodiments, Z is -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl). In some embodiments, Z is -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl). In some embodiments, Z is -C(O)-N(R1A)-S(O)2-R7.

[0271] In some embodiments, Z is -C(O)-C(O)-N(R1A)-R5. In some embodiments, Z is -C(O)- C(O)-N(R1A)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-C(O)-N(R1A)(R1B). In some embodiments, Z is -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl). In some embodiments, Z is -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5-membered heteroaryl containing 1-4 nitrogen atoms). In some embodiments, Z is -C(O)-C(O)-R4. In some embodiments, Z is -C(O)-C(O)-OH.

[0272] In some embodiments, Z is -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)-N(R1A)(R1B). In some embodiments, Z is -C(O)-O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))- (C1-4 hydroxyalkyl). In some embodiments, Z is -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9).

[0273] In some embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl). In some embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)(R1C). In some embodiments, Z is -N(R1A)-C(O)- C(O)-N(R1B)-(C1-4alkylene)-N(R1C)-C(O)-(C1-4alkyl). In some embodiments, Z is -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl).

[0274] In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl). In some embodiments, Z is -N(R1A)-C(O)-N(R1B)(R1C). In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl). In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-[(C1- 4 alkylene)-O-]x-R6. In some embodiments, Z is -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R1A)-C(O)- (morpholinyl). In some embodiments, Z is-N(R1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH).

[0275] In some embodiments, Z is -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl). In some embodiments, Z is -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl). In some embodiments, Z is -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6. In some embodiments, Z is - N(R1A)-S(O)2-R7. In some embodiments, Z is -N(R1A)-S(O)2-(C0-4alkylene)-N(R1A)(R1B). In some embodiments, Z is -N(R1A)-S(O)2-(C0-6alkylene)-N(R1B)-C(O)-(C1-4alkyl). In some embodiments, Z is -N(R1A)-S(O)2-N(R1B)-C(O)-O-R8. In some embodiments, Z is -N(R1A)- S(O)2-N(R1B)-CO2-(C1-4 alkylene)-(phenyl).

[0276] In some embodiments, Z is -S(O)2-(C1-6hydroxyalkyl). In some embodiments, Z is - S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl). In some embodiments, Z is -S(O)2-(C1-4 alkylene)-C(O)-O- (C1-6 alkyl). In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-R5. In some embodiments, Z is -S(O)2-[(C1-4alkylene)-O-]x-(C1-6alkyl). In some embodiments, Z is -S(O)2-N(R1A)-(C1-6hydroxyalkyl). In some embodiments, Z is -S(O)2-N(R1A)(R1B). In some embodiments, Z is - S(O)2-N(R1A)-C(O)-(C1-6 alkyl). In some embodiments, Z is -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl). In some embodiments, Z is -S(O)2-N(R1A)-C(O)-N(R1B)(R1C).

[0277] In some embodiments, Z is -(C1-6hydroxyalkyl). In some embodiments, Z is -(C1-4alkylene)-C(O)-N(R1A)-(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-N(R1A)- C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-C(O)-OH. In some embodiments, Z is -(C1-4alkylene)-C(O)-O-(C1-6alkyl).

[0278] In some embodiments, Z is a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A. In some embodiments, Z is oxazolidinonyl or imidazolidinonyl substituted with one C1-4 alkyl.

[0279] In certain embodiments, Z isIn certain embodiments, Z is109provided that if B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2, then Z is not.

[0280] In certain embodiments, Z isprovided that if B1is a 6-membered aryl ring substituted with 0 or 1occurrences of R2, orsubstituted with 0 occurrences of R2, then Z is not.

[0281] In certain embodiments,provided1that if B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2, thenZ is not. In certain embodiments,provided that if B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2, then Z is not. In certain embodiments, ZIn certain embodiments, Z isIn certain embodiments, Z is

[0282] In certain embodiments, Z isIn certain embodiments, Z is111, In certain embodiments, Z is. In certain embodiments, Z is

[0283] In certain embodiments, Z is; provided that if B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2, then Z is not.

[0284] In certain embodiments, Z is. In certain embodiments, Z is; provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2. In certain embodiments, Z iscertain embodiments,certain embodiments,embodiments,. In certain embodiments,. In certain embodiments, Z is; provided that B1is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, orsubstituted with 0 occurrences of R2. In certain embodiments,certain embodiments,certain embodiments,. In certain embodiments,. In certain embodiments, Z is. In certain embodiments,. In certain embodiments, Z is. In certain embodiments,embodiments, Z is. In certain embodiments, Z is. In certain embodiments, In certain embodiments, Z is . In certain embodiments,113In certain embodiments, Z isIn certain embodiments,Z is . In certain embodiments, Z isIn certain embodiments, ZIn certain embodiments,

[0285] In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, ZIn certain embodiments, Z is, In certain embodiments, Z is

[0286] As generally defined above, z is 1, 2 or 3. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3.

[0287] In certain embodiments, the definition of each of variables R1A, R1B, R1C, R2, R4, R5, R6, R7, R8, R9, p, and x is one of the embodiments described above in connection with Formula I.

[0288] The description above describes multiple embodiments relating to compounds of Formula I-D. The patent application specifically contemplates all combinations of the embodiments.

[0289] Another aspect of the invention provides a compound represented by Formula I-1:(I-1) or a pharmaceutically acceptable salt thereof; wherein:A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A2is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4alkyl; R2represents independently for each occurrence halo; R3is halo or C1-4alkyl; Z is -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-OH, -C(O)-O-(C1-6alkyl), -C(O)- N(R1A)(R1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6 alkyl), - S(O)2-(C3-7cycloalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2- N(R1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-N(R1B)(R1C), -S(O)2-[(C1-4 alkylene)-O-]x- R5, -N(R1A)-C(O)-(C1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl), -N(R1A)-C(O)-O-[(C1-4alkylene)-O-]x-R6, - N(R1A)-C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6, -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -N(R1A)-C(O)-N(R1B)-[(C1-6hydroxyalkyl), -C(O)-(C1-4alkylene)- [O-(C1-4alkylene)-]y-(C1-6alkoxyl), -C(O)N(R1B)-(C1-4alkylene)-[O-(C1-4alkylene)-]y-(C1-6alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R1A)(R1B), -N(R1A)-C(O)-(C1-6 hydroxyalkyl), - C(O)-C(O)-N(R1A)-R5, -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -C(O)-N(R1A)-S(O)2-R7, -N(R1A)- S(O)2-R7, -N(R1A)-S(O)2-N(R1B)-CO2-(C1-4alkylene)-phenyl, -C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)-(5 memberedsaturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9), or hydrogen; R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), or C1-6 alkoxyl; R6is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl; R7is C1-4alkyl, C1-4alkoxyl, -(C1-4alkylene)-(C1-4alkoxyl), -(C0-4alkylene)- N(R1A)(R1B), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); m is 1 or 2; n is 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4alkylene)-R4.

[0290] 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).

[0291] In certain embodiments, the compound is a compound of Formula I-1.

[0292] As defined generally above, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A1issubstituted with p occurrences of R2, wherein B1is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur.

[0293] In certain embodiments,, each of which is substituted by p occurrences of halo. In certain embodiments, A1substituted by p occurrences of halo. In certain embodiments, A1issubstituted by p occurrences of halo. In certain embodiments, A1issubstituted by p occurrences of halo. In certain embodiments, A1issubstituted by p occurrences of halo.

[0294] In certain embodiments, A1isIn1certain embodiments, A In certain embodiments, A1is In certain embodiments, A1In certain embodiments, A1is In certain embodiments, A1In certain embodiments, A1is In c1ertain embodiments, A is In certain embodiments, A1isIn certain embodiments,A1is . In certain embodiments, A1is In certai1n e mbodiments, A In certain embodimen1 1ts, A isIn certain embodiments, A is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0295] As defined generally above, A2is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated orpartially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3. In certain embodiments,, , each of which is substituted with 0 or 1 occurrences of R3, or a covalent bond, wherein ***is the point of attachment to Z. In certain embodiments, A2is a 6- membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, wherein the monocyclic carbocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a 5-8 membered saturated bicyclic carbocyclylene, wherein the bicyclic carbocyclylene is substituted with 0 or 1 occurrences of R3. In certain embodiments, A2is a covalent bond. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2is each of which is substituted with 0 or 1 occurrences of R3,wherein ***is the point of attachment to Z. In certain embodiments, A2is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0296] As defined generally above, R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R1Ais hydrogen. In certain embodiments, R1Ais C1-4 alkyl. In certain embodiments, R1Bis hydrogen. In certain embodiments, R1Bis C1-4alkyl. In certain embodiments, R1Cis hydrogen. In certain embodiments, R1Cis C1-4 alkyl. In certain embodiments, R1Aand R1Bare both hydrogen. In certain embodiments, R1Aand R1Bare both methyl. In certain embodiments, R1Ais selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0297] As defined generally above, R2represents independently for each occurrence halo. In certain embodiments, R2is fluoro or chloro. In certain embodiments, R2is fluoro. In certain embodiments, R2is chloro. In certain embodiments, R2is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0298] As defined generally above, R3is halo or C1-4 alkyl. In certain embodiments, R3is halo. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is fluoro. In certain embodiments, R3is chloro. In certain embodiments, R3is methyl. In certain embodiments, R3is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0299] As defined generally above, Z is -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-OH, - C(O)-O-(C1-6alkyl), -C(O)-N(R1A)(R1B), -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)- N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C3-7 cycloalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)- C(O)-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-N(R1B)(R1C), -S(O)2- [(C1-4alkylene)-O-]x-R5, -N(R1A)-C(O)-(C1-4alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R1A)-C(O)-O-(C1-4 alkylene)-(phenyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6, -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -N(R1A)-C(O)-N(R1B)-[(C1-6 hydroxyalkyl), -C(O)- (C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R1A)(R1B), -N(R1A)-C(O)-(C1-6hydroxyalkyl), -C(O)-C(O)-N(R1A)-R5, -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -C(O)-N(R1A)-S(O)2- R7, -N(R1A)-S(O)2-R7, -N(R1A)-S(O)2-N(R1B)-CO2-(C1-4 alkylene)-phenyl, -C(O)-C(O)-N(R1A)- S(O)2-(C1-6alkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-(5membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9), or hydrogen.

[0300] In certain embodiments, Z is hydrogen. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isorIn certain embodiments, Z is122, In certain embodiments, Z isIn certain embodiments, Z is, In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is In certain embodiments, Z is. In certain embodiments, Z is In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments,. In certain embodiments, Z is . In certain embodiments, Z is. In certain embodiments, Z is n certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments,certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z isIn certain embodiments, Z is In certainembodiments, Z is . In certain embodiments, Z is . In certainembodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is. In certain embodiments,certain embodiments,. In certain embodiments, Z iscertain embodiments, Z is. In certain embodiments,In certain embodiments, Z i. In certain embodiments, Z is . In certain embodiments, Z i. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z is. ain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z i. In certain embodiments, Z is . In certain embodiments,. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z isIn certain embodiments, Z is

[0301] In certain embodiments, Z is -C(O)R4. In certain embodiments, Z is -C(O)-(C1-4 alkylene)-R4. In certain embodiments, Z is -C(O)-OH. In certain embodiments, Z is -C(O)-O- (C1-6 alkyl). In certain embodiments, Z is -C(O)-N(R1A)(R1B). In certain embodiments, Z is -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)-N(R1A)(R1B). In certain embodiments, Z is -C(O)-O- (C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl). In certain embodiments, Z is -S(O)2-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In certain embodiments, Z is -S(O)2-N(R1A)(R1B). In certain embodiments, Z is -S(O)2-N(R1A)- C(O)-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R1A)-C(O)-N(R1B)(R1C). In certain embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-R5. In certain embodiments, Z is -N(R1A)-C(O)-(C1-4alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom). In certain embodiments, Z is -N(R1A)-C(O)- O-(C1-4 alkylene)-(phenyl). In certain embodiments, Z is -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x- R6. In certain embodiments, Z is -N(R1A)-C(O)-N(R1B)-[(C1-4alkylene)-O-]x-R6. In certain embodiments, Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl). In certain embodiments, Z is -C(O)- N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B). In certain embodiments, Z is -N(R1A)- C(O)-N(R1B)-[(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6alkoxyl). In certain embodiments, Z is -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-C(O)-N(R1A)(R1B). In certain embodiments, Z is -N(R1A)-C(O)-(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-C(O)-N(R1A)-R5. In certain embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)(R1C). In certain embodiments, Z is -C(O)-N(R1A)-S(O)2-R7. In certain embodiments, Z is -N(R1A)-S(O)2-R7. In certain embodiments, Z is -C(O)-C(O)-N(R1A)- S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms). In certain embodiments, Z is -C(O)-O-(C1-4alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9). In certain embodiments, Z is hydrogen.

[0302] In certain embodiments, Z is -C(O)-N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl). In certain embodiments, Z is -C(O)N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl). In certain embodiments, Z is -N(R1A)-S(O)2-N(R1B)-CO2-(C1-4 alkylene)-phenyl.

[0303] In certain embodiments, Z is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0304] As defined generally above, R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is C1-6hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is C1-6hydroxyalkyl. In certain embodiments, R4is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 5 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 5-7 membereddi-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen. In certain embodiments, R4is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0305] As defined generally above, R5is C1-6alkyl, C1-6hydroxyalkyl, -(C1-4alkylene)-(C1-4alkoxyl), or C1-6 alkoxyl. In certain embodiments, R5is C1-6 alkyl, C1-6 hydroxalkyl, or C1-6 alkoxyl. In certain embodiments, R5is C1-6 alkyl. In certain embodiments, R5is C1-6 hydroxalkyl. In certain embodiments, R5is C1-6alkoxyl. In certain embodiments, R5is -(C1-4alkylene)-(C1-4 alkoxyl). In certain embodiments, R5is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0306] As defined generally above, R6is C1-4alkyl, C1-4hydroxyalkyl, or C1-4haloalkyl. In certain embodiments, R6is C1-4alkyl. In certain embodiments, R6is C1-4hydroxyalkyl. In certain embodiments, R6is C1-4 haloalkyl. In certain embodiments, R6is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0307] As defined generally above, R7is C1-4alkyl, C1-4alkoxyl, -(C1-4alkylene)-(C1-4alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), or -N(R1B)-C(O)-O-R8. In certain embodiments, R7is C1- 4 alkyl, C1-4 alkoxyl, -(C0-4 alkylene)-N(R1A)(R1B), or -N(R1B)-C(O)-O-R8. In certain embodiments, R7is C1-4alkyl. In certain embodiments, R7is C1-4alkoxyl. In certain embodiments, R7is -(C0-4 alkylene)-N(R1A)(R1B). In certain embodiments, R7is -N(R1B)-C(O)- O-R8. In certain embodiments, R7is -(C1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R7is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0308] As defined generally above, R8is C1-4alkyl or -(C0-4alkylene)-(phenyl). In certain embodiments, R8is C1-4 alkyl. In certain embodiments, R8is -(C0-4 alkylene)-(phenyl). In certain embodiments, R8is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0309] As defined generally above, R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl). In certain embodiments, R9is oxo. In certain embodiments, R9is C1-4 alkyl. In certain embodiments, R9is hydroxyl. In certain embodiments, R9is -C(O)-O-(C1-4alkyl). In certain embodiments, R9is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0310] As defined generally above, m is 1 or 2. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0311] As defined generally above, n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0312] As defined generally above, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0313] As defined generally above, x is 1, 2, 3, 4, or 5. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0314] As defined generally above, y and z are independently 1, 2, or 3. In certain embodiments, y is 1. In certain embodiments, y is selected from a corresponding value in the groups depicted in the compounds in Table 1, below. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below.

[0315] The description above describes multiple embodiments relating to compounds of Formula I-1. The patent application specifically contemplates all combinations of the embodiments.

[0316] In certain embodiments, the compound of Formula I is further defined by Formula Ia:or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables A1, A2, R1, and Z is one of the embodiments described above in connection with Formula I. Incertain embodiments, the definition of variables A1, A2, R1, and Z is one of the embodiments described above in connection with Formula I-1.

[0317] In certain embodiments, the compound of Formula I is further defined by Formula Ib:or a pharmaceutically acceptable salt thereof, wherein: B1is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R2.

[0318] In certain embodiments, the definition of variables A2, R1, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A2, R1, and Z is one of the embodiments described above in connection with Formula I-1.

[0319] In certain embodiments,each of which is substituted by 0, 1, 2, 3, or 4 occurrences of halo. In certain embodiments, B1is

[0320] The description above describes multiple embodiments relating to compounds of Formula Ib. The patent application specifically contemplates all combinations of the embodiments.

[0321] In certain embodiments, the compound of Formula I is further defined by Formula Ic:or a pharmaceutically acceptable salt thereof, wherein: B1is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R2. In certain embodiments, the definition of variables A2, R1, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A2, R1, and Z is one of the embodiments described above in connection with Formula I-1. In certain embodiments, B1iseach of which is substituted by 0, 1, 2, 3, or 4 occurrences of halo. In certain embodiments, B1is

[0322] The description above describes multiple embodiments relating to compounds of Formula Ic. The patent application specifically contemplates all combinations of the embodiments.

[0323] In certain embodiments, the compound of Formula I is further defined by Formula Id:or a pharmaceutically acceptable salt thereof, wherein X is -C(H)- or -N-. In certain embodiments, X is -C(H)-. In certain embodiments, X is -C(R2)-, and the aromatic ring of the isoindoline is substituted with 0, 1, 2, or 3 additional occurrences of R2. In certain embodiments, X is -C(R2)-, and the aromatic ring of the isoindoline is not substituted with any additional occurrences of R2. In certain embodiments, X is -C(R2)-, and the aromatic ring of the isoindoline is substituted with 1 additional occurrence of R2. In certain embodiments, X is -C(R2)-, and the aromatic ring of the isoindoline is substituted with 2 additional occurrences of R2. In certain embodiments, X is -N-. In certain embodiments, the definition of variables A2, R2, p, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A2, R2, p, and Z is one of the embodiments described above in connection with Formula I-1.

[0324] In certain embodiments, the compound of Formula I is further defined by Formula Ie:or a pharmaceutically acceptable salt thereof, wherein Y and Q each represent independently N or S. In certain embodiments, the definition of variables A2and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A2and Z is one of the embodiments described above in connection with Formula I-1.

[0325] In certain embodiments, the compound of Formula I is further defined by Formula If, Ig, Ih, or Ii:or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables R2, p, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables R2, p, and Z is one of the embodiments described above in connection with Formula I-1.

[0326] In certain embodiments, the compound of Formula I is further defined by Formulae Ij or Ik:or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables R2, p, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables R2, p, and Z is one of the embodiments described above in connection with Formula I-1.

[0327] In certain embodiments, the compound of Formula I is further defined by Formula Il:or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variable Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variable Z is one of the embodiments described above in connection with Formula I-1.

[0328] The description above describes multiple embodiments relating to compounds of Formula Il. The patent application specifically contemplates all combinations of the embodiments.

[0329] Another aspect of the invention provides a compound represented by Formula I-A:(I-A) or a pharmaceutically acceptable salt thereof; wherein: A1iseach of which is substituted by p occurrences of halo; A2is a covalent bond; or A2iseach of which is substituted with 0 or 1occurrences of R3, wherein ***is the point of attachment to Z; R1A, R1B, and R1Crepresent independently for each occurrence hydrogen or C1-4 alkyl;R3is halo or C1-4alkyl; Z is -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)- N(R1A)(R1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4hydroxyalkyl), -S(O)2-(C1-6alkyl), - S(O)2-(C3-7 cycloalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-N(R1B)(R1C), -S(O)2-[(C1-4 alkylene)-O-]x- R5, -N(R1A)-C(O)-(C1-4alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R1A)-C(O)-O-(C1-4 alkylene)-(phenyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6, - N(R1A)-C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6, -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)- N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -N(R1A)-C(O)-N(R1B)-[(C1-6hydroxyalkyl), -C(O)-(C1-4alkylene)-[O-(C1-4alkylene)-]y-(C1-6alkoxyl), -C(O)-C(O)-OH, - C(O)-C(O)-N(R1A)(R1B), -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R1A)-R5, - N(R1A)-C(O)-C(O)-N(R1B)(R1C), -C(O)-N(R1A)-S(O)2-R7, -N(R1A)-S(O)2-R7, -C(O)-C(O)- N(R1A)-S(O)2-(C1-6alkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)- (5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom), or hydrogen, wherein the heterocyclyl is substituted with z occurrences of R9); R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxalkyl or C1-6 alkoxyl; R6is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl; R7is C1-4alkyl, C1-4alkoxyl, -(C0-4alkylene)-N(R1A)(R1B), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4 alkyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; andy and z are independently 1, 2, or 3.

[0330] The definitions of variables in Formula I-A above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[0331] In certain embodiments, the compound is a compound of Formula I-A.

[0332] As defined generally above, A1is, , , or, each of which is substituted by p occurrences of halo. In certain embodiments, A1issubstituted by p occurrences of halo. In certain embodiments, A1is substituted by p occurrences of halo. In certain embodiments, A1issubstituted by p occurrences of halo. In certain embodiments, A1issubstituted by p occurrences of halo. In certain embodiments, A1isIn certain139embodiments, A1is In certain embodiments, A1is In certain embodiments, A1is In certain embodiments, A1is In certain embodiments, A1isIn certain embodiments, A1isIn certain embodiments, A1isIn certain embodiments, A1isIn certain embodiments,In certain embodiments,certain embodiments, A1is. In certain embodiments, A1iscertain embodiments, A1is selected from the groups depicted in the compounds in Table 1, below.

[0333] As defined generally above, A2is a covalent bond; or,which is substituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2is a covalent bond. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2is substituted with 0 or31 occurrences of R , wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2issubstituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2is, each of which is substituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z. In certain embodiments, A2is selected from the groups depicted in the compounds in Table 1, below.

[0334] As defined generally above, R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4alkyl. In certain embodiments, R1Ais hydrogen. In certain embodiments, R1Ais C1-4 alkyl. In certain embodiments, R1Bis hydrogen. In certain embodiments, R1Bis C1-4alkyl. In certain embodiments, R1Cis hydrogen. In certain embodiments, R1Cis C1-4alkyl. In certain embodiments, R1Aand R1Bare both hydrogen. In certain embodiments, R1Aand R1Bare both methyl. In certain embodiments, R1Ais selected from the groups depicted in the compounds in Table 1, below.

[0335] As defined generally above, R3is halo or C1-4alkyl. In certain embodiments, R3is halo. In certain embodiments, R3is C1-4alkyl. In certain embodiments, R3is fluoro. In certain embodiments, R3is chloro. In certain embodiments, R3is methyl. In certain embodiments, R3is selected from the groups depicted in the compounds in Table 1, below.

[0336] As defined generally above, Z is -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-OH, -C(O)-O- (C1-6 alkyl), -C(O)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)- O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4hydroxyalkyl), -S(O)2-(C1-6alkyl), -S(O)2-(C3-7cycloalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2- N(R1A)-C(O)-O-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-N(R1B)(R1C), -S(O)2-[(C1-4 alkylene)-O-]x-R5, - N(R1A)-C(O)-(C1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), - N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl), -N(R1A)-C(O)-O-[(C1-4alkylene)-O-]x-R6, -N(R1A)- C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6, -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -N(R1A)-C(O)-N(R1B)-[(C1-6hydroxyalkyl), -C(O)- (C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R1A)(R1B), - N(R1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R1A)-R5, -N(R1A)-C(O)-C(O)-N(R1B)(R1C), - C(O)-N(R1A)-S(O)2-R7, -N(R1A)-S(O)2-R7, -C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), -S(O)2-(C1-4alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom), or hydrogen, wherein the heterocyclyl is substituted with z occurrences of R9. In certain embodiments, Z is hydrogen. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z isor. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is, ,In certain embodiments, Z is, In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z is. In certain embodiments,certain embodiments, Z i. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is In certain embodiments,. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z isIn certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z is. In certain embodiments, Z iscertain embodiments, Z is. In certain embodiments, Z is . Incertain embodiments, Z is . In certain embodiments, Z is . Incertain embodiments, Z is . In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z i. In certain embodiments, Z is . In certain embodiments, Z i. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is . In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is In certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is certain embodiments, Z is. In certain embodiments, Z is ain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is Incertain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z isIn certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments, Z is. In certain embodiments,. In certain embodiments, Z is. In certain embodiments, Z isIn certain embodiments, Z is In certain embodiments, Z is

[0337] In certain embodiments, Z is -C(O)R4. In certain embodiments, Z is -C(O)-(C1-4 alkylene)-R4. In certain embodiments, Z is -C(O)-OH. In certain embodiments, Z is -C(O)-O- (C1-6 alkyl). In certain embodiments, Z is -C(O)-N(R1A)(R1B). In certain embodiments, Z is -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)-N(R1A)(R1B). In certain embodiments, Z is -C(O)-O- (C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl). In certain embodiments, Z is -S(O)2-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In certain embodiments, Z is -S(O)2-N(R1A)(R1B). In certain embodiments, Z is -S(O)2-N(R1A)- C(O)-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R1A)-C(O)-N(R1B)(R1C). In certain embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-R5. In certain embodiments, Z is -N(R1A)-C(O)-(C1-4alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom). In certain embodiments, Z is -N(R1A)-C(O)- O-(C1-4 alkylene)-(phenyl). In certain embodiments, Z is -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x- R6. In certain embodiments, Z is -N(R1A)-C(O)-N(R1B)-[(C1-4alkylene)-O-]x-R6. In certain embodiments, Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl). In certain embodiments, Z is -C(O)- N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B). In certain embodiments, Z is -N(R1A)- C(O)-N(R1B)-[(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6alkoxyl). In certain embodiments, Z is -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-C(O)-N(R1A)(R1B). In certain embodiments, Z is -N(R1A)-C(O)-(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-C(O)-N(R1A)-R5. In certain embodiments, Z is -N(R1A)-C(O)-C(O)-N(R1B)(R1C). In certain embodiments, Z is -C(O)-N(R1A)-S(O)2-R7. In certain embodiments, Z is -N(R1A)-S(O)2-R7. In certain embodiments, Z is -C(O)-C(O)-N(R1A)- S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms). In certain embodiments, Z is -C(O)-O-(C1-4alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9). In certain embodiments, Z is hydrogen. In certain embodiments, Z is selected from the groups depicted in the compounds in Table 1, below.

[0338] As defined generally above, R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is C1-6 hydroxyalkyl. In certain embodiments, R4is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3 membered saturatedheterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 5 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R4is selected from the groups depicted in the compounds in Table 1, below.

[0339] As defined generally above, R5is C1-6alkyl, C1-6hydroxalkyl, or C1-6alkoxyl. In certain embodiments, R5is C1-6 alkyl. In certain embodiments, R5is C1-6 hydroxalkyl. In certain embodiments, R5is C1-6 alkoxyl. In certain embodiments, R5is selected from the groups depicted in the compounds in Table 1, below.

[0340] As defined generally above, R6is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl. In certain embodiments, R6is C1-4 alkyl. In certain embodiments, R6is C1-4 hydroxyalkyl. In certain embodiments, R6is C1-4haloalkyl. In certain embodiments, R6is selected from the groups depicted in the compounds in Table 1, below.

[0341] As defined generally above, R7is C1-4alkyl, C1-4alkoxyl, -(C0-4alkylene)- N(R1A)(R1B), or -N(R1B)-C(O)-O-R8. In certain embodiments, R7is C1-4 alkyl. In certain embodiments, R7is C1-4 alkoxyl. In certain embodiments, R7is -(C0-4 alkylene)-N(R1A)(R1B). In certain embodiments, R7is -N(R1B)-C(O)-O-R8. In certain embodiments, R7is selected from the groups depicted in the compounds in Table 1, below.

[0342] As defined generally above, R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl). In certain embodiments, R8is C1-4alkyl. In certain embodiments, R8is -(C0-4alkylene)-(phenyl). In certain embodiments, R8is selected from the groups depicted in the compounds in Table 1, below.

[0343] As defined generally above, R9is oxo, C1-4alkyl, or -C(O)-O-(C1-4alkyl). In certain embodiments, R9is oxo. In certain embodiments, R9is C1-4alkyl. In certain embodiments, R9is -C(O)-O-(C1-4 alkyl). In certain embodiments, R9is selected from the groups depicted in the compounds in Table 1, below.

[0344] As defined generally above, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is selected from a corresponding value in the groups depicted in the compounds in Table 1, below.

[0345] As defined generally above, x is 1, 2, 3, 4, or 5. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is selected from a corresponding value in the groups depicted in the compounds in Table 1, below.

[0346] As defined generally above, y and z are independently 1, 2, or 3. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, y is selected from a corresponding value in the groups depicted in the compounds in Table 1, below. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is selected from a corresponding value in the groups depicted in the compounds in Table 1, below.

[0347] The description above describes multiple embodiments relating to compounds of Formula I-A. The patent application specifically contemplates all combinations of the embodiments.

[0348] The definitions of variables in Formula I-A above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). Exemplary Specific Compounds

[0349] In certain embodiments, the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is a compound selected from I-1 through I- 180 in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from I-1 through I-180 in Table 1. TABLE 1. Exemplary Compounds198

[0350] In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” or “B” in one of the biochemical assays in Table 3. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” in one of the biochemical assays in Table 3. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” or “B” in one of the cell-based assays in Table 3. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” in one of the cell- based assays in Table 3.

[0351] In certain embodiments, the compound is a compound in Table 1, wherein the compound has at least one activity of “A” or “B” in one of the biochemical assays in Table 3. In certain embodiments, the compound is a compound in Table 1, wherein the compound has at least one activity of “A” in one of the biochemical assays in Table 3. In certain embodiments, the compound is a compound in Table 1, wherein the compound has at least one activity of “A” or “B” in one of the cell-based assays in Table 3. In certain embodiments, the compound is acompound in Table 1, wherein the compound has at least one activity of “A” in one of the cell- based assays in Table 3.

[0352] In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in Table 1, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I- C. In certain embodiments, the compound is a compound in Table 1, wherein the compound is a compound of Formula I-C. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I- D. In certain embodiments, the compound is a compound in Table 1, wherein the compound is a compound of Formula I-D.

[0353] In certain embodiments, the compound is a compound in the table below, or a pharmaceutically acceptable salt thereof:216.

[0354] In certain embodiments, the compound is a compound in the table above. In certain embodiments, the compound is a compound in the table above, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in the table above, or apharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-C. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-C. In certain embodiments, the compound is a compound in the table above, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-D. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-D.

[0355] In certain embodiments, the compound is one of the following:Synthetic Methods

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

[0357] Scheme 1 illustrates a general method for preparing heteroaryl compounds F. Amine A is coupled with a protected piperidine or other suitable reagent (e.g., a cyclohexane, bicyclo[2.2.2.]octane, dihydropyridine, etc.) using, for example, a Suzuki or Stille coupling to afford compound B. Compound B is reacted with an acyl chloride to form carbamate C. Carbamate C is then reacted with an optionally substituted isoindoline or other heteroaryl compound (e.g., a pyrrolo-pyridine, pyrrolo-pyrazine, a pyrolo-thiazole, etc.) to form protected isoindoline compound D. Deprotection of compound D affords the free amine compound E, which is then reacted with a carboxylic acid to form heteroaryl compound F. Depending on the type of Z group and A2ring present in Formula I, I-1, I-A, I-B, I-C, or I-D above, other conventional methodologies may be employed for the conversion of compound E into heteroaryl F in place of the amine-carboxylic acid coupling step. SCHEME 1.

[0358] In the Scheme, 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 be apparent 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”, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference. The modular synthetic route illustrated in Scheme 1 can also be readily modified by one of skill in the art to provide additional 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). II. Therapeutic Applications

[0359] The heteroaryl compounds described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I, provide therapeutic benefits to subjects suffering a disease or condition mediated by NAMPT. Description of exemplary therapeutic applications are provided herein below.

[0360] One aspect of the invention provides a method of treating a disease or condition mediated by NAMPT. 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, I-1, I-A, I-B, I-C, or I-D, to treat the disease or condition.

[0361] Another aspect of the invention provides a method of treating a disease or condition described herein. 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, I-1, I-A, I-B, I-C, or I-D, to treat the disease or condition.

[0362] Another aspect of the invention provides a method of inhibiting the activity of NAMPT. The method comprises contacting a NAMPT with an effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to inhibit the activity of said NAMPT.

[0363] In certain embodiments, the disease or condition is selected from a proliferative disorder (e.g., cancer, neoplasia), inflammatory disorder (e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), autoimmune disorder, fibrotic disorder, metabolic disorder, cardiovascular disorder, cerebrovascular disorder, and myeloid cell-driven hyper-inflammatory response in a COVID-19 infection.

[0364] In certain embodiments, the disease or condition mediated by NAMPT is a NAPRT- negative cancer. In certain embodiments, the disease or condition mediated by NAMPT is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease. In certain embodiments, the disease or condition mediated by NAMPT is inflammatory bowel disease.

[0365] In certain embodiments, the heteroaryl compounds described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I, provide therapeutic benefits to subjects suffering from cancer (e.g., pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, lymphoma, leukemia), intestinal or inflammatory bowel disease, diseases of overactive T-cells, psoriasis, neurodegenerative diseases, acute kidney disease, inflammation, stroke, acute infarct, inflammatory bowel disease, acute lung injury, rheumatoid arthritis, nephropathy, fibrosis, or sepsis.

[0366] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D 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 a proliferative disorder, inflammatory disorder, or metabolic disorder.

[0367] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I) for treating a disease or condition, such as a disease or condition described herein.

[0368] 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

[0369] Exemplary diseases and disorders include but are not limited to those described herein. In certain embodiments, the disease or condition is a proliferative disorder (e.g., cancer, neoplasia), an inflammatory disorder (e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), an autoimmune disorder, a fibrotic disorder, a metabolic disorder, a cardiovascular disorder, a cerebrovascular disorder, or a myeloid cell-driven hyper- inflammatory response in COVID-19 infections. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the proliferative disease is pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, lymphoma, leukemia, or a combination thereof. In certain embodiments, the disease or condition is an inflammatory disorder (e.g., intestinal or inflammatory bowel disease, diseases of overactive T-cells, psoriasis, neurodegenerative diseases, acute kidney disease, inflammation, stroke, acute infarct, inflammatory bowel disease, acute lung injury, rheumatoid arthritis, nephropathy, fibrosis, or sepsis. In certain embodiments, the disease or condition is a NAPRT- negative cancer. In certain embodiments, the disease or condition is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease. In certain embodiments, the disease or condition is inflammatory bowel disease.

[0370] Exemplary proliferative diseases include but are not limited to those described herein. In certain embodiments, the proliferative disease or condition to be treated or prevented using the compounds described herein is cancer.

[0371] Additional exemplary cancers include but are not limited to acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullarycarcinoma of the breast, triple negative breast cancer (TNBC)); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g.,squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; vulvar cancer (e.g., Paget's disease of the vulva); Burkitt lymphoma; primary intraocular lymphoma; classic Hodgkin lymphoma; biphenotypic acute leukemia; T cell lymphoma; nasal-type T cell lymphoma; enteropathy-type T-cell lymphoma; subcutaneous panniculitis-like T-cell lymphoma; blastic NK- cell lymphoma; T-cell prolymphocytic leukemia, and NK-cell leukemia.

[0372] In certain embodiments, the cancer is a hematological malignancy. Exemplary hematological malignancies include but are not limited to leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)), acute non-lymphocytic leukemia (ANLL), acute promyelocytic leukemia (APL), and acute myelomonocytic leukemia (AMMoL); lymphoma, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non- Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt’s lymphoma, Waldenstrom’s macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, central nervous system (CNS) lymphoma (e.g., primary CNS lymphoma and secondary CNS lymphoma); and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma,and anaplastic large cell lymphoma); lymphoma of an immune privileged site (e.g., cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphoma of the fetus, testicular lymphoma); a mixture of one or more leukemia / lymphoma as described above; myelodysplasia; multiple myeloma (MM); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), polycythemia vera, Wilm’s tumor, and Ewing’s sarcoma.

[0373] In certain embodiments, said disease or condition is a cancer. In certain embodiments, said disease or condition is an angiogenesis disorder. In certain embodiments, said disease or condition is a multiple myeloma. In certain embodiments, said disease or condition is a leukemia (e.g., acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, or promyelocytic leukemia).

[0374] In certain embodiments, the cancer is a solid tumor, leukemia, or lymphoma. In certain embodiments, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, or thyroid cancer.

[0375] In certain embodiments, said disease or condition is a lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, hairy cell lymphoma, Burkitt’s lymphoma, mast cell tumors, Hodgkin's disease or non-Hodgkin’s disease). In certain embodiments, said disease or condition is myelodysplastic syndrome. In certain embodiments, said disease or condition is fibrosarcoma. In certain embodiments, said disease or condition is rhabdomyosarcoma. In certain embodiments, said disease or condition is astrocytoma. In certain embodiments, said disease or condition is neuroblastoma. In certain embodiments, said disease or condition is glioma and schwannomas. In certain embodiments, said disease or condition is melanoma. In certain embodiments, said disease or condition is seminoma. In certain embodiments, said disease or condition is teratocarcinoma. In certain embodiments, said disease or condition is osteosarcoma. In certain embodiments, said disease or condition is xenoderma pigmentosum. In certain embodiments, said disease or condition is keratoctanthoma. In certain embodiments, said disease or condition is thyroid follicular cancer. In certainembodiments, said disease or condition is Kaposi's sarcoma. In certain embodiments, said disease or condition is melanoma. In certain embodiments, said disease or condition is teratoma. In certain embodiments, said disease or condition is rhabdomyosarcoma. In certain embodiments, said disease or condition is a metastatic and bone disorder. In certain embodiments, said disease or condition is cancer of the bone. In certain embodiments, said disease or condition is cancer of the mouth / pharynx. In certain embodiments, said disease or condition is cancer of the esophagus. In certain embodiments, said disease or condition is cancer of the larynx. In certain embodiments, said disease or condition is cancer of the stomach. In certain embodiments, said disease or condition is cancer of the intestine. In certain embodiments, said disease or condition is cancer of the colon. In certain embodiments, said disease or condition is cancer of the rectum. In certain embodiments, said disease or condition is cancer of the lung (e.g., non-small cell lung cancer or small cell lung cancer). In certain embodiments, said disease or condition is cancer of the liver. In certain embodiments, said disease or condition is cancer of the pancreas. In certain embodiments, said disease or condition is cancer of the nerve. In certain embodiments, said disease or condition is cancer of the brain (e.g., glioma or glioblastoma multiforme). In certain embodiments, said disease or condition is cancer of the head and neck. In certain embodiments, said disease or condition is cancer of the throat. In certain embodiments, said disease or condition is cancer of the ovary. In certain embodiments, said disease or condition is cancer of the uterus. In certain embodiments, said disease or condition is cancer of the prostate. In certain embodiments, said disease or condition is cancer of the testis. In certain embodiments, said disease or condition is cancer of the bladder. In certain embodiments, said disease or condition is cancer of the kidney. In certain embodiments, said disease or condition is cancer of the breast. In certain embodiments, said disease or condition is cancer of the gall bladder. In certain embodiments, said disease or condition is cancer of the cervix. In certain embodiments, said disease or condition is cancer of the thyroid. In certain embodiments, said disease or condition is cancer of the prostate. In certain embodiments, said disease or condition is cancer of the skin (e.g., skin squamous cell carcinoma). In certain embodiments, said disease or condition is a solid tumor. In certain embodiments, said disease or condition is gastric cancer. In certain embodiments, said disease or condition is hepatocellular carcinoma. In certain embodiments, said disease or condition is aperipheral nerve sheath tumor. In certain embodiments, said disease or condition is pulmonary arterial hypertension.

[0376] In certain embodiments, the disease is a cancer associated with a viral infection. In certain embodiments, the disease is a cancer resulting from infection with an oncovirus. In certain embodiments, the oncovirus is hepatitis A, hepatitis B, hepatitis C, human T- lymphotropic virus (HTLV), human papillomavirus (HPV), Kaposi's sarcoma-associated herpesvirus (HHV-8), Merkel cell polyomavirus, or Epstein-Barr virus (EBV). In certain embodiments, the disease is human T-lymphotropic virus. In certain embodiments, the disease is Kaposi’s sarcoma-associated herpesvirus. In certain embodiments, the disease is Epstein-Barr virus. Leukemias and lymphomas which may be associated with an oncoviral include: for HTLV, adult T-cell leukemia; for HHV-8, Castleman's disease and primary effusion lymphoma; and for EBV, Burkitt's lymphoma, Hodgkin’s lymphoma, and post-transplant lymphoproliferative disease.

[0377] In certain embodiments, said disease or condition is an inflammatory disorder or allergic disorder. In certain embodiments, said disease or condition is an inflammatory disorder, such as autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto- inflammatory disorders, fibrotic disorders, metabolic disorders, neoplasias, cardiovascular or cerebrovascular disorders, and myeloid cell-driven hyper-inflammatory response in COVID-19 infections. In certain embodiments, said disease or condition is an allergic disorder, such as asthma and allergic rhinitis.

[0378] In certain embodiments, said disease or condition is a disease or disorder of tissues and systemic disease [e.g., systemic lupus erythematosus (SLE); immune thrombocytopenic purpura (ITP); autoimmune hemolytic anemia (AHA); autoimmune neutropenia (AIN); Evans syndrome; proliferative and hyperproliferative diseases, such as cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, cirrhosis of the liver; and Acquired Immunodeficiency Syndrome (AIDS)]. In certain embodiments, said disease or condition is an immunologically-mediated disease, such as allograft rejection (e.g., rejection of transplanted organs or tissues). In certain embodiments, said disease or condition is a tissue injury (e.g., associated with organ transplant or revascularization procedures). In certain embodiments, said disease or condition is a disease or disorder of the respiratory tract (e.g., asthma). In certain embodiments, said disease or condition is allergic rhinitis. In certainembodiments, said disease or condition is a disease or disorder of the bone and joints (e.g., arthritis, rheumatoid arthritis). In certain embodiments, said disease or condition is a disease or disorder of the skin. In certain embodiments, said disease or condition is a disease or disorder of the gastrointestinal tract.

[0379] Exemplary diseases of the respiratory tract include but are not limited to those described herein. In certain embodiments, said disease or condition is a reversible obstructive airways disease, such as asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma). In certain embodiments, said disease or condition is chronic or inveterate asthma (e.g., late asthma airways hyper-responsiveness). In certain embodiments, said disease or condition is bronchitis. In certain embodiments, said disease or condition is a condition characterized by an inflammation of the nasal mucus membrane. In certain embodiments, said disease or condition is acute rhinitis. In certain embodiments, said disease or condition is allergic rhinitis. In certain embodiments, said disease or condition is atrophic rhinitis. In certain embodiments, said disease or condition is chronic rhinitis (e.g., rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca, and rhinitis medicamentosa). In certain embodiments, said disease or condition is membranous rhinitis (e.g., croupous rhinitis, fibrinous rhinitis, pseudomembranous rhinitis, and scrofoulous rhinitis). In certain embodiments, said disease or condition is seasonal rhinitis [e.g., rhinitis nervosa (hay fever), vasomotor rhinitis, sarcoidosis, farmer's lung, and related diseases, such as fibroid lung and idiopathic interstitial pneumonia].

[0380] Exemplary diseases of the bone and joints include but are not limited to those described herein. In certain embodiments, said disease or condition includes pannus formation. In certain embodiments, said disease or condition does not include pannus formation. In certain embodiments, said disease or condition is rheumatoid arthritis. In certain embodiments, said disease or condition is seronegative spondyloarthropathis (e.g., ankylosing spondylitis, psoriatic arthritis, and Reiter's disease). In certain embodiments, said disease or condition is Behcet's disease. In certain embodiments, said disease or condition is Sjogren's syndrome. In certain embodiments, said disease or condition is systemic sclerosis.

[0381] Exemplary diseases and disorders of the skin include but are not limited to those described herein. In certain embodiments, said disease or condition is psoriasis. In certainembodiments, said disease or condition is systemic sclerosis. In certain embodiments, said disease or condition is dermatitis. In certain embodiments, said disease or condition is atopical dermatitis. In certain embodiments, said disease or condition is contact dermatitis. In certain embodiments, said disease or condition is eczematous dermatitis. In certain embodiments, said disease or condition is seborrhoetic dermatitis. In certain embodiments, said disease or condition is Lichen planus. In certain embodiments, said disease or condition is Pemphigus. In certain embodiments, said disease or condition is bullous Pemphigus. In certain embodiments, said disease or condition is epidermolysis bullosa. In certain embodiments, said disease or condition is urticaria. In certain embodiments, said disease or condition is angiodermas. In certain embodiments, said disease or condition is vasculitides. In certain embodiments, said disease or condition is erythemas. In certain embodiments, said disease or condition is cutaneous eosinophilias. In certain embodiments, said disease or condition is uveitis. In certain embodiments, said disease or condition is alopecia. In certain embodiments, said disease or condition is areata. In certain embodiments, said disease or condition is alopecia areata. In certain embodiments, said disease or condition is vernal conjunctivitis.

[0382] Exemplary diseases and disorders of the gastrointestinal tract include but are not limited to those described herein. In certain embodiments, said disease or condition is Coeliac disease. In certain embodiments, said disease or condition is proctitis. In certain embodiments, said disease or condition is eosinophilic gastro-enteritis. In certain embodiments, said disease or condition is mastocytosis. In certain embodiments, said disease or condition is pancreatitis. In certain embodiments, said disease or condition is Crohn's disease. In certain embodiments, said disease or condition is ulcerative colitis. In certain embodiments, said disease or condition is a food-related allergy having effects remote from the gut (e.g., migraine, rhinitis, and eczema).

[0383] Exemplary diseases and disorders of other tissues and systemic disease include but are not limited to those described herein. In certain embodiments, said disease or condition is multiple sclerosis. In certain embodiments, said disease or condition is atherosclerosis. In certain embodiments, said disease or condition is acquired immunodeficiency syndrome (AIDS). In certain embodiments, said disease or condition is lupus. In certain embodiments, said disease or condition is lupus erythematosus. In certain embodiments, said disease or condition is systemic lupus erythematosus. In certain embodiments, said disease or condition is Hashimoto's thyroiditis. In certain embodiments, said disease or condition is myasthenia gravis. In certainembodiments, said disease or condition is type I diabetes. In certain embodiments, said disease or condition is nephrotic syndrome. In certain embodiments, said disease or condition is eosinophilia fasciitis. In certain embodiments, said disease or condition is hyper IgE syndrome. In certain embodiments, said disease or condition is lepromatous leprosy. In certain embodiments, said disease or condition is sezary syndrome. In certain embodiments, said disease or condition is idiopathic thrombocytopenia purpura. In certain embodiments, said disease or condition is restenosis following angioplasty. In certain embodiments, said disease or condition is a tumor (e.g., leukemia, lymphomas). In certain embodiments, said disease or condition is atherosclerosis.

[0384] Exemplary allograft rejections include but are not limited to those described herein. In certain embodiments, said disease or condition is acute chronic allograft rejection (e.g., following transplantation of kidney, heart, liver, lung, bone marrow, skin, or cornea). In certain embodiments, said disease or condition is chronic allograft rejection (e.g., following transplantation of kidney, heart, liver, lung, bone marrow, skin, or cornea). In certain embodiments, said disease or condition is chronic graft-versus-host disease.

[0385] In certain embodiments, said disease or condition is an acute inflammatory disorder. In certain embodiments, said disease or condition is an auto-inflammatory disorder. In certain embodiments, said disease or condition is a fibrotic disorder. In certain embodiments, said disease or condition is a metabolic disorder. In certain embodiments, said disease or condition is a neoplasia. In certain embodiments, said disease or condition is a cardiovascular or cerebrovascular disorder. In certain embodiments, said disease or condition is a myeloid cell- driven hyper-inflammatory response in COVID-19 infections.

[0386] In certain embodiments, said disease or condition is an autoimmune disorder. In certain embodiments, said disease or condition is a chronic inflammatory disorder. In certain embodiments, said disease or condition is an acute inflammatory disorder. In certain embodiments, said disease or condition is an auto-inflammatory disorder. In certain embodiments, said disease or condition is a combination of one, two, or all three of a chronic inflammatory disorder, an acute inflammatory disorder, and an auto-inflammatory disorder.

[0387] Exemplary autoimmune and / or inflammatory and / or auto-inflammatory disorders include but are not limited to those described herein. In certain embodiments, said disease or conditionis an inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s disease). In certain embodiments, said disease or condition is multiple sclerosis. In certain embodiments, said disease or condition is psoriasis. In certain embodiments, said disease or condition is arthritis. In certain embodiments, said disease or condition is rheumatoid arthritis. In certain embodiments, said disease or condition is osteoarthritis. In certain embodiments, said disease or condition is juvenile arthritis. In certain embodiments, said disease or condition is psoriatic arthritis. In certain embodiments, said disease or condition is reactive arthritis. In certain embodiments, said disease or condition is ankylosing spondylitis. In certain embodiments, said disease or condition is cryopyrin-associated periodic syndromes. In certain embodiments, said disease or condition is Muckle-Wells syndrome. In certain embodiments, said disease or condition is familial cold auto-inflammatory syndrome. In certain embodiments, said disease or condition is neonatal-onset multisystem inflammatory disease. In certain embodiments, said disease or condition is TNF receptor-associated periodic syndrome. In certain embodiments, said disease or condition is acute and chronic pancreatitis. In certain embodiments, said disease or condition is atherosclerosis. In certain embodiments, said disease or condition is gout. In certain embodiments, said disease or condition is a fibrotic disorder (e.g., hepatic fibrosis or idiopathic pulmonary fibrosis). In certain embodiments, said disease or condition is nephropathy. In certain embodiments, said disease or condition is sarcoidosis. In certain embodiments, said disease or condition is scleroderma. In certain embodiments, said disease or condition is anaphylaxis. In certain embodiments, said disease or condition is diabetes (e.g., diabetes mellitus type 1 or diabetes mellitus type 2). In certain embodiments, said disease or condition is diabetic retinopathy. In certain embodiments, said disease or condition is Still's disease. In certain embodiments, said disease or condition is vasculitis. In certain embodiments, said disease or condition is sarcoidosis. In certain embodiments, said disease or condition is pulmonary inflammation. In certain embodiments, said disease or condition is respiratory failure. In certain embodiments, said disease or condition is acute respiratory distress syndrome. In certain embodiments, said disease or condition is chronic eosinophilic pneumonia. In certain embodiments, said disease or condition is wet and dry age-related macular degeneration. In certain embodiments, said disease or condition is autoimmune hemolytic syndromes. In certain embodiments, said disease or condition is autoimmune and inflammatory hepatitis. In certain embodiments, said disease or condition is autoimmune neuropathy. In certain embodiments, saiddisease or condition is autoimmune ovarian failure. In certain embodiments, said disease or condition is autoimmune orchitis. In certain embodiments, said disease or condition is autoimmune thrombocytopenia. In certain embodiments, said disease or condition is silicone implant-associated autoimmune disease. In certain embodiments, said disease or condition is Sjogren's syndrome. In certain embodiments, said disease or condition is familial Mediterranean fever. In certain embodiments, said disease or condition is systemic lupus erythematosus. In certain embodiments, said disease or condition is vasculitis syndromes (e.g., temporal, Takayasu’s and giant cell arteritis, Behcet’s disease or Wegener's granulomatosis). In certain embodiments, said disease or condition is vitiligo. In certain embodiments, said disease or condition is ichthyosis. In certain embodiments, said disease or condition is secondary hematologic manifestation of autoimmune diseases (e.g., anemias). In certain embodiments, said disease or condition is drug-induced autoimmunity. In certain embodiments, said disease or condition is Hashimoto’s thyroiditis. In certain embodiments, said disease or condition is hypophysitis. In certain embodiments, said disease or condition is idiopathic thrombocytic pupura. In certain embodiments, said disease or condition is metal-induced autoimmunity. In certain embodiments, said disease or condition is myasthenia gravis. In certain embodiments, said disease or condition is pemphigus. In certain embodiments, said disease or condition is autoimmune deafness (e.g., Meniere's disease). In certain embodiments, said disease or condition is Goodpasture's syndrome. In certain embodiments, said disease or condition is Graves’ disease. In certain embodiments, said disease or condition is an HW-related autoimmune syndromes. In certain embodiments, said disease or condition is Guillain-Barre disease. In certain embodiments, said disease or condition is Addison’s disease. In certain embodiments, said disease or condition is anti-phospholipid syndrome. In certain embodiments, said disease or condition is asthma. In certain embodiments, said disease or condition is atopic dermatitis. In certain embodiments, said disease or condition is Celiac disease. In certain embodiments, said disease or condition is Cushing’s syndrome. In certain embodiments, said disease or condition is dermatomyositis. In certain embodiments, said disease or condition is idiopathic adrenal atrophy. In certain embodiments, said disease or condition is idiopathic thrombocytopenia. In certain embodiments, said disease or condition is Kawasaki syndrome. In certain embodiments, said disease or condition is Lambert-Eaton Syndrome. In certain embodiments, said disease or condition is pernicious anemia. In certain embodiments, saiddisease or condition is pollinosis. In certain embodiments, said disease or condition is polyarteritis nodosa. In certain embodiments, said disease or condition is primary biliary cirrhosis. In certain embodiments, said disease or condition is primary sclerosing cholangitis. In certain embodiments, said disease or condition is Raynaud’s disease. In certain embodiments, said disease or condition is Raynaud’s phenomenon. In certain embodiments, said disease or condition is Reiter’s Syndrome. In certain embodiments, said disease or condition is relapsing polychondritis. In certain embodiments, said disease or condition is Schmidt’s syndrome. In certain embodiments, said disease or condition is thyrotoxidosis. In certain embodiments, said disease or condition is sepsis. In certain embodiments, said disease or condition is septic shock. In certain embodiments, said disease or condition is endotoxic shock. In certain embodiments, said disease or condition is exotoxin-induced toxic shock. In certain embodiments, said disease or condition is gram negative sepsis. In certain embodiments, said disease or condition is toxic shock syndrome. In certain embodiments, said disease or condition is glomerulonephritis. In certain embodiments, said disease or condition is peritonitis. In certain embodiments, said disease or condition is interstitial cystitis. In certain embodiments, said disease or condition is hyperoxia-induced inflammations. In certain embodiments, said disease or condition is chronic obstructive pulmonary disease (COPD). In certain embodiments, said disease or condition is emphysema. In certain embodiments, said disease or condition is nasal inflammation. In certain embodiments, said disease or condition is vasculitis. In certain embodiments, said disease or condition is graft vs. host reaction (e.g., graft vs. host disease). In certain embodiments, said disease or condition is allograft rejections (e.g., acute allograft rejection or chronic allograft rejection). In certain embodiments, said disease or condition is early transplantation rejection (e.g., acute allograft rejection). In certain embodiments, said disease or condition is reperfusion injury. In certain embodiments, said disease or condition is pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia). In certain embodiments, said disease or condition is a chronic infection. In certain embodiments, said disease or condition is meningitis. In certain embodiments, said disease or condition is encephalitis. In certain embodiments, said disease or condition is myocarditis. In certain embodiments, said disease or condition is gingivitis. In certain embodiments, said disease or condition is post-surgical trauma. In certain embodiments, said disease or condition is tissue injury. In certain embodiments, said disease or condition is traumatic brain injury. In certain embodiments, said disease or condition is enterocolitis. Incertain embodiments, said disease or condition is sinusitis. In certain embodiments, said disease or condition is uveitis. In certain embodiments, said disease or condition is ocular inflammation. In certain embodiments, said disease or condition is optic neuritis. In certain embodiments, said disease or condition is gastric ulcers. In certain embodiments, said disease or condition is esophagitis. In certain embodiments, said disease or condition is peritonitis. In certain embodiments, said disease or condition is periodontitis. In certain embodiments, said disease or condition is dermatomyositis. In certain embodiments, said disease or condition is gastritis. In certain embodiments, said disease or condition is myositis. In certain embodiments, said disease or condition is polymyalgia. In certain embodiments, said disease or condition is pneumonia. In certain embodiments, said disease or condition is bronchitis. In certain embodiments, the disease or condition is endometriosis. In certain embodiments, the disease or condition is necrotizing vasculitis. In certain embodiments, the disease or condition is lymphadenitis. In certain embodiments, the disease or condition is peri-arteritis nodosa. In certain embodiments, the disease or condition is anti-phospholipid antibody syndrome. In certain embodiments, the disease or condition is pemphigus vulgaris. In certain embodiments, the disease or condition is Lyme disease. In certain embodiments, the disease or condition is cardiomyopathy. In certain embodiments, the disease or condition is rheumatic fever. In certain embodiments, the disease or condition is a blistering disorder. In certain embodiments, the disease or condition is an antibody-mediated vasculitis syndrome. In certain embodiments, the disease or condition is an immune-complex vasculitide. In certain embodiments, the disease or condition is oedema. In certain embodiments, the disease or condition is embolism. In certain embodiments, the disease or condition is fibrosis. In certain embodiments, the disease or condition is silicosis. In certain embodiments, the disease or condition is BENTA disease. In certain embodiments, the disease or condition is berylliosis.

[0388] Exemplary fibrotic disorders include but are not limited to those described herein. In certain embodiments, said disease or condition is systemic sclerosis / scleroderma. In certain embodiments, said disease or condition is lupus nephritis. In certain embodiments, said disease or condition is connective tissue disease. In certain embodiments, said disease or condition is wound healing. In certain embodiments, said disease or condition is surgical scarring. In certain embodiments, said disease or condition is spinal cord injury. In certain embodiments, said disease or condition is CNS scarring. In certain embodiments, said disease or condition is acutelung injury. In certain embodiments, said disease or condition is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis). In certain embodiments, said disease or condition is chronic obstructive pulmonary disease. In certain embodiments, said disease or condition is adult respiratory distress syndrome. In certain embodiments, said disease or condition is acute lung injury. In certain embodiments, said disease or condition is drug- induced lung injury. In certain embodiments, said disease or condition is glomerulonephritis. In certain embodiments, said disease or condition is kidney disease. In certain embodiments, said disease or condition is chronic kidney disease (e.g., diabetic nephropathy). In certain embodiments, said disease or condition is hypertension-induced nephropathy. In certain embodiments, said disease or condition is alimentary track or gastrointestinal fibrosis. In certain embodiments, said disease or condition is renal fibrosis. In certain embodiments, said disease or condition is hepatic or biliary fibrosis. In certain embodiments, said disease or condition is liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma). In certain embodiments, said disease or condition is cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease, such as alcoholic and nonalcoholic steatosis). In certain embodiments, said disease or condition is radiation-induced fibrosis (e.g., head and neck, gastrointestinal or pulmonary). In certain embodiments, said disease or condition is primary sclerosing cholangitis. In certain embodiments, said disease or condition is restenosis. In certain embodiments, said disease or condition is cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis). In certain embodiments, said disease or condition is ophthalmic scarring. In certain embodiments, said disease or condition is fibrosclerosis. In certain embodiments, said disease or condition is a fibrotic cancer. In certain embodiments, said disease or condition is fibroids. In certain embodiments, said disease or condition is fibroma. In certain embodiments, said disease or condition is a fibroadenoma. In certain embodiments, said disease or condition is a fibrosarcoma. In certain embodiments, said disease or condition is transplant arteriopathy. In certain embodiments, said disease or condition is keloid. In certain embodiments, said disease or condition is mediastinal fibrosis. In certain embodiments, said disease or condition is myelofibrosis. In certain embodiments, said disease or condition is retroperitoneal fibrosis. In certain embodiments, said disease or condition is progressive massive fibrosis. In certain embodiments, said disease or condition is nephrogenic systemic fibrosis.

[0389] Exemplary metabolic disorders include but are not limited to those described herein. In certain embodiments, said disease or condition is obesity. In certain embodiments, said disease or condition is steroid-resistance. In certain embodiments, said disease or condition is glucose intolerance. In certain embodiments, said disease or condition is metabolic syndrome.

[0390] Exemplary cardiovascular or cerebrovascular disorders include but are not limited to those described herein. In certain embodiments, said disease or condition is atherosclerosis. In certain embodiments, said disease or condition is restenosis of an atherosclerotic coronary artery. In certain embodiments, said disease or condition is acute coronary syndrome. In certain embodiments, said disease or condition is myocardial infarction. In certain embodiments, said disease or condition is cardiac-allograft vasculopathy. In certain embodiments, said disease or condition is stroke. In certain embodiments, said disease or condition is a central nervous system disorder with an inflammatory or apoptotic component. In certain embodiments, said disease or condition is Alzheimer's disease. In certain embodiments, said disease or condition is Parkinson's disease. In certain embodiments, said disease or condition is Huntington’s disease. In certain embodiments, said disease or condition is amyotrophic lateral sclerosis. In certain embodiments, said disease or condition is spinal cord injury. In certain embodiments, said disease or condition is neuronal ischemia. In certain embodiments, said disease or condition is peripheral neuropathy.

[0391] In certain embodiments, said disease or condition is a disease or disorder associated with a coronavirus (e.g., SARS-CoV-2). In certain embodiments, said coronavirus is SARS-CoV-2. In certain embodiments, the disease or disorder associated with SARS-CoV-2 is COVID-19.

[0392] In certain embodiments, the disease or condition is a rheumatic disease. In certain embodiments, the disease or condition is an inflammatory arthropathy. In certain embodiments, the disease or condition is rheumatoid arthritis, juvenile arthritis, Still's disease, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's Syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile IdiopathicArthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis, secondary osteoarthritis from an inflammatory disease.

[0393] In certain embodiments, the disease or condition is a connective tissue disease. In certain embodiments, the disease or condition is lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, nephritis, Sjögren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenon, juvenile scleroderma, polymyositis, dermatomyositis, polymyositis- dermatomyositis, polymyalgia rheumatica, a mixed connective tissue disease, sarcoidosis, fibromyalgia, vasculitis microscopic polyangiitis, vasculitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss Syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, Henoch-Schönlein purpura, idiopathic thrombocytopenic thrombotic purpura, juvenile vasculitis, polyarteritis nodossa (also known as panarteritis nodosa, periarteritis nodosa Kussmaul disease, Kussmaul-Maier disease or PAN), serum sickness, myasthenia gravis, Takayasu's arteritis, Behçet’s syndrome, Kawasaki’s disease (mucocutaneous lymph node syndrome), Buerger’s disease (thromboangiitis obliterans), Vogt–Koyanagi–Harada syndrome, Addison’s disease, Hashimoto’s thyroiditis, primary biliary sclerosis, autoimmune hepatitis, chronic aggressive hepatitis, nonalcoholic hepatic steatosis, sclerosing cholangitis, membranous glomerulopathy, polymyositis, myositis, atherosclerosis, autoimmune hemolytic anemia, autoimmune orchitis, Goodpasture's disease,

[0394] In certain embodiments, the disease or condition is a neurodegenerative disease or neuroinflammatory disease. In certain embodiments, the disease or condition is multiple sclerosis, amyotropic lateral sclerosis, Guillain-Barre disease, autoimmune encephalomyelitis, Alzheimer's disease, major depressive disorder, traumatic brain injury, epilepsy, Parkinson’s disease, or bipolar disorder.

[0395] In certain embodiments, the disease or condition is an inflammatory bowel disease (IBD). In certain embodiments, the disease or condition is Crohn's disease, ulcerative colitis, Celiac Sprue, Celiac disease, proctitis, eosinophilic gastroenteritis, autoimmune atrophic gastritis of pernicious anemia, or mastocytosis.

[0396] In certain embodiments, the disease or condition is a skin autoimmune disorder. In certain embodiments, the disease or condition is psoriasis. In certain embodiments, the disease or condition is eczema. In certain embodiments, the disease or condition is plaque psoriasis,Guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, rosacea, pruritus, alopecia areata, vitiligo, epidermal hyperplasia, juvenile dermatomyositis, dermatomyositis, or hidradenitis suppurativa. In certain embodiments, said disease or condition is hidradenitis suppurativa.

[0397] In certain embodiments, the disease or condition is an organ or cell transplant rejection. In certain embodiments, the disease or condition is graft-versus-host disease. In certain embodiments, the disease or condition is chronic graft-versus-host disease, acute graft-versus- host disease, or organ or cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, or xeno transplantation.

[0398] In certain embodiments, the disease or condition is an autoimmune disease of the eye. In certain embodiments, the disease or condition is Graves' disease, noninfectious uveitis, dry eye syndrome, sympathetic ophthalmia, Cogan's syndrome, keratoconjunctivitis, vernal conjunctivitis, uveitis (e.g., uveitis associated with Behcet's disease and lens-induced uveitis), keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, or ocular neovascularization

[0399] In certain embodiments, the disease or condition is an ocular manifestation of an autoimmune disease.

[0400] In certain embodiments, the disease or condition is a respiratory disease. In certain embodiments, the disease or condition is asthma, chronic obstructive pulmonary disease, or acute respiratory disease.

[0401] In certain embodiments, the disease or condition is diabetes. In certain embodiments, the disease or condition is Type I diabetes mellitus, Type II diabetes mellitus, or juvenile onset diabetes.

[0402] In certain embodiments, the disease or condition is thyroid cancer, duodenal, neuroendocrine carcinoma (NEC), uterine cancer, small cell lung cancer (SCLC), hepatocellularcarcinoma, mesothelioma, breast cancer, sarcoma, ovarian cancer, renal cell carcinoma, rectal cancer, head and neck cancer, prostate cancer, pancreatic cancer, melanoma, colorectal cancer, cervix cancer, non-small cell lung cancer (NSCLC), cholangiocarcinoma, or endometrial cancer.

[0403] In certain embodiments, the disease or condition is an autoimmune disease or atherosclerosis.

[0404] In certain embodiments, the disease or condition is ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin’s disease, viral infections, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, dermatitis, atopic dermatitis, psoriasis, systemic lupus erythematosus, multiple Sclerosis, psoriatic arthritis, ankylosing spondylitis, graft-versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephritis, metabolic Syndrome, non-Small cell lung cancer, Small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamous cell cancers, kidney cancer, urethral and bladder cancers, cancers of head and neck, cancers of the brain and central nervous system (CNS).

[0405] In certain embodiments, the disease or condition is cancer, an autoimmune disease, viral disease, fungal disease, neurological / neurodegenerative disorder, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease. In certain embodiments, the disease or condition is a carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including Small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and pro myelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma,neuroblastoma, glioma and Schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, Xeroderma pigmentosum, keratocanthoma, thyroid follicular cancer and Kaposi's sarcoma.

[0406] Without being bound by theory, there are multiple instances where decreasing NAD levels through NAMPT inhibition or in general have been associated with positive outcome in treating disease. For example, it has previously been shown that activated T-cells require increased NAD levels, and are more sensitive to NAMPTi than quiescent cells (Bruzzone et al. (2009) in PLoS ONE 4(11): e7897). Therefore NAMPT inhibitors show promise in immunosuppression of auto-immune disease, decreasing hyperactivation of the immune system in IBD (Gerner et al. in Gut 2018; 67:1813-1823), Psoriasis (Arroyo et al. in Int. J. Mol. Sci.2023, 24(9), 7992), vitiligo (Becatti et al. in J Cell Mol Med. (2014) vol.18(3): 514–529) and alopecia among others (Mercurio et al. in Int. J. Mol. Sci.2021, 22(13), 6860; Martínez- Morcillo et al. (2021) in PLoS Biol 19(11): e3001455).

[0407] NAMPT expression has also been positively correlated with markers of inflammation, and NAMPTi decreases the expression of these same inflammation markers (Gerner et al. in Gut 2018; 67:1813-1823). Multiple mouse models of lung injury have demonstrated a significant benefit to treatment with NAMPT inhibitors (Geng-Chin Wu et al. in Respiratory Research 2017;18(1):71; Moreno-Vinasco et al. in Am J Respir Cell Mol Biol.2014 Aug; 51(2): 223–228). NAMPT is also found to be upregulated in COPD and negatively correlated with lung function (Huang Y, Niu Y, Wang X, Li X, He Y and Liu X (2024) in Identification of novel biomarkers related to neutrophilic inflammation in COPD. Front. Immunol.).

[0408] NAMPT knockdown has been shown to reduce atherosclerosis by promoting cholesterol efflux and macrophage RCT through the PPARa-LXRa-ABCA1 / G1 pathway both in vitro and in vivo (Li et al. in Scientific Reports volume 6, Article number: 26746 (2016)).

[0409] In graft-versus-host disease (GVHD), NAMPT is highly expressed in both serum and T-cells. NAMPT inhibition strongly attenuates symptoms of GVHD in in vivo models and depletes NAD levels in activated T-cells (Gerner RR et al. in Leukemia 2020; 34(7):1885-1897). In rheumatoid arthritis, miR-23b is associated with RA where it is downregulated. It has been demonstrated to target NAMPT so NAMPT inhibitors are understood to provide a benefit intreating rheumatoid arthritis (Lv, R., Yu, J. & Sun, Q. in Future Oncol. (Lond. Engl.) 16(10), 541–458; and Liu, X. et al. in Gene 712(143911), 143911). Medical Uses

[0410] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as cancer.

[0411] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein, such as cancer.

[0412] Compounds described herein may also be used as a component in an antibody-drug conjugate. For example, compounds described herein may be conjugated to an antibody to form an antibody-drug conjugate. The antibody-drug conjugate may be used to treat disorder and conditions described herein. III. Combination Therapy

[0413] Another aspect of the invention provides for combination therapy. Heteroaryl compounds described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D 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.

[0414] Accordingly, in some 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 some embodiments, the method includes co-administering one additional therapeutic a...

Claims

Claims:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt thereof; wherein:substituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A2is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3; A3is phenylene substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4 alkyl; R2represents independently for each occurrence halo, C1-4haloalkyl, C1-4alkoxyl, C1-4alkyl, or C1-4hydroxyalkyl; R3represents independently for each occurrence halo or C1-4 alkyl; Z is one of the following: a) -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4alkylene)-O-(C1-4alkyl), -C(O)-(C1-4alkylene)-[O-(C1-4alkylene)-]y- (C1-6alkoxyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which issubstituted with one C1-4alkyl and one -OH), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4alkylene)- N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6alkyl), -C(O)-O-(C1-4alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6alkylene)-N(R1C)-S(O)2-(C1-4alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH);f) -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)- O-]x-R6, -N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- (C3-7cycloalkyl), -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)- C(O)-N(R1B)(R1C); h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-OH, or -(C1-4alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; or j) hydrogen; R4is C1-6hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R1A)(R1B), or -(C1-6 alkylene)-N(R1A)-C(O)-O-(C1-6 alkyl); R6is C1-4alkyl, C1-4hydroxyalkyl, C1-4haloalkyl, or -(C1-4alkylene)-(C1-4alkoxyl); R7is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), -(C0-6 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -N(R1B)-C(O)-O-R8; R8is C1-4alkyl or -(C0-4alkylene)-(phenyl); R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl);m and n are independently 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4 alkylene)-R4.

2. The compound of claim 1, wherein A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen.

3. The compound of claim 1 or 2, wherein m and n are 1.

4. The compound of any one of claims 1-3, wherein A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6- membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R3.

5. The compound of any one of claims 1-4, wherein A3is para-phenylene substituted with 0 or 1 occurrences of R3.

6. The compound of any one of claims 1-5, wherein the compound is a compound of Formula I.

7. The compound of any one of claims 1-5, wherein the compound is represented by Formula I- B:(I-B) or a pharmaceutically acceptable salt thereof; wherein:A1issubstituted with p occurrences of R2,substituted with 1, 2 or 3 occurrences of R2, orsubstituted with 2, 3, or 4 occurrences of R2; A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4alkyl; R2represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4hydroxyalkyl; R3is halo or C1-4 alkyl; Z is one of the following: a) -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6alkoxyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6 alkyl), -C(O)-N(R1A)-(C1-4 haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6alkoxyl), -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-(C1-6hydroxyalkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6alkyl), -C(O)-O-(C1-4alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6alkylene)-N(R1C)-S(O)2-(C1-4alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH); f) -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)- O-]x-R6, -N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- (C3-7cycloalkyl), -S(O)2-N(R1A)-(C1-6hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6 alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)- C(O)-N(R1B)(R1C);h) -(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-N(R1A)-(C1-6hydroxyalkyl), -(C1-4alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; or j) hydrogen; R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R1A)(R1B), or -(C1-6alkylene)-N(R1A)-C(O)-O-(C1-6alkyl); R6is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R7is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), -(C0-6alkylene)-N(R1B)-C(O)-(C1-4alkyl), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3.

8. The compound of claim 7, wherein the compound is a compound of Formula I-B.

9. The compound of any one of claims 1-8, wherein A2iseach of which is substituted with 0 or 1 occurrences of R3, wherein the nitrogen atom of A2is attached to Z.

10. The compound of any one of claims 1-8, wherein A2iswherein the saturated carbon is attached to Z, wherein A2is substituted with 0 or 1 occurrences of R3.

11. The compound of any one of claims 1-8, wherein A2issubstituted with 0 or 1 occurrences of R3.

12. The compound of any one of claims 1-8, wherein A2issubstituted with 0 or 1 occurrences of R3.

13. A compound represented by Formula I-C:or a pharmaceutically acceptable salt thereof; wherein: A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen; A2is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, each of which is substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4 alkyl; R2represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4 hydroxyalkyl; R3is halo or C1-4alkyl;Z is one of the following: a) -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4alkylene)-O-(C1-4alkyl), -C(O)-(C1-4alkylene)-[O-(C1-4alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1B)-(C1-4alkylene)-[O-(C1-4alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-O-(C1-6alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4 alkylene)- N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)-O-(C1-4 alkylene)-O-(C1-4alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5- membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6alkylene)-N(R1C)-S(O)2-(C1-4alkyl);e) -N(R1A)-C(O)-N(R1B)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4 haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH); f) -N(R1A)-C(O)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)- O-]x-R6, -N(R1A)-C(O)-O-(C1-4alkylene)-(phenyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6hydroxyalkyl), -S(O)2-(C1-6alkyl), -S(O)2-(C1-4alkylene)-(C1-6alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2- (C3-7 cycloalkyl), -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2- N(R1A)-C(O)-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl), or -S(O)2-N(R1A)- C(O)-N(R1B)(R1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-OH, or -(C1-4alkylene)-C(O)-O-(C1-6 alkyl); i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; or j) hydrogen; R4is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R1A)(R1B), or -(C1-6 alkylene)-N(R1A)-C(O)-O-(C1-6 alkyl);R6is C1-4alkyl, C1-4hydroxyalkyl, C1-4haloalkyl, or -(C1-4alkylene)-(C1-4alkoxyl); R7is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R1A)(R1B), -(C0-6 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -N(R1B)-C(O)-O-R8; R8is C1-4alkyl or -(C0-4alkylene)-(phenyl); R9is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3.

14. The compound of claim 13, wherein the compound is a compound of Formula I-C.

15. The compound of claim 13 or 14, wherein A2issubstituted with 0 or 1 occurrences of R3.

16. The compound of any one of claims 1-5, wherein the compound is represented by Formula I-(I-D) or a pharmaceutically acceptable salt thereof; wherein: A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen; A2is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3;R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4alkyl; R2represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4hydroxyalkyl; R3is halo or C1-4 alkyl; Z is one of the following: a) -C(O)R4, -C(O)-(C1-4alkylene)-R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH), or -C(O)-(C3-7cycloalkyl substituted with one - N(R1A)-S(O)2-(C1-6 alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-6alkyl), -C(O)-N(R1A)-(C1-4haloalkyl), -C(O)- N(R1A)-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-O-(C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4alkylene)-N(R1B)-S(O)2-R6, -C(O)-N(R1A)-(C1-4alkylene)- N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4 alkylene)-(C3-7 cycloalkyl), or -C(O)-N(R1A)- S(O)2-R7; c) -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)-N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R1A)-S(O)2-(C1-6 alkyl), -C(O)- C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, -C(O)-C(O)-OH, -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)- N(R1A)(R1B), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R1A)(R1B))- (C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclylcontaining 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)- C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)-S(O)2-(C1-4 alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-N(R1B)-(C1-4haloalkyl), -N(R1A)-C(O)- N(R1B)-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)-C(O)-(morpholinyl), or -N(R1A)- C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH); f) -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6, or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6alkyl), -S(O)2-N(R1A)- C(O)-O-(C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C); h) -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6hydroxyalkyl), -(C1-4alkylene)-C(O)-OH, or -(C1-4alkylene)-C(O)-O-(C1-6alkyl); or i) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A; R4is C1-6hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl;R5is C1-6alkyl, C1-6hydroxyalkyl, -(C1-4alkylene)-(C1-4alkoxyl), C1-6alkoxyl, -(C1-6alkylene)-N(R1A)(R1B), or -(C1-6 alkylene)-N(R1A)-C(O)-O-(C1-6 alkyl); R6is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1-4 alkylene)-(C1-4 alkoxyl); R7is C1-4alkyl, C1-4alkoxyl, C1-6hydroxyalkyl, -(C1-4alkylene)-(C1-4alkoxyl), -(C0-4alkylene)-N(R1A)(R1B), -(C0-6 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4alkyl, hydroxyl, or -C(O)-O-(C1-4alkyl); p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and z is 1, 2, or 3; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, or B1issubstituted with 0 occurrences of R2, then Z is not -C(O)R4or -C(O)- (C1-4 alkylene)-R4.

17. The compound of claim 16, wherein the compound is a compound of Formula I-D.

18. The compound of claim 16 or 17, wherein A2iseach of which is substituted with 0 or 1 occurrences of R3, wherein the nitrogen atom of A2is attached to Z.

19. The compound of claim 16 or 17, wherein A2iswherein the saturated carbon is attached to Z, wherein A2is substituted with 0 or 1 occurrences of R3.

20. The compound of claim 16 or 17, wherein A2issubstituted with 0 or 1 occurrences of R3.

21. The compound of claim 16 or 17, wherein A2issubstituted with 0 or 1 occurrences of R3.

22. The compound of any one of claims 1-6 or 13-21, wherein A1issubstituted with p occurrences of R2.

23. The compound of any one of claims 1-6 or 13-21, wherein.

24. The compound of any one of claims 1-21, wherein A1is substituted with 2, 3, or 4 occurrences of R2.

25. The compound of any one of claims 1-21, wherein.

26. The compound of any one of claims 1-21, wherein A1issubstituted with 1, 2 or 3 occurrences of R2.

27. The compound of any one of claims 1-21, wherein28. The compound of any one of claims 1-21, wherein A1substituted with p occurrences of R2.

29. The compound of any one of claims 1-21, wherein A1is.

30. The compound of any one of claims 1-22 or 28, wherein p is 1, 2, or 3.

31. The compound of any one of claims 1-30, wherein R2represents independently for each occurrence halo.

32. The compound of any one of claims 1-30, wherein R2is fluoro.

33. The compound of any one of claims 1-6 or 13-21, wherein.

34. The compound of any one of claims 1-21, wherein.

35. The compound of any one of claims 1-21, wherein36. The compound of any one of claims 1-21, wherein A1is.

37. The compound of any one of claims 1-36, wherein A2is substituted with 0 occurrences of R3.

38. The compound of any one of claims 1-37, wherein Z is one of the following: a) -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R1A)-C(O)-(C1-4 alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-C(O)- R4, -C(O)-(C1-4alkylene)-N(R1A)-C(O)-(C3-8cycloalkyl substituted with z occurrenceof R9), or -C(O)-(C3-7cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6 alkyl)); b) -C(O)-N(R1A)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R1A)(R1B), -C(O)-N(R1A)-(C1-4alkylene)-N(R1B)-C(O)-(C1-4alkyl), or -C(O)- N(R1A)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl); c) -C(O)-C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-N(R1A)- C(O)-(C1-4alkyl), -C(O)-C(O)-N(R1A)-S(O)2-(C1-6alkyl), or -C(O)-C(O)-(C1-6hydroxyalkyl); d) -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6alkylene)- N(R1C)-S(O)2-(C1-4alkyl); e) -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo); f) -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4alkyl), or -N(R1A)-S(O)2-R7; g) -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)-C(O)- (C1-6 alkyl), or -S(O)2-N(R1A)-C(O)-O-(C1-6 alkyl); or h) a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A.

39. The compound of any one of claims 1-37, wherein Z is -C(O)R4or -C(O)-(C1-4 alkylene)-R4.

40. The compound of any one of claims 1-37, wherein Z is -C(O)-(C1-4alkylene)-N(R1A)-C(O)- (C1-4alkyl), -C(O)-(C1-4alkylene)-N(R1A)-S(O)2-(C1-4alkyl), or -C(O)-(C1-4alkylene)- N(R1A)-C(O)-R4.

41. The compound of any one of claims 1-40, wherein R4is C1-6 hydroxyalkyl.

42. The compound of any one of claims 1-37, wherein Z is -C(O)-(C1-4alkylene)-N(R1A)-C(O)- (C3-8 cycloalkyl substituted with z occurrence of R9), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R1A)-S(O)2-(C1-6alkyl) or -N(R1A)-C(O)-(C1-6alkyl)).

43. The compound of any one of claims 1-37, wherein Z is -C(O)-N(R1A)-(C1-6hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R1A)(R1B), -C(O)-N(R1A)-(C1-6 alkyl), or -C(O)-N(R1A)-(C1-4 haloalkyl).

44. The compound of any one of claims 1-37, wherein Z is -C(O)-N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)- N(R1A)-(C1-4 alkylene)-N(R1B)-C(O)-(C1-4 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1B)-C(O)-O- (C1-6 alkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-C(O)-(C1-6 hydroxyalkyl), -C(O)-N(R1A)-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R1B)-S(O)2-R6, -C(O)- N(R1A)-(C1-4alkylene)-N(R1B)-S(O)2-(C1-4alkyl), -C(O)-N(R1A)-(C0-4alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R1A)-(C1-4alkylene)-(C3-7cycloalkyl), or -C(O)-N(R1A)-S(O)2-R7.

45. The compound of any one of claims 1-37, wherein Z is -C(O)-C(O)-N(R1A)-R5, -C(O)-C(O)- N(R1A)(R1B), -C(O)-C(O)-N(R1A)-(C1-4alkylene)-N(R1A)-C(O)-(C1-4alkyl),-C(O)-C(O)- N(R1A)-S(O)2-(C1-6 alkyl), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R4, or -C(O)-C(O)-OH.

46. The compound of any one of claims 1-37, wherein Z is -C(O)-C(O)-N(R1A)-(C1-6hydroxyalkyl).

47. The compound of any one of claims 1-37, wherein Z is -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4hydroxyalkyl), or -C(O)-O-(C1-4alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9).

48. The compound of any one of claims 1-37, wherein Z is -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6hydroxyalkyl), -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -N(R1A)-C(O)-C(O)-N(R1B)-(C1-4 alkylene)-N(R1C)-C(O)-(C1-4 alkyl), or -N(R1A)-C(O)-C(O)-N(R1B)-(C1-6 alkylene)-N(R1C)- S(O)2-(C1-4alkyl).

49. The compound of any one of claims 1-37, wherein Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R1A)-C(O)-N(R1B)(R1C),-N(R1A)-C(O)-N(R1B)-(C1-4haloalkyl), -N(R1A)-C(O)-N(R1B)-[(C1-4alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R1A)- C(O)-(morpholinyl), or -N(R1A)-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4alkyl and one -OH).

50. The compound of any one of claims 1-37, wherein Z is -N(R1A)-C(O)-N(R1B)-(C1-6 hydroxyalkyl).

51. The compound of any one of claims 1-37, wherein Z is -N(R1A)-C(O)-(C1-4alkylene)- N(R1B)-C(O)-(C1-4 alkyl), -N(R1A)-C(O)-(C1-4 alkylene)-N(R1B)-S(O)2-(C1-4 alkyl), or -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6.

52. The compound of any one of claims 1-37, wherein Z is -N(R1A)-S(O)2-R7.

53. The compound of any one of claims 1-37, wherein Z is -S(O)2-(C1-6hydroxyalkyl), -S(O)2- (C1-4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R5, -S(O)2-N(R1A)-(C1-6 hydroxyalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)- C(O)-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-O-(C1-6alkyl), or -S(O)2-N(R1A)-C(O)-N(R1B)(R1C).

54. The compound of any one of claims 1-37, wherein Z is -(C1-6 hydroxyalkyl), -(C1-4 alkylene)- C(O)-N(R1A)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R1A)-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or -(C1-4alkylene)-C(O)-O-(C1-6alkyl).

55. The compound of any one of claims 1-37, wherein Z is a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R1A.

56. The compound of any one of claims 1-37, wherein Z is -S(O)2-(C1-6hydroxyalkyl).

57. The compound of any one of claims 1-37, wherein,58. The compound of any one of claims 1-37, wherein Z is.

59. The compound of any one of claims 1-37, wherein60. The compound of any one of claims 1-37, wherein.

61. The compound of any one of claims 1-37, wherein.

62. The compound of any one of claims 1-55, wherein R1A, R1B, and R1Care hydrogen.

63. A compound represented by Formula I-1:or a pharmaceutically acceptable salt thereof; wherein: A1issubstituted with p occurrences of R2, wherein B1is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A2is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R3; R1A, R1B, and R1Ceach represent independently for each occurrence hydrogen or C1-4 alkyl; R2represents independently for each occurrence halo; R3is halo or C1-4 alkyl; Z is -C(O)R4, -C(O)-(C1-4 alkylene)-R4, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)- N(R1A)(R1B), -C(O)-O-(C1-4alkylene)-O-(C1-4alkylene)-N(R1A)(R1B), -C(O)-O-(C1-4alkylene substituted with 1 occurrence of -N(R1A)(R1B))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C3-7 cycloalkyl), -S(O)2-N(R1A)(R1B), -S(O)2-N(R1A)-C(O)-(C1-6 alkyl), -S(O)2- N(R1A)-C(O)-O-(C1-6alkyl), -S(O)2-N(R1A)-C(O)-N(R1B)(R1C), -S(O)2-[(C1-4alkylene)-O-]x- R5, -N(R1A)-C(O)-(C1-4alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom), -N(R1A)-C(O)-O-(C1-4 alkylene)-(phenyl), -N(R1A)-C(O)-O-[(C1-4 alkylene)-O-]x-R6, -N(R1A)-C(O)-N(R1B)-[(C1-4 alkylene)-O-]x-R6, -C(O)-N(R1A)-(C1-6 hydroxyalkyl), -C(O)- N(R1A)-(C1-4alkylene)-O-(C1-6hydroxyalkyl), -C(O)-N(R1A)-[(C1-4alkylene)-O-]x-(C1-4alkylene)-N(R1A)(R1B), -N(R1A)-C(O)-N(R1B)-[(C1-6hydroxyalkyl), -C(O)-(C1-4alkylene)- [O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)N(R1B)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)-C(O)-OH, -C(O)-C(O)-N(R1A)(R1B), -N(R1A)-C(O)-(C1-6 hydroxyalkyl), -C(O)-C(O)-N(R1A)-R5, -N(R1A)-C(O)-C(O)-N(R1B)(R1C), -C(O)-N(R1A)-S(O)2-R7, -N(R1A)- S(O)2-R7, -N(R1A)-S(O)2-N(R1B)-CO2-(C1-4 alkylene)-phenyl, -C(O)-C(O)-N(R1A)-S(O)2-(C1- 6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R1A)-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-O-(C1-4alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R9), or hydrogen; R4is C1-6hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl; R5is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), or C1-6 alkoxyl; R6is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl; R7is C1-4alkyl, C1-4alkoxyl, -(C1-4alkylene)-(C1-4alkoxyl), -(C0-4alkylene)- N(R1A)(R1B), or -N(R1B)-C(O)-O-R8; R8is C1-4 alkyl or -(C0-4 alkylene)-(phenyl); R9is oxo, C1-4alkyl, hydroxyl, or -C(O)-O-(C1-4alkyl); m is 1 or 2; n is 1 or 2; p is 0, 1, 2, 3, or 4; x is 1, 2, 3, 4, or 5; and y and z are independently 1, 2, or 3; provided that when B1is a 6-membered aryl ring substituted with 0 or 1 occurrences of R2, then Z is not -C(O)R4or -C(O)-(C1-4alkylene)-R4.

64. The compound of claim 63, wherein the compound is a compound of Formula I-1.

65. The compound of claim 63 or 64, wherein A1is.

66. The compound of claim 63 or 64, wherein A1is.

67. The compound of any one of claims 63-66, wherein A2is, each of which issubstituted with 0 or 1 occurrences of R3, or a covalent bond, wherein *** is the point of attachment to Z.

68. The compound of claim 63, wherein the compound is a compound of Formula Id:or a pharmaceutically acceptable salt thereof, wherein X is -C(H)- or -N-.

69. The compound of any one of claims 63-68, wherein, each of which is substituted with 0 or 1 occurrences of R3, wherein ***is the point of attachment to Z.

70. The compound of any one of claims 63-69, wherein Z is,.

71. The compound of any one of claims 63-69, wherein Z is.

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

73. The compound of claim 72, wherein the compound is a compound in the table below, or a pharmaceutically acceptable salt thereof:

713.

74. A pharmaceutical composition comprising a compound of any one of claims 1-73 and a pharmaceutically acceptable carrier.

75. A method for treating a disease or condition mediated by NAMPT, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-73 to treat the disease or condition.

76. The method of claim 75, wherein said disease or condition mediated by NAMPT is a proliferative disorder.

77. The method of claim 75, wherein said disease or condition mediated by NAMPT is an inflammatory disorder.

78. The method of claim 75, wherein said disease or condition mediated by NAMPT is a metabolic disorder.

79. The method of claim 75, wherein said disease or condition mediated by NAMPT is selected from cancer, neoplasia, chronic inflammatory disorder, acute inflammatory disorder, auto- inflammatory disorder, metabolic disorder, and a combination thereof.

80. The method of claim 75, wherein said disease or condition mediated by NAMPT is cancer.

81. The method of claim 80, wherein the cancer is pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, a lymphoma, leukemia, ovarian cancer, uterine cancer, endometrial cancer, testicular cancer, brain cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, sebaceous gland carcinoma, gallbladder cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, urothelial cancer, colorectal cancer, or glioblastoma multiforme.

82. The method of claim 80, wherein the cancer is thyroid cancer, duodenal, neuroendocrine carcinoma (NEC), uterine cancer, small cell lung cancer (SCLC), hepatocellular carcinoma, mesothelioma, breast cancer, sarcoma, ovarian cancer, renal cell carcinoma, rectal cancer, head and neck cancer, prostate cancer, pancreatic cancer, melanoma, colorectal cancer, cervix cancer, non-small cell lung cancer (NSCLC), cholangiocarcinoma, or endometrial cancer.

83. The method of any one of claims 79-82, wherein the cancer is a NAPRT-negative cancer.

84. The method of claim 75, wherein said disease or condition mediated by NAMPT 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.

85. The method of claim 75, wherein said disease or condition mediated by NAMPT is multiple sclerosis, ankylosing spondylitis, arthritis, osteoarthritis, juvenile arthritis, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, acquired immunodeficiency syndrome (AIDS), Coeliac disease, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn’s disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, asthma, uveitis, rosacea, dermatitis, alopecia areata, vitiligo, arthritis, Type 1 diabetes, lupus erythematosus, systemic lupus erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, nephrotic syndrome, eosinophilia fasciitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome, idiopathic thrombocytopenia purpura, restenosis following angioplasty, a tumor, or atherosclerosis.

86. The method of claim 75, wherein said disease or condition mediated by NAMPT is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease.

87. The method of claim 75, wherein said disease or condition mediated by NAMPT is inflammatory bowel disease (IBD).

88. The method of claim 75, wherein said disease or condition mediated by NAMPT is an autoimmune disease or atherosclerosis.

89. The method of any one of claims 75-88, wherein the subject is a human.

90. A method of inhibiting the activity of NAMPT, comprising contacting a NAMPT with an effective amount of a compound of any one of claims 1-73 to inhibit the activity of said NAMPT.

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