Compounds for inhibiting or degrading ITK, compositions containing same, methods for making same, and methods for using same

Abstract

Inhibition and / or degradation of IL-2 inducible T cell kinase (ITK). Treatment of inflammatory, autoimmune, and proliferative diseases and disorders. [Solution] Provided herein are compounds for inhibiting and / or degrading IL-2 inducible T cell kinase (ITK), compositions comprising the compounds, methods of making the same, and methods of using them to treat diseases or disorders, including cancer, inflammatory diseases, and autoimmune diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a PCT international application claiming the benefit of U.S. Provisional Patent Application No. 63 / 183,617, filed May 3, 2021, the entire contents of which are incorporated herein by reference.

[0002] Technical Field

[0002] Provided herein are compounds for inhibiting and / or degrading IL-2-inducible T cell kinase, compositions containing the compounds, methods for making the same, and methods for using them to treat diseases or disorders including cancer, inflammatory diseases, and autoimmune diseases. [Background technology]

[0003] background IL-2-inducible T cell kinase (ITK) is a tyrosine protein kinase and a member of the TEC family of kinases. Gibson et al., 1993, Blood 82(5):1561-1572. ITK is highly expressed in T cells. Gomez-Rodriguez et al., 2011, FEBS J. 278(12):1980-1989. ITK has been reported to be activated downstream of the T cell receptor (TCR) by phosphorylation from Lck kinase. Gomez-Rodriguez et al., 2011. ITK is thought to activate phospholipase Cγ1 (PLCγ1) to drive T cell function and immune responses. Gomez-Rodriguez et al., 2011; Kosaka et al., 2006, Trends Immunol. 27(10):453-60. ITK has been shown to be involved in many inflammatory, autoimmune, and proliferative diseases, including allergic asthma, atopic dermatitis, aplastic anemia, inflammatory bowel disease, neuroinflammation, and T-cell lymphoma. (Lechner et al., 2020, J. Mol. Medicine 98:1385-1395) ITK provides a promising target for therapeutics to treat several inflammatory, autoimmune, and proliferative diseases and disorders. Summary of the Invention [Means for solving the problem]

[0004] overview Provided herein are compounds capable of binding to, inhibiting, and / or degrading ITK, which are useful for treating or preventing inflammatory, autoimmune, and proliferative diseases and disorders in a subject in need thereof.

[0005] In a first aspect, a compound represented by formula (A): ITK Hook-Linker-Ubiquitin Ligase Harness (A) Provided herein are compounds comprising an ITK hook. The ITK hook is a moiety capable of binding to ITK in vitro, in vivo, and / or in cells. Useful ITK hooks are described herein. The ubiquitin ligase harness is a moiety capable of linking to a ubiquitin ligase in vitro, in vivo, and / or in cells. In certain embodiments, the ubiquitin ligase is an E3 ligase. In certain embodiments, the ubiquitin ligase is cereblon. Useful ubiquitin ligase harnesses are described herein. The compounds further comprise a linker. A linker is any moiety that covalently binds to the harness and hook, allowing each to bind or link to its target. By linking to a ubiquitin ligase and binding to ITK, the compounds can target ITK for degradation under appropriate conditions, e.g., in cells. As shown in the examples herein, the compounds degrade ITK in splenocytes and in vivo. Degrading ITK provides a useful mechanism for treating inflammatory, autoimmune, and proliferative diseases and disorders in subjects in need thereof.

[0006] In one embodiment, a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof: [ka] are provided herein. The left side of the molecule is the ubiquitin ligase harness. The right side of the molecule is the ITK hook. The middle part of the molecule is a linker. The compounds are described in detail herein.

[0007]

[0007] In another aspect, provided herein is a pharmaceutical composition, which comprises a compound together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0008]

[0008] In another aspect, provided herein are methods of treating or preventing a disease or disorder in a subject in need thereof. In certain embodiments, the disease or disorder is an inflammatory disease or disorder. In certain embodiments, the disease or disorder is an autoimmune disease or disorder. In certain embodiments, the disease or disorder is a proliferative disease or disorder, such as T-cell lymphoma. In another aspect, provided herein are compounds and compositions for use in therapy. In another aspect, provided herein are compounds and compositions for use in the treatment or prevention of inflammatory, autoimmune, or proliferative diseases and disorders. In another aspect, provided herein are uses of compounds and compositions for the manufacture of a medicament. In another aspect, provided herein are uses of compounds and compositions for the manufacture of a medicament for the treatment or prevention of inflammatory, autoimmune, or proliferative diseases and disorders.

[0009]

[0009] In another aspect, provided herein are methods of making the compounds or compositions, the synthetic procedures for their preparation being described in detail herein.

[0010] The compounds and compositions are useful for binding to, inhibiting, and / or degrading ITK in vitro, in vivo, and / or intracellularly, and are therefore useful for treating or preventing inflammatory, autoimmune, or proliferative diseases and disorders. [Brief explanation of the drawings]

[0011] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0011] Figure 1 shows in vitro degradation of ITK in the HiBiT cell line. [Figure 2]

[0012] 1 shows the in vivo degradation of ITK in mouse splenocytes. [Figure 3A]

[0013] 1 shows the in vivo degradation of ITK in mouse splenocytes following administration of compounds provided herein, as observed by Western blotting. [Figure 3B]

[0013] Figure 1 shows a graph of ITK levels in mouse splenocytes after administration of compounds provided herein. [Figure 4A]

[0014] 1 shows the in vivo degradation of ITK in mouse splenocytes following administration of compounds provided herein, as observed by Western blotting. [Figure 4B]

[0014] Figure 1 shows a graph of ITK levels in mouse splenocytes after administration of compounds provided herein. [Figure 4C]

[0014] Figure 1 shows compound concentrations over time in vivo. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description of the Preferred Embodiments

[0015] Provided herein are compounds for inhibiting and / or degrading IL-2-inducible T cell kinase, compositions comprising the compounds, methods for making the same, and methods for using them to treat diseases or disorders, including cancer, inflammatory diseases, and autoimmune diseases.

[0013] definition

[0016] For purposes of this specification, chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0014]

[0017] As used herein, a "protecting group" refers to a moiety or functional group that is introduced into a molecule by chemical modification of the functional group to obtain chemoselectivity in a subsequent chemical reaction. Standard protecting groups are listed in Wuts and Greene: "Greene's Protective Groups in Organic Synthesis," 4th Ed., Wuts, P.G.M. and Greene, T.W., Wiley-Interscience, New York: 2006.

[0015]

[0018] As described herein, the compounds herein may be optionally substituted with one or more substituents such as those generally set forth herein, or as exemplified by the specific classes, subclasses, and species herein.

[0016]

[0019] As used herein, the term "hydroxyl" or "hydroxy" refers to an --OH moiety.

[0017]

[0020] As used herein, the term "aliphatic" encompasses the terms alkyl, alkenyl, and alkynyl, each of which is optionally substituted as described below.

[0018]

[0021] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1 to 12 (e.g., 1 to 8, 1 to 6, or 1 to 4) carbon atoms. The alkyl group can be straight-chained or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. Alkyl groups include halo, phospho, alicyclic (e.g., cycloalkyl or cycloalkenyl), heteroalicyclic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic)carbonyl, (alicyclic)carbonyl, or (heteroalicyclic)carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, and the like). and optionally substituted with one or more substituents such as aryl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g., aliphatic amino, cycloaliphatic amino, or heteroalicyclic amino), sulfonyl (e.g., aliphatic -SO2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.Some examples of substituted alkyl include, but are not limited to, carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (alicyclic)alkyl, or haloalkyl.

[0019]

[0022] As used herein, an "alkenyl" group refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 4 or 2 to 6) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight-chained or branched. Examples of alkenyl groups include, but are not limited to, allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl. Alkenyl groups include halo, phospho, alicyclic (e.g., cycloalkyl or cycloalkenyl), heteroalicyclic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic)carbonyl, (alicyclic)carbonyl, or (heteroalicyclic)carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkenyl, The alkyl group may be optionally substituted with one or more substituents such as alkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g., aliphatic amino, alicyclic amino, heteroalicyclic amino, or aliphatic sulfonylamino), sulfonyl (e.g., alkyl-SO2-, alicyclic-SO2-, or aryl-SO2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, alicyclicoxy, heteroalicyclicoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.Some examples of substituted alkenyls include, but are not limited to, cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-SO2-amino)alkenyl), aminoalkenyl, amidoalkenyl, (alicyclic)alkenyl, or haloalkenyl.

[0020]

[0023] As used herein, an "alkynyl" group refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 4 or 2 to 6) carbon atoms and having at least one triple bond. Alkynyl groups can be straight-chained or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups include aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl (e.g., aliphatic sulfanyl or alicyclic sulfanyl), sulfinyl (e.g., aliphatic sulfinyl or alicyclic sulfinyl), sulfonyl (e.g., aliphatic -SO2-, aliphatic amino-SO2-, or alicyclic -SO2-), amido (e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl,

[0047] The cycloaliphatic amino group may be optionally substituted with one or more substituents such as cycloaliphatic, ...

[0021]

[0024] As used herein, "amide" encompasses both "aminocarbonyl" and "carbonylamino." These terms, when used alone or with another group, include -N(R X )-C(O)-R Y or -C(O)-N(RX )2, and -C(O)-N(R when used internally X )- or -N(R X )-C(O)-, where R X and R Y can be aliphatic, alicyclic, aryl, araliphatic, heteroalicyclic, heteroaryl, or heteroaraliphatic. Examples of amide groups include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heteroalicyclic)amide, (heteroaralkyl)amide, (heteroaryl)amide, (heterocycloalkyl)alkylamide, arylamide, aralkylamide, (cycloalkyl)alkylamide, or cycloalkylamide.

[0022]

[0025] As used herein, an "amino" group is -NR X R Y where R X and R Y is independently hydrogen (H or -H), aliphatic, alicyclic, (alicyclic)aliphatic, aryl, araliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which is defined herein and optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), it is not an -NR X - where R X has the same meaning as defined above.

[0023]

[0026] As used herein, an "aryl" group, used alone or as part of a larger moiety, such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, or tetrahydroindenyl); and tricyclic (e.g., fluorenyltetrahydrofluorenyl, tetrahydroanthracenyl, or anthracenyl) ring systems, where the monocyclic ring system is aromatic or at least one of the rings of the bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2- to 3-membered carbocyclic rings. For example, benzo-fused groups include groups having two or more C 4~8 Included are phenyls fused to carbocyclic moieties. Aryl includes aliphatic (e.g., alkyl, alkenyl, or alkynyl); alicyclic; (alicyclic)aliphatic; heteroalicyclic; (heteroalicyclic)aliphatic; aryl; heteroaryl; alkoxy; (alicyclic)oxy; (heteroalicyclic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on the non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl (e.g., (aliphatic)carbonyl; (alicyclic)carbonyl). Aryl is optionally substituted with one or more substituents including: ((alicyclic)aliphatic)carbonyl; (araliphatic)carbonyl; (heteroalicyclic)carbonyl; ((heteroalicyclic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl); sulfonyl (e.g., aliphatic -SO2- or amino-SO2-); sulfinyl (e.g., aliphatic -S(O)- or alicyclic -S(O)-); sulfanyl (e.g., aliphatic -S-); cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamido; or carbamoyl. Alternatively, aryl can be unsubstituted.

[0024]

[0027] Non-limiting examples of substituted aryls include haloaryls (e.g., mono-, di-(p,m-dihaloaryls, etc.), and (trihalo)aryls); (carboxy)aryls (e.g., (alkoxycarbonyl)aryls, ((aralkyl)carbonyloxy)aryls, and (alkoxycarbonyl)aryls); (amido)aryls (e.g., (aminocarbonyl)aryls, (((alkylamino)alkyl)aminocarbonyl)aryls, (alkylcarbonyl)aminoaryls, (arylaminocarbonyl)aryls, and (((heteroaryl)amino)carbonyl)aryls); aminoaryls (e.g., ((alkylsulfonyl)amino)aryls or ((dialkyl)amino)aryls); (cyanoalkyl)aryls; (alkoxy)aryls; (sulfamoyl)aryls (e.g., (amino) (aminosulfonyl)aryl; (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heteroalicyclic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heteroalicyclic)-o-(alkyl))aryl.

[0025]

[0028] As used herein, "araliphatic," such as an "aralkyl" group, refers to an aliphatic group substituted with an aryl group (e.g., C 1~4 "Aliphatic", "alkyl", and "aryl" are defined herein. An example of an araliphatic, such as an aralkyl, group is benzyl.

[0026]

[0029] As used herein, an "aralkyl" group refers to an alkyl group substituted with an aryl group (e.g., C 1~4 "Alkyl" and "aryl" are both defined above. An example of an aralkyl group is benzyl. Aralkyl refers to an aliphatic (e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl, including trifluoromethyl), alicyclic (e.g., cycloalkyl or cycloalkenyl), (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyl and optionally substituted with one or more substituents such as aryloxy, amido (e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino), cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0027]

[0030] As used herein, "bicyclic ring system" includes 6- to 12-membered (e.g., 8- to 12-membered or 9-, 10-, or 11-membered) structures forming two rings, where the two rings have at least one atom in common (e.g., two atoms in common). Bicyclic ring systems include bicycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryl, and bicyclic heteroaryl.

[0028]

[0031] As used herein, an "alicyclic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which is optionally substituted as described below.

[0029]

[0032] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0030]

[0033] As used herein, a "cycloalkenyl" group refers to a non-aromatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-dienyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0031]

[0034] A cycloalkyl or cycloalkenyl group can be phospho, aliphatic (e.g., alkyl, alkenyl, or alkynyl), alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or or (heteroaraliphatic)carbonylamino), nitro, carboxy (e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy), acyl (e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl), cyano, halo, hydroxy, mercapto, sulfonyl (e.g., alkyl-SO- and aryl-SO-), sulfinyl (e.g., alkyl-S(O)-), sulfanyl (e.g., alkyl-S-), sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0032]

[0035] As used herein, the term "heteroalicyclic" encompasses heterocycloalkyl and heterocycloalkenyl groups, each of which is optionally substituted as described below.

[0033]

[0036] As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered monocyclic or bicyclic (fused, bridged, or spiro) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure in which one or more of the ring atoms is a heteroatom (e.g., nitrogen (N), oxygen (O), sulfur (S), or a combination thereof). Non-limiting examples of heterocycloalkyl groups include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholinyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, o- ... octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, decahydro-2,7-naphthyridine, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydro-1H-pyrrolo[3,4-b]pyridine, and 2,6-dioxa-tricyclo[3.3.1.0]octyl. 3,7 Monocyclic heterocycloalkyl groups can be fused with a phenyl moiety to form structures such as tetrahydroisoquinoline, which can be classified as heteroaryls.

[0034]

[0037] As used herein, a "heterocycloalkenyl" group refers to a monocyclic or bicyclic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds, in which one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicyclic heteroalicyclic rings are numbered according to standard chemical nomenclature.

[0035]

[0038] A heterocycloalkyl or heterocycloalkenyl group can be phospho, aliphatic (e.g., alkyl, alkenyl, or alkynyl), alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or or (heteroaraliphatic)carbonylamino), nitro, carboxy (e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy), acyl (e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl), nitro, cyano, halo, hydroxy, mercapto, sulfonyl (e.g., alkylsulfonyl or arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0036]

[0039] As used herein, a "heteroaryl" group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, one or more of which is a heteroatom (e.g., N, O, S, or a combination thereof), and in which the monocyclic ring system is aromatic or in which at least one of the rings of a bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo-fused ring systems having two to three rings. For example, benzo-fused groups include benzo (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophen-yl, quinolinyl, or isoquinolinyl) fused with one or two 4- to 8-membered heteroalicyclic moieties. Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolidyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl. Other examples of heteroaryls include 1,2,3,4-tetrahydroisoquinoline and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

[0037]

[0040] Monocyclic heteroaryls include, but are not limited to, furyl, thiophen-yl, 2H-pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0038]

[0041] Bicyclic heteroaryls include, but are not limited to, indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0039]

[0042] Heteroaryl includes aliphatic (e.g., alkyl, alkenyl, or alkynyl); alicyclic; (alicyclic)aliphatic; heteroalicyclic; (heteroalicyclic)aliphatic; aryl; heteroaryl; alkoxy; (alicyclic)oxy; (heteroalicyclic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl (e.g., aliphatic carbonyl; (alicyclic)carbonyl). Heteroaryl is optionally substituted with one or more substituents such as carbonyl; ((alicyclic)aliphatic)carbonyl; (araliphatic)carbonyl; (heteroalicyclic)carbonyl; ((heteroalicyclic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl; sulfonyl (e.g., aliphatic sulfonyl or aminosulfonyl); sulfinyl (e.g., aliphatic sulfinyl); sulfanyl (e.g., aliphatic sulfanyl); nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamido; or carbamoyl. Alternatively, heteroaryl can be unsubstituted.

[0040]

[0043] Non-limiting examples of substituted heteroaryls include (halo)heteroaryls (e.g., mono- and di-(halo)heteroaryls); (carboxy)heteroaryls (e.g., (alkoxycarbonyl)heteroaryls); cyanoheteroaryls; aminoheteroaryls (e.g., ((alkylsulfonyl)amino)heteroaryls and ((dialkyl)amino)heteroaryls); (amido)heteroaryls (e.g., aminocarbonylheteroaryls, ((alkylcarbonyl)amino)heteroaryls, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryls, (((heteroaryl)amino)carbonyl)heteroaryls, ((heteroalicyclic)carbonyl)heteroaryls, and ((alkylcarbonyl)amino)heteroaryls); (cyanoalkyl)heteroaryls; (alkoxy)heteroaryls; (sulfamoyl)heteroaryls. Heteroaryl (e.g., (aminosulfonyl)heteroaryl); (sulfonyl)heteroaryl (e.g., (alkylsulfonyl)heteroaryl); (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl)heteroaryl; (heteroalicyclic)heteroaryl; (alicyclic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl (e.g., (alkylcarbonyl)heteroaryl); (alkyl)heteroaryl; or (haloalkyl)heteroaryl (e.g., trihaloalkylheteroaryl).

[0041]

[0044] As used herein, a "heteroaraliphatic" (e.g., heteroaralkyl) group refers to an aliphatic group (e.g., C 1~4 "Aliphatic," "alkyl," and "heteroaryl" are defined above.

[0042]

[0045] As used herein, a "heteroaralkyl" group refers to an alkyl group substituted with a heteroaryl group (e.g., C 1~4 "Heteroaralkyl" refers to alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, and optionally substituted with one or more substituents such as carboxyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0043]

[0046] As used herein, "cyclic moiety" and "cyclic group" refer to monocyclic, bicyclic, and tricyclic ring systems, including alicyclic, heteroalicyclic, aryl, or heteroaryl, each of which has been previously defined.

[0044]

[0047] As used herein, "bridged bicyclic ring system" refers to a bicyclic heteroalicyclic ring system or a bicyclic alicyclic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0]octyl. 3,7 Bridged bicyclic ring systems include alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, and the like. The heteroarylcarbonylamino may be optionally substituted with one or more substituents such as aryl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0045]

[0048] As used herein, an "acyl" group refers to a formyl group or R X -C(O)- (e.g., alkyl-C(O)-, also known as "alkylcarbonyl"), where R X and "alkyl" has been previously defined. Acetyl and pivaloyl are examples of acyl groups.

[0046]

[0049] As used herein, "aroyl" or "heteroaroyl" refers to aryl-C(O)- or heteroaryl-C(O)-, where the aryl and heteroaryl portions of the aroyl or heteroaroyl are optionally substituted as previously defined herein.

[0047]

[0050] As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" has been previously defined herein.

[0048]

[0051] As used herein, a "carbamoyl" group refers to a group having the structure -O-CO-NR X R Y or -NR X -CO-OR Z where R X and R Y is defined above, and R Z can be aliphatic, aryl, araliphatic, heteroalicyclic, heteroaryl, or heteroaraliphatic.

[0049]

[0052] As used herein, a "carboxy" group refers to -COOH when used as a terminal group; or -OC(O)-, or -C(O)O- when used as an internal group.

[0050]

[0053] As used herein, an ester is an ester when used as a terminal group. X or -COOR when used as an internal group X - refers to where R X is defined above.

[0051]

[0054] As used herein, formate refers to —OC(O)H.

[0052]

[0055] As used herein, acetate is —OC(O)RX where R X is defined above.

[0053]

[0056] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with one to three halogens. For example, the term haloalkyl includes the group -CF.

[0054]

[0057] As used herein, a "mercapto" or a "sulfhydryl" group refers to --SH.

[0055]

[0058] As used herein, a "sulfo" group is -SO3H when used terminally, or -SO3R X , or S(O)3- when used internally.

[0056]

[0059] As used herein, a "sulfamido" group has the structure -NR when used terminally. X -S(O)2-NR Y R Z , and -NR when used internally X -S(O)2-NR Y - refers to where R X , R Y , and R Z is defined above.

[0057]

[0060] As used herein, a "sulfamoyl" group refers to a group having the structure -OS(O)-NR Y R Z where R Y , and R Z is defined above.

[0058]

[0061] As used herein, a "sulfonamide" group has the structure -S(O)-NR when used terminally. X R Y , or -NR X -S(O)2-R Z or -S(O)2-NR when used internallyX - or -NR X -S(O)2-, where R X , R Y , and R Z is defined above.

[0059]

[0062] As used herein, a "sulfanyl" group is defined as -SR when used terminally. X , and when used internally refers to -S-, where R X is defined above. Examples of sulfanyl include aliphatic-S-, alicyclic-S-, aryl-S-, and the like.

[0060]

[0063] As used herein, a "sulfinyl" group when used terminally is -S(O)-R X , and when used internally refers to -S(O)-, where R X is defined above. Examples of sulfinyl groups include aliphatic -S(O)-, aryl-S(O)-, (alicyclic (aliphatic))-S(O)-, cycloalkyl-S(O)-, heteroalicyclic-S(O)-, heteroaryl-S(O)-, and the like.

[0061]

[0064] As used herein, a "sulfonyl" group refers to a group that is -S(O)-R when used terminally. X and when used internally refers to -S(O)2-, where R X is defined above. Examples of sulfonyl groups include aliphatic -S(O)-, aryl-S(O)-, (alicyclic(aliphatic))-S(O)-, alicyclic-S(O)-, heteroalicyclic-S(O)-, heteroaryl-S(O)-, (alicyclic(amido(aliphatic)))-S(O)-, and the like.

[0062]

[0065] As used herein, a "sulfoxy" group refers to a group that, when used terminally, is -OS(O)-R X , or -S(O)-OR X, and when used internally refers to -OS(O)-, or -S(O)-O-, where R X is defined above.

[0063]

[0066] As used herein, a "halogen" or "halo" group refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0064]

[0067] As used herein, "alkoxycarbonyl," encompassed by the term carboxy, used alone or with another group, refers to groups such as alkyl-OC(O)-.

[0065]

[0068] As used herein, "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, where alkyl is defined above.

[0066]

[0069] As used herein, "carbonyl" refers to --C(O)--.

[0067]

[0070] As used herein, "oxo" refers to =O.

[0068]

[0071] As used herein, the term "phospho" refers to phosphinates and phosphonates. Examples of phosphinates and phosphonates include -P(O)(R P )2, where R P is aliphatic, alkoxy, aryloxy, heteroaryloxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryl, heteroaryl, alicyclic or amino.

[0069]

[0072] As used herein, an “aminoalkyl” refers to a group having the structure (R X )2N-alkyl-.

[0070]

[0073] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.

[0071]

[0074] As used herein, a "urea" group has the structure -NR X -CO-NR Y R Z and "thiourea" groups have the structure -NR when used at the terminal end. X -CS-NR Y R Z , and -NR when used internally, respectively. X -CO-NR Y -or-NR X -CS-NR Y - refers to where R X , R Y , and R Z is defined above.

[0072]

[0075] As used herein, a "guanidine" group refers to a group having the structure -N=C(N(R X R Y ))N(R X R Y ) or -NR X -C(=NR X )NR X R Y where R X and R Y is defined above.

[0073]

[0076] As used herein, the term "amidino" group refers to a group having the structure -C=(NR X )N(R X R Y ), where R X and R Y is defined above.

[0074]

[0077] As used herein, the term "vicinal" generally refers to the arrangement of substituents on a group containing two or more carbon atoms where the substituents are attached to adjacent carbon atoms.

[0075]

[0078] As used herein, the term "geminal" generally refers to the arrangement of substituents on a group containing two or more carbon atoms, wherein the substituents are attached to the same carbon atom.

[0076]

[0079] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal if it is at the end of the substituent and is not further attached to the remainder of the chemical structure. Carboxyalkyl (i.e., R X An example of a carboxy group used terminally is an alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and an alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally. An example of a carboxy group used terminally is an alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and an alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0077]

[0080] As used herein, "aliphatic chain" refers to a branched or straight-chain aliphatic group (e.g., an alkyl group, an alkenyl group, or an alkynyl group). A straight-chain aliphatic chain has the structure -[CH] v -, where v is 1 to 12. A branched aliphatic chain is a linear aliphatic chain substituted with one or more aliphatic groups. A branched aliphatic chain has the structure -[CQQ] v where each Q is independently hydrogen (H or -H) or an aliphatic group; provided that Q is an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

[0078]

[0081] The phrase "optionally substituted" is used interchangeably herein with the phrase "substituted or unsubstituted." As described herein, the compounds herein can be optionally substituted with one or more substituents, such as those generally set forth above or exemplified by specific classes, subclasses, and species herein. As described herein, the variables R, R included in formulas (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), and (VIb) described herein can be optionally substituted with one or more substituents. 1 , R 2 , L, and Z 1 , and other variables encompass specific groups such as alkyl and aryl. Unless otherwise specified, the variables R, R 10 , R A , R 1 , R 2 , L, L 1 Each specific group for D, W, E, V, G, Y, and Z, as well as the other variables contained therein, can be optionally substituted with one or more substituents described herein. Each substituent of a specific group can be further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, alicyclic, heteroalicyclic, heteroaryl, haloalkyl, and alkyl. For example, an alkyl group can be substituted with alkylsulfanyl, which can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As a further example, the cycloalkyl portion of (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atoms to which they are bound.

[0079]

[0082] As used herein, the term "substituted," whether preceded by the term "optionally" or not, generally refers to the replacement of a hydrogen atom in a given structure with a radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and their examples. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and when two or more positions in any given structure may be substituted with two or more substituents selected from a specified group, the substituents may be the same or different at each position. A ring substituent, such as a heterocycloalkyl, can be bonded to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. Non-limiting examples of spiro-heterocycloalkyl include:

[0083] [ka] Spiro compounds represented by overlapping rings indicate that the rings can be attached at any vertex. For example, a spiro group [ka] In the formula (I), the two rings can be joined at any of the three available vertex atoms on either ring.

[0080]

[0084] One skilled in the art will recognize that combinations of substituents envisioned by this description are those that result in the formation of stable or chemically feasible compounds.

[0081]

[0085] As used herein, the phrase "stable or chemically feasible" refers to a compound that does not change substantially when subjected to conditions that allow for the production, detection, and recovery, purification, and use of the compounds for one or more of the purposes disclosed herein. In certain embodiments, a stable compound or a chemically feasible compound is one that does not change substantially when kept at a temperature of 40° C. or less in the absence of moisture or other chemically reactive conditions for at least one week.

[0082]

[0086] As used herein, "effective amount" is defined as the amount required to provide a therapeutic effect to the treated patient, and is typically determined based on the patient's age, surface area, weight, and condition. The correlation of dosages for animals and humans (based on milligrams per square meter of body surface area) is described in Freireich et al., Cancer Chemother. Rep., 50:219 (1966). Body surface area can be approximately determined from the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

[0083]

[0087] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and that does not contain additional ingredients that are unacceptably toxic to the individual to whom the formulation or composition may be administered. Such a formulation or composition may be sterile.

[0084]

[0088] As used herein, the term "excipient" includes a pharmaceutically acceptable excipient, carrier, vehicle, or stabilizer that is non-toxic to cells or mammals exposed thereto at the dosages and concentrations employed. In certain embodiments, the physiologically acceptable excipient is an aqueous pH buffered solution.

[0085]

[0089] The terms "treating" or "treatment" of a disease refer to carrying out a protocol that may include administering one or more therapeutic agents to an individual (human or otherwise) to obtain a beneficial or desired result in the individual, including a clinical result. In certain embodiments, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, reduction in the extent of the disease, a stable (i.e., not worsening) state of the disease, prevention of disease spread, delay or slowing of disease progression, improvement or reduction in disease symptoms, and remission (whether partial or total). In certain embodiments, "treatment" can also mean prolonging survival as compared to the expected survival of an individual not receiving treatment. In certain embodiments, "treating" and "treatment" may occur by administration of a single dose of one or more therapeutic agents, or may occur over the administration of a series of doses of one or more therapeutic agents. In certain embodiments, "treating" or "treatment" does not require complete alleviation of signs or symptoms, and does not require a cure. In certain embodiments, "treatment" may also refer to clinical intervention, such as administering to an individual one or more therapeutic agents designed to alter the natural course of the individual or cell being treated (i.e., to alter the course of the individual or cell that would occur in the absence of clinical intervention). In certain embodiments, the term "therapeutic agent" may refer to a CTM drug, or composition thereof, that induces proteolysis of tyrosine-protein kinase (ITK).

[0086]

[0090] The terms "individual," "patient," or "subject" refer to mammals. In certain embodiments, "mammals" for treatment include humans; non-human primates; domestic and farm animals; and zoo animals, sport animals, or pets, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. In some embodiments, the individual or subject is human.

[0087]

[0091] As used herein, the term "about" means within ±10% of a value. For example, a dose of about 100 mg / kg indicates that the dose can be from 90 mg / kg to 110 mg / kg. As a further example, an amount of an additional therapeutic agent in the range of about 50% to about 100% indicates that the amount of additional therapeutic agent ranges from 45-55% to 90-110%. Those of skill in the art will understand the range and application of the term "about" when used to describe other values ​​disclosed herein.

[0088]

[0092] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the (R)- and (S)-configuration for each asymmetric center, the (Z)- and (E)-double bond isomers, and the (Z)- and (E)-conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of this specification. Alternatively, as used herein, "enantiomeric excess (ee)" refers to a dimensionless molar ratio that represents the purity of a chiral material containing, for example, a single stereocenter. For example, an enantiomeric excess of 0 would indicate a racemate (e.g., a 50:50 mixture of enantiomers, or one enantiomer in excess of the other). As a further example, an enantiomeric excess of 99 would indicate a nearly stereochemically pure enantiomeric compound (i.e., one enantiomer is in large excess over the other). Percentage enantiomeric excess, % ee = ([(R)-compound] - [(S)-compound]) / ([(R)-compound] + [(S)-compound]) × 100, where (R)-compound > (S)-compound; or % ee = ([(S)-compound] - [(R)-compound]) / ([(S)-compound] + [(R)-compound]) × 100, where (S)-compound > (R)-compound. Furthermore, as used herein, "diastereomeric excess (de)" refers to a dimensionless molar ratio that represents the purity of a chiral substance containing two or more stereocenters. For example, a diastereomeric excess of 0 would indicate an equimolar mixture of diastereoisomers. As a further example, a diastereomeric excess of 99 would indicate a nearly stereochemically pure diastereomeric compound (i.e., one diastereomer is in large excess over the other). Diastereomeric excess can be calculated in a similar manner to ee. As will be understood by those skilled in the art, de is usually reported as percent de (% de). % de can be calculated in a similar manner to % ee.

[0089]

[0093] In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de of greater than 0. For example, in certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de of 10. In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de of 25. In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de of 50. In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de of 75.

[0090]

[0094] In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de range of 90-100. In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de range of 95-100. In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de range of 97-100. In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de range of 98-100. In certain embodiments, the compounds or inhibitors described herein have an ee, de, %ee, or %de range of 99-100.

[0091]

[0095] In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 1. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 2. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 3. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 4. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 5. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 6. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 7. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 8. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 9. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 10. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 11. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 12. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 13. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 14. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 15. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 16. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 17. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 18.In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 19. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 20. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 21. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 22. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 23. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 24. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 25. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 26. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 27. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 28. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 29. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 30. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 31. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 32. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 33. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 34. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 35. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 36.In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 37. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 38. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 39. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 40. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 41. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 42. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 43. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 44. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 45. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 46. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 47. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 48. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 49. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 50. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 51. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 52. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 53. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 54.In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 55. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 56. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 57. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 58. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 59. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 60. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 61. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 62. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 63. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 64. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 65. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 66. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 67. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 68. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 69. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 70. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 71. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 72.In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 73. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 74. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 75. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 76. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 77. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 78. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 79. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 80. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 81. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 82. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 83. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 84. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 85. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 86. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 87. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 88. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 89. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 90.In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 91. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 92. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 93. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is 94. In one embodiment of a compound or inhibitor described herein, ee, de, %ee, or %de is. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 95. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 96. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 97. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 98. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 99. In one embodiment of a compound or inhibitor described herein, the ee, de, %ee, or %de is 100. In certain embodiments, a compound or inhibitor described in Table 1 herein has the ee, de, %ee, or %de as described in this paragraph. In certain embodiments, a compound or inhibitor described in the Examples and / or Biological Examples has the ee, de, %ee, or %de as described in this paragraph. Unless otherwise specified, all tautomers of the compounds herein are within the scope of this specification. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures, except for the replacement of a carbon by a C-enriched carbon, are within the scope of this specification. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0092]

[0096] As used herein, the term "&1" means that a compound containing the designation "&1" at a particular chemical element or atom (e.g., carbon) within that compound was prepared as a mixture of two stereoisomers at the indicated chemical element or atom (e.g., a diastereomeric mixture having de or % de as described above).

[0093]

[0097] Chemical structures and nomenclature are from ChemDraw, version 19.0, Cambridge, MA.

[0094]

[0098] It is noted that the use of descriptors such as "first," "second," "third," etc. are used to distinguish between separate elements (e.g., solvents, reaction steps, processes, reagents, etc.) and may or may not refer to the relative order or relative chronology of the elements described.

[0095] compound

[0099] In one aspect, provided herein are compounds of formula (I), and stereoisomers and pharmaceutically acceptable salts thereof: [ka]

[0096] [000100] In formula (I), R 1 is hydrogen or C 1~3 alkyl; R 2 is hydrogen, substituted or unsubstituted C 1~5 Alkyl, or substituted or unsubstituted C 1~5 Alkoxy; R 3 is methyl, or R 4 is a methylene bonded to form a substituted or unsubstituted cyclopropyl; R 4 is hydrogen or R 3 is a methylene bonded to form a substituted or unsubstituted cyclopropyl. 3 and R 4When X forms a substituted cyclopropyl, the cyclopropyl is substituted with difluoro. 1 is CH or N. In certain embodiments, R 10 is hydrogen or substituted or unsubstituted C 1~8 In certain embodiments, R 10 is hydrogen or methyl. 1 is CH;R 10 is hydrogen. In certain embodiments, X 1 is C;R 10 is methyl. In certain embodiments, X 1 is N;R 10 is hydrogen.

[0097] [000101] In one embodiment, provided herein are compounds of formula (I), and stereoisomers and pharmaceutically acceptable salts thereof: [ka]

[0098] [000102] In formula (I), R 1 is hydrogen or methyl; R 2 is methyl; R 3 is methyl, or R 4 is a methylene bonded to form a substituted cyclopropyl; R 4 is hydrogen or R 3 is a methylene bonded to form a substituted cyclopropyl. 3 and R 4 When X forms a substituted cyclopropyl, the cyclopropyl is substituted with difluoro. 1 is CH or N. In certain embodiments, R 10 is hydrogen or C 1~8 In certain embodiments, R 10 is hydrogen or methyl. 1 is CH;R10 is hydrogen. In certain embodiments, X 1 is C;R 10 is methyl. In certain embodiments, X 1 is N;R 10 is hydrogen.

[0099] [000103] In certain embodiments, compounds of formula II, and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0100] [000104] In certain embodiments, compounds of formula (III), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0101] [000105] In certain embodiments, compounds of formula (IIIa), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0102] [000106] In certain embodiments, compounds of formula (IV), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0103] [000107] In certain embodiments, compounds of formula (IVa), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0104] [000108] In certain embodiments, compounds of formula (V), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0105] [000109] In certain embodiments, compounds of formula (Va), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0106] [000110] In certain embodiments, compounds of formula (Vb), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0107] [000111] In certain embodiments, compounds of formula (VI), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0108] [000112] In certain embodiments, compounds of formula (VIa), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0109] [000113] In certain embodiments, compounds of formula (VIb), and stereoisomers and pharmaceutically acceptable salts thereof: [ka] is provided herein, where the variables are described below.

[0110] [000114] In formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), X 1 is CH or nitrogen. 1 is a heterocycle or -N(R 1 )-heterocycle. In certain embodiments, Z 1 but, [ka] In certain embodiments, each R 6 is hydrogen, halogen, or -C1-C3 alkyl. 6 is hydrogen. In certain embodiments, each R 6 is methyl. In certain embodiments, R a In certain embodiments, o is 1, 2, or 3.

[0111] [000115] In subformulas herein, a wavy line indicates a bond to the rest of the molecule. Unless otherwise specified, a multivalent moiety may be attached to the rest of the molecule in any orientation. When an orientation is specific, a letter is used to indicate the direction of attachment. For example, Z 1 In [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0112] [000116] In formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), L is a linker. The linker can be any linker suitable for connecting the right and left portions of a molecule. In certain embodiments, the linker does not interfere with the harness or hook function of the molecule. In advantageous embodiments, the linker provides useful solubility, flexibility, and / or distance between portions of the molecule. In certain embodiments, L is a group of formula -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 Each group L xare described in detail below. In certain embodiments, the linker comprises at least one heterocyclic group. In certain embodiments, the linker comprises one heterocyclic group. In certain embodiments, the linker comprises two heterocyclic groups. In certain embodiments, the linker comprises three heterocyclic groups. In certain embodiments, the linker comprises at least one spiro bicyclic heterocycloalkylene group. In certain embodiments, the linker comprises one spiro bicyclic heterocycloalkylene group. In certain embodiments, the linker comprises two spiro bicyclic heterocycloalkylene groups. In certain embodiments, the linker comprises three spiro bicyclic heterocycloalkylene groups. In certain embodiments, the linker comprises at least one heterocycloalkylene group and at least one spiro bicyclic heterocycloalkylene. The remaining groups of the linker are selected for chemical compatibility with adjacent groups, as will be recognized by those of skill in the art.

[0113] [000117] In certain embodiments, L is of the formula -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 In certain embodiments, -L 1 -but non-existence, -N(R 21 )-;C(R 22 )-;C 1~8 Alkylene; C 2~8 Alkynylene; Q 1 ; or Q 2 In certain embodiments, each -L 2 -, -L 3 -, -L 4 - and -L 5 - but independently, non-existence; -N(R 21 )-;C(R 22 )-;-C(O)-;-O-;-(CH2-CH2-O) 1~8 -;C 1~8 Alkylene; C 2~8 Alkynylene; Q 1 ;Q2 ; or Q 3 In certain embodiments, each -L 6 - and -L 7 - but independently, non-existence; -N(R 21 )-;-C(R 22 )-;-C(O)-;-C(O)-N(R 21 )-;-N(R 21 )-C(O); or -C(R 22 )-C(O)-N(R 21 In certain embodiments, L is selected from the group consisting of at least one Q 1 In certain embodiments, L is one Q 1 In certain embodiments, L is selected from the group consisting of two Q 1 In certain embodiments, L comprises three Q 1 In certain embodiments, L comprises at least one Q 2 In certain embodiments, L is one Q 2 In certain embodiments, L includes two Q2. In certain embodiments, L includes three Q 2 In certain embodiments, L comprises at least one Q 1 and at least one Q 2 In certain embodiments, L is one Q 1 and one Q 2 Includes:

[0114] [000118] In certain embodiments, each Q 1 is a 3- to 8-membered heterocycloalkylene containing at least one nitrogen, where the heterocycloalkylene is optionally substituted. 2 is a 5- to 13-membered spiro bicyclic heterocycloalkylene containing at least one nitrogen, wherein the heterocycloalkylene is optionally substituted. 3 is a 3- to 6-membered cycloalkylene, where the cycloalkylene is optionally substituted. In certain embodiments, each R 21 is hydrogen or methyl. In certain embodiments, each R22 is hydrogen, methyl, aryl, or heteroaryl.

[0115] [000119] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 2 but, [ka] where R 7 is hydrogen, halogen, or -C1-C3 alkyl; R 5 is hydrogen, halogen, or -C1-C3 alkyl. 7 is hydrogen; R 5 is hydrogen. In certain embodiments, R 5 is -F. In certain embodiments, Z 2 but, [ka] In certain embodiments, Z 2 but, [ka] In certain embodiments, Z 2 but, [ka] In certain embodiments, Z 2 but, [ka] is.

[0116] [000120] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0117] [000121] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0118] [000122] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0119] [000123] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0120] [000124] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0121] [000125] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents a bond to L. In certain embodiments, R a In certain embodiments, o is 1, 2, or 3.

[0122] [000126] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0123] [000127] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0124] [000128] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] wherein: [ka] But X 1 represents a bond to; [ka] represents the bond to L.

[0125] [000129] In certain embodiments of formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), L is [ka] At least one -Q represented by 1 -, wherein n 1 is 1 or 2, and n 2 is 1 or 2.

[0126] [000130] In certain embodiments of formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), L is -Q 1 -N(Me)-CH2-Q 1 -C(O)-; -N(Me)-Q 1 -CH2-Q 1 -C(O)-; -Q 2 -CH2-Q 1 -C(O)-; -Q 1 -CH2-Q 1 -C(O)-; -Q 1 -Q 1 -C(O)-; -Q 1 -CH2-N(Me)-Q 1 -C(O)-; -Q 1 -CH2-Q 1 -CH2-C(O)-N(Me)-; -Q 1 -N(Me)-CH2-Q 1 -C(O)-; -Q 1 -CH2-Q 1 -; -Q 1 -CH2-Q 2 -; -Q 1 -CH2-CH2-Q 1 -; -Q 1 -CH2-CH2-Q 2 -; -Q 1 -C(O)-Q 1 -; -Q 1 -C(O)-Q 2 -; -Q 1 -CH2-Q 1 -N(Me)-C(O)-; -CH2-CH2-CH2-CH2-Q 1 -C(O)-; -Q 1 -CH2-Q 1 -C(O)-; -Q 1 -C(O)-; -Q 1 -C(O)-Q 1 -C(C6H5)-; -C≡CCH2-Q 1 -C(O)-; -Q 1 -C(O)-Q 2 -; -Q 1 -CH2-CH2-Q 2 -; -Q 1 -CH2-Q 1 -N-C(O)-; -CH2-CH2-CH2-Q 1 -C(O)-; -Q 1 -CH2-Q 1 -C(Me)-C(O)-N(Me)-; -Q 1 -Q 1 -C(O)-; -CH2-Q 1 -; -Q 1 -C(O)-Q 1 -CH2-; -N(H)-(CH2)5-C(O)-Q 1 -C(C6H5)-; -N(H)-(CH2)2-O-(CH2)2-C(O)-Q 1 -C(C6H5)-; -Q1 -(CH2)3-C(O)-Q 1 -C(C6H5)-; -Q 2 -C(O)-Q 1 -C(C6H5)-; -Q 2 -CH2-C(O)-Q 1 -C(C6H5)-; -Q 2 -(CH2)3-C(O)-Q 1 -C(C6H5)-; -Q 2 -(CH2)2-C(O)-Q 1 -C(C6H5)-; -(CH2)6-Q 1 -C(C6H5)-; -Q 1 -Q 1 -C(O)-Q 1 -C(C6H5)-; -Q 1 -CH2-C(O)-Q 1 -C(C6H5)-; -Q 1 -(CH2)2-C(O)-Q 1 -C(C6H5)-; -Q 1 -(CH2)3-C(O)-Q 1 -C(C6H5)-; -(CH2)3-C(O)-Q 1 -C(C6H5)-; -(CH2)4-C(O)-Q 1 -C(C6H5)-; -(CH2)5-C(O)-Q 1 -C(C6H5)-; -(CH2)6-C(O)-Q 1 -C(C6H5)-; -(CH2)3-Q 1 -CH2-C(O)-Q 1 -C(C6H5)-; -(CH2)6-Q 1 -C(C6H5)-; -(CH2)6-Q 1 -C(チアゾリル)-; -(CH2)3-OQ3 -C(O)-Q 1 -C(C6H5)-; -(CH2)3-O-(CH2)2-C(O)-Q 1 -C(C6H5)-; -(CH2)3-O-(CH2)2-C(O)-Q 1 -C(thiazolyl)-; -(CH2)3-O-(CH2)2-C(O)-Q 1 -C(pyrid-2-yl)-; -(CH2)4-Q 1 -C(C6H5)-; -(CH2)5-Q 1 -C(C6H5)-; -(CH2)6-Q 1 -C(C6H5)-; -(CH2)6-Q 1 -C(thiazolyl)-; -(CH2)6-Q 1 -C(pyrid-2-yl)-; -(CH2)7-Q 1 -C(C6H5)-; -(CH2)7-Q 1 -C(Me)-C(O)-N(Me)-; -N(H)-(CH2)2-O-(CH2)2-Q 1 -C(Me)-C(O)-N(Me)-; -(CH2)3-O-(CH2)2-C(O)-Q 1 -C(Me)-C(O)-N(Me)-; -N(H)-(CH2)2-O-(CH2)2-Q 1 -C(C6H5)-; -N(H)-(CH2)2-O-(CH2)2-C(O)-Q 1 -C(C6H5)-; -N(H)-(CH2)2-[O-(CH2)2]2-C(O)-Q 1 -C(C6H5)-; -N(H)-(CH2)2-[O-(CH2)2]3-C(O)-Q 1 -C(C6H5)-; -N(H)-(CH2)2-[O-(CH2)2]4-C(O)-Q 1-C(C6H5)-; -N(H)-(CH2)2-[O-(CH2)2]5-C(O)-Q 1 -C(C6H5)-; -N(H)-(CH2)2-[O-(CH2)2]6-C(O)-Q 1 -C(C6H5)-; -N(H)-(CH2)2-[O-(CH2)2]7-C(O)-Q 1 -C(C6H5)-; -N(H)-(CH2)2-[O-(CH2)2]8-C(O)-Q 1 -C(C6H5)-; -N(H)-Q 3 -O-(CH2)2-CH2-; -N(H)-(CH2)3-Q 1 -(CH2)2-; -C(O)-N(H)-[(CH2)3-O]3-(CH2)2-NH-; -C(O)-N(H)-[(CH2)3-O]3-(CH2)2-; -Q 1 -C(O)-[(CH2)2-O]3-(CH2)2-NH-; -Q 1 -(CH2)3-O-CH2-; -Q 1 -C(O)-(C6H6)-CH2-; -Q 1 -(2-ピリジル)-O-CH2-; -N(H)-Q 3 -X-(2-ピリジル)-O-; -N(H)-Q 3 -X-(4-ピリジル)-; -N(H)-(CH2)2-Q 3 -X-(2-ピリジル)-O-CH2-; -CH≡C-(CH2)2Q 1 -; -Q 1 -; -Q 1 -CH2-C(O)-N(CH3)-; -Q 1 -CH2-Q 1 -C(O)-; -Q1 -CH2-CH2-Q 1 -C(O)-; -Q 1 -N(CH3)-C(O)-Q 1 -C(O)-; -CH2-Q 1 -C(O)-; -Q 1 -CH2-Q 1 -; -Q 1 -CH2-C(O)-Q 1 -; -OQ 1 -C(O)-Q 1 -; -C(O)-Q 1 -; -Q 1 -C(O)-Q 1 -; -CH2-C(O)-Q 1 -; -C(O)-Q 1 -CH2-Q 1 -; -C(O)-Q 1 -CH2-Q 1 -C(O)-; -CH2-Q 1 -CH2-Q 1 -C(O)-; -C(O)-Q 1 -CH2-Q 1 -CH2-; -Q 1 -CH2-Q 1 -CH2-; -Q 1 -C(O)-Q 1 -CH2-; and -CH2-Q 1 In certain embodiments, X is oxygen or sulfur.

[0127] [000131] In certain embodiments, L is [ka] At least one -Q selected from the group consisting of 1-, wherein -Q 1 - is optionally mono- or di-substituted with groups independently selected from -F, -CH3, and -CH2CH3.

[0128] [000132] In certain embodiments, L is [ka] At least one -Q represented by 2 -, wherein n 3 is 1 or 2.

[0129] [000133] In certain embodiments, L is [ka] At least one -Q represented by 2 -Includes.

[0130] [000134] In certain embodiments, L is [ka] At least one -Q represented by 2 -, wherein n 4 is 1 or 2, and n 5 is 1 or 2, and n 6 is 1 or 2.

[0131] [000135] In certain embodiments, L is [ka] At least one -Q represented by 2 -Includes.

[0132] [000136] In certain embodiments, L is [ka] At least one -Q represented by 2 -, wherein n 8 is 1 or 2, where -Q 2 - is optionally mono- or di-substituted with groups independently selected from -F, -CH3, and -CH2CH3.

[0133] [000137] In certain embodiments, L is [ka] At least one -Q represented by 2 -, wherein -Q 2 - is optionally mono- or di-substituted with groups independently selected from -F, -CH3, and -CH2CH3.

[0134] [000138] In certain embodiments, L is [ka] At least one -Q represented by 2 -, wherein n 18 and n 19 is 2, or piperidinyl; or n 18 If is 2, then n 19 is 3, or azepanyl; or n 18 If is 3, then n 19 is 2, or azepanil.

[0135] [000139] In certain embodiments, L is [ka] At least one -Q represented by 2 -Includes.

[0136] [000140] In certain embodiments, L is [ka] At least one -Q represented by 2 -, wherein n 22 is 0 to 2; n 23 is 0 to 2, and n 24 is 1 or 2. In certain embodiments, n 22 If is 2, then n 23 and n 24 is 1; or n 22 If is 2, then n 23 and n 24 is 2.

[0137] [000141] In certain embodiments, L is [ka] At least one -Q represented by 2 -Includes.

[0138] [000142] In certain embodiments, L is [ka] At least one -Q represented by 2 -Includes.

[0139] [000143] In certain embodiments, L is [ka] At least one -Q represented by 3 -, wherein n 1 is 1 or 2, and n 2 is 1 or 2.

[0140] [000144] In certain embodiments, L is [ka] At least one -Q selected from the group consisting of 3 -Includes.

[0141] [000145] In certain embodiments, the linker group L is -C(O)-.

[0142] [000146] In certain embodiments of any compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), the linker group L is [ka] [ka] [ka] [ka] [ka] is selected from: [ka] represents the bond to Z; where X is oxygen or sulfur.

[0143] [000147] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0144] [000148] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0145] [000149] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0146] [000150] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0147] [000151] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0148] [000152] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0149] [000153] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0150] [000154] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0151] [000155] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0152] [000156] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0153] [000157] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0154] [000158] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0155] [000159] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), or (IIIa), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0156] [000160] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is -F;R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is -F;R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is -F;R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is -F;R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R7 is methyl.

[0157] [000161] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0158] [000162] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0159] [000163] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0160] [000164] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0161] [000165] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0162] [000166] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0163] [000167] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0164] [000168] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0165] [000169] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl.

[0166] [000170] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0167] [000171] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0168] [000172] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0169] [000173] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0170] [000174] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl. In certain embodiments of this paragraph, R a is halogen, -C1-C3 alkyl, or -C1-C3 alkoxy. In certain embodiments of this paragraph, R a is halogen. In certain embodiments of this paragraph, R a is -C1-C3 alkyl. In certain embodiments of this paragraph, R a is -C1-C3 alkoxy. In certain embodiments of this paragraph, o is 1, 2, 3, or 4. In certain embodiments of this paragraph, o is 1. In certain embodiments of this paragraph, o is 2. In certain embodiments of this paragraph, o is 3. In certain embodiments of this paragraph, o is 4.

[0171] [000175] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl. In certain embodiments of this paragraph, R a is halogen, -C1-C3 alkyl, or -C1-C3 alkoxy. In certain embodiments of this paragraph, R a is halogen. In certain embodiments of this paragraph, R a is -C1-C3 alkyl. In certain embodiments of this paragraph, R a is -C1-C3 alkoxy. In certain embodiments of this paragraph, o is 1, 2, 3, or 4. In certain embodiments of this paragraph, o is 1. In certain embodiments of this paragraph, o is 2. In certain embodiments of this paragraph, o is 3. In certain embodiments of this paragraph, o is 4.

[0172] [000176] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0173] [000177] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0174] [000178] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0175] [000179] In certain embodiments of formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0176] [000180] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl. In certain embodiments of this paragraph, R a is halogen, -C1-C3 alkyl, or -C1-C3 alkoxy. In certain embodiments of this paragraph, R a is halogen. In certain embodiments of this paragraph, R a is -C1-C3 alkyl. In certain embodiments of this paragraph, R a is -C1-C3 alkoxy. In certain embodiments of this paragraph, o is 1, 2, 3, or 4. In certain embodiments of this paragraph, o is 1. In certain embodiments of this paragraph, o is 2. In certain embodiments of this paragraph, o is 3. In certain embodiments of this paragraph, o is 4.

[0177] [000181] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0178] [000182] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), or (VIb), Z 1 but, [ka] and Z 2 but, [ka] In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1is CH;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is hydrogen; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is hydrogen; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is CH;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is hydrogen; R 7 is methyl. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is hydrogen. In certain embodiments of this paragraph, R 1 is methyl; R 10 is methyl; X 1 is N;R 5 is a halogen; R 7 is methyl. In certain embodiments of this paragraph, R 6 is hydrogen. In certain embodiments of this paragraph, R 6 is methyl.

[0179] [000183] In certain embodiments, provided herein are the following compounds in Table 1, and stereoisomers and pharmaceutically acceptable salts thereof:

[0180] [Table 1]

[0181] Table 2

[0182] Table 3

[0183] Table 4

[0184] Table 5

[0185] Table 6

[0186] Table 7

[0187] Table 8

[0188] Table 9

[0189] Table 10

[0190] Table 11

[0191] Table 12

[0192] Table 13

[0193] Table 14

[0194] Table 15

[0195] Table 16

[0196] Table 17

[0197] Table 18

[0198] Table 19

[0199] Table 20

[0200] Table 21

[0201] Table 22

[0202] [Table 23]

[0203] [Table 24]

[0204] [Table 25]

[0205] [Table 26]

[0206] [Table 27]

[0207] [Table 28]

[0208] [Table 29]

[0209] [Table 30]

[0210] [Table 31]

[0211] [Table 32]

[0212] [000184] In certain embodiments, the compound is selected from the compounds in Table 1.

[0213] Pharmaceutical Composition [000185] The compounds described herein can be formulated into pharmaceutical compositions further comprising a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the present disclosure provides a pharmaceutical composition comprising the compound described above and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the present disclosure is a pharmaceutical composition comprising an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients, or carriers suitably selected for the intended form of administration and consistent with conventional pharmaceutical practice.

[0214] [000186] According to another embodiment, the present disclosure provides a composition comprising a compound herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The pharmaceutical composition herein comprises a therapeutically effective amount of a compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (Vb), (VI), (VIa), and / or (VIb), where a "therapeutically effective amount" is (a) an amount effective to measurably degrade ITK (or reduce the amount of ITK) in a biological sample or in a patient; or (b) an amount effective to treat and / or ameliorate a disease or disorder mediated by ITK.

[0215] [000187] As used herein, the term "patient" means an animal, or mammal, or human.

[0216] [000188] It will also be understood that certain compounds of the present disclosure may exist for therapy in free form or, if desired, as a pharmaceutically acceptable derivative thereof (e.g., salt). In accordance with the present disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable prodrug, salt, ester, salt of such ester, or any other adduct / educt or derivative that, upon administration to a patient in need thereof, is capable of directly or indirectly providing a compound otherwise described herein, or a metabolite, or residue thereof.

[0217] [000189] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like.

[0218] [000190] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977,66,1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4(alkyl) 4 salts. The present specification also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, optionally formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate.

[0219] [000191] Pharmaceutically acceptable carriers may contain inactive ingredients that do not excessively inhibit the biological activity of compounds. Pharmaceutically acceptable carriers should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or should not cause other undesirable reactions or side effects when administered to subjects. Standard pharmaceutical formulation techniques can be used.

[0220] [000192] As used herein, pharmaceutically acceptable carriers, adjuvants, or vehicles include any solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, that are appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used to formulate pharmaceutically acceptable compositions and known techniques for their preparation. To the extent that any conventional carrier medium is incompatible with the compounds described herein, for example, by producing any undesirable biological effects or by interacting in a deleterious manner with any other components of the pharmaceutically acceptable composition, the use of such conventional carrier medium is considered to be within the scope of the present invention. As used herein, the phrase "side effects" encompasses undesirable and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). While side effects are always unwanted, unwanted effects are not necessarily harmful. Adverse effects of a therapy (e.g., a prophylactic or therapeutic agent) can be harmful, uncomfortable, or dangerous. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, nephrotoxicity, kidney toxicity (including conditions such as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), bone marrow toxicity (including leukopenia, bone marrow suppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolonged pregnancy, weakness, drowsiness, pain (including muscle pain, bone pain, and headache), hair loss, asthenia, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders, and sexual dysfunction.

[0221] [000193] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropylmethylcellulose, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and acetic acid. The following ingredients may be used: cellulose; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free distilled water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solution, and other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings, and fragrances. Preservatives and antioxidants may also be present in the composition, according to the discretion of the formulator.

[0222] [000194] As used herein, the term "measurably degrade" means (a) a measurable decrease in ITK activity between a sample containing a compound herein and ITK and an equivalent sample containing ITK without the compound; or (b) a measurable decrease in the concentration of ITK in a sample over time.

[0223] Administration [000195] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be formulated as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0224] [000196] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation.

[0225] [000197] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweeteners, flavorings or colorings can also be added.

[0226] [000198] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore can melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol, or suppository waxes that are solid at ambient temperature but liquid at body temperature, and therefore can melt in the rectum or vaginal cavity to release the active compound.

[0227] [000199] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0228] [000200] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0229] [000201] For topical application, the pharmaceutically acceptable composition can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0230] [000202] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline or other aqueous solution, with or without a preservative such as benzalkonium chloride, or preferably as a solution in isotonic, pH-adjusted, sterile saline or other aqueous solution. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0231] [000203] In certain embodiments, the compositions of the present disclosure are administered orally. The pharmaceutically acceptable compositions herein can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweeteners, flavorings, or colorings can also be added.

[0232] [000204] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds herein, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and perfumes.

[0233] [000205] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound herein is mixed with at least one inert pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate), and / or a) fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid); b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia); c) humectants (e.g., glycerol); d) disintegrants (e.g., agar, carbonate, Calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders (e.g., paraffin); f) absorption accelerators (e.g., quaternary ammonium compounds); g) wetting agents (e.g., cetyl alcohol and glycerol monostearate); h) absorbents (e.g., kaolin and bentonite clay); and i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0234] [000206] Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Solid dosage forms may optionally contain opacifying agents. These solid dosage forms may also be composed so as to release the active ingredient only in a certain part of the intestinal tract, optionally, with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0235] [000207] The active compounds herein may also be in microencapsulated form containing one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may also optionally contain opacifying agents and may be of a composition that releases the active ingredient only in a certain part of the intestinal tract, for example, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0236] [000208] The compounds herein are formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the phrase "unit dosage form" refers to a physically discrete unit of drug appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure may be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and dietary habits; the administration time, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used, and similar factors well known in the medical field.

[0237] [000209] The amount of the compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors. The compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compound or inhibitor can be administered to a patient receiving these compositions.

[0238] [000210] Depending on the particular condition, or disease, to be treated or prevented, additional therapeutic agents normally administered to treat or prevent that condition may also be present in the compositions of the present disclosure. As used herein, additional therapeutic agents normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease, or condition being treated."

[0239] [000211] The compound or composition may be administered simultaneously with, prior to, or subsequent to one or more additional therapeutically active agents. Generally, each agent will be administered at a dose and / or schedule determined for that agent. It will further be understood that the additional therapeutically active agents used in this combination may be administered together in a single composition or separately in different compositions. The particular combination to use in a regimen will take into account the compatibility of the compounds of the present invention with the additional therapeutically active agents and / or the desired therapeutic effect to be achieved. In general, it is expected that the additional therapeutically active agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels used individually. Additional therapeutically active agents include, but are not limited to, small organic molecules, e.g., drug compounds (e.g., compounds approved by the Food and Drug Administration as set forth in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional therapeutically active agent is an anti-cancer agent (e.g., a biological or chemotherapeutic anti-cancer agent). In other embodiments, the additional therapeutically active agent is an anti-inflammatory agent.

[0240] [000212] The amount of additional therapeutic agent present in the compositions of the present disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0241] How to use [000213] The bifunctional compounds described herein are useful for degrading ITK in biological samples or patients via the ubiquitin proteolytic pathway. Accordingly, one embodiment of the present disclosure provides a method for treating an ITK-mediated disease or disorder. As used herein, the term "ITK-mediated disease or disorder" refers to any disease, disorder, or other deleterious condition in which ITK is known to play a role. In some cases, the ITK-mediated disease or disorder is a proliferative disease or autoimmune disease. Examples of proliferative diseases include cancer.

[0242] [000214] In one aspect, provided herein are methods for treating or preventing cancer in a subject in need thereof. In certain embodiments, the method comprises orally administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of ITK. In certain embodiments, the amount is effective to treat or prevent cancer.

[0243] [000215] In certain embodiments, the cancer is any cancer described below. In certain embodiments, the cancer comprises a solid tumor. In certain embodiments, the cancer is a B-cell malignancy. In certain embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), transformed CLL or Richter's transformation, small cell lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), and central nervous system (CNS) lymphoma. In certain embodiments, the cancer is chronic lymphocytic leukemia. In certain embodiments, the cancer is small cell lymphoma. In certain embodiments, the cancer is follicular lymphoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma. In certain embodiments, the cancer is non-Hodgkin's lymphoma. In certain embodiments, the cancer is mantle cell lymphoma. In certain embodiments, the cancer is marginal zone lymphoma. In certain embodiments, the cancer is Waldenstrom's macroglobulinemia. In certain embodiments, the cancer is small lymphocytic lymphoma (SLL). In certain embodiments, the cancer is CNS lymphoma. In certain embodiments, the cancer is transformed CLL or Richter's transformed.

[0244] [000216] In another aspect, provided herein is a method for degrading ITK in a subject in need thereof. The method comprises orally administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of ITK. In certain embodiments, the amount is effective to degrade ITK in the subject. ITK can be expressed in any cell or tissue of the subject. In certain embodiments, ITK is expressed in splenocytes. In certain embodiments, ITK is expressed in peripheral blood mononuclear cells.

[0245] [000217] In another aspect, provided herein is a method of preventing B cell activation in a subject in need thereof. The method comprises orally administering to the subject an amount of a bifunctional compound capable of inducing proteolysis of ITK. In certain embodiments, the amount is effective to prevent B cell activation. In certain embodiments, the B cells express CD69. In certain embodiments, the B cells express CD86. In certain embodiments, the B cells express CD69 and CD86.

[0246] [000218] In this method, the bifunctional compound comprises a moiety capable of specifically binding to ITK and further comprises a moiety capable of recruiting ubiquitin ligase to degrade ITK. Specific compounds are described herein. The compound can be administered in any form, including pharmaceutically acceptable salts and pharmaceutical compositions.

[0247] [000219] The bifunctional compound may be administered at any dose deemed appropriate by a skilled practitioner. In certain embodiments, the dose is 0.1 to 1000 mg / kg. In certain embodiments, the dose is 0.1 to 900 mg / kg. In certain embodiments, the dose is 0.1 to 800 mg / kg. In certain embodiments, the dose is 0.1 to 700 mg / kg. In certain embodiments, the dose is 0.1 to 600 mg / kg. In certain embodiments, the dose is 0.1 to 500 mg / kg. In certain embodiments, the dose is 0.1 to 400 mg / kg. In certain embodiments, the dose is 0.1 to 300 mg / kg. In certain embodiments, the dose is 0.1 to 200 mg / kg. In certain embodiments, the dose is 0.1 to 100 mg / kg. In certain embodiments, the dose is selected from the group consisting of 100 mg / kg, 200 mg / kg, 300 mg / kg, 450 mg / kg, 600 mg / kg, 800 mg / kg, and 1000 mg / kg. In certain embodiments, the dose is about 25 mg / kg. In certain embodiments, the dose is about 50 mg / kg. In certain embodiments, the dose is about 75 mg / kg. In certain embodiments, the dose is about 100 mg / kg. In certain embodiments, the dose is about 150 mg / kg. In certain embodiments, the dose is about 200 mg / kg. In certain embodiments, the dose is about 250 mg / kg. In certain embodiments, the dose is about 300 mg / kg. In certain embodiments, the dose is about 400 mg / kg. In certain embodiments, the dose is about 450 mg / kg. In certain embodiments, the dose is about 500 mg / kg. In certain embodiments, the dose is about 600 mg / kg. In certain embodiments, the dose is about 700 mg / kg. In certain embodiments, the dose is about 750 mg / kg. In certain embodiments, the dose is about 800 mg / kg. In certain embodiments, the dose is about 900 mg / kg. In certain embodiments, the dose is about 1000 mg / kg.

[0248] [000220] The dose may be administered on a schedule deemed suitable by one skilled in the art. In certain embodiments, the dose is administered once daily. In certain embodiments, the dose is administered twice daily. In certain embodiments, the dose is administered three times daily. In certain embodiments, the dose is administered four times daily. In certain embodiments, the dose is administered in divided doses. In certain embodiments, the dose is administered two times daily in divided doses. In certain embodiments, the dose is administered three times daily in divided doses. In certain embodiments, the dose is administered four times daily in divided doses.

[0249] [000221] Administration may continue for any length of time deemed suitable by one of skill in the art. In certain embodiments, a dose is administered daily for 14 days. In certain embodiments, a dose is administered daily for 13 days. In certain embodiments, a dose is administered daily for 12 days. In certain embodiments, a dose is administered daily for 11 days. In certain embodiments, a dose is administered daily for 10 days. In certain embodiments, a dose is administered daily for 9 days. In certain embodiments, a dose is administered daily for 8 days. In certain embodiments, a dose is administered daily for 7 days. In certain embodiments, a dose is administered daily for 6 days. In certain embodiments, a dose is administered daily for 5 days. In certain embodiments, a dose is administered daily for 4 days. In certain embodiments, a dose is administered daily for 3 days. In certain embodiments, a dose is administered daily for 2 days. In certain embodiments, a dose is administered for 1 day.

[0250] [000222] In the dosing schedule, doses may be administered on consecutive days or periodically, according to the judgment of the skilled practitioner. In certain embodiments, doses are administered on consecutive days. In certain embodiments, doses are administered with an interval between doses. In certain embodiments, the interval is 1 day. In certain embodiments, the interval is 2 days. In certain embodiments, the interval is 3 days. In certain embodiments, the interval is 4 days. In certain embodiments, the interval is 5 days. In certain embodiments, the interval is 6 days.

[0251] [000223] In certain embodiments, the dose is administered weekly. In certain embodiments, the dose is administered twice weekly. In certain embodiments, the dose is administered three times weekly.

[0252] [000224] In certain embodiments, doses are administered over a period of time with a first interval between doses, and then doses are re-administered for a period of time after the first interval between doses, where this dosing regimen can be repeated (i.e., cyclically or periodically, e.g., after a second, third, etc. interval between subsequent administrations of doses) according to the discretion of the skilled practitioner. For example, in one embodiment, a first dose is administered for one week, followed by a first interval of one week without administration of the first dose; then a second dose is re-administered for another week, followed by a second interval of one week without administration of the first or second dose, and so on, periodically thereafter. Other permutations of first, second, third, etc. doses, followed by permutations of first, second, third, etc. intervals, and combinations thereof, are contemplated herein, as will be understood by the skilled practitioner and according to the needs of the patient. For example, in one embodiment, a first dose is administered daily for one week, followed by a first interval of three weeks without administration of the first daily dose; then a second dose is re-administered every other week for another week, followed by a second interval of four weeks without administration of the first daily dose or the second biweekly dose, and so on.

[0253] [000225] The compounds may be administered by any route of administration deemed suitable by the skilled practitioner. In certain embodiments, the dose is administered orally. Formulations and techniques for administration are described in detail below.

[0254] [000226] In certain embodiments, the term "cancer" includes, but is not limited to, the following cancers: epidermoid oral: oral cavity, lip, tongue, mouth, pharynx, head and neck squamous cell carcinoma (HNSCC); cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma, non-small cell lung cancer (NSCLC); gastrointestinal: gastric cancer, esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (small bowel or small intestine) (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (large bowel or large intestine) (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectum, colorectum, microsatellite stable colorectal cancer (MSS CRC), rectum; genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, urachal carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriomas, sarcomas, stromal cell carcinoma, fibromas, fibroadenomas, adenomatous tumors, lipomas), metastatic castration-resistant prostate cancer (mCRPC), muscle-invasive urothelial carcinoma; liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangiomas, biliary tract carcinoma; bone: osteosarcoma (osteogenic sarcoma) (osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma (MM), malignant giant cell tumor chordoma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);Gynecological: Uterus (endometrial cancer), Cervix (cervical cancer, cervical carcinoma, preneoplastic cervical dysplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), Fallopian tube (carcinoma), Breast, Triple-negative breast cancer (TNBC), Platinum-resistant epithelial ovarian cancer (EOC); Hematological: Blood (myeloid leukemia ( lymphoid disorders (e.g., mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and follicular lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, dysplastic nevi (moles); dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; adrenal gland: neuroblastoma; and metastatic melanoma.

[0255] [000227] In certain embodiments, the term "autoimmune disease" includes, but is not limited to, the following autoimmune diseases: urticaria, graft-versus-host disease (GVHD), acute graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune urticaria, ... Infectious pancreatitis, autoimmune retinopathy, axonal and neuronal (AMAN), Barro's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid Lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (acne contralateral), hypogammaglobulinemia, IgA nephropathy, IgG4 Associated sclerosing disorders, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis,Narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome types I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis , reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

[0256] [000228] In certain embodiments, the term "inflammatory disease" includes, but is not limited to, the following inflammatory diseases: encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitis externa, otitis media, otitis interna, mastoiditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, mediastinitis, stomatitis, gingivitis, gingivostomatitis, glossitis, tonsillitis, sialadenitis / parotitis, cheilitis, pulpitis, jaw inflammation, esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenal ulcers, Enteritis, ileitis, appendicitis, proctitis, hepatitis, ascending cholangitis, cholecystitis, pancreatitis, peritonitis, dermatitis, folliculitis, cellulitis, hidradenitis, arthritis, dermatomyositis, soft tissue, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendonitis, panniculitis, osteochondritis: osteitis / osteomyelitis, spondylitis, periostitis, chondritis, nephritis, glomerulonephritis , pyelonephritis, ureteritis, cystitis, urethritis, oophoritis, salpingitis, endometritis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis, omphalitis, insulitis, hypophysitis, thyroiditis, perithyroiditis, adrenalitis, lymphangitis, and lymphadenitis.

[0257] Products and Kits [000229] Also provided are articles of manufacture containing any of the compounds or pharmaceutical compositions described herein. The articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions. Examples of suitable containers include, but are not limited to, bottles, vials, syringes, intravenous bags, or tubing.

[0258] [000230] Kits containing any of the compounds or pharmaceutical compositions described herein are also provided. The kits may contain the compounds or pharmaceutical compositions in suitable containers or packaging, including, but not limited to, bottles, vials, syringes, intravenous bags, or tubing. The kits may include compounds or pharmaceutical compositions for administration to an individual in single-dose or multi-dose form. The kits may further include instructions or labels for administering the compounds or pharmaceutical compositions to an individual according to any of the methods disclosed herein. The kits may further include equipment for administering the compounds or pharmaceutical compositions to an individual, including, but not limited to, needles, syringes, tubing, or intravenous bags. The kits may further include instructions for producing any of the compounds or pharmaceutical compositions disclosed herein.

[0259] [000231] Also provided are articles of manufacture containing any of the compounds, vaccines, or pharmaceutical compositions described herein. The articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions. The articles of manufacture include suitable containers or packaging materials for the compounds, oncolytic viruses, or pharmaceutical compositions. Examples of suitable containers include, but are not limited to, bottles, vials, syringes, intravenous bags, or tubing.

[0260] [000232] The present disclosure will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the present disclosure. It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various changes or modifications will be suggested to those skilled in the art in light of them and are within the spirit and scope of the present application and the scope of the appended claims. [Example]

[0261] Example [000233] Further embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0262] [000234] Analytical methods and equipment Proton nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Ascend™ 500 MHz spectrometer. NMR spectra are reported as follows: chemical shift δ (ppm), multiplicity, coupling constant J (Hz), and integral. The abbreviations s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad are used throughout. Mass spectral data were measured using a Waters Acquity i-Class ultra-performance liquid chromatography (UPLC) system equipped with an Acquity photodiode array detector, an Acquity evaporative light scattering detector (ELSD), and a Waters ZQ mass spectrometer. Data were acquired using Waters MassLynx 4.1 software, and purity was characterized by UV wavelength 220 nm, evaporative light scattering detection (ELSD), and electrospray cation ionization (ESI) (column: Acquity UPLC BEH C18 1.7μ ι 2.1 × 50 mm). Solvent used: acetonitrile / water containing 0.1% formic acid; flow rate 0.7 mL / min. Preparative HPLC purification was performed with a flow rate of 15 mL / min and detection at UV wavelengths of 214 nm and 254 nm (column: Jupiter© 10 μM Proteo 90 Å, 250 × 21.2 mm A, solvent: acetonitrile / water containing modifiers such as 0.1% trifluoroacetic acid).

[0263] [000235] Abbreviations used in the examples include the following:

[0264] [Table 33]

[0265] [Table 34]

[0266] General scheme for preparing LHP building blocks [000236] CRBN-targeted LHMs can generally be prepared according to Scheme B1. Scheme B1 [ka] [000237] In Scheme B1, functionalized thalidomide was first coupled to a linker precursor (amino tert-butyl ester). The linker precursor (amino tert-butyl ester) contains "Linker A" (i.e., representing one or more linker segments including L5) and two terminal reactive groups, an amine in ester form and a protected carboxylic acid. Step 1 below describes the initial coupling step in more detail using an exemplary amino ester linker precursor.

[0267] Step 1: A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (0.26 mmol), amino ester (0.26 mmol), ethylbis(propan-2-yl)amine (0.52 mmol), and DMF (1 mL) was stirred overnight at 90° C. The mixture was cooled and purified by HPLC (5-95% MeCN in HO containing 0.1% TFA) to give the tert-butyl ester intermediate.

[0268] The tert-butyl ester intermediate is then hydrolyzed (see Step 2) to give a CRBN-targeting LHP building block with a carboxylic acid-terminated "Linker A," which can be further conjugated to another moiety.

[0269] Step 2: A mixture of tert-butyl 4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butanoate (0.10 mmol), CHCl (1 mL), and TFA (1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give the carboxylic acid product.

[0270] [000238] Further examples of CRBN-targeting LHM building blocks that can be prepared according to Scheme B1 are described below.

[0271] Example 1. 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid (HCB1) [ka] Step 1 product: tert-butyl 3-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]propanoate (1.8 g, 51.9%). LCMS: C 22 H 27 Required value for N3O7: 445, Measured value: m / z = 468 [M+Na] + .

[0272] Step 2 product: 3-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]propanoic acid (HCB1) (526 mg, 32%). LCMS: C 18 H 19 Required value for N3O7: 389, Measured value: m / z = 390 [M+H] + .

[0273] Example 2. 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (HCB2) [ka] Step 1 product: tert-butyl 3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]propanoate (1.6 g, 41%). LCMS: C 26 H 35Required value for N3O9: 533, Measured value: m / z = 534 [M+H] + .

[0274] Step 2 product: 3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]propanoic acid (HCB2) (1.2 g, 73.62%). LCMS: C 22 H 27 Required value for N3O9: 477, Measured value: m / z = 478 [M+H] + .

[0275] Example 3. 3-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (HCB3) [ka] Step 1 product: 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (1.75 g, 6.32 mmol) treated with tert-butyl 3-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]propanoate (2.1 g, 5.75 mmol) gave tert-butyl 3-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoate (1.8 g, 2.9 mmol, 50.39%) as a yellow oil. LCMS: C 30 H 43 N3O 11 Required value: 621, Measured value: m / z = 622 [M+H] + .

[0276] Step 2 product: Starting from tert-butyl 3-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoate (1.8 g, 2.9 mmol) gave the desired product (HCB3) (1.2 g, 2.07 mmol, 71.51%) as a yellow oil. LCMS: C 26 H 35 N3O 11 Required value: 565, Measured value: m / z = 566 [M+H] + .

[0277] Example 4. 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoic acid (HCB4) [ka] Step 1 product: 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (2 g, 7.24 mmol) treated with tert-butyl 3-[2-[2-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoate (3.6 g, 7.24 mmol) ) afforded tert-butyl 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoate (1.5 g, 1.93 mmol, 26.66%) as a yellow oil. LCMS: C 36 H 55 N3O 14 Required value: 753, Measured value: m / z = 754 [M+H] + .

[0278] Step 2 product: Starting with tert-butyl 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoate (HCB4) (1.5 g, 1.93 mmol) gave the desired product (1.21 g, 1.53 mmol, 80%) as a yellow gum. LCMS: C 32 H 47 N3O 14 Required value: 697, Measured value: m / z = 698 [M+H] + .

[0279] Example 5. 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid (HCB5) [ka] Step 1: tert-Butyl 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoate [000239] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (250 mg, 0.91 mmol), tert-butyl 6-aminohexanoate hydrochloride (203 mg, 0.91 mmol) in NMP (3 mL) was added N,N-diisopropylethylamine (0.6 mL) with heating at 85 °C overnight. The crude reaction mixture was purified by silica gel chromatography using EtOAc:hexanes (0-100%) to give tert-butyl 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoate (111 mg, 28%). LCMS: C 23 H 29 N3O6, required value: 443.5, observed value: m / z = 444.4 [M+H] + .

[0280] Step 2: 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid [000240] To a solution of tert-butyl 6-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino}hexanoate (111 mg, 0.25 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 30 minutes, and then the reaction mixture was concentrated to give 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid (HCB5) (78 mg, 78%). 1 H NMR (500MHz, DMSO-d6)δ 12.00(s,1H), 11.06(s,1H), 7.57(d,J=8.3Hz, 1H), 7.11(s,1H), 6.95(d,J=2.1Hz, 1H), 6.85(dd,J=8.4, 2.1Hz, 1H), 5.04(dd,J=12.7, 5 .4Hz, 1H), 3.16(q,J=6.4Hz, 2H), 2.23(t,J=7.4Hz, 2H), 2.03-1.97(m,1H), 1.56(dq,J=14.8, 7.2Hz, 4H), 1.39(q,J=7.9Hz, 2H).LCMS:C 19 H 21 Required N3O6 value: 387.4, Measured value: m / z = 388.4 [M+H] + .

[0281] Example 6. 3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}propanoic acid (HCB6) [ka] Step 1: tert-Butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoate [000241] To a solution of tert-butyl 3-(piperazin-1-yl)propanoate (HCB6b) (400.00 mg, 1.87 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (HCB6a) (515.56 mg, 1.87 mmol) in NMP (10 mL) was added N,N-diisopropylethylamine (0.65 mL, 0.48 g, 3.73 mmol) while heating at 85-90 °C for 16 h. The reaction was partitioned between EtOAc:water (2x). The organic layer was then washed with brine, dried over sodium sulfate, and concentrated. Silica gel column purification using 10-100% EtOAc:hexanes gave the desired product (823 mg). LCMS: C 24 H 30 Required N4O6 value: 470.5, Measured value: m / z = 471.8 [M+H] + .

[0282] Step 2: 3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}propanoic acid (HCB6) [000242] tert-Butyl 3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}propanoate (820.00 mg, 1.74 mmol) was dissolved in trifluoroacetic acid (9.94 g, 87.14 mmol). After 1 hour, the TFA was removed. Lyophilization gave 3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl}propanoic acid (HCB6) (722 mg, 100%). LCMS: C 20 H 22 Required N4O6 value: 414.4, Measured value: m / z = 415.4 [M+H] + .

[0283] Example 7. 2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetic acid (HCB7) [ka] Step 1: Benzyl 2-{2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate (HCB7b) [000243] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (HCB6a) (70.00 mg, 0.25 mmol) and benzyl 2-{2,7-diazaspiro[3.5]nonan-7-yl}acetate (HCB7a) (69.53 mg, 0.25 mmol) in NMP (2 mL) was added N,N-diisopropylethylamine (0.13 mL) and the reaction was heated to 85°C overnight. The crude mixture was purified by column chromatography eluting with EtOAc:hexanes (10-100%) to give benzyl 2-{2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate (HCB7b) (68 mg, 51%). LCMS: C 29 H 30 Required value for N4O6: 530, Measured value: m / z = 531 [M+H] + .

[0284] Step 2: 2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)acetic acid (HCB7) [000244] To a solution of benzyl 2-{2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate (HCB7b) (68.00 mg, 0.13 mmol) in EtOH (5 mL) and DCM (2 mL) was added palladium on carbon (6 mg, 0.06 mmol). The reaction mixture was sparged with hydrogen and maintained under 1 atmosphere of hydrogen using a balloon. The reaction was stirred at room temperature for 48 hours. The reaction mixture was then filtered through a pad of Celite and concentrated to give benzyl 2-{2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonan-7-yl}acetate (HCB7b) (56 mg, 99%). LCMS: C 22 H 24 Required value for N4O...

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, X 1 is C—H or nitrogen; Z 1 but, 【Chemistry 2】 wherein: 【Transformation 3】 But, X 1 represents a bond to 【Chemistry 4】 represents the bond to L; L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, wherein: -L 1 - is non-existent, -N(R 21 )-; C(R 22 ) -; substituted or unsubstituted C 1 ~ 8 Alkylene; substituted or unsubstituted C 2 ~ 8 Alkynylene; Q 1 or Q 2 and Each -L 2 -, -L 3 -, -L 4 - and -L 5 - is independently absent; -N(R 21 )-; C(R 22 )-;-C(O)-;-O-;-(CH 2 -CH 2 -O) 1 ~ 8 -; substituted or unsubstituted C 1 ~ 8 Alkylene; substituted or unsubstituted C 2 ~ 8 Alkynylene; Q 1 ;Q 2 or Q 3 and Each -L 6 - and -L 7 - is independently absent; -N(R 21 ) -;-C(R 22 )-;-C(O)-;-C(O)-N(R 21 ) -; -N(R 21 )—C(O); or —C(R 22 )-C(O)-N(R 21 ) and Each Q 1 is a 3- to 8-membered heterocycloalkylene containing at least one nitrogen, wherein said heterocycloalkylene is substituted or unsubstituted; Each Q 2 is a 5- to 13-membered spiro bicyclic heterocycloalkylene containing at least one nitrogen, wherein said heterocycloalkylene is substituted or unsubstituted; Each Q 3 is a 3- to 6-membered cycloalkylene, wherein said cycloalkylene is substituted or unsubstituted; Z 2 but, 【Transformation 5】 and R 1 But hydrogen C 1 ~ 3 is alkyl; R 2 is hydrogen, substituted or unsubstituted C 1 ~ 5 Alkyl, or substituted or unsubstituted C 1 ~ 5 is alkoxy; R 3 is methyl, or R 4 is a methylene bonded to form a substituted or unsubstituted cyclopropyl; R 4 is hydrogen, or R 3 is a methylene bonded to form said substituted or unsubstituted cyclopropyl; R 5 is hydrogen, halogen, or -C 1 ~C 3 is alkyl; Each R 6 is hydrogen, halogen, or -C 1 ~C 3 is alkyl; Each R 7 is hydrogen, halogen, or -C 1 ~C 3 is alkyl; R 10 is hydrogen or substituted or unsubstituted C 1 ~ 8 is alkyl; Each R 21 is hydrogen or methyl; Each R 22 is hydrogen, methyl, aryl, or heteroaryl, wherein said aryl and heteroaryl are substituted or unsubstituted; R a But halogen, -C 1 ~C 3 Alkyl, or -C 1 ~C 3 is alkoxy; o is 1, 2, 3, or 4; or their stereoisomers, or A pharmaceutical salt of the compound of formula (I) or a stereoisomer thereof.

2. Z 1 but, 【Transformation 6】 wherein: 【Transformation 7】 But, X 1 represents a bond to 【Transformation 8】 represents the bond to L; L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, wherein: -L 1 - is non-existent, -N(R 21 )-; C(R 22 ) -; C 1 ~ 8 Alkylene; C 2 ~ 8 Alkynylene; Q 1 or Q 2 and Each -L 2 -, -L 3 -, -L 4 - and -L 5 - is independently absent; -N(R 21 )-; C(R 22 )-;-C(O)-;-O-;-(CH 2 -CH 2 -O) 1 ~ 8 -;C 1 ~ 8 Alkylene; C 2 ~ 8 Alkynylene; Q 1 ;Q 2 or Q 3 and Each -L 6 - and -L 7 - is independently absent; -N(R 21 ) -;-C(R 22 )-;-C(O)-;-C(O)-N(R 21 ) -; -N(R 21 )—C(O); or —C(R 22 )-C(O)-N(R 21 ) and Each Q 1 is a 3- to 7-membered heterocycloalkylene containing at least one nitrogen; Each Q 2 is a 5- to 13-membered spiro bicyclic heterocycloalkylene containing at least one nitrogen; Each Q 3 is a 3- to 6-membered cycloalkylene; Z 2 but, 【Chemistry 9】 and R 1 is hydrogen or methyl; R 2 is methyl; R 3 is methyl, or R 4 is a methylene bonded to form a substituted cyclopropyl; R 4 is hydrogen, or R 3 is a methylene bonded to form said substituted cyclopropyl; R 5 is hydrogen or halogen; Each R 6 is hydrogen or methyl; Each R 7 is hydrogen or methyl; R 10 is hydrogen or C 1 ~ 8 is alkyl; Each R 21 is hydrogen or methyl; Each R 22 is hydrogen, methyl, aryl, or heteroaryl; a compound of claim 1 or a stereoisomer thereof, or a pharmaceutical salt of a compound of claim 1 or a stereoisomer thereof.

3. Z 1 but, 【Chemistry 10】 wherein: 【Chemistry 11】 But, X 1 represents a bond to 【Chemistry 12】 represents the bond to L; L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, wherein: -L 1 - is non-existent, -N(R 21 )-; C(R 22 ) -; substituted or unsubstituted C 1 ~ 8 Alkylene; substituted or unsubstituted C 2 ~ 8 Alkynylene; Q 1 or Q 2 and Each -L 2 -, -L 3 -, -L 4 - and -L 5 - is independently absent; -N(R 21 )-; C(R 22 )-;-C(O)-;-O-;-(CH 2 -CH 2 -O) 1 ~ 8 -; substituted or unsubstituted C 1 ~ 8 Alkylene; substituted or unsubstituted C 2 ~ 8 Alkynylene; Q 1 ;Q 2 or Q 3 and Each -L 6 - and -L 7 - is independently absent; -N(R 21 ) -;-C(R 22 )-;-C(O)-;-C(O)-N(R 21 ) -; -N(R 21 )—C(O); or —C(R 22 )-C(O)-N(R 21 ) and Each Q 1 is a 3- to 7-membered heterocycloalkylene containing at least one nitrogen, wherein said heterocycloalkylene is substituted or unsubstituted; Each Q 2 is a 5- to 13-membered spiro bicyclic heterocycloalkylene containing at least one nitrogen, wherein said heterocycloalkylene is substituted or unsubstituted; Each Q 3 is a 3- to 6-membered cycloalkylene, wherein said cycloalkylene is substituted or unsubstituted; Z 2 but, 【Chemistry 13】 and R 1 But hydrogen, C 1 ~ 3 is alkyl; R 2 is hydrogen, substituted or unsubstituted C 1 ~ 5 Alkyl, or substituted or unsubstituted C 1 ~ 5 is alkoxy; R 3 is methyl, or R 4 is a methylene bonded to form a substituted or unsubstituted cyclopropyl; R 4 is hydrogen, or R 3 is a methylene bonded to form said substituted or unsubstituted cyclopropyl; R 5 is hydrogen, halogen, or -C 1 ~C 3 is alkyl; Each R 6 is hydrogen, halogen, or -C 1 ~C 3 is alkyl; Each R 7 is hydrogen, halogen, or -C 1 ~C 3 is alkyl; R 10 is hydrogen or substituted or unsubstituted C 1 ~ 8 is alkyl; Each R 21 is hydrogen or methyl; Each R 22 is hydrogen, methyl, aryl, or heteroaryl, wherein said aryl and heteroaryl are substituted or unsubstituted; R a But halogen, -C 1 ~C 3 Alkyl, or -C 1 ~C 3 is alkoxy; 2. A compound according to claim 1, wherein o is 1, 2, or 3; or a stereoisomer thereof; or a pharmaceutical salt of a compound according to claim 1, or a stereoisomer thereof.

4. R 3 and R 4 2. The compound of claim 1, wherein when forms said substituted cyclopropyl, said cyclopropyl is substituted with difluoro.

5. Z 2 but, 【Chemistry 14】 wherein R 5 The compound of claim 1 , wherein is hydrogen or —F.

6. Z 2 but, 【Chemistry 15】 2. The compound of claim 1, wherein:

7. Z 2 but, 【Chemistry 16】 2. The compound of claim 1, wherein:

8. Z 2 but, 【Chemistry 17】 2. The compound of claim 1, wherein:

9. R 2 is methyl; R 3 is methyl; R 4 The compound of claim 1 , wherein is hydrogen.

10. R 2 is hydrogen, methyl, -CH 2 OH, or -CH 2 OCH 3 and R 3 is methyl; R 4 The compound of claim 1 , wherein is hydrogen.

11. R 3 But, R 4 is a methylene attached to form a substituted cyclopropyl substituted with difluoro.

12. R 3 But, R 4 is a methylene attached to form an unsubstituted cyclopropyl.

13. R a But -F, -CH 3 , or -OCH 3 2. The compound of claim 1, wherein:

14. The compound of claim 1 , wherein o is 1.

15. R 2 is hydrogen; R 3 and R 4 The compound of claim 1 , wherein

16. X 1 is C; R 10 The compound of claim 1 , wherein is hydrogen.

17. X 1 is C; R 10 The compound of claim 1 , wherein is methyl.

18. X 1 is N; R 10 The compound of claim 1 , wherein is hydrogen.

19. Z 1 but, [Chemistry 18] wherein: 【Chemistry 19】 But, X 1 represents a bond to 【Chemistry 20】 The compound of claim 1 , wherein represents a bond to L.

20. Z 1 but, 【Chemistry 21】 where: 【Chemistry 22】 But, X 1 represents a bond to 【Chemistry 23】 The compound of claim 1 , wherein represents a bond to L.

21. Z 1 but, 【Chemistry 24】 wherein: 【Chemistry 25】 But, X 1 represents a bond to 【Chemistry 26】 The compound of claim 1 , wherein represents a bond to L.

22. Z 1 but, 【Chemistry 27】 wherein: 【Chemistry 28】 But, X 1 represents a bond to 【Chemistry 29】 The compound of claim 1 , wherein represents a bond to L.

23. Z 1 but, 【Transformation 30】 where: 【Chemistry 31】 But, X 1 represents a bond to 【Chemistry 32】 The compound of claim 1 , wherein represents a bond to L.

24. Z 1 but, 【Transformation 33】 wherein: 【Transformation 34】 But, X 1 represents a bond to 【Chemistry 35】 The compound of claim 1 , wherein represents a bond to L.

25. Z 1 but, 【Transformation 36】 wherein: 【Chemistry 37】 But, X 1 represents a bond to 【Transformation 38】 The compound of claim 1 , wherein represents a bond to L.

26. Z 1 but, 【Chemistry 39】 where: 【Chemistry 40】 But, X 1 represents a bond to 【Chemistry 41】 The compound of claim 1 , wherein represents a bond to L.

27. Z 1 but, 【Chemistry 42】 where: 【Chemistry 43】 But, X 1 represents a bond to 【Chemistry 44】 The compound of claim 1 , wherein represents a bond to L.

28. L, 【Chemistry 45】 At least one -Q represented by 1 -, wherein n 1 is 1 or 2, and n 2 is 1 or 2, where -Q 1 2. The compound of claim 1, wherein - is unsubstituted, mono- or disubstituted.

29. -Q 1 28. The compound of claim 27, wherein - is unsubstituted.

30. -Q 1 - is halogen and -C 1 ~C 3 28. The compound of claim 27, which is mono- or di-substituted with groups independently selected from alkyl.

31. -Q 1 -, -F, -CH 3 , and -CH 2 CH 3 30. The compound of claim 29, wherein the compound is mono- or di-substituted with groups independently selected from:

32. L, a.-Q 1 -N(Me)-CH 2 -Q 1 -C(O)-; b.-N(Me)-Q 1 -CH 2 -Q 1 -C(O)-; c.-Q 2 -CH 2 -Q 1 -C(O)-; d.-Q 1 -CH 2 -Q 1 -C(O)-; e.-Q 1 -Q 1 -C(O)-; f.-Q 1 -CH 2 -N(Me)-Q 1 -C(O)-; g.-Q 1 -CH 2 -Q 1 -CH 2 -C(O)-N(Me)-; h.-Q 1 -N(Me)-CH 2 -Q 1 -C(O)-; i.-Q 1 -CH 2 -Q 1 -; j.-Q 1 -CH 2 -Q 2 -; k.-Q 1 -CH 2 -CH 2 -Q 1 -; l.-Q 1 -CH 2 -CH 2 -Q 2 -; m.-Q 1 -C(O)-Q 1 -; n.-Q 1 -C(O)-Q 2 -; o.-Q 1 -CH 2 -Q 1 -N(Me)-C(O)-; p.-CH 2 -CH 2 -CH 2 -CH 2 -Q 1 -C(O)-; q.-Q 1 -CH 2 -Q 1 -C(O)-; r.-Q 1 -C(O)-; s.-Q 1 -C(O)-Q 1 -C(C 6 H 5 )-; t.-C≡CCH 2 -Q 1 -C(O)-; u.-Q 1 -C(O)-Q 2 -; v.-Q 1 -CH 2 -CH 2 -Q 2 -; w.-Q 1 -CH 2 -Q 1 -N-C(O)-; x.-CH 2 -CH 2 -CH 2 -Q 1 -C(O)-; y.-Q 1 -CH 2 -Q 1 -C(Me)-C(O)-N(Me)-; z.-Q 1 -Q 1 -C(O)-; aa.-CH 2 -Q 1 -; bb.-Q 1 -C(O)-Q 1 -CH 2 -; cc.-N(H)-(CH 2 ) 5 -C(O)-Q 1 -C(C 6 H 5 )-; dd.-N(H)-(CH 2 ) 2 -O-(CH 2 ) 2 -C(O)-Q 1 -C(C 6 H 5 )-; ee.-Q 1 -(CH 2 ) 3 -C(O)-Q 1 -C(C 6 H 5 )-; ff.-Q 2 -C(O)-Q 1 -C(C 6 H 5 )-; gg.-Q 2 -CH 2 -C(O)-Q 1 -C(C 6 H 5 )-; hh.-Q 2 -(CH 2 ) 3 -C(O)-Q 1 -C(C 6 H 5 )-; ii.-Q 2 -(CH 2 ) 2 -C(O)-Q 1 -C(C 6 H 5 )-; jj.-(CH 2 ) 6 -Q 1 -C(C 6 H 5 )-; kk.-Q 1 -Q 1 -C(O)-Q 1 -C(C 6 H 5 )-; ll.-Q 1 -CH 2 -C(O)-Q 1 -C(C 6 H 5 )-; mm.-Q 1 -(CH 2 ) 2 -C(O)-Q 1 -C(C 6 H 5 )-; nn.-Q 1 -(CH 2 ) 3 -C(O)-Q 1 -C(C 6 H 5 )-; oo.-(E 2 ) 3 -C (O) -Q 1 -C(C 6 H 5 )-; pp.-(CH 2 ) 4 -C(O)-Q 1 -C(C 6 H 5 )-; qq.-(CH 2 ) 5 -C(O)-Q 1 -C(C 6 H 5 )-; rr.-(CH 2 ) 6 -C(O)-Q 1 -C(C 6 H 5 )-; ss.-(CH 2 ) 3 -Q 1 -CH 2 -C(O)-Q 1 -C(C 6 H 5 )-; tt.-(CH 2 ) 6 -Q 1 -C(C 6 H 5 )-; uu. - (CH 2 ) 6 -Q 1 -C(thiazolyl)-; vv.-(CH 2 ) 3 -O-Q 3 -C(O)-Q 1 -C(C 6 H 5 )-; ww.-(CH 2 ) 3 -O-(CH 2 ) 2 -C(O)-Q 1 -C(C 6 H 5 )-; xx. -(CH 2 ) 3 -O-(CH 2 ) 2 -C(O)-Q 1 -C(thiazolyl)-; yy. -(CH 2 ) 3 -O-(CH 2 ) 2 -C(O)-Q 1 -C(pyrid-2-yl)-; zz.-(CH 2 ) 4 -Q 1 -C(C 6 H 5 )-; aaa.-(CH 2 ) 5 -Q 1 -C(C 6 H 5 )-; bbb.-(CH 2 ) 6 -Q 1 -C(C 6 H 5 )-; ccc. - (CH 2 ) 6 -Q 1 -C(thiazolyl)-; dddd. -(CH 2 ) 6 -Q 1 -C(pyrid-2-yl)-; eee.-(CH 2 ) 7 -Q 1 -C(C 6 H 5 )-; fff.-(CH 2 ) 7 -Q 1 -C(Me)-C(O)-N(Me)-; ggg.-N(H)-(CH 2 ) 2 -O-(CH 2 ) 2 -Q 1 -C(Me)-C(O)-N(Me)-; hhh.-(CH 2 ) 3 -O-(CH 2 ) 2 -C(O)-Q 1 -C(Me)-C(O)-N(Me)-; iii.-N(H)-(CH 2 ) 2 -O-(CH 2 ) 2 -Q 1 -C(C 6 H 5 )-; jjj.-N(H)-(CH 2 ) 2 -O-(CH 2 ) 2 -C(O)-Q 1 -C(C 6 H 5 )-; kkk.-N(H)-(CH 2 ) 2 -[O-(CH 2 ) 2 ] 2 -C(O)-Q 1 -C(C 6 H 5 )-; lll.-N(H)-(CH 2 ) 2 -[O-(CH 2 ) 2 ] 3 -C(O)-Q 1 -C(C 6 H 5 )-; mmm.-N(H)-(CH 2 ) 2 -[O-(CH 2 ) 2 ] 4 -C(O)-Q 1 -C(C 6 H 5 )-; nnn.-N(H)-(CH 2 ) 2 -[O-(CH 2 ) 2 ] 5 -C(O)-Q 1 -C(C 6 H 5 )-; ooo.-N(H)-(CH 2 ) 2 -[O-(CH 2 ) 2 ] 6 -C(O)-Q 1 -C(C 6 H 5 )-; ppp. -N(H)-(CH 2 ) 2 -[O-(CH 2 ) 2 ] 7 -C(O)-Q 1 -C(C 6 H 5 ) -; and qqq.-N(H)-(CH 2 ) 2 -[O-(CH 2 ) 2 ] 8 -C(O)-Q 1 -C(C 6 H 5 )-; rrr.-N(H)-Q 3 -O-(CH 2 ) 2 -CH 2 -; sss.-N(H)-(CH 2 ) 3 -Q 1 -(CH 2 ) 2 -; ttt.-C(O)-N(H)-[(CH 2 ) 3 -O] 3 -(CH 2 ) 2 -NH-; uuu.-C(O)-N(H)-[(CH 2 ) 3 -O] 3 -(CH) 2 ) 2 -; www.-Q 1 -C(O)-[(CH 2 ) 2 -O] 3 -(CH) 2 ) 2 -NH-; www.-Q 1 -(CH 2 ) 3 -O-CH 2 -; xxx.-Q 1 -C(O)-(C 6 H 6 )-CH 2 -; yyy.-Q 1 -(2-pyridyl)-O-CH 2 -; Zzz. -N(H)-Q 3 —X-(2-pyridyl)-O—; aaaa. -N(H)-Q 3 -X-(4-pyridyl)-; and bbbb. -N(H)-(CH 2 ) 2 -Q 3 —X-(2-pyridyl)-O—CH 2 -, cccc. -CH≡C-(CH 2 ) 2 Q 1 -; and dddd.-Q 1 -; eeee.-Q 1 -CH 2 -C(O)-N(CH 3 )-; ffff.-Q 1 -CH 2 -Q 1 -C(O)-; gggg.-Q 1 -CH 2 -CH 2 -Q 1 -C(O)-; hhhh.-Q 1 -N(CH 3 )-C(O)-Q 1 -C(O)-; iiiiii.-E 2 -Q 1 -C(O)-; jjjj.-Q 1 -CH 2 -Q 1 -; kkkkk.-Q 1 - CH 2 - C ( O) - Q 1 -; l��-O-Q 1 -C(O)-Q 1 -; mmmm.-C(O)-Q 1 -; .nnn.-Q 1 -C(O)-Q 1 -; oooo.-CH 2 -C(O)-Q 1 -; pppp.-C(O)-Q 1 -CH 2 -Q 1 -; qqqq.-C(O)-Q 1 -CH 2 -Q 1 -C(O)-; rrrr.32 2 -Q 1 -32 2 -Q 1 -C(O)-; ssss.-C(O)-Q 1 -CH 2 -Q 1 -CH 2 -; tttt.-Q 1 -CH 2 -Q 1 -CH 2 -; uuuu. -Q 1 -C(O)-Q 1 -CH 2 -; and vvvv.-CH 2 -Q 1 -, wherein X is oxygen or sulfur.

33. L, 【Chemistry 46】 At least one -Q selected from the group consisting of 1 -, wherein -Q 1 - is unsubstituted or -F, -CH 3 , and -CH 2 CH 3 10. The compound of claim 1, wherein the compound is mono- or di-substituted with groups independently selected from the group consisting of:

34. L, 【Chemistry 47】 At least one -Q represented by 2 -, wherein n 3 The compound according to claim 1, wherein is 1 or 2.

35. L, 【Chemistry 48】 At least one -Q represented by 2 The compound of claim 1, comprising:

36. L, 【Chemistry 49】 At least one -Q represented by 2 -, wherein n 4 is 1 or 2, and n 5 is 1 or 2, and n 6 The compound according to claim 1, wherein is 1 or 2.

37. L, [Transformation 50] At least one -Q represented by 2 The compound of claim 1, comprising:

38. L, 【Chemistry 51】 At least one -Q represented by 2 -, wherein n 8 is 1 or 2, where -Q 2 - is unsubstituted or -F, -CH 3 , and -CH 2 CH 3 10. The compound of claim 1, wherein the compound is mono- or di-substituted with groups independently selected from:

39. L, 【Chemistry 52】 At least one -Q represented by 2 -, wherein -Q 2 - is unsubstituted or -F, -CH 3 , and -CH 2 CH 3 10. The compound of claim 1, wherein the compound is mono- or di-substituted with groups independently selected from:

40. L, 【Chemistry 53】 At least one -Q represented by 2 -, wherein n 18 , and n 19 is 2, or piperidinyl; or n 18 If is 2, then n 19 is 3, or azepanyl; or n 18 If n is 3, 19 The compound of claim 1, wherein is 2 or azepanyl.

41. L, 【Chemistry 54】 At least one -Q represented by 2 The compound of claim 1, comprising:

42. L, 【Transformation 55】 At least one -Q represented by 2 -, wherein n 22 is 0 to 2; n 23 is 0 to 2, and n 24 The compound according to claim 1, wherein is 1 or 2.

43. n 22 If is 2, then n 23 and n 24 is 1; or n 22 If is 2, then each n 23 and n 24 43. The compound of claim 42, wherein is 2.

44. L, 【Transformation 56】 At least one -Q represented by 2 The compound of claim 1, comprising:

45. L, 【Chemistry 57】 At least one -Q represented by 2 The compound of claim 1, comprising:

46. L, 【Transformation 58】 At least one -Q represented by 3 -, wherein n 1 is 1 or 2, and n 2 is 1 or 2. The compound of claim 1.

47. L, 【Chemistry 59】 At least one -Q selected from the group consisting of 3 The compound of claim 1, comprising:

48. The linker group is —C(O)—. The compound of claim 1.

49. The linker group is 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 is selected from: 【Transformation 65】 But Z 2 2. The compound of claim 1, wherein X represents a bond to:

50. The following formula (II): 【Chemical Formula 66】 2. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

51. The following formula (III): 【Transformation 67】 2. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

52. The following formula (IIIa): 【Transformation 68】 52. The compound of formula (III) according to claim 51, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

53. The following formula (IV): 【Transformation 69】 2. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

54. The following formula (IVa): 【Transformation 70】 54. The compound of formula (IV) according to claim 53, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

55. Below formula (V): 【Chemistry 71】 2. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

56. The following formula (Va): 【Chemistry 72】 56. The compound of formula (V) according to claim 55, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

57. The following formula (Vb): 【Transformation 73】 56. The compound of formula (V) according to claim 55, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

58. The following formula (VI): 【Chemistry 74】 2. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

59. The following formula (VIa): 【Chemistry 75】 59. The compound of formula (VI) according to claim 58, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

60. The following formula (VIb): 【Transformation 76】 59. The compound of formula (VI) according to claim 58, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

61. The compound of claim 1, wherein the compound is selected from the group consisting of compounds 1 to 227. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 。

62. 62. A pharmaceutical composition comprising a compound according to any one of claims 1 to 61 and a pharmaceutically acceptable carrier, excipient, or diluent.

63. 62. The compound of any one of claims 1 to 61, administered in a therapeutically effective amount to a subject in need thereof to treat a disease or disorder in the subject.

64. 64. The compound of claim 63, wherein the disease or disorder is cancer.

65. A compound according to any one of claims 1 to 61 for use in therapy.

66. A compound according to any one of claims 1 to 61 for use in the treatment of cancer.

67. The pharmaceutical composition of claim 62, administered in a therapeutically effective amount to a subject in need thereof to treat a disease or disorder in the subject.

68. The pharmaceutical composition described in claim 67, wherein the disease or disorder is cancer.

69. The pharmaceutical composition of claim 62 for use in a therapeutic method.

70. The pharmaceutical composition of claim 62 for use in the treatment of cancer.

Images