STAT6 inhibitors and uses thereof

Abstract

The present disclosure provides compounds, compositions, and methods of using the same.

Description

Attorney Docket No.: KME-310WOSTAT6 INHIBITORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U. S. Provisional Application No.63 / 734,701, filed December 16, 2024; U. S. Provisional Application No. 63 / 735,289, filed December 17, 2024; U. S. Provisional Application No. 63 / 767,480, filed March 5, 2025; and U. S. Provisional Application No. 63 / 837,702, filed July 2, 2025, each of which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates to compounds and methods useful for modulating (e.g., inhibiting) signal transducer and activator of transcription 6 (“STAT6”). The present disclosure also provides pharmaceutically acceptable compositions comprising compounds disclosed herein and methods of using said compositions in the treatment of various disorders.BACKGROUND

[0003] Signal transducer and activator of transcription 6 (STAT6 or Interleukin-4-Stat / IL4-STAT) is an undruggable transcription factor belonging to the structurally conserved Signal Transducer and Activator of Transcription (STAT) family of proteins (STAT1 through STAT6). Activation of STAT6, like other STAT proteins, is triggered upon binding of hormones, immunomodulatory cytokines or growth factors to specific receptors on the cell surface. Once activated, the phosphorylation of a C-terminal tyrosine residue occurs, leading to translocation and transmission of signals from the cytosol to the nucleus, resulting in activation of gene expression.

[0004] STAT6 is implicated in driving Type 2 immunity, allergies. It may participate in IL-4 / IL- 13 -mediated allergic reaction, and play a vital role in the differentiation of T-helper type 2 (Th2) cells (Hebenstreit et al. " Signaling mechanisms, interaction partners, and target genes of STAT6." Cytokine & growth factor reviews 17.3 (2006): 173-188; Chapoval et al. " Regulation of the T helper cell type 2 (Th2) / T regulatory cell (Treg) balance by IL-4 and STAT6." Journal of leukocyte biology 87.6 (2010): 1011-1018). STAT6 is a key node primarily activated in the Janus Kinase (JAK) pathway by inflammatory cytokines, interleukin-4 (IL4) and interleukin- 13 (IL13) and their cognate receptors, which are produced by Th2 cells, mast cells and basophils. Human STAT6 mutations have been associated with severe allergies such as asthma and eczema (Goenka and Kaplan. " Transcriptional regulation byPage l of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOSTAT6." Immunologic research 50.1 (2011): 87-96.). There is a need to discover and develop STAT6 drugs, for example to treat allergic / inflammatory diseases (Glosson et al. " Wheezing and itching: The requirement for STAT proteins in allergic inflammation." Jak-Stat 1.1 (2012): 3-15.

[0005] Accordingly, there remains a need to develop STAT6 inhibitors useful as therapeutic agents.SUMMARY

[0006] Disclosed herein, in some embodiments, is a compound of Formula Z:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0007] Disclosed herein, in some embodiments, is an inhibitor compound of Formula Z:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0008] Disclosed herein, in some embodiments, is a compound of Formula X”:Page 2 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0009] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X”:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0010] Disclosed herein, in some embodiments, is a compound of Formula X’:Formula X’,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0011] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X’:Page 3 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0012] Disclosed herein, in some embodiments, is a compound of Formula X:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0013] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0014] Disclosed herein, in some embodiments, is a compound of Formula I’:Page 4 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0015] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I’:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0016] Disclosed herein, in some embodiments, is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0017] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I:Page 5 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0018] Disclosed herein, in some embodiments, is a compound of Formula II’:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0019] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II’:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0020] Disclosed herein, in some embodiments, is a compound of Formula II:Page 6 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0021] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II:(RA)aFormula II,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0022] Compounds disclosed herein, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating STAT6 protein. Such diseases, disorders, or conditions include those described herein.

[0023] Compounds disclosed herein are also useful for the study of STAT6 protein in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new STAT6 inhibitors or other regulators of cell cycling, metastasis, angiogenesis, and immune cell evasion, in vitro or in vivo.DETAILED DESCRIPTION

[0024] As generally described herein, the present disclosure features compounds, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula Z, Formula X”, Formula X’, Formula X, Formula I”, Formula I’, Formula I, Formula II”, Formula II’, Formula II, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof), compositions comprising said compounds, and methods useful forPage 7 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOtreating diseases or disorders (e.g., a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder).

[0025] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present disclosure and / or in methods of the present disclosure, unless otherwise understood from the context. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein.Definitions

[0026] As used herein, the following definitions apply to the terms as used to describe the present disclosure, unless otherwise indicated or apparent from context. Unless explicitly indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the art to which it pertains. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.

[0027] Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.Page 8 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0028] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is substituted or unsubsliluled and is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. A carbocyclic ring may include one or more bridged bicyclic and / or spirocyclic ring. A carbocyclic ring may include a bridged bicyclic carbocycle and a bridged bicyclic heterocycle.

[0029] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge and is substituted or unsubstituted. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Exemplary bridged bicyclics include:Page 9 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOH

[0030] As used herein, the term “bridged bicyclic carbocycle” refers to any bicyclic carbocyclic ring system, saturated or partially unsaturated, having at least one bridge and is substituted or unsubstituted. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic carbocycle has 7-12 carbon ring members. Such bridged bicyclic carbocycles are well known in the art and include those groups set forth below where each group is atached to the rest of the molecule at any substitutable carbon atom. Unless otherwise specified, a bridged bicyclic carbocycle is optionally substituted with one or more substituents as set forth for aliphatic groups. Exemplary bridged bicyclic carbocycles

[0031] As used herein, the term “bridged bicyclic heterocycle” refers to any bicyclic heterocyclic ring system, saturated or partially unsaturated, having at least one bridge and is substituted or unsubstituted. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).Page 10 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOIn some embodiments, a bridged bicyclic heterocycle has 7-12 ring members and 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic heterocycles are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.

[0032] Additionally or allernali vely, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic heterocycles include:

[0033] As used herein, the term “spirocyclic ring” refers to a spirocyclic ring system, where two rings are connected through exactly one shared atom. In an embodiment, the shared atom is a quaternary carbon atom. In an embodiment, the shared atom is a nitrogen atom. The rings may each independently be a carbocyclic or heterocyclic ring. Each ring can be a saturated or partially unsaturated ring. In an embodiment, one ring is carbocyclic and one ring is heterocyclic. In an embodiment, the two rings are carbocyclic rings. In an embodiment, the two rings are heterocyclic rings.

[0034] The term “lower alkyl” refers to a Ci-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0035] The term “haloalkyl” refers to a Ci-6 straight or branched alkyl group that is substituted with one or more halogen atoms and “lower haloalkyl” refers to a Ci-4 straight or branched alkyl group that is substituted with one or more halogen atoms. The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-subsliluled pyrrolidinyl)).

[0036] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0037] As used herein, the term “bivalent Ci-8 (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.Page 11 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0038] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a subsli luted aliphatic group.

[0039] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. As used herein, the terms “cyclopropylenyl” and“cyclopropylene” refer to a bivalent cyclopropyl group of the following structure:.

[0040] The term “halogen” means -F, -Cl, -Br, or -I.

[0041] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxy alkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members (preferably six to fourteen ring members), wherein at least one ring in the system is aromatic (preferably a 6-carbon atom ring in the system is aromatic) and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings (preferably one or more cycloaliphatic rings). Exemplary aryl groups include, but are not limited to, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, and tetrahydronaphthyl. The term “arylenyl” refers to bivalent aryl groups (e.g., phenylenyl).

[0042] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 14 (e.g., 5 to 10) ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 % electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,Page 12 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOpurinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic.” The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl. The term “heteroarylenyl” refers to bivalent heteroaryl groups (e.g., pyridylenyl). In some embodiments, the term “heteroaryl” includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings.

[0043] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N-substituted pyrrolidinyl).

[0044] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. The term “heterocyclylalkyl”Page 13 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOrefers to an alkyl group substituted by a heterocyclyl. In some embodiments, the terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” include groups in which a heterocyclyl ring is fused to one or more aryl or cycloaliphatic rings.

[0045] As used herein, the term “hydroxyalkyl” refers to refers to alkyl, as defined above, substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, and -C(CHs)2OH.

[0046] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0047] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, a group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned in the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0048] Suitable monovalent substituents on a substitutable carbon atom group are independently halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)o-4R°, -0-(CH2)o-4C(0)OR°; -(CH2)O4CH(OR°)2; -(CH2)O-4SR°; -(CIUjc Ph, which may be substituted with R°; -(CEbjo-40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)O-40(CH2)O-I -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CIEjo-4N(R°)2; -(CH2)O-4N(R°)C(0)R0; -N(R°)C(S)R°; -(CH2)O-4N(RO)C(O)NRO2; -N(RO)C(S)NR°2; -(CH2)O-4N(R°)C(0)OR0;N(R°)N(R°)C(O)R°; -N(RO)N(R°)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(0)R°; -C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; -(CH2)o-4C(0)OSiR03; -(CH2)o-40C(0)R°; -OC(0)(CH2)O-4S R°; -(CH2)O-4SC(0)R°; -(CH2)O-4C(0)NR02; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O-40C(0)NR02; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -Page 14 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOC(NOR°)R°; -(CH2)O-4SSR°; -(CH2)O-4S(0)2R°; -(CH2)O-4S(0)2OR°; -(CH2)O-4OS(0)2R°; -S(O)2NR°2; -(CH2)O-4S(0)R°; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -(CH2)O-4P(0)2R°; -(CH2)O-4P(0)R°2; -(CH2)O. _4OP(O)RO2; -(CH2)O_ _4OP(O)(ORO)2; SiR°3; -(Ci-4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is, independently, hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having ( - heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having ( - heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0049] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)O_2OH, -(CH2)O 2OR*, -(CH2)O 2CH(OR*)2; -O(haloR*), -CN, -N3, -(CH2)O-2C(0)R‘, -(CH2)O-2C(0)OH, -(CH2)O-2C(0)OR‘, -(CH2)O2SR*, -(CH2)O2SH, -(CH2)0 2NH2, -(CH2)O 2NHR*, -(CH2)O 2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(Ci4straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is, independently, selected from C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0050] Suitable divalent substituents on a saturated carbon atom of a group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having ( - heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of a group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Page 15 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0051] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is, independently, C1-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having C heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] Suitable substituents on a substitutable nitrogen of a group include -R\ -NR'2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, -C(O)CH2C(O)Rf, -S(O)2Rf, -S(O)2NRf2, -C(S)NRf2, -C(NH)NRf2, or -NCR^SCO)^; wherein each R' is, independently, hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having (M heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having (M heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0053] Suitable substituents on the aliphatic group of R' are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is, independently, C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having (M heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds Page 16 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOformed during chromotagraphic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0055] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure. 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, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0056] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0057] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits STAT6 protein with measurable affinity.

[0058] As used herein, an “inhibitor compound” is a compound that binds a protein of interest. In some embodiments, an inhibitor compound binds a protein of interest and decreases its activity. In some embodiments, binding of an inhibitor compound to a protein of interest does not result in degradation of the protein of interest. In another embodiment, an inhibitor compound does not bind an E3 ligase in a manner that results in degradation of the protein of interest. In another embodiment, an inhibitor compound does not, in vivo or in vitro, bind an E3 ligase in a manner that results in degradation of the protein of interest. In some embodiments, an inhibitor compound binds STAT6. In some embodiments, an inhibitor compound binds STAT6 and decreases its activity. In some embodiments, binding of an inhibitor compound to STAT6 does not result in degradation of STAT6. In another embodiment, an inhibitor compound but does not bind an E3 ligase in a manner that results in degradation of the STAT6. In some embodiments, an inhibitor compound binds a protein of interest (e.g., STAT6) but does not bind an E3 ligase. In some embodiments, an E3 ligase is selected from a cereblon E3 ubiquitin ligase, a VHL E3 ubiquitin ligase, a DCAF E3 ubiquitin ligase, (e.g., a DCAF1 E3Page 17 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOubiquitin ligase, a DCAF15 E3 ubiquitin ligase, or a DCAF16 E3 ubiquitin ligase), an IAP E3 ubiquitin ligase, an MDM2 E3 ligase, or a KLHDC2 E3 ubiquitin ligase. It will be understood that, throughout this disclosure, reference to a “compound” or a “provided compound” refers to an inhibitor compound as defined above. In some embodiments, an E3 ligase is a cereblon E3 ubiquitin ligase. In certain embodiments, an inhibitor compound has an IC50 and / or binding constant of less than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0059] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in STAT6 protein activity between a sample comprising a compound of the present disclosure, or composition thereof, and STAT6 protein, and an equivalent sample comprising STAT6 protein, in the absence of said compound, or composition thereof.

[0060] As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. In some embodiments, a “reference” sample or subject is one that is sufficiently similar to a particular sample or subject of interest to permit a relevant comparison. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.Compounds

[0061] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein.

[0062] Compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) are useful as inhibitors of STAT6 protein. In some embodiments, a compound disclosed herein modulates STAT6. In some embodiments, a compound disclosed herein inhibits STAT6.Formula Z

[0063] Disclosed herein, in some embodiments, is a compound of Formula Z:Page 18 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula Z,or a pharmaceutically acceptable salt thereof, wherein:Vais N or CRE4;Vbis N or CRE3;Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;Hj) RE1is absent or selected from the group consisting of (R)c, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, -NRN3eS(O)i-2RC2e, -NRNleC(O)-CRC4eRc5e-NR101R102, -NRNleRN2eC(O)-NR101R102, -C(O)-NRN3eR103, -Page 19 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WONRN3eC(O)R104, -C(O)-CRC4eRc5e-NR101R102, -NRN3eC(O)-CRC4eRc5e-R105, -C(0)- NRNleCH2CHOHCH2NRNleRN2e, -C(O)-NRNle(CH2)i.2ORole, -NRNleC(O)ORole, - OC(O)NRNleRN2e, and -S(O)i-2-Rsle;Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of R101and R102is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, -C(O)-Ci-C6alkyl, and R1000, or R101and R102on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 8- membered monocyclic heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 8- membered monocyclic heterocyclyl is unsubstituted or substituted with 1-4 instances of R1000a;R1000is selected from the group consisting of 3- to 8- membered monocyclic carbocyclyl, 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen,Page 20 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOoxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R1000is unsubstituted or substituted with 1-4 instances of RlOOOb.each R1000ais, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NRNlzRN2z;each R1000bis, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NRNlyRN2y;each of R103and R104is, independently, selected from the group consisting of phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of R103and R104is, independently, unsubstituted or substituted with 1-4 instances of R1000c; each R1000cis, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NRNlxRN2x;R105is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, -C(O)-Ci-C6alkyl, and R1005;R1005is selected from the group consisting of 3- to 8- membered monocyclic carbocyclyl, 3- to 8 -membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms Page 21 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOindependently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R1005is unsubstituted or substituted with 1-4 instances of R1005a.each R1005ais, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NR^WR 2W.Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 -membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and 6- membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;b is 0, 1, 2, 3, 4, 5, or 6;each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, -(Ci-C6alkyl)-ORolbb, and RB1;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RB1is selected from the group consisting of -(C2-C4 alkynyl)-( 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) and 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RB1is unsubstituted or substituted with 1-4 occurrences of RBla;each RBlais, independently, selected from the group consisting halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy;Page 22 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOEH RE2is absent or selected from the group consisting of (R, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleeRN2ee _QRC4eepC5ee ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee _ NRN3eeS(O)i.2RC2ee, -NRNleeC(O)-CRC4eeRc5ee-NR201R202, -NRNleeRN2eeC(O)-NR20iR202, -C(O)-NRN3eeR203, -NRN3eeC(O)R204, -C(O)-CRC4eeRc5ee-NR201R202, - NRN3eeC(O)-CRC4eeRc5ee-R205, -C(O)-NRNleeCH2CHOHCH2NRNleeRN2ee, -C(O)- NRNlee(CH2)i-2ORolee, -NRNleeC(O)ORolee, -OC(O)NRNleeRN2ee, and -S(O)i-2-Rslee, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd;or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of R201and R202is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, -C(O)-Ci-C6alkyl, and R2000, or R201and R202on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 8- membered monocyclic heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 8- membered monocyclic heterocyclyl is unsubstituted or substituted with 1-4 instances of R2000a;Page 23 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOR2000is selected from the group consisting of 3- to 8- membered monocyclic carbocyclyl, 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2000is unsubstituted or substituted with 1-4 instances of R2000b.each R2000ais, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NR^ZZ2ZZ.each R2000bis, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NRN1yyRN2yy.each of R203and R204is, independently, selected from the group consisting of phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of R203and R204is, independently, unsubstituted or substituted with 1-4 instances of R2000c; each R2000Cis, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NR^XX2XX.R205is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, -C(O)-Ci-C6alkyl, and R2005;Page 24 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOR2005is selected from the group consisting of 3- to 8- membered monocyclic carbocyclyl, 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2005is unsubstituted or substituted with 1-4 instances of R2005a.each R2005ais, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NR^w wRN2 w w■RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -memberedPage 25 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOmonocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;V1is selected from the group consisting of a covalent bond, -O-, -NRE10-, -CRE11RE12-,-CRE11RE12CRE11RE12_ _CRE11RE12NRE10-, -NRE10CRE11RE12-, -CRE11RE12O-, and - OCRE11RE12-;V2is selected from the group consisting of -C(O)-, -C(S)-, -S(O)-, and -S(O)2-;RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;RE11is, independently, is selected from the group consisting of hydrogen, halogen, -OR0111, -NRNIHRN2115 C1. C6 alkyl> C1. C6 haloalkyl> and-(Ci-Ce alkyl)-NRN111RN211, and RE12is, independently, selected from the group consisting of hydrogen, halogen, -OR0112, -NRNii2RN2i2> C1. C6 alkyl> C1. C6 haloalkyl> and_(Ci-C6alkyl)-NRN112RN212, or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5- membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;each of RO1, Rolaa, Rolbb, Rolcc, Roldd, Role, Rolee, R°13, R°14, R°19, RO111, and R°112, is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola;each Rolais, independently, selected from the group consisting of -(Ci-Ce alkylene)-NRN1RN2, -(3- to 8-membered monocyclic carbocyclylene)- NRN1RN2, -(Ci-Ce alkylene)-(4- to 8 -membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 4- to 8-membered monocyclic heterocyclyl with 1- Page 26 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10- membered bridged heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 10-membered spirocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3;each Of R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4ee|^\I 3 RN23 |^\I4 RN24 |^\I 9 RN29 RNIII RN211 RN112 RN212 NIW N2W NIWW N2WW NIX N2X NIXX N2XX Nly N2y Nlyy N2yy NIZ N2Z RN1ZZ, and RN2ZZ, is, independently, selected from the group consisting of hydrogen, Ci- Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5 -membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, RN112and RN212, RNlwand RN2w, RNlwwand RN2ww, RNlxand RN2x, RN1XXand RN2XX, RNlyand RN2y, RNlyyand RN2yy, RNlzand RN2z, or RNlzzand RN2ZZon the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RC3is, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy;each of RC4, Rc5, RC6, RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy,or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which both groups are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,Page 27 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl; and each of Rsleand Rsleeis, independently, selected from the group consisting of Ci-Ce alkyl and Ci-C6haloalkyl.

[0064] In some embodiments, RE1and RE2are not both simultaneously absent.

[0065] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0066] Disclosed herein, in some embodiments, is an inhibitor compound of Formula Z:Formula Z,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0067] In some embodiments, the compound is of Formula X”.

[0068] In some embodiments, the compound is of Formula X’.

[0069] In some embodiments, the compound is of Formula X.

[0070] In some embodiments, the compound is of Formula I”.

[0071] In some embodiments, the compound is of Formula I’.

[0072] In some embodiments, the compound is of Formula I.

[0073] In some embodiments, the compound is of Formula II”.

[0074] In some embodiments, the compound is of Formula II’.

[0075] In some embodiments, the compound is of Formula II.

[0076] In some embodiments, the compound is of Formula I-a.

[0077] In some embodiments, the compound is of any one of Formula I-a-1 to Formula I-a- 86.

[0078] In some embodiments, the compound is of Formula I-b.Page 28 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0079] In some embodiments, the compound is of any one of Formula I-b-1 to Formula I-b-27.

[0080] In some embodiments, the compound is of Formula I-c.

[0081] In some embodiments, the compound is of any one of Formula I-c-1 to Formula I-c-22.Formula X”

[0082] Disclosed herein, in some embodiments, is a compound of Formula X”:X \ Rt6vb" V / RE7,' ^pE2KE8N RE9v2-v1RE1'aFormula X”,or a pharmaceutically acceptable salt thereof, wherein:Vais N or CRE4;Vbis N or CRE3;Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected fromPage 29 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOnitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;cRE1is absent or selected from the group consistingof (R)c, -C(O)-NRNleRN2e, - NRN3eC(O)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, -(Ci-C6alkyl)-ORolbb, and RB1;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,Page 30 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOwherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RB1is selected from the group consisting of -(C2-C4 alkynyl)-( 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) and 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RB1is unsubstituted or substituted with 1-4 occurrences of RBla;each RBlais, independently, selected from the group consisting halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy;RE2is absent or selected from the group consisting of ^RU^d, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2eeand -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd;or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;Page 31 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;V1is selected from the group consisting of a covalent bond, -O-, -NRE10-, -CRE11RE12-, and —CR 11R 12CR 11R 12_‘V2is selected from the group consisting of -C(O)-, -C(S)-, -S(O)-, and -S(O)2-;RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;RE11is, independently, is selected from the group consisting of hydrogen, halogen, -OR0111, - NRN111RN211, Ci-C6alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN111RN211, andPage 32 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORE12is, independently, selected from the group consisting of hydrogen, halogen, -OR0112, -NRN112RN212,C1. C6 alkyl> C 1. C6 haloalkyl> and_(C!-C6 alkyl)-NRN112RN212, or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, and R°112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola; Rolais -(Ci-C6alkylene)-(4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) or 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubsli luted or substituted with 1-4 occurrences of RC3;each Of R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211 RN112an(j RN212, is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, orRN112andRN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;each of Rcle, RC2e, Rclee, andRC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Page 33 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOeach RC3is, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, Ci-C6haloalkyl, and Ci-Ce alkoxy; andeach of RC4, Rc5, RC6, RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-C6alkoxy,or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which both groups are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0083] In some embodiments, RE1and RE2are not both simultaneously absent.

[0084] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0085] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X”:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0086] In some embodiments, the compound is of Formula X’.

[0087] In some embodiments, the compound is of Formula X.

[0088] In some embodiments, the compound is of Formula I”.

[0089] In some embodiments, the compound is of Formula I’.

[0090] In some embodiments, the compound is of Formula I.

[0091] In some embodiments, the compound is of Formula II”.Page 34 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0092] In some embodiments, the compound is of Formula II’.

[0093] In some embodiments, the compound is of Formula II.

[0094] In some embodiments, the compound is of Formula I-a.

[0095] In some embodiments, the compound is of any one of Formula I-a-1 to Formula I-a-86.

[0096] In some embodiments, the compound is of Formula I-b.

[0097] In some embodiments, the compound is of any one of Formula I-b-1 to Formula I-b-27.

[0098] In some embodiments, the compound is of Formula I-c.

[0099] In some embodiments, the compound is of any one of Formula I-c-1 to Formula I-c-22.Formula X’

[0100] An inhibitor compound of Formula X’:Formula X’,or a pharmaceutically acceptable salt thereof, wherein:Vais N or CRE4;Vbis N or CRE3;Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;Page 35 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE1is absent or selected from the group consistingof (rC)c, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;Page 36 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOeach RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;i RE2is absent or selected from the group consisting of ^RD^d, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2eeand -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;Page 37 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, Ci-Ce alkyl, and Ci-Ce haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -OR014, -NRN14RN24, Ci-Ce alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR01, -NRN1RN2, Ci- Ce alkyl, and Ci-Ce haloalkyl;V1is selected from the group consisting of a covalent bond, -O-, -NRE10-, -CRE11RE12-, and —CR 11R 12CR 11R 12_‘V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;RE11is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN111RN211, andPage 38 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORE12is selected from the group consisting of hydrogen, halogen, -OR0112, -NRN112RN212, CI- C6alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN112RN212,or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, R°112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;each Of R^2J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211an(j RN112isindependently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, or RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which both groups are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,Page 39 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0101] In some embodiments, RE1and RE2are not both simultaneously absent.

[0102] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0103] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X’:Formula X’,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0104] In some embodiments, the compound is of Formula X.

[0105] In some embodiments, the compound is of Formula I”.

[0106] In some embodiments, the compound is of Formula I’.

[0107] In some embodiments, the compound is of Formula I.

[0108] In some embodiments, the compound is of Formula II”.

[0109] In some embodiments, the compound is of Formula II’.

[0110] In some embodiments, the compound is of Formula II.

[0111] In some embodiments, the compound is of Formula I-a.

[0112] In some embodiments, the compound is of any one of Formula I-a-1 to Formula I-a- 86.

[0113] In some embodiments, the compound is of Formula I-b.

[0114] In some embodiments, the compound is of any one of Formula I-b-1 to Formula I-b- 27.

[0115] In some embodiments, the compound is of Formula I-c.

[0116] In some embodiments, the compound is of any one of Formula I-c-1 to Formula I-c- 22.Page 40 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula X

[0117] Disclosed herein, in some embodiments, is a compound of Formula X:E1 )— RE1(RA)aFormula X,or a pharmaceutically acceptable salt thereof, wherein:Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE1is absent or selected from the group consistingof ")c, -C(O)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e;Page 41 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORing Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;Page 42 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORE2is absent or selected from the group consisting of (RD)d, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2eeand -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected fromPage 43 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOnitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;V1is selected from the group consisting of a covalent bond, -O-, -NRE10-, -CRE11RE12-, and —CR 11R 12CR 11R 12_‘V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;RE11is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN1RN2,RE12is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN111RN211,or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, and Roll2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;Page 44 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO each Of RN2 J^^laa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211 RN112an(j RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, and RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur; each of Rcle, RC2e, Rclee, and RC2eeis independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0118] In some embodiments, RE1and RE2are not both simultaneously absent.

[0119] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0120] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X:Page 45 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula X,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0121] In some embodiments, the compound is of Formula I”.

[0122] In some embodiments, the compound is of Formula I’.

[0123] In some embodiments, the compound is of Formula I.

[0124] In some embodiments, the compound is of Formula II”.

[0125] In some embodiments, the compound is of Formula II’.

[0126] In some embodiments, the compound is of Formula II.

[0127] In some embodiments, the compound is of Formula I-a.

[0128] In some embodiments, the compound is of any one of Formula I-a-1 to Formula I-a- 86.

[0129] In some embodiments, the compound is of Formula I-b.

[0130] In some embodiments, the compound is of any one of Formula I-b-1 to Formula I-b- 27.

[0131] In some embodiments, the compound is of Formula I-c.

[0132] In some embodiments, the compound is of any one of Formula I-c-1 to Formula I-c- 22.Formula I”

[0133] Disclosed herein, in some embodiments is a compound of Formula I”:Page 46 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I”,or a pharmaceutically acceptable salt thereof, wherein:Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRN1RN2, and -(Ci-C6alkyl)-ORolaa;or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE1is absent or selected from the group consistingof (R)c, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6-Page 47 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOmembered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE2is absent or selected from the group consisting of (RD)d, -C(0)-NRNleeRN2ee, -NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)-Page 48 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee and -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,Page 49 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;V1is selected from the group consisting of -O-, -NRE10-, -CRE11RE12-, and - CR^IIR^12CR^HR^12_*V2is selected from the group consisting of -C(O)-, -C(S)-, -S(O)-, and -S(O)2-;RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;RE11is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN1RN2,RE12is selected from the group consisting of hydrogen, halogen, -OR0112, -NRN112RN212, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN1RN2,or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, and Roll2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola; Rolais -(Ci-C6alkylene)-(4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) or 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences ofRC3;Page 50 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO each Of RN2 J^^laa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211 RN112an(j RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, or RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RC3is, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy; andeach of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0134] In some embodiments, RE1and RE2are not both simultaneously absent.

[0135] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0136] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I”:Page 51 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0137] In some embodiments, the compound is of Formula I’.

[0138] In some embodiments, the compound is of Formula I.

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

[0140] In some embodiments, the compound is of any one of Formula I-a-1 to Formula I-a-86.

[0141] In some embodiments, the compound is of Formula I-b.

[0142] In some embodiments, the compound is of any one of Formula I-b-1 to Formula I-b-27.

[0143] In some embodiments, the compound is of Formula I-c.

[0144] In some embodiments, the compound is of any one of Formula I-c-1 to Formula I-c-22.Formula I’

[0145] Disclosed herein, in some embodiments, is a compound of Formula I’:or a pharmaceutically acceptable salt thereof, wherein:Page 52 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORing El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;H£)CRE1is absent or selected from the group consistingof *-R, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-memberedPage 53 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOmonocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE2is absent or selected from the group consisting of, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee and -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;Page 54 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOeach RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected fromPage 55 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOnitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;V1is selected from the group consisting of -O-, -NRE10-, -CRE11RE12-, and - CR^IIR^12CR^HR^12_*V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;RE11is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN1RN2,RE12is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN111RN211,or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, and Roll2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl; each Of R^ R^ J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211 RN112an(j RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, or RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- memberedPage 56 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOheterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2aW^^D2b, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0146] In some embodiments, RE1and RE2are not both simultaneously absent.

[0147] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0148] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I’:(RA)aFormula I’,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0149] In some embodiments, the compound is of Formula I.

[0150] In some embodiments, the compound is of Formula I-a.Page 57 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0151] In some embodiments, the compound is of any one of Formula I-a-1 to Formula I-a-86.

[0152] In some embodiments, the compound is of Formula I-b.

[0153] In some embodiments, the compound is of any one of Formula I-b-1 to Formula I-b-27.

[0154] In some embodiments, the compound is of Formula I-c.

[0155] In some embodiments, the compound is of any one of Formula I-c-1 to Formula I-c-22.Formula I

[0156] Disclosed herein, in some embodiments, is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring El is selected from the group consisting of phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, -ORolaa, -NRNiaaRN2aa,C 1. C6 alkyl>_C(O)-Ci-C6alkyl, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected fromPage 58 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOnitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;Hj)RE1is absent or selected from the group consistingof (R, -C(O)-NRNleRN2e, - NRN3eC(O)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, -ORolcc, -NRNICCRN2CC,C1-C6 alkyl>_C(O)-C1-C6alkyl, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl, or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 selected from the group consisting of phenyl and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;b is 0, 1, 2, 3, 4, 5, or 6;each RBis, independently, selected from the group consisting of halogen, -ORolbb, -NRNibbRN2bb,C1-C6 alkyl>_C(O)-Ci-C6alkyl, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected fromPage 59 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOnitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;i RE2is absent or selected from the group consisting of (RD)d, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2eeand -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, -ORoldd, -NRNiddRN2dd,C1-C6 alkyl>_C(O)-Ci-C6alkyl, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl, or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, -OR013, -NRN13RN23, Ci-Ce alkyl, and Ci-Ce haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, -OR014, -NRN14RN24, Ci-Ce alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl and Ci-C6haloalkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,Page 60 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOwherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, -OR019, -NRN19RN29, Ci-Ce alkyl, and Ci-Ce haloalkyl;V1is selected from the group consisting of -O-, -NRE10-, and -CRE11RE12-;RE1° is selected from the group consisting of hydrogen, halogen, -OR01, -NRN1RN2, Ci-Ce alkyl, and Ci-Ce haloalkyl;each of RE11and RE12is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, and R°19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;each of RN1RN2RNlaaRX2aaRNlbbRN2bbRNlccRN2CCRNlddRN2ddRNleRN2eRN3eRN4e RNlee, RN2ee, RN3ee, RN4ee, RN13, RN23, RN14, RN24, RN19, and RN29is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)- Page 61 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOCi-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0157] In some embodiments, RE1and RE2are not both simultaneously absent.

[0158] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0159] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I:Page 62 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0160] In some embodiments, the compound is of Formula I-a.

[0161] In some embodiments, the compound is of any one of Formula I-a-1 to Formula I-a- 86.

[0162] In some embodiments, the compound is of Formula I-b.

[0163] In some embodiments, the compound is of any one of Formula I-b-1 to Formula I-b- 27.

[0164] In some embodiments, the compound is of Formula I-c.

[0165] In some embodiments, the compound is of any one of Formula I-c-1 to Formula I-c- 22.Formula II”

[0166] Disclosed herein, in some embodiments, is a compound of Formula II”:Formula II”,or a pharmaceutically acceptable salt thereof, wherein:Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;Page 63 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;cRE1is absent or selected from the group consistingof (R, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;Page 64 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOeach RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRN1RN2, and -(Ci-C6alkyl)-ORolbb;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE2is absent or selected from the group consisting of, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3)-NRNleeRN2ee, -C(N0RN4)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2eeand -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;Page 65 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;V2is selected from the group consisting of -C(O)-, -C(S)-, -S(O)-, and -S(O)2-;each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, and Rol9is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola;Rolais -(Ci-C6alkylene)-(4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) or 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences ofRC3;Page 66 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO each Of RN2 J^^laa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4eRNiee, RN2ee, RN3ee, RN4ee, RI\ RN23, RN14, RN24, RN19,AND RN29is>independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)- Ci-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RC3is, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy; andeach of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2aV?^pD2b*, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0167] In some embodiments, RE1and RE2are not both simultaneously absent.

[0168] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0169] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II”:Page 67 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula II”,or a pharmaceutically acceptable salt thereof.Formula IF

[0170] Disclosed herein, in some embodiments, is a compound of Formula II’:Formula II’,or a pharmaceutically acceptable salt thereof, wherein:Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,Page 68 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOwherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE1is absent or selected from the group consistingof (R, -C(O)-NRNleRN2e, - NRN3eC(O)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;c is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-memberedPage 69 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOmonocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;i RE2is absent or selected from the group consisting of (R°)d, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleepN2ee _ Q Q^C4eej^C5ee) ^j^Nleej^N2ee _ Qj^C4eej^C5eej^C6ee _ S(O)12 NR^ leeJ^N2eeand -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,Page 70 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, and R°19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;each Of R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4eRNiee, RN2ee, RN3ee, RN4ee, RI\ RN23, RN14, RN24, RN19,AND RN29is>independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)- Ci-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;Page 71 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORN1and RN2, RNlaaand RN2aa, RNlbband RN2bb, RNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29is, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0171] In some embodiments, RE1and RE2are not both simultaneously absent.

[0172] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0173] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II’:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 72 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula II

[0174] Disclosed herein, in some embodiments, is a compound of Formula II:RE7RE8R RE2 E9E1 )— RE1Formula II,or a pharmaceutically acceptable salt thereof, wherein:Ring El is selected from the group consisting of 8- to 10-membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, 3, 4, 5, or 6;each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE1is absent or selected from the group consistingof <RC)C, -C(O)-NRNleRN2e, - NRN3eC(O)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Page 73 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOc is 0, 1, 2, 3, 4, 5, or 6;each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;RE2is absent or selected from the group consisting of, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee and -NRN3eeS(O)i-2RC2ee;Page 74 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORing F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;d is 0, 1, 2, 3, 4, 5, or 6;each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, CI-C6alkyl, and Ci-Ce haloalkyl;RE4is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, CI-C6alkyl, and Ci-Ce haloalkyl;each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered Page 75 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOmonocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, and R°19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;each Of R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4eRNlee, RN2ee, RN3ee, RN4ee, RN13, RN23, RN14, RN24, RN19, and RN29is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)- Ci-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,Page 76 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2aR, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0175] In some embodiments, RE1and RE2are not both simultaneously absent.

[0176] In some embodiments, when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

[0177] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.SubformulasFormula I-a

[0178] In some embodiments, the compound or the inhibitor compound is of Formula I-a:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-1

[0179] In some embodiments, the compound is of Formula I-a-1:Page 77 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-1,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-2

[0180] In some embodiments, the compound or the inhibitor compound is of Formula I-a-2:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-3

[0181] In some embodiments, the compound or the inhibitor compound is of Formula I-a-3:Formula I-a-3,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-4

[0182] In some embodiments, the compound or the inhibitor compound is of Formula I-a-4:Page 78 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-5

[0183] In some embodiments, the compound or the inhibitor compound is of Formula I-a-5:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-6

[0184] In some embodiments, the compound or the inhibitor compound is of Formula I-a-6:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-7

[0185] In some embodiments, the compound or the inhibitor compound is of Formula I-a-7:Page 79 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-8

[0186] In some embodiments, the compound or the inhibitor compound is of Formula I-a-8:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-9

[0187] In some embodiments, the compound or the inhibitor compound is of Formula I-a-9:Formula I-a-9,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-10

[0188] In some embodiments, the compound or the inhibitor compound is of Formula I-a-10:Page 80 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-11

[0189] In some embodiments, the compound or the inhibitor compound is of Formula I-a-11:Formula I-a-11,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-12

[0190] In some embodiments, the compound or the inhibitor compound is of Formula I-a-12:Formula I-a-12,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 81 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-13

[0191] In some embodiments, the compound or the inhibitor compound is of Formula I-a-13:(RA)aFormula I-a-13,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-14

[0192] In some embodiments, the compound or the inhibitor compound is of Formula I-a-14:Formula I-a-14,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-15

[0193] In some embodiments, the compound or the inhibitor compound is of Formula I-a-15:Formula I-a-15,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 82 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-16

[0194] In some embodiments, the compound or the inhibitor compound is of Formula I-a-16:RE\5RE6HNFormula I-a-16,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-17

[0195] In some embodiments, the compound or the inhibitor compound is of Formula I-a-17:O N X HN'N' OFormula I-a-17,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-18

[0196] In some embodiments, the compound or the inhibitor compound is of Formula I-a-18:RE9Formula I-a-18,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 83 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-19

[0197] In some embodiments, the compound or the inhibitor compound is of Formula I-a-19:Formula I-a-19,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-20

[0198] In some embodiments, the compound or the inhibitor compound is of Formula I-a-20:Formula I-a-20,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-21

[0199] In some embodiments, the compound or the inhibitor compound is of Formula I-a-21:Formula I-a-21,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 84 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-22

[0200] In some embodiments, the compound or the inhibitor compound is of Formula I-a-22:Formula I-a-22,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-23

[0201] In some embodiments, the compound or the inhibitor compound is of Formula I-a-23:OFormula I-a-23,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-24

[0202] In some embodiments, the compound or the inhibitor compound is of Formula I-a-24:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 85 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-25

[0203] In some embodiments, the compound or the inhibitor compound is of Formula I-a-25:RE5RES£.O / NNI pE9 / £RoFormula I-a-25,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-26

[0204] In some embodiments, the compound or the inhibitor compound is of Formula I-a-26:RE5RE61.pE9 / RoFormula I-a-26,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-27

[0205] In some embodiments, the compound or the inhibitor compound is of Formula I-a-27:R£.O I pE9 / £RoFormula I-a-27,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 86 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-28

[0206] In some embodiments, the compound or the inhibitor compound is of Formula I-a-28:1 N <RE9Formula I-a-28,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-29

[0207] In some embodiments, the compound or the inhibitor compound is of Formula I-a-29: / N1 N - I RE9(RA)aFormula I-a-29,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-30

[0208] In some embodiments, the compound or the inhibitor compound is of Formula I-a-30:L N <RE9Formula I-a-30,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 87 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-31

[0209] In some embodiments, the compound or the inhibitor compound is of Formula I-a-31:Formula I-a-31,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-32

[0210] In some embodiments, the compound or the inhibitor compound is of Formula I-a-32:Formula I-a-32,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-33

[0211] In some embodiments, the compound or the inhibitor compound is of Formula I-a-33:Formula I-a-33,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 88 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-34

[0212] In some embodiments, the compound or the inhibitor compound is of Formula I-a-34:(RA)aFormula I-a-34,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-35

[0213] In some embodiments, the compound or the inhibitor compound is of Formula I-a-35:(RA)aFormula I-a-35,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-36

[0214] In some embodiments, the compound or the inhibitor compound is of Formula I-a-36:Formula I-a-36,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 89 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-37

[0215] In some embodiments, the compound or the inhibitor compound is of Formula I-a-37:Formula I-a-37,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-38

[0216] In some embodiments, the compound or the inhibitor compound is of Formula I-a-38:Formula I-a-38,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-39

[0217] In some embodiments, the compound or the inhibitor compound is of Formula I-a-39:(RA)aFormula I-a-39,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 90 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-40

[0218] In some embodiments, the compound or the inhibitor compound is of Formula I-a-40:(RA)aFormula I-a-40,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-41

[0219] In some embodiments, the compound or the inhibitor compound is of Formula I-a-41:Formula I-a-41,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-42

[0220] In some embodiments, the compound or the inhibitor compound is of Formula I-a-42:Formula I-a-42,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 91 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-43

[0221] In some embodiments, the compound or the inhibitor compound is of Formula I-a-43:(RA)aFormula I-a-43,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-44

[0222] In some embodiments, the compound or the inhibitor compound is of Formula I-a-44:Formula I-a-44,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-45

[0223] In some embodiments, the compound or the inhibitor compound is of Formula I-a-45:Formula I-a-45,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 92 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-46

[0224] In some embodiments, the compound or the inhibitor compound is of Formula I-a-46:(RA)aFormula I-a-46,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-47

[0225] In some embodiments, the compound or the inhibitor compound is of Formula I-a-47:Formula I-a-47,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-48

[0226] In some embodiments, the compound or the inhibitor compound is of Formula I-a-48:Formula I-a-48,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 93 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-49

[0227] In some embodiments, the compound or the inhibitor compound is of Formula I-a-49:Formula I-a-49,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-50

[0228] In some embodiments, the compound or the inhibitor compound is of Formula I-a-50:Formula I-a-50,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-51

[0229] In some embodiments, the compound or the inhibitor compound is of Formula I-a-51:Formula I-a-51,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 94 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-52

[0230] In some embodiments, the compound is of Formula I-a-52:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-53

[0231] In some embodiments, the compound is of Formula I-a-53:Formula I-a-53,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-54

[0232] In some embodiments, the compound is of Formula I-a-54:Formula I-a-54,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 95 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-55

[0233] In some embodiments, the compound is of Formula I-a-55:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-56

[0234] In some embodiments, the compound is of Formula I-a-56:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-57

[0235] In some embodiments, the compound is of Formula I-a-57:Formula I-a-57,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 96 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-58

[0236] In some embodiments, the compound is of Formula I-a-58:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-59

[0237] In some embodiments, the compound is of Formula I-a-59:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-60

[0238] In some embodiments, the compound is of Formula I-a-60:Formula I-a-60,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 97 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-61

[0239] In some embodiments, the compound is of Formula I-a-61:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-62

[0240] In some embodiments, the compound is of Formula I-a-62:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-63

[0241] In some embodiments, the compound is of Formula I-a-63:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 98 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-64

[0242] In some embodiments, the compound is of Formula I-a-64:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-65

[0243] In some embodiments, the compound is of Formula I-a-65:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-66

[0244] In some embodiments, the compound is of Formula I-a-66:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 99 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-67

[0245] In some embodiments, the compound is of Formula I-a-67:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-68

[0246] In some embodiments, the compound is of Formula I-a-68:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-69

[0247] In some embodiments, the compound is of Formula I-a-69:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 100 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-70

[0248] In some embodiments, the compound is of Formula I-a-70:Formula I-a-70,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-71

[0249] In some embodiments, the compound is of Formula I-a-71:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-72

[0250] In some embodiments, the compound is of Formula I-a-72:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 101 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-73

[0251] In some embodiments, the compound is of Formula I-a-73:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula l-a-74

[0252] In some embodiments, the compound is of Formula I-a-74:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-75

[0253] In some embodiments, the compound is of Formula I-a-75:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 102 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-76

[0254] In some embodiments, the compound is of Formula I-a-76:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula l-a-77

[0255] In some embodiments, the compound is of Formula I-a-77:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-78

[0256] In some embodiments, the compound is of Formula I-a-78:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 103 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-a-79

[0257] In some embodiments, the compound is of Formula I-a-79:Formula I-a-79,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-80

[0258] In some embodiments, the compound is of Formula I-a-80:(RA)aFormula I-a-80,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-81

[0259] In some embodiments, the compound is of Formula I-a-81:Page 104 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-82

[0260] In some embodiments, the compound is of Formula I-a-82:Formula I-a-82,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-83

[0261] In some embodiments, the compound is of Formula I-a-83:Formula I-a-83,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-84

[0262] In some embodiments, the compound is of Formula I-a-84:Formula I-a-84,Page 105 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-85

[0263] In some embodiments, the compound is of Formula I-a-85:L N > R1RE9N-NFormula I-a-85,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-a-86

[0264] In some embodiments, the compound is of Formula I-a-86:L N > REHRE9Formula I-a-86,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b

[0265] In some embodiments, the compound or the inhibitor compound is of Formula I-b:R!9R \ RE6■B)b IV7NKE2RE9NH’aFormula I-b,Page 106 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-1

[0266] In some embodiments, the compound or the inhibitor compound is of Formula I-b-1:Formula I-b-1,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-2

[0267] In some embodiments, the compound or the inhibitor compound is of Formula I-b-2:Formula I-b-2,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-3

[0268] In some embodiments, the compound or the inhibitor compound is of Formula I-b-3:Page 107 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-4

[0269] In some embodiments, the compound or the inhibitor compound is of Formula I-b-4:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-5

[0270] In some embodiments, the compound or the inhibitor compound is of Formula I-b-5:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-6

[0271] In some embodiments, the compound or the inhibitor compound is of Formula I-b-6:Page 108 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-7

[0272] In some embodiments, the compound or the inhibitor compound is of Formula I-b-7:Formula I-b-7,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-8In some embodiments, the compound or the inhibitor compound is of Formula I-b-8:Formula I-b-8,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-9

[0273] In some embodiments, the compound or the inhibitor compound is of Formula I-b-9:Formula I-b-9,Page 109 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-10

[0274] In some embodiments, the compound or the inhibitor compound is of Formula I-b-10:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-11

[0275] In some embodiments, the compound or the inhibitor compound is of Formula I-b-11:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-12

[0276] In some embodiments, the compound or the inhibitor compound is of Formula I-b-12:Page 110 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-b-12,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-13

[0277] In some embodiments, the compound or the inhibitor compound is of Formula I-b-13:(RA)aFormula I-b-13,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-14

[0278] In some embodiments, the compound or the inhibitor compound is of Formula I-b-14:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-15

[0279] In some embodiments, the compound or the inhibitor compound is of Formula I-b-15:Page 111 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-b-15,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-16

[0280] In some embodiments, the compound or the inhibitor compound is of Formula I-b-16:RE5RE61 N - RE9HNFormula I-b-16,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-17

[0281] In some embodiments, the compound or the inhibitor compound is of Formula I-b-17:o r / N-^NI RE9HNo NFormula I-b-17,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-18

[0282] In some embodiments, the compound or the inhibitor compound is of Formula I-b-18:, E61 N >RE9NHFormula I-b-18,Page 112 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-19

[0283] In some embodiments, the compound or the inhibitor compound is of Formula I-b-19:Formula I-b-19,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-20

[0284] In some embodiments, the compound or the inhibitor compound is of Formula I-b-20:Formula I-b-20,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-21

[0285] In some embodiments, the compound or the inhibitor compound is of Formula I-b-21:OFormula I-b-21,Page 113 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-22

[0286] In some embodiments, the compound or the inhibitor compound is of Formula I-b-22:Formula I-b-22,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-23

[0287] In some embodiments, the compound or the inhibitor compound is of Formula I-b-23:OzNFormula I-b-23,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-24

[0288] In some embodiments, the compound or the inhibitor compound is of Formula I-b-24:Formula I-b-24,Page 114 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-25

[0289] In some embodiments, the compound or the inhibitor compound is of Formula I-b-25:Formula I-b-25,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-26

[0290] In some embodiments, the compound or the inhibitor compound is of Formula I-b-26:Formula I-b-26,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-b-27

[0291] In some embodiments, the compound or the inhibitor compound is of Formula I-b-27:Formula I-b-27,Page 115 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c

[0292] In some embodiments, the compound or the inhibitor compound is of Formula I-c:Formula I-c,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-1

[0293] In some embodiments, the compound or the inhibitor compound is of Formula I-c-1:Formula I-c-1,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-2

[0294] In some embodiments, the compound or the inhibitor compound is of Formula I-c-2:Page 116 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-c-2,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-3

[0295] In some embodiments, the compound or the inhibitor compound is of Formula I-c-3:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-4

[0296] In some embodiments, the compound or the inhibitor compound is of Formula I-c-4:(RA)aFormula I-c-4,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-5

[0297] In some embodiments, the compound or the inhibitor compound is of Formula I-c-5:Page 117 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO(RA)aFormula I-c-5,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-6

[0298] In some embodiments, the compound or the inhibitor compound is of Formula I-c-6:Formula I-c-6,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-7

[0299] In some embodiments, the compound or the inhibitor compound is of Formula I-c-7:Formula I-c-7,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Page 118 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-c-8

[0300] In some embodiments, the compound or the inhibitor compound is of Formula I-c-8:Formula I-c-8,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-9

[0301] In some embodiments, the compound or the inhibitor compound is of Formula I-c-9:Formula I-c-9,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-10

[0302] In some embodiments, the compound or the inhibitor compound is of Formula I-c-10:Formula I-c-10,Page 119 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-11

[0303] In some embodiments, the compound or the inhibitor compound is of Formula I-c-11:Formula I-c-11,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-12

[0304] In some embodiments, the compound or the inhibitor compound is of Formula I-c-12:Formula I-c-12,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-13

[0305] In some embodiments, the compound or the inhibitor compound is of Formula I-c-13:Page 120 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-c-13,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-14

[0306] In some embodiments, the compound or the inhibitor compound is of Formula I-c-14:Formula I-c-14,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-15

[0307] In some embodiments, the compound or the inhibitor compound is of Formula I-c-15:Formula I-c-15,Page 121 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-16

[0308] In some embodiments, the compound is of Formula I-c-16:Formula I-c-16,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-17

[0309] In some embodiments, the compound or the inhibitor compound is of Formula I-c-17:(RA)aFormula I-c-17,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-18

[0310] In some embodiments, the compound or the inhibitor compound is of Formula I-c-18:Page 122 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOFormula I-c-18,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-19

[0311] In some embodiments, the compound or the inhibitor compound is of Formula I-c-19:Formula I-c-19,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-20

[0312] In some embodiments, the compound or the inhibitor compound is of Formula I-c-20:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula I-c-21

[0313] In some embodiments, the compound or the inhibitor compound is of Formula I-c-21:Formula I-c-21,Page 123 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOor a pharmaceutically acceptable salt thereof, wherein W is CH2, NH, or O, and each of the remaining variables are as defined herein.Formula I-c-22

[0314] In some embodiments, the compound or the inhibitor compound is of Formula I-c-22:Formula I-c-22,or a pharmaceutically acceptable salt thereof, wherein W is CH2, NH, or O, and each of the remaining variables are as defined herein.Variables

[0315] It should be understood that the variables described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular variable (e.g., in any one of Formula Z, Formula X”, Formula X’, Formula X, Formula I”, Formula I’, Formula I, Formula II”, Formula II’, Formula II, and subformulas thereof, e.g., Formulas I-a, Formulas I-a-1 to I-a-86, Formula I-b, Formulas I-b-1 to I-b-27, Formula I-c, and Formulas I-c-1 to I-c-22), that variable can be used in various embodiments of compositions of the present disclosure and / or in methods of the present disclosure, unless otherwise understood from the context. Where variable are presented as lists, each subgroup of the variable is also disclosed, and any variable(s) can be removed from the group. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all variables described and depicted herein can be applicable to all aspects and embodiments of the disclosure(s) described and depicted herein. As used herein, “in some embodiments” refers to any of the aspects and embodiments of the disclosure(s) described and depicted herein.ya

[0316] In some embodiments, Vais N.Page 124 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0317] In some embodiments, Vais CRE4.

[0318] In some embodiments, Vais selected from the groups in the compounds in Table 1.

[0319] In some embodiments, Vaa group in any one of the compounds in Table 1.Vb

[0320] In some embodiments, Vbis N.

[0321] In some embodiments, Vbis CRE3.

[0322] In some embodiments, Vbis selected from the groups in the compounds in Table 1.

[0323] In some embodiments, Vba group in any one of the compounds in Table 1.V1

[0324] In some embodiments, V1is a covalent bond.

[0325] In some embodiments, V1is selected from the group consisting of -O-, -NRE10-, -CRE11RE12- and -CRE11RE12CRE11RE12-.

[0326] In some embodiments, V1is selected from the group consisting of -O-, -NRE10-, and -CRE11RE12-.

[0327] In some embodiments, V1is -O- or -NRE10-.

[0328] In some embodiments, V1is -CRE11RE12-.

[0329] In some embodiments, V1is -O-.

[0330] In some embodiments, V1is -NRE10-.

[0331] In some embodiments, V1is selected from the group consisting of -CRE11RE12NH-, -NHCRE11RE12-, -CRE11RE12O-, and -OCRE11RE12-.

[0332] In some embodiments, V1is -CRE11RE12NH- or -NHCRE11RE12-.

[0333] In some embodiments, V1is -CRE11RE12O- or -OCRE11RE12-.

[0334] In some embodiments, V1is -CRE11RE12NH-

[0335] In some embodiments, V1is-NHCRE11RE12-.

[0336] In some embodiments, V1is -CRE11RE12O-

[0337] In some embodiments, V1is -OCRE11RE12-.

[0338] In some embodiments, V1is selected from the group consisting of -O-, -NH-, -NMe-,Page 125 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0339] In some embodiments, V1is selected from the group consisting of -O-, -NH-, -NMe-,

[0340] In some embodiments, V1is selected from the group consisting of -O-, -NH-, -NMe-,

[0341] In some embodiments, V1is selected from the groups in the compounds in Table 1.

[0342] In some embodiments, V1a group in any one of the compounds in Table 1.V2

[0343] In some embodiments, V2is -C(O)-.

[0344] In some embodiments, V2is -S(O)- or -S(O)2-

[0345] In some embodiments, V2is -C(S)-.

[0346] In some embodiments, V2is selected from the groups in the compounds in Table 1.

[0347] In some embodiments, V2a group in any one of the compounds in Table 1.R01’s

[0348] In some embodiments, each RO1is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.Page 126 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0349] In some embodiments, each RO1is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0350] In some embodiments, each RO1is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0351] In some embodiments, each RO1is, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0352] In some embodiments, each RO1is, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0353] In some embodiments, each RO1is, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0354] In some embodiments, each RO1is, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0355] In some embodiments, each RO1is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -Pr, -nBu, - Bu, -sBu, and - Bu.

[0356] In some embodiments, each RO1is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0357] In some embodiments, each RO1is, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0358] In some embodiments, each RO1is, independently, selected from the group consisting of -Me and -Et.

[0359] In some embodiments, each RO1is, independently, hydrogen.

[0360] In some embodiments, each RO1is, independently, -Me.

[0361] In some embodiments, each RO1is, independently, Rola.

[0362] In some embodiments, each RO1is, independently, selected from the groups in the compounds in Table 1.

[0363] In some embodiments, each RO1is, independently, a group in any one of the compounds in Table 1.

[0364] In some embodiments, each Rolaais, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.Page 127 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0365] In some embodiments, each Rolaais, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0366] In some embodiments, each Rolaais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0367] In some embodiments, each Rolaais, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0368] In some embodiments, each Rolaais, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0369] In some embodiments, each Rolaais, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0370] In some embodiments, each Rolaais, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0371] In some embodiments, each Rolaais, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0372] In some embodiments, each Rolaais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0373] In some embodiments, each Rolaais, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0374] In some embodiments, each Rolaais, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0375] In some embodiments, each Rolaais, independently, selected from the group consisting of -Me and -Et.

[0376] In some embodiments, each Rolaais, independently, hydrogen.

[0377] In some embodiments, each Rolaais, independently, -Me.

[0378] In some embodiments, each Rolaais, independently, Rola.

[0379] In some embodiments, each Rolaais, independently, selected from the groups in the compounds in Table 1.

[0380] In some embodiments, each Rolaais, independently, a group in any one of the compounds in Table 1.nOlbbPage 128 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0381] In some embodiments, each Rolbbis, independently, selected from the group consisting of hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, and Rola.

[0382] In some embodiments, each Rolbbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0383] In some embodiments, each Rolbbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0384] In some embodiments, each Rolbbis, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0385] In some embodiments, each Rolbbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0386] In some embodiments, each Rolbbis, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0387] In some embodiments, each Rolbbis, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0388] In some embodiments, each Rolbbis, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0389] In some embodiments, each Rolbbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0390] In some embodiments, each Rolbbis, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0391] In some embodiments, each Rolbbis, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0392] In some embodiments, each Rolbbis, independently, selected from the group consisting of -Me and -Et.

[0393] In some embodiments, each Rolbbis, independently, hydrogen.

[0394] In some embodiments, each Rolbbis, independently, -Me.

[0395] In some embodiments, each Rolbbis, independently, Rola.

[0396] In some embodiments, each Rolbbis, independently, selected from the groups in the compounds in Table 1.

[0397] In some embodiments, each Rolbbis, independently, a group in any one of the compounds in Table 1.Page 129 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOR°lcc

[0398] In some embodiments, each RO1CCis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.

[0399] In some embodiments, each Rolccis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0400] In some embodiments, each Rolccis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0401] In some embodiments, each Rolccis, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0402] In some embodiments, each Rolccis, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0403] In some embodiments, each Rolccis, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0404] In some embodiments, each Rolccis, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0405] In some embodiments, each Rolccis, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0406] In some embodiments, each Rolccis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0407] In some embodiments, each Rolccis, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0408] In some embodiments, each Rolccis, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0409] In some embodiments, each Rolccis, independently, selected from the group consisting of -Me and -Et.

[0410] In some embodiments, each Rolccis, independently, hydrogen.

[0411] In some embodiments, each Rolccis, independently, -Me.

[0412] In some embodiments, each Rolccis, independently, Rola.

[0413] In some embodiments, each RO1CCis, independently, selected from the groups in the compounds in Table 1.

[0414] In some embodiments, each Rolccis, independently, a group in any one of the compounds in Table 1.Page 130 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO Oldd

[0415] In some embodiments, each Rolddis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.

[0416] In some embodiments, each Rolddis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0417] In some embodiments, each Rolddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0418] In some embodiments, each Rolddis, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0419] In some embodiments, each Rolddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0420] In some embodiments, each Rolddis, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0421] In some embodiments, each Rolddis, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0422] In some embodiments, each Rolddis, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0423] In some embodiments, each Rolddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0424] In some embodiments, each Rolddis, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0425] In some embodiments, each Rolddis, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0426] In some embodiments, each Rolddis, independently, selected from the group consisting of -Me and -Et.

[0427] In some embodiments, each Rolddis, independently, hydrogen.

[0428] In some embodiments, each Rolddis, independently, -Me.

[0429] In some embodiments, each Rolddis, independently, Rola.

[0430] In some embodiments, each Rolddis, independently, selected from the groups in the compounds in Table 1.

[0431] In some embodiments, each Rolddis, independently, a group in any one of the compounds in Table 1.Page 131 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOR013

[0432] In some embodiments, each R°13is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.

[0433] In some embodiments, each R°13is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0434] In some embodiments, each R°13is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0435] In some embodiments, each R°13is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0436] In some embodiments, each R°13is, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0437] In some embodiments, each R°13is, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0438] In some embodiments, each R°13is, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0439] In some embodiments, each R°13is, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0440] In some embodiments, each R°13is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0441] In some embodiments, each R°13is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0442] In some embodiments, each R°13is, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0443] In some embodiments, each R°13is, independently, selected from the group consisting of -Me and -Et.

[0444] In some embodiments, each R°13is, independently, hydrogen.

[0445] In some embodiments, each R°13is, independently, -Me.

[0446] In some embodiments, each R°13is, independently, Rola.

[0447] In some embodiments, each R°13is, independently, selected from the groups in the compounds in Table 1.

[0448] In some embodiments, each R°13is, independently, a group in any one of the compounds in Table 1.Page 132 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOR014

[0449] In some embodiments, each R°14is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.

[0450] In some embodiments, each R°14is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0451] In some embodiments, each Rol4is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0452] In some embodiments, each Rol4is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0453] In some embodiments, each R°14is, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0454] In some embodiments, each Rol4is, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0455] In some embodiments, each Rol4is, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0456] In some embodiments, each R°14is, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0457] In some embodiments, each Rol4is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0458] In some embodiments, each R°14is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0459] In some embodiments, each R°14is, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0460] In some embodiments, each Rol4is, independently, selected from the group consisting of -Me and -Et.

[0461] In some embodiments, each Rol4is, independently, hydrogen.

[0462] In some embodiments, each Rol4is, independently, -Me.

[0463] In some embodiments, each Rol4is, independently, Rola.

[0464] In some embodiments, each R°14is, independently, selected from the groups in the compounds in Table 1.

[0465] In some embodiments, each R°14is, independently, a group in any one of the compounds in Table 1.Page 133 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOR019

[0466] In some embodiments, each R°19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.

[0467] In some embodiments, each R°19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0468] In some embodiments, each R°19is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0469] In some embodiments, each R°19is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0470] In some embodiments, each R°19is, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0471] In some embodiments, each R°19is, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0472] In some embodiments, each R°19is, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0473] In some embodiments, each R°19is, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0474] In some embodiments, each R°19is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0475] In some embodiments, each R°19is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0476] In some embodiments, each R°19is, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0477] In some embodiments, each R°19is, independently, selected from the group consisting of -Me and -Et.

[0478] In some embodiments, each Rol9is, independently, hydrogen.

[0479] In some embodiments, each Rol9is, independently, -Me.

[0480] In some embodiments, each Rol9is, independently, Rola.

[0481] In some embodiments, each R°19is, independently, selected from the groups in the compounds in Table 1.

[0482] In some embodiments, each R°19is, independently, a group in any one of the compounds in Table 1.Page 134 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WORom

[0483] In some embodiments, each RO111is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.

[0484] In some embodiments, each RO111is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0485] In some embodiments, each RO111is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0486] In some embodiments, each RO111is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0487] In some embodiments, each RO111is, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0488] In some embodiments, each RO111is, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0489] In some embodiments, each RO111is, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0490] In some embodiments, each RO111is, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0491] In some embodiments, each RO111is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0492] In some embodiments, each RO111is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0493] In some embodiments, each RO111is, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0494] In some embodiments, each RO111is, independently, selected from the group consisting of -Me and -Et.

[0495] In some embodiments, each RO111is, independently, hydrogen.

[0496] In some embodiments, each RO111is, independently, -Me.

[0497] In some embodiments, each RO111is, independently, Rola.

[0498] In some embodiments, each RO111is, independently, selected from the groups in the compounds in Table 1.

[0499] In some embodiments, each RO111is, independently, a group in any one of the compounds in Table 1.Page 135 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOpom

[0500] In some embodiments, each R°112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola.

[0501] In some embodiments, each R°112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0502] In some embodiments, each Roll2is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0503] In some embodiments, each Roll2is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3.

[0504] In some embodiments, each Roll2is, independently, selected from the group consisting of hydrogen, -Me, -Et, -CF3, -CHF2, and -CH2F.

[0505] In some embodiments, each Roll2is, independently, selected from the group consisting of -Me, -Et, -CF3, -CHF2, and -CH2F.

[0506] In some embodiments, each Roll2is, independently, selected from the group consisting of hydrogen, -Me, -CF3, -CHF2, and -CH2F.

[0507] In some embodiments, each Roll2is, independently, selected from the group consisting of -Me, -CF3, -CHF2, and -CH2F.

[0508] In some embodiments, each Roll2is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0509] In some embodiments, each Roll2is, independently, selected from the group consisting of -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0510] In some embodiments, each Roll2is, independently, selected from the group consisting of hydrogen, -Me, and -Et.

[0511] In some embodiments, each Roll2is, independently, selected from the group consisting of -Me and -Et.

[0512] In some embodiments, each Roll2is, independently, hydrogen.

[0513] In some embodiments, each Roll2is, independently, -Me.

[0514] In some embodiments, each Roll2is, independently, Rola.

[0515] In some embodiments, each R°112is, independently, selected from the groups in the compounds in Table 1.Page 136 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0516] In some embodiments, each R°112is, independently, a group in any one of the compounds in Table 1.j^Ola

[0517] In some embodiments, each Rolais, independently, selected from the group consisting of -(Ci-C6alkylene)-(4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Rolais unsubsliluled or substituted with 1-4 occurrences of RC3.

[0518] In some embodiments, each Rolais, independently, selected from the group consisting of 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3.

[0519] In some embodiments, each Rolais, independently, selected from the group consisting of -(Ci-Ce alkylene)-(5- to 6-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein Rolais unsubsliluled or substituted with 1-2 occurrences of RC3.

[0520] In some embodiments, each Rolais, independently, selected from the group consisting of 5- to 6-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3.

[0521] In some embodiments, each Rolais, independently, selected from the group consistingPage 137 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0523] In some embodiments, each Rolais, independently, selected from the group consisting

[0524] In some embodiments, each Rolais, independently, selected from the group consisting

[0525] In some embodiments, each Rolais, independently, selected from the group consisting

[0526] In some embodiments, each Rolais, independently, selected from the group consisting of-(Ci-C6alkylene)-NRN1RN2, -(3- to 8-membered monocyclic carbocyclylene)- NRN1RN2, 6-to 10-membered bridged heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 10-membered spirocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3.

[0527] In some embodiments, each Rolais, independently, selected from the group consisting of-(Ci-C6alkylene)-NRN1RN2, -(3- to 8-membered monocyclic carbocyclylene)- NRN1RN2, 6-to 10-membered bridged heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 10-membered spirocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0528] In some embodiments, each Rolais, independently, selected from the group consisting of-(Ci-C6alkylene)-NRN1RN2and -(3- to 8-membered monocyclic carbocyclylene)-NRN1RN2, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3.

[0529] In some embodiments, each Rolais, independently, selected from the group consisting of-(Ci-C6alkylene)-NRN1RN2or -(3- to 8-membered monocyclic carbocyclylene)-NRN1RN2.

[0530] In some embodiments, each Rolais, independently, selected from the group consisting of -(Ci-C6alkylene)-NRN1RN2, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3.Page 138 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0531] In some embodiments, each Rolais, independently, selected from the group consisting of-(Ci-C6alkylene)-NRN1RN2.

[0532] In some embodiments, each Rolais, independently, I.

[0533] In some embodiments, each Rolais, independently, selected from the group consisting of -(3- to 8-membered monocyclic carbocyclylene)-NRN1RN2, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3.

[0534] In some embodiments, each Rolais, independently, selected from the group consisting of -(3- to 8-membered monocyclic carbocyclylene)-NRN1RN2.

[0535] In some embodiments, each Rolais, independently, selected from the group consistingof or

[0536] In some embodiments, each Rolais, independently, selected from the group consisting

[0537] In some embodiments, each Rolais, independently, selected from the group consisting of 6- to 10-membered bridged heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences ofRC3.

[0538] In some embodiments, each Rolais, independently, selected from the group consisting of 6- to 9-membered bridged heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences ofRC3.

[0539] In some embodiments, each Rolais, independently, selected from the group consisting of 6- to 8-membered bridged heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences ofRC3.

[0540] In some embodiments, each Rolais, independently, selected from the group consisting of 7- to 8-membered bridged heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences ofRC3.Page 139 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0541] In some embodiments, each Rolais, independently, selected from the group consisting H H HOf H, H H, H, H, and H,

[0542] In some embodiments, each Rolais, independently, selected from the group consisting of 6- to 10-membered spirocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubs muted or substituted with 1-4 occurrences of RC3.

[0543] In some embodiments, each Rolais, independently, selected from the group consisting of 6- to 9-membered spirocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubsli luted or substituted with 1-4 occurrences of RC3.

[0544] In some embodiments, each Rolais, independently, selected from the group consisting of 6- to 8-membered spirocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubsli I uled or substituted with 1-4 occurrences of RC3.

[0545] In some embodiments, each Rolais, independently, selected from the group consisting of 7- to 8-membered spirocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubsli I uled or substituted with 1-4 occurrences of RC3.

[0546] In some embodiments, each Rolais, independently, selected from the group consisting — N ) — |of — NZvV V>7— I 1and '

[0547] In some embodiments, each Rolais, independently, selected from the groups in the compounds in Table 1.

[0548] In some embodiments, each Rolais, independently, a group in any one of the compounds in Table 1.RN1’S

[0549] In some embodiments, each RN1is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Page 140 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0550] In some embodiments, each RN1is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0551] In some embodiments, each RN1is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0552] In some embodiments, each RN1is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0553] In some embodiments, each RN1is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0554] In some embodiments, each RN1is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0555] In some embodiments, each RN1is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0556] In some embodiments, each RN1is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0557] In some embodiments, each RN1is, independently, hydrogen or -Me.

[0558] In some embodiments, RN1is hydrogen.

[0559] In some embodiments, RN1is -Me.

[0560] In some embodiments, each RN1is, independently, selected from the groups in the compounds in Table 1.

[0561] In some embodiments, each RN1is, independently, a group in any one of the compounds in Table 1.

[0562] In some embodiments, each RNlaais, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0563] In some embodiments, each RNlaais, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.Page 141 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0564] In some embodiments, each RNlaais, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0565] In some embodiments, each RNlaais, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0566] In some embodiments, each RNlaais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0567] In some embodiments, each RNlaais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0568] In some embodiments, each RNlaais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0569] In some embodiments, each RNlaais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0570] In some embodiments, each RNlaais, independently, hydrogen or -Me.

[0571] In some embodiments, RNlaais hydrogen.

[0572] In some embodiments, RNlaais -Me.

[0573] In some embodiments, each RNlaais, independently, selected from the groups in the compounds in Table 1.

[0574] In some embodiments, each RNlaais, independently, a group in any one of the compounds in Table 1.Nlbb

[0575] In some embodiments, each RNlbbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0576] In some embodiments, each RNlbbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0577] In some embodiments, each RNlbbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.Page 142 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0578] In some embodiments, each RNlbbis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0579] In some embodiments, each RNlbbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0580] In some embodiments, each RNlbbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0581] In some embodiments, each RNlbbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0582] In some embodiments, each RNlbbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0583] In some embodiments, each RNlbbis, independently, hydrogen or -Me.

[0584] In some embodiments, RNlbbis hydrogen.

[0585] In some embodiments, RNlbbis -Me.

[0586] In some embodiments, each RNlbbis, independently, selected from the groups in the compounds in Table 1.

[0587] In some embodiments, each RNlbbis, independently, a group in any one of the compounds in Table 1.RNlcc

[0588] In some embodiments, each RN1CCis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0589] In some embodiments, each RN1CCis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0590] In some embodiments, each RN1CCis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0591] In some embodiments, each RN1CCis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.Page 143 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0592] In some embodiments, each RN1CCis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0593] In some embodiments, each RN1CCis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0594] In some embodiments, each RN1CCis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0595] In some embodiments, each RN1CCis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0596] In some embodiments, each RN1CCis, independently, hydrogen or -Me.

[0597] In some embodiments, RN1CCis hydrogen.

[0598] In some embodiments, RN1CCis -Me.

[0599] In some embodiments, each RN1CCis, independently, selected from the groups in the compounds in Table 1.

[0600] In some embodiments, each RN1CCis, independently, a group in any one of the compounds in Table 1.Nldd

[0601] In some embodiments, each RNlddis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0602] In some embodiments, each RNlddis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0603] In some embodiments, each RNlddis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0604] In some embodiments, each RNlddis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0605] In some embodiments, each RNlddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -Page 144 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOCF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0606] In some embodiments, each RNlddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0607] In some embodiments, each RNlddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0608] In some embodiments, each RNlddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0609] In some embodiments, each RNlddis, independently, hydrogen or -Me.

[0610] In some embodiments, RNlddis hydrogen.

[0611] In some embodiments, RNlddis -Me.

[0612] In some embodiments, each RNlddis, independently, selected from the groups in the compounds in Table 1.

[0613] In some embodiments, each RNlddis, independently, a group in any one of the compounds in Table 1.Nle

[0614] In some embodiments, each RNleis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0615] In some embodiments, each RNleis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0616] In some embodiments, each RNleis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0617] In some embodiments, each RNleis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0618] In some embodiments, each RNleis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)‘Bu, -C(O)sBu, and -C(O)‘Bu.Page 145 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0619] In some embodiments, each RNleis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0620] In some embodiments, each RNleis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0621] In some embodiments, each RNleis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0622] In some embodiments, each RNleis, independently, hydrogen or -Me.

[0623] In some embodiments, RNleis hydrogen.

[0624] In some embodiments, RNleis -Me.

[0625] In some embodiments, each RNleis, independently, selected from the groups in the compounds in Table 1.

[0626] In some embodiments, each RNleis, independently, a group in any one of the compounds in Table 1.

[0627] In some embodiments, each RNleeis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0628] In some embodiments, each RNleeis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0629] In some embodiments, each RNleeis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0630] In some embodiments, each RNleeis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0631] In some embodiments, each RNleeis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)‘Bu, -C(O)sBu, and -C(O)‘Bu.

[0632] In some embodiments, each RNleeis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.Page 146 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0633] In some embodiments, each RNleeis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0634] In some embodiments, each RNleeis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0635] In some embodiments, each RNleeis, independently, hydrogen or -Me.

[0636] In some embodiments, RNleeis hydrogen.

[0637] In some embodiments, RNleeis -Me.

[0638] In some embodiments, each RNleeis, independently, selected from the groups in the compounds in Table 1.

[0639] In some embodiments, each RNleeis, independently, a group in any one of the compounds in Table 1.

[0640] In some embodiments, each RN13is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0641] In some embodiments, each RN13is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0642] In some embodiments, each RN13is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0643] In some embodiments, each RN13is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0644] In some embodiments, each RN13is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0645] In some embodiments, each RN13is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0646] In some embodiments, each RN13is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.Page 147 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0647] In some embodiments, each RN13is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0648] In some embodiments, each RN13is, independently, hydrogen or -Me.

[0649] In some embodiments, RN13is hydrogen.

[0650] In some embodiments, RN13is -Me.

[0651] In some embodiments, each RN13is, independently, selected from the groups in the compounds in Table 1.

[0652] In some embodiments, each RN13is, independently, a group in any one of the compounds in Table 1.N14

[0653] In some embodiments, each RN14is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0654] In some embodiments, each RN14is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0655] In some embodiments, each RN14is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0656] In some embodiments, each RN14is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0657] In some embodiments, each RN14is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0658] In some embodiments, each RN14is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0659] In some embodiments, each RN14is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0660] In some embodiments, each RN14is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0661] In some embodiments, each RN14is, independently, hydrogen or -Me.Page 148 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0662] In some embodiments, RN14is hydrogen.

[0663] In some embodiments, RN14is -Me.

[0664] In some embodiments, each RN14is, independently, selected from the groups in the compounds in Table 1.

[0665] In some embodiments, each RN14is, independently, a group in any one of the compounds in Table 1.pN19

[0666] In some embodiments, each RN19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0667] In some embodiments, each RN19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0668] In some embodiments, each RN19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0669] In some embodiments, each RN19is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0670] In some embodiments, each RN19is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0671] In some embodiments, each RN19is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0672] In some embodiments, each RN19is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0673] In some embodiments, each RN19is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0674] In some embodiments, each RN19is, independently, hydrogen or -Me.

[0675] In some embodiments, RN19is hydrogen.

[0676] In some embodiments, RN19is -Me.Page 149 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0677] In some embodiments, each RN19is, independently, selected from the groups in the compounds in Table 1.

[0678] In some embodiments, each RN19is, independently, a group in any one of the compounds in Table 1.RNIII

[0679] In some embodiments, eachRN111is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0680] In some embodiments, eachRN111is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0681] In some embodiments, eachRN111is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0682] In some embodiments, eachRN111is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0683] In some embodiments, eachRN111is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0684] In some embodiments, eachRN111is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0685] In some embodiments, eachRN111is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0686] In some embodiments, eachRN111is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0687] In some embodiments, each RN111is, independently, hydrogen or -Me.

[0688] In some embodiments, RN111is hydrogen.

[0689] In some embodiments, RN111is -Me.

[0690] In some embodiments, each RN111is, independently, selected from the groups in the compounds in Table 1.Page 150 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0691] In some embodiments, each RN111is, independently, a group in any one of the compounds in Table 1.RN112

[0692] In some embodiments, each RN112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0693] In some embodiments, each RN112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0694] In some embodiments, each RN112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0695] In some embodiments, each RN112is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0696] In some embodiments, each RN112is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0697] In some embodiments, each RN112is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0698] In some embodiments, each RN112is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0699] In some embodiments, each RN112is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0700] In some embodiments, each RN112is, independently, hydrogen or -Me.

[0701] In some embodiments, RN112is hydrogen.

[0702] In some embodiments, RN112is -Me.

[0703] In some embodiments, each RN112is, independently, selected from the groups in the compounds in Table 1.

[0704] In some embodiments, each RN112is, independently, a group in any one of the compounds in Table 1.Page 151 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO j^Nlw

[0705] In some embodiments, each RNlwis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0706] In some embodiments, each RNlwis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0707] In some embodiments, each RNlwis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0708] In some embodiments, each RNlwis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0709] In some embodiments, each RNlwis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0710] In some embodiments, each RNlwis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0711] In some embodiments, each RNlwis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0712] In some embodiments, each RNlwis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0713] In some embodiments, each RN1Wis, independently, hydrogen or -Me.

[0714] In some embodiments, RN1Wis hydrogen.

[0715] In some embodiments, RN1Wis -Me.

[0716] In some embodiments, each RNlwis, independently, selected from the groups in the compounds in Table 1.

[0717] In some embodiments, each RNlwis, independently, a group in any one of the compounds in Table 1.

[0718] In some embodiments, each RN1WWis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl,Page 152 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOand 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0719] In some embodiments, each RN1WWis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0720] In some embodiments, each RN1WWis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0721] In some embodiments, each RN1WWis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0722] In some embodiments, each RN1WWis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0723] In some embodiments, each RN1WWis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0724] In some embodiments, each RN1WWis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0725] In some embodiments, each RN1WWis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0726] In some embodiments, each RN1WWis, independently, hydrogen or -Me.

[0727] In some embodiments, RN1WWis hydrogen.

[0728] In some embodiments, RN1WWis -Me.

[0729] In some embodiments, each RN1WWis, independently, selected from the groups in the compounds in Table 1.

[0730] In some embodiments, each RN1WWis, independently, a group in any one of the compounds in Table 1.

[0731] In some embodiments, each RNlxis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Page 153 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0732] In some embodiments, each RNlxis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0733] In some embodiments, each RNlxis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0734] In some embodiments, each RNlxis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0735] In some embodiments, each RNlxis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0736] In some embodiments, each RNlxis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0737] In some embodiments, each RNlxis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0738] In some embodiments, each RNlxis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0739] In some embodiments, each RNlxis, independently, hydrogen or -Me.

[0740] In some embodiments, RNlxis hydrogen.

[0741] In some embodiments, RNlxis -Me.

[0742] In some embodiments, each RNlxis, independently, selected from the groups in the compounds in Table 1.

[0743] In some embodiments, each RNlxis, independently, a group in any one of the compounds in Table 1.Nlxx

[0744] In some embodiments, each RN1XXis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0745] In some embodiments, each RN1XXis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.Page 154 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0746] In some embodiments, each RN1XXis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0747] In some embodiments, each RN1XXis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0748] In some embodiments, each RN1XXis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0749] In some embodiments, each RN1XXis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0750] In some embodiments, each RN1XXis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0751] In some embodiments, each RN1XXis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0752] In some embodiments, each RN1XXis, independently, hydrogen or -Me.

[0753] In some embodiments, RN1XXis hydrogen.

[0754] In some embodiments, RN1XXis -Me.

[0755] In some embodiments, each RN1XXis, independently, selected from the groups in the compounds in Table 1.

[0756] In some embodiments, each RN1XXis, independently, a group in any one of the compounds in Table 1.

[0757] In some embodiments, each RNlyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0758] In some embodiments, each RNlyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0759] In some embodiments, each RNlyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.Page 155 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0760] In some embodiments, each RNlyis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0761] In some embodiments, each RNlyis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0762] In some embodiments, each RNlyis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0763] In some embodiments, each RNlyis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0764] In some embodiments, each RNlyis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0765] In some embodiments, each RNlyis, independently, hydrogen or -Me.

[0766] In some embodiments, RNlyis hydrogen.

[0767] In some embodiments, RNlyis -Me.

[0768] In some embodiments, each RNlyis, independently, selected from the groups in the compounds in Table 1.

[0769] In some embodiments, each RNlyis, independently, a group in any one of the compounds in Table 1.Nlyy

[0770] In some embodiments, each RNlyyyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0771] In some embodiments, each RNlyyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0772] In some embodiments, each RNlyyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0773] In some embodiments, each RNlyyis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.Page 156 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0774] In some embodiments, each RN1y is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0775] In some embodiments, each RN1y is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0776] In some embodiments, each RN1y is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0777] In some embodiments, each RN1y is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0778] In some embodiments, each Rxiy- is, independently, hydrogen or -Me.

[0779] In some embodiments, RNlyyis hydrogen.

[0780] In some embodiments, RNlyyis -Me.

[0781] In some embodiments, each RNlyyis, independently, selected from the groups in the compounds in Table 1.

[0782] In some embodiments, each RNlyyis, independently, a group in any one of the compounds in Table 1.Nlz

[0783] In some embodiments, each RNlzis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0784] In some embodiments, each RNlzis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0785] In some embodiments, each RNlzis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0786] In some embodiments, each RNlzis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0787] In some embodiments, each RNlzis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -Page 157 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOCF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0788] In some embodiments, each RNlzis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0789] In some embodiments, each RNlzis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0790] In some embodiments, each RNlzis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0791] In some embodiments, each RNlzis, independently, hydrogen or -Me.

[0792] In some embodiments, RNlzis hydrogen.

[0793] In some embodiments, RNlzis -Me.

[0794] In some embodiments, each RNlzis, independently, selected from the groups in the compounds in Table 1.

[0795] In some embodiments, each RNlzis, independently, a group in any one of the compounds in Table 1.Nlzz

[0796] In some embodiments, each RN1ZZis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0797] In some embodiments, each RN1ZZis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0798] In some embodiments, each RN1ZZis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0799] In some embodiments, each RN1ZZis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0800] In some embodiments, each RN1ZZis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)‘Bu, -C(O)sBu, and -C(O)‘Bu.Page 158 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0801] In some embodiments, each RN1ZZis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0802] In some embodiments, each RN1ZZis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0803] In some embodiments, each RN1ZZis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0804] In some embodiments, each RN1ZZis, independently, hydrogen or -Me.

[0805] In some embodiments, RN1ZZis hydrogen.

[0806] In some embodiments, RN1ZZis -Me.

[0807] In some embodiments, each RN1ZZis, independently, selected from the groups in the compounds in Table 1.

[0808] In some embodiments, each RN1ZZis, independently, a group in any one of the compounds in Table 1.RN2’S

[0809] In some embodiments, each RN2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0810] In some embodiments, each RN2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0811] In some embodiments, each RN2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0812] In some embodiments, each RN2is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0813] In some embodiments, each RN2is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)‘Bu, -C(O)sBu, and -C(O)‘Bu.

[0814] In some embodiments, each RN2is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.Page 159 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0815] In some embodiments, each RN2is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0816] In some embodiments, each RN2is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0817] In some embodiments, each RN2is, independently, hydrogen or -Me.

[0818] In some embodiments, RN2is hydrogen.

[0819] In some embodiments, RN2is -Me.

[0820] In some embodiments, each RN2is, independently, selected from the groups in the compounds in Table 1.

[0821] In some embodiments, each RN2is, independently, a group in any one of the compounds in Table 1.j^N2aa

[0822] In some embodiments, each RN2aais, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0823] In some embodiments, each RN2aais, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0824] In some embodiments, each RN2aais, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0825] In some embodiments, each RN2aais, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0826] In some embodiments, each RN2aais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0827] In some embodiments, each RN2aais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0828] In some embodiments, each RN2aais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.Page 160 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0829] In some embodiments, each RN2aais, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0830] In some embodiments, each RN2aais, independently, hydrogen or -Me.

[0831] In some embodiments, RN2aais hydrogen.

[0832] In some embodiments, RN2aais -Me.

[0833] In some embodiments, each RN2aais, independently, selected from the groups in the compounds in Table 1.

[0834] In some embodiments, each RN2aais, independently, a group in any one of the compounds in Table 1.pN2bb

[0835] In some embodiments, each RN2bbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0836] In some embodiments, each RN2bbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0837] In some embodiments, each RN2bbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0838] In some embodiments, each RN2bbis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0839] In some embodiments, each RN2bbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0840] In some embodiments, each RN2bbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0841] In some embodiments, each RN2bbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0842] In some embodiments, each RN2bbis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0843] In some embodiments, each RN2bbis, independently, hydrogen or -Me.Page 161 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0844] In some embodiments, RN2bbis hydrogen.

[0845] In some embodiments, RN2bbis -Me.

[0846] In some embodiments, each RN2bbis, independently, selected from the groups in the compounds in Table 1.

[0847] In some embodiments, each RN2bbis, independently, a group in any one of the compounds in Table 1.

[0848] In some embodiments, each RN2CCis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0849] In some embodiments, each RN2CCis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0850] In some embodiments, each RN2CCis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0851] In some embodiments, each RN2CCis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0852] In some embodiments, each RN2CCis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0853] In some embodiments, each RN2CCis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0854] In some embodiments, each RN2CCis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0855] In some embodiments, each RN2CCis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0856] In some embodiments, each RN2CCis, independently, hydrogen or -Me.

[0857] In some embodiments, RN2CCis hydrogen.

[0858] In some embodiments, RN2CCis -Me.Page 162 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0859] In some embodiments, each RN2CCis, independently, selected from the groups in the compounds in Table 1.

[0860] In some embodiments, each RN2CCis, independently, a group in any one of the compounds in Table 1.j^N2dd

[0861] In some embodiments, each RN2ddis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0862] In some embodiments, each RN2ddis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0863] In some embodiments, each RN2ddis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0864] In some embodiments, each RN2ddis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0865] In some embodiments, each RN2ddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0866] In some embodiments, each RN2ddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0867] In some embodiments, each RN2ddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0868] In some embodiments, each RN2ddis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0869] In some embodiments, each RN2ddis, independently, hydrogen or -Me.

[0870] In some embodiments, RN2ddis hydrogen.

[0871] In some embodiments, RN2ddis -Me.

[0872] In some embodiments, each RN2ddis, independently, selected from the groups in the compounds in Table 1.Page 163 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0873] In some embodiments, each RN2ddis, independently, a group in any one of the compounds in Table 1.j^N2e

[0874] In some embodiments, each RN2eis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0875] In some embodiments, each RN2eis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0876] In some embodiments, each RN2eis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0877] In some embodiments, each RN2eis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0878] In some embodiments, each RN2eis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0879] In some embodiments, each RN2eis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0880] In some embodiments, each RN2eis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0881] In some embodiments, each RN2eis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0882] In some embodiments, each RN2eis, independently, hydrogen or -Me.

[0883] In some embodiments, RN2eis hydrogen.

[0884] In some embodiments, RN2eis -Me.

[0885] In some embodiments, each RN2eis, independently, selected from the groups in the compounds in Table 1.

[0886] In some embodiments, each RN2eis, independently, a group in any one of the compounds in Table 1.pN2eePage 164 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0887] In some embodiments, each RN2eeis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0888] In some embodiments, each RN2eeis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0889] In some embodiments, each RN2eeis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0890] In some embodiments, each RN2eeis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0891] In some embodiments, each RN2eeis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0892] In some embodiments, each RN2eeis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0893] In some embodiments, each RN2eeis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0894] In some embodiments, each RN2eeis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0895] In some embodiments, each RN2eeis, independently, hydrogen or -Me.

[0896] In some embodiments, RN2eeis hydrogen.

[0897] In some embodiments, RN2eeis -Me.

[0898] In some embodiments, each RN2eeis, independently, selected from the groups in the compounds in Table 1.

[0899] In some embodiments, each RN2eeis, independently, a group in any one of the compounds in Table 1.Rm3

[0900] In some embodiments, each RN23is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl,Page 165 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOand 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0901] In some embodiments, each RN23is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0902] In some embodiments, each RN23is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0903] In some embodiments, each RN23is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0904] In some embodiments, each RN23is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0905] In some embodiments, each RN23is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0906] In some embodiments, each RN23is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0907] In some embodiments, each RN23is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0908] In some embodiments, each RN23is, independently, hydrogen or -Me.

[0909] In some embodiments, RN23is hydrogen.

[0910] In some embodiments, RN23is -Me.

[0911] In some embodiments, each RN23is, independently, selected from the groups in the compounds in Table 1.

[0912] In some embodiments, each RN23is, independently, a group in any one of the compounds in Table 1.N24

[0913] In some embodiments, each RN24is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Page 166 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0914] In some embodiments, each RN24is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0915] In some embodiments, each RN24is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0916] In some embodiments, each RN24is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0917] In some embodiments, each RN24is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0918] In some embodiments, each RN24is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0919] In some embodiments, each RN24is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0920] In some embodiments, each RN24is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0921] In some embodiments, each RN24is, independently, hydrogen or -Me.

[0922] In some embodiments, RN24is hydrogen.

[0923] In some embodiments, RN24is -Me.

[0924] In some embodiments, each RN24is, independently, selected from the groups in the compounds in Table 1.

[0925] In some embodiments, each RN24is, independently, a group in any one of the compounds in Table 1.pN2S>

[0926] In some embodiments, each RN29is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0927] In some embodiments, each RN29is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.Page 167 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0928] In some embodiments, each RN29is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0929] In some embodiments, each RN29is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0930] In some embodiments, each RN29is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0931] In some embodiments, each RN29is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0932] In some embodiments, each RN29is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0933] In some embodiments, each RN29is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0934] In some embodiments, each RN29is, independently, hydrogen or -Me.

[0935] In some embodiments, RN29is hydrogen.

[0936] In some embodiments, RN29is -Me.

[0937] In some embodiments, each RN29is, independently, selected from the groups in the compounds in Table 1.

[0938] In some embodiments, each RN29is, independently, a group in any one of the compounds in Table 1.N211

[0939] In some embodiments, each RN211is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0940] In some embodiments, each RN211is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0941] In some embodiments, each RN211is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.Page 168 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0942] In some embodiments, each RN211is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0943] In some embodiments, eachRN211is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0944] In some embodiments, eachRN211is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0945] In some embodiments, eachRN211is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0946] In some embodiments, eachRN211is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0947] In some embodiments, each RN211is, independently, hydrogen or -Me.

[0948] In some embodiments, RN211is hydrogen.

[0949] In some embodiments, RN211is -Me.

[0950] In some embodiments, each RN211is, independently, selected from the groups in the compounds in Table 1.

[0951] In some embodiments, each RN211is, independently, a group in any one of the compounds in Table 1.N212

[0952] In some embodiments, each RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0953] In some embodiments, each RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0954] In some embodiments, each RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0955] In some embodiments, each RN212is, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.Page 169 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0956] In some embodiments, each RN212is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0957] In some embodiments, each RN212is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0958] In some embodiments, each RN212is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0959] In some embodiments, each RN212is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[0960] In some embodiments, each RN212is, independently, hydrogen or -Me.

[0961] In some embodiments, RN212is hydrogen.

[0962] In some embodiments, RN212is -Me.

[0963] In some embodiments, each RN212is, independently, selected from the groups in the compounds in Table 1.

[0964] In some embodiments, each RN212is, independently, a group in any one of the compounds in Table 1.j^N2w

[0965] In some embodiments, each RN2wis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0966] In some embodiments, each RN2wis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0967] In some embodiments, each RN2wis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0968] In some embodiments, each RN2wis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0969] In some embodiments, each RN2wis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -Page 170 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WOCF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[0970] In some embodiments, each RN2wis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0971] In some embodiments, each RN2wis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0972] In some embodiments, each RN2wis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0973] In some embodiments, each RN2Wis, independently, hydrogen or -Me.

[0974] In some embodiments, RN2Wis hydrogen.

[0975] In some embodiments, RN2Wis -Me.

[0976] In some embodiments, each RN2wis, independently, selected from the groups in the compounds in Table 1.

[0977] In some embodiments, each RN2wis, independently, a group in any one of the compounds in Table 1.

[0978] In some embodiments, each RN2WWis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0979] In some embodiments, each RN2WWis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0980] In some embodiments, each RN2WWis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0981] In some embodiments, each RN2WWis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0982] In some embodiments, each RN2WWis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)‘Bu, -C(O)sBu, and -C(O)‘Bu.Page 171 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0983] In some embodiments, each RN2WWis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0984] In some embodiments, each RN2WWis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0985] In some embodiments, each RN2WWis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0986] In some embodiments, each RN2WWis, independently, hydrogen or -Me.

[0987] In some embodiments, RN2WWis hydrogen.

[0988] In some embodiments, RN2WWis -Me.

[0989] In some embodiments, each RN2WWis, independently, selected from the groups in the compounds in Table 1.

[0990] In some embodiments, each RN2WWis, independently, a group in any one of the compounds in Table 1.j^N2x

[0991] In some embodiments, each RN2xis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0992] In some embodiments, each RN2xis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[0993] In some embodiments, each RN2xis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0994] In some embodiments, each RN2xis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0995] In some embodiments, each RN2xis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)‘Bu, -C(O)sBu, and -C(O)‘Bu.

[0996] In some embodiments, each RN2xis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.Page 172 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[0997] In some embodiments, each RN2xis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[0998] In some embodiments, each RN2xis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, and - Bu.

[0999] In some embodiments, each RN2xis, independently, hydrogen or -Me.

[1000] In some embodiments, RN2xis hydrogen.

[1001] In some embodiments, RN2xis -Me.

[1002] In some embodiments, each RN2xis, independently, selected from the groups in the compounds in Table 1.

[1003] In some embodiments, each RN2xis, independently, a group in any one of the compounds in Table 1.j^N2xx

[1004] In some embodiments, each RN2XXis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[1005] In some embodiments, each RN2XXis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[1006] In some embodiments, each RN2XXis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[1007] In some embodiments, each RN2XXis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[1008] In some embodiments, each RN2XXis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[1009] In some embodiments, each RN2XXis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[1010] In some embodiments, each RN2XXis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.Page 173 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[1011] In some embodiments, each RN2XXis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[1012] In some embodiments, each RN2XXis, independently, hydrogen or -Me.

[1013] In some embodiments, RN2XXis hydrogen.

[1014] In some embodiments, RN2XXis -Me.

[1015] In some embodiments, each RN2XXis, independently, selected from the groups in the compounds in Table 1.

[1016] In some embodiments, each RN2XXis, independently, a group in any one of the compounds in Table 1.N2y

[1017] In some embodiments, each RN2yis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[1018] In some embodiments, each RN2yis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[1019] In some embodiments, each RN2yis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[1020] In some embodiments, each RN2yis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[1021] In some embodiments, each RN2yis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[1022] In some embodiments, each RN2yis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[1023] In some embodiments, each RN2yis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[1024] In some embodiments, each RN2yis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[1025] In some embodiments, each RN2yis, independently, hydrogen or -Me.Page 174 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[1026] In some embodiments, RN2yis hydrogen.

[1027] In some embodiments, RN2yis -Me.

[1028] In some embodiments, each RN2yis, independently, selected from the groups in the compounds in Table 1.

[1029] In some embodiments, each RN2yis, independently, a group in any one of the compounds in Table 1.pN2yy

[1030] In some embodiments, each RN2yyyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[1031] In some embodiments, each RN2yyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[1032] In some embodiments, each RN2yyis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[1033] In some embodiments, each RN2yyis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[1034] In some embodiments, each RN2yyis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, and -C(O)‘Bu.

[1035] In some embodiments, each RN2yyis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[1036] In some embodiments, each RN2yyis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, and -CH2CF3.

[1037] In some embodiments, each RN2yyis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, and -‘Bu.

[1038] In some embodiments, each RN2yyis, independently, hydrogen or -Me.

[1039] In some embodiments, RN2yyis hydrogen.

[1040] In some embodiments, RN2yyis -Me.Page 175 of 738IPTS / 200244060.1Attorney Docket No.: KME-310WO

[1041] In some embodiments, each RX2-- is, independently, selected from the groups in the compounds in Table 1.

[1042] In some embodiments, each RX2-- is, independently, a group in any one of the compounds in Table 1.N2z

[1043] In some embodiments, each RN2zis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[1044] In some embodiments, each RN2zis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

[1045] In some embodiments, each RN2zis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[1046] In some embodiments, each RN2zis, independently, selected from the group consisting of hydrogen and Ci-Ce alkyl.

[1047] In some embodiments, each RN2zis, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)...

Claims

1. Attorney Docket No.: KME-310WO2.CLAIMS3.What is claimed:

1. An inhibitor compound of Formula Z:

6. 8.Formula Z,9.or a pharmaceutically acceptable salt thereof, wherein:10.Vais N or CRE4;11.Vbis N or CRE3;12.Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;13.a is 0, 1, 2, 3, 4, 5, or 6;14.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;15.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,16.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;17.Page 671 of 73818.IPTS / 200244060.1 Attorney Docket No.: KME-310WO19.F(5) c RE1is absent or selected from the group consisting of (R)c, -C(O)-NRNleRN2e, - NRN3eC(O)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, -NRN3eS(O)i-2RC2e, - NRNleC(O)-CRC4eRc5e-NR101R102, -NRNleRN2eC(O)-NR101R102, -C(O)-NRN3eR103, - NRN3eC(O)R104, -C(O)-CRC4eRc5e-NR101R102, -NRN3eC(O)-CRC4eRc5e-R105, -C(O)-20.

21. NRNleCH2CHOHCH2NRNleRN2e, -C(O)-NRNle(CH2)i.2ORole, -NRNleC(O)ORole, - OC(O)NRNleRN2e, and -S(O)i-2-Rsle;22.Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;23.c is 0, 1, 2, 3, 4, 5, or 6;24.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,25.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,26.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of R101and R102is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, -C(O)-Ci-C6alkyl, and R1000, or R101and R102on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 8- membered monocyclic heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 8- membered monocyclic heterocyclyl is unsubstituted or substituted with 1-4 instances of R1000a;27.Page 672 of 73828.IPTS / 200244060.1 Attorney Docket No.: KME-310WO29.R1000is selected from the group consisting of 3- to 8- membered monocyclic carbocyclyl, 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R1000is unsubstituted or substituted with 1-4 instances of RlOOOb.30.each R1000ais, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NRNlzRN2z;31.each R1000bis, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NRNlyRN2y;32.each of R103and R104is, independently, selected from the group consisting of phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of R103and R104is, independently, unsubstituted or substituted with 1-4 instances of R1000c; each R1000cis, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NRNlxRN2x;33.R105is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, -C(O)-Ci-C6alkyl, and R1005;34.Page 673 of 73835.IPTS / 200244060.1 Attorney Docket No.: KME-310WO36.R1005is selected from the group consisting of 3- to 8- membered monocyclic carbocyclyl, 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R1005is unsubstituted or substituted with 1-4 instances of R1005a.37.each R1005ais, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NR^wRN2 w■38.Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 -membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and 6- membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;39.b is 0, 1, 2, 3, 4, 5, or 6;40.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, -(Ci-C6alkyl)-ORolbb, and RB1;41.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,42.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RB1is selected from the group consisting of -(C2-C4 alkynyl)-( 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and Page 674 of 73843.IPTS / 200244060.1 Attorney Docket No.: KME-310WO44.sulfur) and 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RB1is unsubstituted or substituted with 1-4 occurrences of RBla;45.each RBlais, independently, selected from the group consisting halogen, cyano, Ci-Ce alkyl, Ci-C6haloalkyl, and Ci-Ce alkoxy;46.RE2is absent or selected from the group consisting of (R, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleeRN2ee _QRC4eepC5ee ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee _ NRN3eeS(O)i-2RC2ee, -NRNleeC(O)-CRC4eeRc5ee-NR201R202, -NRNleeRN2eeC(O)-NR20iR202, -C(O)-NRN3eeR203, -NRN3eeC(O)R204, -C(O)-CRC4eeRc5ee-NR201R202, - NRN3eeC(O)-CRC4eeRc5ee-R205, -C(O)-NRNleeCH2CHOHCH2NRNleeRN2ee, -C(O)-47.

48. NRNlee(CH2)i.2ORolee, -NRNleeC(O)ORolee, -OC(O)NRNleeRN2ee, and -S(O)i.2-Rslee, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;49.d is 0, 1, 2, 3, 4, 5, or 6;50.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd;51.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,52.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of R201and R202is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, -C(O)-Ci-C6alkyl, and R2000, or R201and R202on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 8- membered monocyclic53.Page 675 of 73854.IPTS / 200244060.1 Attorney Docket No.: KME-310WO55.heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 8- membered monocyclic heterocyclyl is unsubstituted or substituted with 1-4 instances of R2000a;56.R2000is selected from the group consisting of 3- to 8- membered monocyclic carbocyclyl, 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2000is unsubstituted or substituted with 1-4 instances of R2000b.57.each R2000ais, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NR^ZZ2ZZ.58.each R2000bis, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NRN1yyRN2yy.59.each of R203and R204is, independently, selected from the group consisting of phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of R203and R204is, independently, unsubstituted or substituted with 1-4 instances of R2000c;60.Page 676 of 73861.IPTS / 200244060.1 Attorney Docket No.: KME-310WO62.each R2000Cis, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NR^XXR 2XX.63.R205is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, -C(O)-Ci-C6alkyl, and R2005;64.R2005is selected from the group consisting of 3- to 8- membered monocyclic carbocyclyl, 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, napthyl, 5- to 14-membered fused bicyclic carbocyclyl, 5- to 14-membered bridged carbocyclyl, 5- to 14-membered spirocyclic carbocyclyl, 5- to 14 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered fused bicyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 14-membered bridged heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2005is unsubstituted or substituted with 1-4 instances of R2005a.65.each R2005ais, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, and -(Ci-Ce alkyl)- NR^w WR 2 w w.66.RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;67.RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;68.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,69.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,70.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;71.Page 677 of 73872.IPTS / 200244060.1 Attorney Docket No.: KME-310WO73.each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,74.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,75.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;76.V1is selected from the group consisting of a covalent bond, -O-, -NRE10-, -CRE11RE12-,-CRE11RE12CRE11RE12_ _CRE11RE12NRE10_, -NRE10CRE11RE12-, -CRE11RE12O-, and - OCRE11RE12-;77.V2is selected from the group consisting of -C(O)-, -C(S)-, -S(O)-, and -S(O)2-;78.RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;79.RE11is, independently, is selected from the group consisting of hydrogen, halogen, -OR0111, -NRNIHRN2115 C1-C6 alkyl> C1-C6 haloalkyl> and_(Ci-C6alkyl)-NRN111RN211, and RE12is, independently, selected from the group consisting of hydrogen, halogen, -OR0112, -NRNii2RN2i2> C1. C6 alkyl> C1. C6 haloalkyl> and-(Ci-Ce alkyl)-NRN112RN212, or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,80.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5- membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;81.each of RO1, Rolaa, Rolbb, Rolcc, Roldd, Role, Rolee, R°13, R°14, R°19, RO111, and R°112, is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola;82.Page 678 of 73883.IPTS / 200244060.1 Attorney Docket No.: KME-310WO84.each Rolais, independently, selected from the group consisting of -(Ci-Ce alkylene)-NRN1RN2, -(3- to 8-membered monocyclic carbocyclylene)- NRN1RN2, -(Ci-Ce alkylene)-(4- to 8 -membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 4- to 8-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10- membered bridged heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 10-membered spirocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3;85.each O86.

87. f R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4epNlee pN2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 RN29 RNIII RN211 RN112 RN212 J^NIW N2W NIWW N2WW NIX N2X NIXX N2XX Nly N2V Nlyy j^N2yy NIZ N2Z RN1ZZ, and RN2ZZ, is, independently, selected from the group consisting of hydrogen, Ci- Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5 -membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or88.RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, RN112and RN212, RNlwand RN2w, RNlwwand RN2ww, RNlxand RN2x, RN1XXand RN2XX, RNlyand RN2y, RNlyyand RN2yy, RNlzand RN2z, or RNlzzand RN2ZZon the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;89.each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;90.each RC3is, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy;91.each of RC4, Rc5, RC6, RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy,92.Page 679 of 73893.IPTS / 200244060.1 Attorney Docket No.: KME-310WO94.or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which both groups are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a96.

97. R98.wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl; and each of Rsleand Rsleeis, independently, selected from the group consisting of Ci-Ce alkyl and Ci-C6haloalkyl,99.wherein RE1and RE2are not both simultaneously absent,100.provided wherein:101.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

2. An inhibitor compound of Formula X”:103.vbx, RE7104.RE8105.N106.E2107.RE9 V2-V1109. 111.Formula X”,112.or a pharmaceutically acceptable salt thereof, wherein:113.Vais N or CRE4;114.Vbis N or CRE3;115.Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;116.a is 0, 1, 2, 3, 4, 5, or 6;117.Page 680 of 738118.IPTS / 200244060.1 Attorney Docket No.: KME-310WO119.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;120.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,121.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;122.RE1is absent or selected from the group consisting123.

124. of (R)c, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;125.c is 0, 1, 2, 3, 4, 5, or 6;126.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,127.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,128.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;129.Page 681 of 738130.IPTS / 200244060.1 Attorney Docket No.: KME-310WO131.Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;132.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, -(Ci-C6alkyl)-ORolbb, and RB1;133.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,134.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RB1is selected from the group consisting of -(C2-C4 alkynyl)-( 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) and 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RB1is unsubstituted or substituted with 1-4 occurrences of RBla;135.each RBlais, independently, selected from the group consisting halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy;136.RE2is absent or selected from the group consisting of (RH, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)- RNleepN2ee _ Q^C4eej^C5ee ^j^Nleej^N2ee _ j^C4eej^C5eej^C6ee _ S(O)12 NR^ leeJ^N2ee and -NRN3eeS(O)i-2RC2ee;137.Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;138.d is 0, 1, 2, 3, 4, 5, or 6;139.Page 682 of 738140.IPTS / 200244060.1 Attorney Docket No.: KME-310WO141.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd;142.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,143.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;144.RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;145.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,146.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,147.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,148.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,149.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from150.Page 683 of 738151.IPTS / 200244060.1 Attorney Docket No.: KME-310WO152.nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;153.V1is selected from the group consisting of a covalent bond, -O-, -NRE10-, -CRE11RE12-, and —CR 11R 12CR 11R 12_‘154.V2is selected from the group consisting of -C(O)-, -C(S)-, -S(O)-, and -S(O)2-;155.RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;156.RE11is, independently, is selected from the group consisting of hydrogen, halogen, -OR0111, - NRN111RN211, Ci-C6alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN111RN211, and RE12is, independently, selected from the group consisting of hydrogen, halogen, -OR0112, -NRNii2RN2i2> C1. C6 alkyl> C 1. C6 haloalkyl> and-(Ci-Ce alkyl)-NRN112RN212, or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,157.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, and R°112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola; Rolais -(Ci-C6alkylene)-(4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) or 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubsli luted or substituted with 1-4 occurrences ofRC3;158.each Of R^ R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4ee|^\I3 RN23 |^\I4 RN24 |^\I9 RN29 RNIII RN211 RN112an(j RN212, is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or159.Page 684 of 738160.IPTS / 200244060.1 Attorney Docket No.: KME-310WO161.RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, or RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;162.each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;163.each RC3is, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy; and164.each of RC4, Rc5, RC6, RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy,165.or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which both groups are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to formRD2a167.

168. , wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,169.provided wherein:170.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

3. An inhibitor compound of Formula X’:172.Page 685 of 738173.IPTS / 200244060.1 Attorney Docket No.: KME-310WO175. 177.Formula X’,178.or a pharmaceutically acceptable salt thereof, wherein:179.Vais N or CRE4;180.Vbis N or CRE3;181.Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;182.a is 0, 1, 2, 3, 4, 5, or 6;183.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;184.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,185.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;186.[—187.RE1is absent or selected from the group consisting188.

189. of (RC)C, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e;190.Page 686 of 738191.IPTS / 200244060.1 Attorney Docket No.: KME-310WO192.Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;193.c is 0, 1, 2, 3, 4, 5, or 6;194.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,195.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,196.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;197.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;198.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,199.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;200.Page 687 of 738201.IPTS / 200244060.1 Attorney Docket No.: KME-310WO202.RE2is absent or selected from the group consisting of (R, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleepN2ee > Q Q^C4eej^C5ee) ^j^Nleej^N2ee > Qj^C4eej^C5eej^C6ee > S(O)12 NR^ leeJ^N2ee203.

204. and -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;205.d is 0, 1, 2, 3, 4, 5, or 6;206.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,207.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,208.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;209.RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;210.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,211.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,212.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from213.Page 688 of 738214.IPTS / 200244060.1 Attorney Docket No.: KME-310WO215.nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,216.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,217.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR01, -NRN1RN2, Ci- Ce alkyl, and Ci-Ce haloalkyl;218.V1is selected from the group consisting of a covalent bond, -O-, -NRE10-, -CRE11RE12-, and —CR 11R 12CR 11R 12_‘219.V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;220.RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;221.RE11is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN111RN211, and222.RE12is selected from the group consisting of hydrogen, halogen, -OR0112, -NRN112RN212, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN112RN212,223.or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,224.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, R°112is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;225.Page 689 of 738226.IPTS / 200244060.1 Attorney Docket No.: KME-310WO each O227.

228. f RN2 J^^laa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211an(j RN112isindependently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or229.RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, or RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;230.each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and231.each of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which both groups are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to formRD23233.

234. *, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,235.provided wherein:236.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

4. An inhibitor compound of Formula X:238.Page 690 of 738239.IPTS / 200244060.1 Attorney Docket No.: KME-310WO241.

242. (RA)a243.Formula X,244.or a pharmaceutically acceptable salt thereof, wherein:245.Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;246.a is 0, 1, 2, 3, 4, 5, or 6;247.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;248.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,249.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;250.RE1is absent or selected from the group consisting251.

252. of (R)c, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6-253.Page 691 of 738254.IPTS / 200244060.1 Attorney Docket No.: KME-310WO255.membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;256.c is 0, 1, 2, 3, 4, 5, or 6;257.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,258.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,259.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;260.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;261.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,262.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;263.RE2is absent or selected from the group consisting of (R)d, -C(0)-NRNleeRN2ee, -264.

265. NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)-266.Page 692 of 738267.IPTS / 200244060.1 Attorney Docket No.: KME-310WO NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee a268.

269. nd -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;270.d is 0, 1, 2, 3, 4, 5, or 6;271.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,272.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,273.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;274.RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;275.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,276.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,277.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,278.Page 693 of 738279.IPTS / 200244060.1 Attorney Docket No.: KME-310WO280.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,281.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;282.V1is selected from the group consisting of a covalent bond, -O-, -NRE10-, -CRE11RE12-, and —CR 11R 12CR 11R 12_‘283.V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;284.RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;285.RE11is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN1RN2,286.RE12is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN111RN211,287.or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,288.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, and Roll2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl; each Of R^ R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211 RN112an(j RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-289.Page 694 of 738290.IPTS / 200244060.1 Attorney Docket No.: KME-310WO291.membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or292.RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, and RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur; each of Rcle, RC2e, Rclee, and RC2eeis independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and293.each of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a294.W^pD2b295.’, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,296.provided wherein:297.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

5. An inhibitor compound of Formula I”:299.Page 695 of 738300.IPTS / 200244060.1 Attorney Docket No.: KME-310WO302.

303. (RA)a304.Formula I”,305.or a pharmaceutically acceptable salt thereof, wherein:306.Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;307.a is 0, 1, 2, 3, 4, 5, or 6;308.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRN1RN2, and -(Ci-C6alkyl)-ORolaa;309.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,310.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;311.RE1is absent or selected from the group consisting312.

313. of (R)c, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6-314.Page 696 of 738315.IPTS / 200244060.1 Attorney Docket No.: KME-310WO316.membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;317.c is 0, 1, 2, 3, 4, 5, or 6;318.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,319.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,320.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;321.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;322.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,323.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;324.EH RE2is absent or selected from the group consisting of (R, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)-325.Page 697 of 738326.IPTS / 200244060.1 Attorney Docket No.: KME-310WO NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee a327.

328. nd -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;329.d is 0, 1, 2, 3, 4, 5, or 6;330.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,331.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,332.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;333.RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;334.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,335.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,336.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,337.Page 698 of 738338.IPTS / 200244060.1 Attorney Docket No.: KME-310WO339.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,340.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;341.V1is selected from the group consisting of -O-, -NRE10-, -CRE11RE12-, and - CR^IIR^12CR^HR^12_*342.V2is selected from the group consisting of -C(O)-, -C(S)-, -S(O)-, and -S(O)2-;343.RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;344.RE11is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN1RN2,345.RE12is selected from the group consisting of hydrogen, halogen, -OR0112, -NRN112RN212, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN1RN2,346.or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,347.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, and Roll2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola; Rolais -(Ci-C6alkylene)-(4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) or 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences ofRC3;348.Page 699 of 738349.IPTS / 200244060.1 Attorney Docket No.: KME-310WO each O350.

351. f RN2 J^^laa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211 RN112an(j RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or352.RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, or RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;353.each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;354.each RC3is, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy; and355.each of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a356.X\RD2b357.’, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,358.provided wherein:359.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.360.Page 700 of 738361.IPTS / 200244060.1 Attorney Docket No.: KME-310WO6. An inhibitor compound of Formula I’:

364.

365. (RA)a366.Formula I’,367.or a pharmaceutically acceptable salt thereof, wherein:368.Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;369.a is 0, 1, 2, 3, 4, 5, or 6;370.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;371.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,372.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;373.RE1is absent or selected from the group consisting374.

375. of (R, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e;376.Page 701 of 738377.IPTS / 200244060.1 Attorney Docket No.: KME-310WO378.Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;379.c is 0, 1, 2, 3, 4, 5, or 6;380.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,381.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,382.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;383.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;384.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,385.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;386.Page 702 of 738387.IPTS / 200244060.1 Attorney Docket No.: KME-310WO388.RE2is absent or selected from the group consisting of (R, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee389.

390. and -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;391.d is 0, 1, 2, 3, 4, 5, or 6;392.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,393.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,394.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;395.RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;396.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,397.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,398.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from399.Page 703 of 738400.IPTS / 200244060.1 Attorney Docket No.: KME-310WO401.nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,402.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,403.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;404.V1is selected from the group consisting of -O-, -NRE10-, -CRE11RE12-, and - CR^IIR^12CR^HR^12_*405.V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;406.RE1° is selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;407.RE11is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN1RN2,408.RE12is selected from the group consisting of hydrogen, halogen, -OR0111, -NRN111RN211, Ci- Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-NRN111RN211,409.or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,410.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, R°19, RO111, and Roll2is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;411.Page 704 of 738412.IPTS / 200244060.1 Attorney Docket No.: KME-310WO each O413.

414. f RN2 J^^laa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4ej^Xlee j^N2ee pN3ee RN4eeRN13 RN23 RN14 RN24 RN19 |^\29 pNlll RN211 RN112an(j RN212is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-C6haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or415.RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, RN19and RN29, RN111and RN211, or RN112and RN212on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 addilional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;416.each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and417.each of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to formRD2a419.

420. , wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,421.provided wherein:422.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

7. The compound of any one of claims 1 to 6, wherein V1is selected from the group consisting of -O-, -NRE10-, and -CRE11RE12-.424.Page 705 of 738425.IPTS / 200244060.1 Attorney Docket No.: KME-310WO8. The compound of any one of claims 1 to 6, wherein V1is a covalent bond.

9. The compound of any one of claims 1 to 6, wherein V2is selected from the group consisting of -C(O)- and -S(O)2- 10. The compound of any one of claims 1 to 6, wherein V2is -C(O)-.

11. The compound of any one of claims 1 to 6, wherein V2is -S(O)2- 12. An inhibitor compound of Formula Z:

430. 432.Vais CRE4;433.Vbis CRE3;434.Ring El is selected from the group consisting of phenyl and pyridinyl, and pyrimidinyl; a is 0, 1, 2, 3, 4, 5, or 6;435.each RAis, independently, selected from the group consisting of halogen and Ci-Ce alkyl; RE1is selected from the group consisting of -NRNleC(O)-CRC4eRc5e-NR101R102, - NRNleRN2eC(O)-NR101R102, _c(O)-NRN3eR103, -NRN3eC(O)R104, -C(O)-CRC4eRc5e-NR1O1R1O2 _NRN3eC(O)-CRC4eRc5e-R105, -C(O)-NRNleCH2CHOHCH2NRNleRN2e, - C(O)-NRNle(CH2)i-2ORole, -NRNleC(O)ORole, -OC(O)NRNleRN2e, and -S(O)i-2-Rsle; each of R101and R102is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and R1000, or436.R101and R102on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 8- membered monocyclic heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 8- membered monocyclic heterocyclyl is unsubstituted or substituted with 1-4 instances of R1000a;437.R1000is selected from the group consisting of 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl,438.Page 706 of 738439.IPTS / 200244060.1 Attorney Docket No.: KME-310WO440.napthyl, and 5- to 14-membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R1000is unsubstituted or substituted with 1-4 instances of R1000b;441.each R1000ais, independently, selected from the group consisting of halogen and Ci-Ce alkyl; each R1000bis, independently, selected from the group consisting of halogen and Ci-Ce alkyl; each of R103and R104is, independently, selected from the group consisting of 5- to 14- membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of R103and R104is, independently, unsubstituted or substituted with 1-4 instances of R1000c;442.each R1000cis, independently, selected from the group consisting of halogen and Ci-Ce alkyl; R105is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, -C(O)-Ci-C6alkyl, and R1005;443.R1005is selected from the group consisting of 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 14- membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R1005is unsubstituted or substituted with 1-4 instances of R1005a;444.each R1005ais, independently, selected from the group consisting of halogen and Ci-Ce alkyl; Ring E2 is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; b is 0, 1, 2, 3, 4, 5, or 6;445.each RBis, independently, selected from the group consisting of halogen and Ci-Ce alkyl; RE2is selected from the group consisting of, -C(O)-NRNleeRN2ee, and-NRN3eeC(O)Rclee, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;446.d is 0, 1, 2, 3, 4, 5, or 6;447.each RDis, independently, selected from the group consisting of halogen and Ci-Ce alkyl; RE3is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;448.RE4is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;449.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5-membered monocyclic carbocyclylene;450.each of RE7and RE8is hydrogen;451.Page 707 of 738452.IPTS / 200244060.1 Attorney Docket No.: KME-310WO453.RE9is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;454.V1is selected from the group consisting of -CRE11RE12NRE10-, -NRE10CRE11RE12-, - CRE11RE12O—, and -OCRE11RE12-;455.V2is -C(O)-;456.RE1° is selected from the group consisting of hydrogen and Ci-Ce alkyl;457.RE11is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;458.RE12is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;459.each of RNle, RN2e, RN3e, RN4e, RNlee, and RN2eeis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;460.each of Rcle, RC2e, and Rcleeis, independently, selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;461.each of RC4e, Rc5e, and RC6eis, independently, selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;462.Rsleis selected from the group consisting of Ci-Ce alkyl and Ci-Ce haloalkyl,463.wherein RE1and RE2are not both simultaneously absent.

13. An inhibitor compound of Formula I-c:

466. 468.Formula I-c,469.or a pharmaceutically acceptable salt thereof, wherein:470.Ring El is selected from the group consisting of phenyl and pyridinyl, and pyrimidinyl; a is 0, 1, 2 or 3;471.each RAis, independently, selected from the group consisting of halogen and Ci-Ce alkyl; RE1is selected from the group consisting of -NRNleC(O)-CRC4eRc5e-NR101R102, - NRNleRN2eC(O)-NR101R102, _c(O)-NRN3eR103, -NRN3eC(O)R104, -C(O)-CRC4eRc5e-NR1O1R1O2 _NRN3eC(O)-CRC4eRc5e-R105, -C(O)-NRNleCH2CHOHCH2NRNleRN2e, - C(O)-NRNle(CH2)i-2ORole, and -NRNleC(O)ORole;472.each of R101and R102is, independently, selected from the group consisting of hydrogen and Ci-C6alkyl, or473.Page 708 of 738474.IPTS / 200244060.1 Attorney Docket No.: KME-310WO475.R101and R102are taken together with the nitrogen atom to which both groups are attached to form 3- to 8- membered monocyclic heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 8- membered monocyclic heterocyclyl is unsubstituted or substituted with 1-4 instances of R1000a; each R1000ais, independently, selected from the group consisting of halogen and Ci-Ce alkyl; each of R103and R104is, independently, selected from the group consisting of 5- to 14- membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of R103and R104is, independently, unsubstituted or substituted with 1-4 instances of R1000c;476.each R1000cis, independently, selected from the group consisting of halogen and Ci-Ce alkyl; R105is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, -C(O)-Ci-C6alkyl, and R1005;477.R1005is selected from the group consisting of 3- to 8-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 14- membered spirocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R1005is unsubstituted or substituted with 1-4 instances of R1005a;478.each R1005ais, independently, selected from the group consisting of halogen and Ci-Ce alkyl; Ring E2 is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;479.b is 0, 1, 2, or 3;480.each RBis, independently, selected from the group consisting of halogen and Ci-Ce alkyl; RE2is selected from the group consisting of-C(O)-NRNleeRN2ee, and-NRN3eeC(O)Rclee; RE3is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;481.RE4is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;482.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5-membered monocyclic carbocyclylene;483.each of RE7and RE8is hydrogen;484.RE9is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;485.RE1° is selected from the group consisting of hydrogen and Ci-Ce alkyl;486.RE11is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;487.RE12is selected from the group consisting of hydrogen, halogen, and Ci-Ce alkyl;488.Page 709 of 738489.IPTS / 200244060.1 Attorney Docket No.: KME-310WO490.each of RNle, RN2e, RN3e, RN4e, RNlee, and RN2eeis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;491.each of Rcle, RC2e, and Rcleeis, independently, selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;492.each of RC4e, Rc5e, and RC6eis, independently, selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;493.Rsleis selected from the group consisting of Ci-Ce alkyl and Ci-Ce haloalkyl.

14. An inhibitor compound of Formula I:

496. 498.or a pharmaceutically acceptable salt thereof, wherein:499.Ring El is selected from the group consisting of phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;500.a is 0, 1, 2, 3, 4, 5, or 6;501.each RAis, independently, selected from the group consisting of halogen, -ORolaa, -NRNiaaRN2aa,C 1. C6 alkyl>_C(O)-Ci-C6alkyl, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,502.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;503.Page 710 of 738504.IPTS / 200244060.1 Attorney Docket No.: KME-310WO505.HE)506.RE1is absent or selected from the group consisting of (Rc507.)c, -C(O)-NRNleRN2e, - NRN3eC(O)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;508.c is 0, 1, 2, 3, 4, 5, or 6;509.each Rcis, independently, selected from the group consisting of halogen, -ORolcc, -NRNICCRN2CC,C1-C6 alkyl>_C(O)-C1-C6alkyl, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl, or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,510.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 selected from the group consisting of phenyl and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;511.b is 0, 1, 2, 3, 4, 5, or 6;512.each RBis, independently, selected from the group consisting of halogen, -ORolbb, -NRNibbRN2bb,C1. C6 alkyl>_C(0).C1. C6 aikyi, Ci-C6haloalkyl, and Ci-C6hydroxyalkyl, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,513.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;514.Page 711 of 738515.IPTS / 200244060.1 Attorney Docket No.: KME-310WO516.RE2is absent or selected from the group consisting of (R, -C(O)-NRNleeRN2ee, - NRN3eeC(O)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(NORN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee517.

518. and -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;519.d is 0, 1, 2, 3, 4, 5, or 6;520.each RDis, independently, selected from the group consisting of halogen, -ORoldd, -NRNiddRN2dd,C1. C6 alkyl>_C(O).C1. C6alkyl, C1-C6haloalkyl, and Ci-C6hydroxyalkyl, or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,521.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, -OR013, -NRN13RN23, Ci-Ce alkyl, and Ci-Ce haloalkyl;522.RE4is selected from the group consisting of hydrogen, halogen, -OR014, -NRN14RN24, Ci-Ce alkyl, and Ci-Ce haloalkyl;523.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl and Ci-C6haloalkyl,524.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,525.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from526.Page 712 of 738527.IPTS / 200244060.1 Attorney Docket No.: KME-310WO528.nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,529.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,530.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, -OR019, -NRN19RN29, Ci-Ce alkyl, and Ci-Ce haloalkyl;531.V1is selected from the group consisting of -O-, -NRE10-, and -CRE11RE12-;532.RE1° is selected from the group consisting of hydrogen, halogen, -OR01, -NRN1RN2, Ci-Ce alkyl, and Ci-Ce haloalkyl;533.each of RE11and RE12is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,534.or RE11and RE12are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,535.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, and R°19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;536.each O537.

538. f R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4eRNiee, RN2ee, RN3ee, RN4ee, RI\ RN23, RN14, RN24, RN19,AND RN29is>independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)- Ci-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or Page 713 of 738539.IPTS / 200244060.1 Attorney Docket No.: KME-310WO540.RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;541.each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and542.each of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a544.

545. *, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,546.provided wherein:547.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

15. An inhibitor compound of Formula II ”:

550. 552.Page 714 of 738553.IPTS / 200244060.1 Attorney Docket No.: KME-310WO554.or a pharmaceutically acceptable salt thereof, wherein:555.Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;556.a is 0, 1, 2, 3, 4, 5, or 6;557.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;558.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,559.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;560.HE)561.RE1is absent or selected from the group consisting of )Rc562.)c, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;563.c is 0, 1, 2, 3, 4, 5, or 6;564.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,565.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered566.Page 715 of 738567.IPTS / 200244060.1 Attorney Docket No.: KME-310WO568.monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,569.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;570.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRN1RN2, and -(Ci-C6alkyl)-ORolbb;571.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,572.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;573.RE2is absent or selected from the group consisting of (R, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3)-NRNleeRN2ee, -C(N0RN4)- NRNleepN2ee _ Q Q^C4eej^C5ee) ^j^Nleej^N2ee Qj^C4eej^C5eej^C6ee S(O)12 NR^ leeJ^N2ee574.

575. and -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;576.d is 0, 1, 2, 3, 4, 5, or 6;577.Page 716 of 738578.IPTS / 200244060.1 Attorney Docket No.: KME-310WO579.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,580.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,581.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;582.RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;583.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,584.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,585.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,586.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,587.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from588.Page 717 of 738589.IPTS / 200244060.1 Attorney Docket No.: KME-310WO590.nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;591.V2is selected from the group consisting of -C(O)-, -C(S)-, -S(O)-, and -S(O)2-;592.each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, and Rol9is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and Rola;593.Rolais -(Ci-C6alkylene)-(4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) or 4- to 8-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rolais unsubstituted or substituted with 1-4 occurrences of RC3;594.each O595.

596. f R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4eRNiee, RN2ee, RN3ee, RN4ee, RI\ RN23, RN14, RN24, RN19,AND RN29is>independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)- Ci-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;597.each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;598.each RC3is, independently, selected from the group consisting of halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy; and599.each of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6-600.Page 718 of 738601.IPTS / 200244060.1 Attorney Docket No.: KME-310WO602.membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a604.

605. , wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,606.provided wherein:607.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

16. An inhibitor compound of Formula II’:

610. 612.Formula II’,613.or a pharmaceutically acceptable salt thereof, wherein:614.Ring El is selected from the group consisting of phenyl, 3- to 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, 3- to 6-membered monocyclic heterocyclyl with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10- membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;615.a is 0, 1, 2, 3, 4, 5, or 6;616.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;617.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered618.Page 719 of 738619.IPTS / 200244060.1 Attorney Docket No.: KME-310WO620.monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,621.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;622.Hj)623.RE1is absent or selected from the group consisting624.

625. of (R, -C(O)-NRNleRN2e, - NRN3eC(O)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;626.c is 0, 1, 2, 3, 4, 5, or 6;627.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,628.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,629.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;630.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;631.Page 720 of 738632.IPTS / 200244060.1 Attorney Docket No.: KME-310WO633.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,634.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;635.RE2is absent or selected from the group consisting of (R, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee636.

637. and -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;638.d is 0, 1, 2, 3, 4, 5, or 6;639.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,640.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,641.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, C1-C6alkyl, and C1-C6haloalkyl;642.RE4is selected from the group consisting of hydrogen, halogen, cyano, -ORO14, -NRN14RN24, C1-C6alkyl, and Ci-Ce haloalkyl;643.Page 721 of 738644.IPTS / 200244060.1 Attorney Docket No.: KME-310WO645.each of and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,646.or and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,647.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,648.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,649.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, alkyl, and Ci-Ce haloalkyl;650.V2is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)2-;651.each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, and R°19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;652.each o653.

654. f RN1RN2RNlaaRX2aaRNlbbRN2bbRNlccRNlddRN2ddRNleRN2eRN3eRN4e R655.

656. Nlee, RN2“RN3eeRN4ee,RN13RN23RN14,RN24RN19,and RN29 independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)- Ci-Ce alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional Page 722 of 738657.IPTS / 200244060.1 Attorney Docket No.: KME-310WO658.heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;659.RN1and RN2, RNlaaand RN2aa, RNlbband RN2bb, RNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29is, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and660.each of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a662.

663. , wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,664.provided wherein:665.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.

17. An inhibitor compound of Formula II:

668. 670.Page 723 of 738671.IPTS / 200244060.1 Attorney Docket No.: KME-310WO672.or a pharmaceutically acceptable salt thereof, wherein:673.Ring El is selected from the group consisting of 8- to 10-membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;674.a is 0, 1, 2, 3, 4, 5, or 6;675.each RAis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolaa, -NRNlaaRN2aa, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlaaRN2aa, and -(Ci-C6alkyl)-ORolaa;676.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,677.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;678.RE1is absent or selected from the group consisting679.

680. of (R)c, -C(0)-NRNleRN2e, - NRN3eC(0)Rcle, -C(S)-NRNleRN2e, -C(NRN3e)-NRNleRN2e, -C(NORN4e)-NRNleRN2e, - C(RC4eRc5e)-NRNleRN2e, -CRC4eRc5eRC6e, -S(O)i-2-NRNleRN2e, and -NRN3eS(O)i-2RC2e; Ring Fl is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;681.c is 0, 1, 2, 3, 4, 5, or 6;682.each Rcis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolcc, -NRNlccRN2cc, C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -(C1-C6alkyl)-NRN1ccRN2cc, and -(C1-C6alkyl)-ORO1cc,683.or two Rcgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,684.Page 724 of 738685.IPTS / 200244060.1 Attorney Docket No.: KME-310WO686.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heteroaryl with 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; b is 0, 1, 2, 3, 4, 5, or 6;687.each RBis, independently, selected from the group consisting of halogen, cyano, nitro, -ORolbb, -NRNlbbRN2bb, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlbbRN2bb, and -(Ci-C6alkyl)-ORolbb;688.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,689.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl;690.RE2is absent or selected from the group consisting of (R, -C(0)-NRNleeRN2ee, - NRN3eeC(0)Rclee, -C(S)-NRNleeRN2ee, -C(NRN3ee)-NRNleeRN2ee, -C(N0RN4ee)- NRNleeRN2ee —(2 (RC4eepC5ee) ^j^Nleej^N2ee _Qj^C4eej^C5eej^C6ee ^j^Nleej^N2ee691.

692. and -NRN3eeS(O)i-2RC2ee; Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 4- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;693.d is 0, 1, 2, 3, 4, 5, or 6;694.each RDis, independently, selected from the group consisting of halogen, cyano, nitro, -ORoldd, -NRNlddRN2dd, Ci-C6alkyl, -C(O)-Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, - (Ci-C6alkyl)-NRNlddRN2dd, and -(Ci-C6alkyl)-ORoldd,695.Page 725 of 738696.IPTS / 200244060.1 Attorney Docket No.: KME-310WO697.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,698.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE3is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, CI-C6alkyl, and Ci-Ce haloalkyl;699.RE4is selected from the group consisting of hydrogen, halogen, cyano, -OR013, -NRN13RN23, CI-C6alkyl, and Ci-Ce haloalkyl;700.each of RE5and RE6is, independently, selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce hydroxy alkyl,701.or RE5and RE6are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,702.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; each of RE7and RE8is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl,703.or RE7and RE8are taken together with the carbon atom to which each is attached to form 3- to 5 -membered monocyclic carbocyclylene or 3- to 5 -membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,704.wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl; RE9is selected from the group consisting of hydrogen, halogen, cyano, -OR019, -NRN19RN29, CI-C6alkyl, and Ci-Ce haloalkyl;705.Page 726 of 738706.IPTS / 200244060.1 Attorney Docket No.: KME-310WO707.V2is selected from the group consisting of -C(O)-, -S(O)- and -S(O)2-;708.each of RO1, Rolaa, Rolbb, Rolcc, Roldd, R°13, R°14, and R°19is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl;709.each O710.

711. f R^2 J^Nlaa pN2aa pNlbb j^N2bb RNICC RN2CC pNldd pN2dd j^Nle j^N2e pN3e RN4eRNiee, RN2ee, RN3ee, RN4ee, RI\ RN23, RN14, RN24, RN19,AND RN29is>independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)- Ci-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2, RNlaaand RN2aa, RNlbband RN2bbRNlccand RN2cc, RNlddand RN2dd, RNleand RN2e, RNleeand RN2ee, RN13and RN23, RN14and RN24, or RN19and RN29on the same nitrogen atom are taken together with the nitrogen atom to which both groups are attached to form 3- to 10- membered heterocyclyl with 0-4 additional heteroatoms (e.g., 1-4 additional heteroatoms) independently selected from nitrogen, oxygen, and sulfur;712.each of Rcle, RC2e, Rclee, and RC2eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and713.each of RC4e, Rc5e, RC6e, RC4ee, Rc5ee, and RC6eeis, independently, selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, and Ci-Ce alkoxy, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are taken together with the carbon atom to which RC4and Rc5are attached to form a ring selected from 3- to 6- membered carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4eand Rc5e, RC4eeand Rc5ee, or RC4and Rc5are optionally taken together to form RD2a714.V^RD2b715.’, wherein each of RD2aand RD2bis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl, wherein RE1and RE2are not both simultaneously absent,716.provided wherein:717.when Ring El is 6-membered monocyclic heterocyclyl, then Ring El includes at least one nitrogen atom.718.Page 727 of 738719.IPTS / 200244060.1 Attorney Docket No.: KME-310WO18. The inhibitor compound of any one of claims 1 to 17, wherein RE1is selected from the721.c722.group consisting o723.

724. f (R)c, -C(O)-NRNleRN2e, and -NRN3eC(O)Rcle.

19. The inhibitor compound of any one of claims 1 to 18, wherein RNleis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5-membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

20. The inhibitor compound of any one of claims 1 to 19, wherein RN1is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

21. The inhibitor compound of any one of claims 1 to 20, wherein RN2eis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5-membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

22. The inhibitor compound of any one of claims 1 to 21, wherein RN2eis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

23. The inhibitor compound of any one of claims 1 to 22, wherein RE1is -C(O)-NRNleRN2e.

729.

730.

24. The inhibitor compound of any one of claims 1 to 23, wherein RE1is O731.b, b, O, O, O, O, b, or Me733.

734. O25. The inhibitor compound of any one of claims 1 to 17, wherein RE1is absent.

26. The inhibitor compound of any one of claims 1 to 25, wherein a is 0.

27. The inhibitor compound of any one of claims 1 to 25, wherein a is 1, 2, 3, or 4.738.Page 728 of 738739.IPTS / 200244060.1 Attorney Docket No.: KME-310WO28. The inhibitor compound of any one of claims 1 to 25, wherein each RAis, independently, selected from the group consisting of -F, -Cl, -Br, cyano, -OH, -OMe, -OEt, -OnPr, -O‘Pr, -OnBu, -O'Bu, -OsBu, -OlBu, -NH2, -NHMe, -NMe2, -Me, -Et, -nPr, -‘Pr, -nBu, -Bu, -sBu, -‘Bu, -C(O)Me, -C(O)Et, -C(O)nPr, -C(OyPr, -C(O)nBu, -C(O)iBu, -C(O)sBu, -C(O)‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, and -CH2CHOHCH3,741.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

29. The inhibitor compound of any one of claims 1 to 25, wherein each RAis, independently, selected from the group consisting of -F, -Cl, -Br, -OH, -OMe, -OEt, -OnPr, -O‘Pr, -OnBu, -O'Bu, -OsBu, -O‘Bu, -NH2, -NHMe, -NMe2, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -C(0)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(0)nBu, -C(0)iBu, -C(0)sBu, -C(0)‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, and -CH2CHOHCH3,743.or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene30. The inhibitor compound of any one of claims 1 to 29, wherein Ring El is selected from the group consisting of phenyl, 3-membered monocyclic carbocyclyl, 4-membered monocyclic carbocyclyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

31. The inhibitor compound of any one of claims 1 to 29, wherein Ring El is selected from the group consisting of phenyl, cyclopropanyl, cyclopentenyl, cyclohexanyl, pyrazolyl, triazolyl, thiazolinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, oxetanyl, azelidinyl, pyridinonyl, piperidinyl, morpholinyl, dihydropyridinyl, hexahydropyrimidinyl, pyrrolidinyl, and thiazolidinyl.746.Page 729 of 738747.IPTS / 200244060.1 Attorney Docket No.: KME-310WO32. The inhibitor compound of any one of claims 1 to 29, wherein Ring El is selected from the group consisting of phenyl, cyclohexanyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, and dihydropyridinyl.

33. The inhibitor compound of any one of claims 1 to 29, wherein Ring El is selected from the group consisting of 8- to 10-membered partially unsaturated, fused bicyclic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

34. The inhibitor compound of any one of claims 1 to 29, wherein Ring El is selected from the group consisting of 5,6,7,8-tetrahydroimidazo[l,2-c]pyrimidinyl, 5, 6,7,8-tetrahydroimidazo[l,5-a]pyridinyl, 6,7-dihydro-5H-pyrrolo[l,2-a]imidazolyl, and 4, 5,6,7-tetrahydrobenzo [d]isoxazole.

35. The inhibitor compound of any one of claims 1 to 30, wherein Ring El is selected752.from the group consisting of753.

756.

36. The inhibitor compound of any one of claims 1 to 35, wherein RE2is selected from the759.group consisting o760.

761. f, -C(O)-NRNleeRN2ee, and -NRN3eeC(O)Rclee37. The inhibitor compound of any one of claims 1 to 36, wherein d is 0, 1, 2, 3, or 4.

38. The inhibitor compound of any one of claims 1 to 36, wherein each RDis, independently, selected from the group consisting of -F, -Cl, -Br, -OH, -OMe, -OEt, -OnPr, -O‘Pr, -OnBu, -O'Bu, -OsBu, -OlBu, -NH2, -NHMe, -NMe2, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -Bu, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, -C(O)tBu,-CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, and -CH2CHOHCH3.763.Page 730 of 738764.IPTS / 200244060.1 Attorney Docket No.: KME-310WO765.or two RDgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

39. The inhibitor compound of any one of claims 1 to 36, wherein RE2is767.

40. The inhibitor compound of any one of claims 1 to 36, wherein770.

771. (RDki is selected772.^|=N from the group consisting of773.

774. (RD)d (RD)d(RD)d, and776.

777. (RD)d,41. The inhibitor compound of any one of claims 1 to 36, wherein779.

780. (R)d is selected781.from the group consisting of782.

783. , and42. The inhibitor compound of any one of claims 1 to 36, wherein785.

786. (R)d is788. 790.Page 731 of 738791.IPTS / 200244060.1 Attorney Docket No.: KME-310WO793. 795.The inhibitor compound of any one of claims 1 to 36, wherein796. 798.O800.

801.

44. The inhibitor compound of any one of claims 1 to 36, wherein RNleeis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5-membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

45. The inhibitor compound of any one of claims 1 to 36, wherein RNleeis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

46. The inhibitor compound of any one of claims 1 to 36, wherein RN2eeis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5-membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

47. The inhibitor compound of any one of claims 1 to 36, wherein RN2eeis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.804.Page 732 of 738805.IPTS / 200244060.1 Attorney Docket No.: KME-310WO48. The inhibitor compound of any one of claims 1 to 36, wherein RN3eeis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5-membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

49. The inhibitor compound of any one of claims 1 to 36, wherein RN3eeis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

50. The inhibitor compound of any one of claims 1 to 36, wherein Rcleeis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, 3- to 5-membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

51. The inhibitor compound of any one of claims 1 to 36, wherein Rcleeis selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)-Ci-Ce alkyl.

52. The inhibitor compound of any one of claims 1 to 36, wherein RE2is -C(O)- NR^eeR 2ee810.

811.

53. The inhibitor compound of any one of claims 1 to 36, wherein RE2is O812.,z / H / H / H / lYle.lYleT if ifMeifMe|fMe“ ifMeifMe813. 814.0o O O O O O, or Me815. / 'yN'Me816.O54. The inhibitor compound of any one of claims 1 to 36, wherein RE2is -NRN3eeC(O)Rclee.818.O820.

821.

55. The inhibitor compound of any one of claims 1 to 36, wherein R is H823. 825.Page 733 of 738826.IPTS / 200244060.1 Attorney Docket No.: KME-310WO56. The inhibitor compound of any one of claims 1 to 35, wherein RE2is absent.

57. The inhibitor compound of any one of claims 1 to 56, wherein b is 0.

58. The inhibitor compound of any one of claims 1 to 56, wherein b is 1, 2, 3, or 4.

59. The inhibitor compound of any one of claims 1 to 56, wherein each RBis, independently, selected from the group consisting of -F, -Cl, -Br, cyano, -OH, -OMe, -OEt, -OnPr, -O‘Pr, -OnBu, -O'Bu, -OsBu, -OlBu, -NH2, -NHMe, -NMe2, -Me, -Et, -nPr, -‘Pr, -nBu, -Bu, -sBu, -‘Bu, -C(O)Me, -C(O)Et, -C(O)nPr, -C(OyPr, -C(O)nBu, -C(O)iBu, -C(O)sBu, -C(O)‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -CH2OMe, -CH2OEt, -CH2OnPr, -CH^Pr, -CH2OnBu, -CH2O‘BU, -CH2OSBU, and -CH2O‘Bu,831.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

60. The inhibitor compound of any one of claims 1 to 56, wherein each RBis, independently, selected from the group consisting of -F, -Cl, -Br, -OH, -OMe, -OEt, -OnPr, -O‘Pr, -OnBu, -O'Bu, -OsBu, -O‘Bu, -NH2, -NHMe, -NMe2, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -C(0)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, -C(O)‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3and -CH2CF3,833.or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

61. The inhibitor compound of any one of claims 1 to 60, wherein Ring E2 is selected from the group consisting of phenyl, 6-membered heteroaryl with 1-3 nitrogen atoms, and 5-membered heteroaryl with 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur.

62. The inhibitor compound of any one of claims 1 to 60, wherein Ring E2 is selected from the group consisting of phenyl, pyridinonyl, pyridinyl, pyrimidinyl, and thiophenyl.

63. The inhibitor compound of any one of claims 1 to 60, wherein Ring E2 is selected from the group consisting of phenyl and 6-membered heteroaryl with 1-3 nitrogen atoms.

64. The inhibitor compound of any one of claims 1 to 60, wherein Ring E2 is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl.836.Page 734 of 738837.IPTS / 200244060.1 Attorney Docket No.: KME-310WO65. The inhibitor compound of any one of claims 1 to 64, wherein RE3is hydrogen.

66. The inhibitor compound of any one of claims 1 to 65, wherein RE4is hydrogen.

67. The inhibitor compound of any one of claims 1 to 66, wherein RE7is hydrogen or - Me.

68. The inhibitor compound of any one of claims 1 to 67, wherein RE7is hydrogen.

69. The inhibitor compound of any one of claims 1 to 68, wherein RE8is hydrogen.

70. The inhibitor compound of any one of claims 1 to 69, wherein RE5is selected from the group consisting of -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, -Bu, -CF3, -CHF2, -CH2F, - OH OH OH840.C841.

842. F2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, Y^CH3, V^CH3,andV> H371. The inhibitor compound of any one of claims 1 to 69, wherein RE5is selected from the group consisting of -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, - Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3 and -CH2CF372. The inhibitor compound of any one of claims 1 to 70, wherein RE6is selected from the group consisting of -Me, -Et, -nPr, - Pr, -nBu, - Bu, -sBu, - Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3 and -CH2CF3.

73. The inhibitor compound of any one of claims 1 to 72, wherein RE5is -Me and RE6is -Me.

74. The inhibitor compound of any one of claims 1 to 69, wherein RE5and RE6are taken together with the carbon atom to which each is attached to form cyclopropylene, cyclobutylene, oxetanylene, or tetrahydrofuranylene.

75. The inhibitor compound of any one of claims 1 to 69, wherein RE5and RE6are taken together with the carbon atom to which each is attached to form cyclopropylene, cyclobutylene, or oxetanylene.

76. The inhibitor compound of any one of claims 1 to 75, wherein RE9is selected from the group consisting of hydrogen, halogen, -OH, -OMe, -OEt, -OnPr, -O‘Pr, -OnBu, -O'Bu, -849.Page 735 of 738850.IPTS / 200244060.1 Attorney Docket No.: KME-310WO851.OsBu, -O'Bu, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3and -CH2CF3.

77. The inhibitor compound of any one of claims 1 to 76, wherein each of RE11and RE12is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, -Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, and854.

78. The inhibitor compound of any one of claims 1 to 76, wherein each of RE11and RE12is, independently, selected from the group consisting of hydrogen, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, -Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3and -CH2CF3.

79. The inhibitor compound of any one of claims 1 to 77, wherein V1is selected from the857.group consisting of-O-, -NH-, -NMe-, -CH2-,859.

860.

80. The inhibitor compound of any one of claims 1 to 77, wherein V1is selected from the861.group consisting of-O-, -NH-, -NMe-, -CH2-,863.

864.

81. A compound selected from any one of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

82. A pharmaceutical composition comprising an inhibitor compound of any one of claims 1 to 80 or a compound of claim 81, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

83. A method of modulating STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or the biological sample an inhibitor867.Page 736 of 738868.IPTS / 200244060.1 Attorney Docket No.: KME-310WO869.compound of any one of claims 1 to 80, a compound of claim 81, or a pharmaceutical composition of claim 82.

84. A method of treating a STAT-6-mediated disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject an inhibitor compound of any one of claims 1 to 80, a compound of claim 81, or a pharmaceutical composition of claim 82.

85. The method of claim 84, wherein the STAT6-mediated disease or disorder is a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.872.Page 737 of 738873.IPTS / 200244060.1

Images