BR112019001732B1 - CHEMOKINE RECEPTOR MODULATORS AND THEIR USES - Google Patents

Abstract

THE PRESENT DOCUMENT DISCLOSES, AMONG OTHERS, COMPOUNDS AND METHODS OF USING THEM FOR MODULATING CCR4 ACTIVITY.

Description

CROSS-REFERENCE TO RELATED ORDERS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/368,848, filed July 29, 2016, and U.S. Provisional Application No. 62/426,087, filed November 23, 2016. The disclosure in each of the prior applications is deemed a part of, and is incorporated by reference into, the disclosure in this application.

BACKGROUND

[0002] The successful operation of the host defense system is the result of several processes that work together to eliminate exogenous pathogens. Coordinated innate and adaptive immune responses are required, and several secreted and cell-associated factors have been identified as important mediators that coordinate and regulate these two arms of host defense. Chemokines are a family of cytokines that act as chemoattractants to guide leukocyte migration. They are secreted by a wide variety of cells and can be functionally divided into two groups, hemostatic chemokines and inflammatory chemokines. Hemostatic chemokines are constitutively produced in certain tissues and control cells of the immune system during immune inspection processes, such as homing of lymphocytes to lymph nodes to allow them to screen for invading pathogens. Inflammatory chemokines are released from cells in response to a pathological event (e.g., proinflammatory stimuli such as IL-1 or viruses). They function primarily as chemoattractants as part of the inflammatory response and serve to guide cells of both the innate and adaptive immune systems to the site of inflammation. The C-C chemokine receptor type 4 (CCR4) plays a role in the progression of numerous inflammation-related and other disorders. Identifying compounds that modulate CCR4 function is an ongoing challenge. Solutions to these and other problems in the art are disclosed in this document, among others.

BRIEF SUMMARY OF THE INVENTION

[0003] In one aspect provided herein is a compound having the structural formula (I): or a pharmaceutically acceptable salt thereof. X1 is CR8 or N. X2 is CR9 or N. X3 is CR10 or N. The symbols n1, n2, n3, n4, n5, n6, n7, n8, n9, and n10 are independently an integer from 0 to 4. The symbol z3 is an integer from 0 to 11. In embodiments, z3 is independently an integer from 0 to 4. The symbols m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9, and v10 are independently 1 or 2. The symbol z1 is an integer from 0 to 5. The symbol z2 is an integer from 0 to 4. In embodiments, z2 is an integer from 0 to 2. The symbol z4 is an integer from 0 to 2. L7 is a bond, -O-, -S-, -NR7.2B-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R1 is hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -N3, - SOn1R1A, -SOv1NR1BR1C, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, - NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, - C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, - NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl. R2 is hydrogen, halogen, -CX2.1, -CHX2.12, -CH2X2.1, -CN, -N3 , -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, - ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, - C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, - NR2BC(O)R2D, -NR2BC(O)OR2D, -NR2BOR2D, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl. R3 is independently hydrogen, halogen, -CX3.13, -CHX3.12, - CH2X3.1, -CN, -N3-SOn3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, - NHC(O)NHNR3BR3C, -NHC(O)NR3BR3C, -N(O)m3, -nr3Br3C, -C(O)R3D, - C(O)OR3D, -C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, - NR3BC(O)OR3D, -NR3BOR3D, -OCX3.13, -OCHX3.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, aryl substituted or unsubstituted or substituted or unsubstituted heteroaryl. R4 is hydrogen, halogen, -CX4.13, -CHX4.12, -CH2X4.1, -CN, -N3, -SON4R4A, -SOV4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(O)NHNR4BR4C, - NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, -C(O)R4D, -C(O)OR4D, - C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, -NR4BC(O)OR4D, - NR4BOR4D, -OCX4.13, -OCHX4.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl. R5 is independently hydrogen, halogen, oxo, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, -SOv5NR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, - NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, - C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D, - NR5BOR5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R6 is independently hydrogen, halogen, oxo, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, - NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, - C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, -NR6BC(O)R6D, -NR6BC(O)OR6D, - NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R7 is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, - ONR7BR7C, -NHC(O)NHNR7BR7C, -NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, - C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, - NR7BC(O)R7D, -NR7BC(O)OR7D, -NR7BOR7D, -OCX7.13 -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R8 is hydrogen, halogen, -CX8.13, -CHX8.12, -CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, -ONR8BR8C, -NHC(O)NHNR8BR8C, - NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, -C(O)R8D, -C(O)OR8D, - C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, -NR8BC(O)R8D, -NR8BC(O)OR8D, - NR8BOR8D, -OCX8.13, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl. R9 is hydrogen, halogen, -CX9.13, -CHX9.12, -CH2X9.1, -CN, -N3, -SOn7R9A, -SOv9NR9BR9C, -NHNR9BR9C, - ONR9BR9C, -NHC(O)NHNR9BR9C, -NHC(O)NR9BR9C, -N(O)m9, -NR9BR9C, - C(O)R9D, -C(O)OR9D, -C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, - NR9BC(O)R9D, -NR9BC(O)OR9D, -NR9BOR9D, -OCX9.13, -OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl. R10 is hydrogen, halogen, -CX10.13, -CHX10.12, -CH2X10.1, -CN, -N3, -SOn10R10A, -SOv10NR10BR10C, -NHNR10BR10C, -ONR10BR10C, - NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, -N(O)m10, -NR10BR10C, - C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, -NR10BSO2R10A, - NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, -OCX10.13, -OCHX10.12, alkyl substituted or unsubstituted, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3b, R3C, R3D, R4A, R4B, R4D, R5A, R5b, R5D, R6A, R6B, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2B, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D, R10A, R10B, R10C, and R10D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; the substituents R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B, R9C, R10B, and R10C attached to the same nitrogen atom can optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1, and X10.1 are independently -Cl, -Br, -I, or -F. At least one of X1, X2, and X3 is N.

[0004] In one aspect, a pharmaceutical composition is provided, which includes a compound as described herein, including embodiments, or structural Formula (I), (II), (IIa), (IIb), (IIc), (IId), (III), (IV), (V), (VI), or (VII), and a pharmaceutically acceptable excipient.

[0005] In another aspect, a method of inhibiting C-C chemokine receptor type 4 (CCR4) is provided, wherein the method comprises contacting CCR4 with a compound as described herein, including embodiments, or structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof.

[0006] In one aspect, a method of treating or preventing a CCR4-mediated disease or disorder is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, including embodiments, or structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, provided herein is a kit that includes a compound described herein (e.g., a CCR4 inhibitor) or pharmaceutical compositions thereof, wherein the kits are generally in the form of a physical structure that houses various components, as described below, and can be used, for example, in practicing the methods described above.

DETAILED DESCRIPTION

[0008] Provided herein, for example, are compounds and compositions for inhibiting C-C chemokine receptor type 4, and pharmaceutical compositions comprising the same. Also provided herein, for example, are methods of treating or preventing a disease, disorder or condition, or a symptom thereof, mediated by modulation (e.g., inhibition) of CCR4.

I. Definitions

[0009] Abbreviations used in this document have their conventional meaning within the chemical and biological arts. The chemical structures and formulas presented in this document are constructed according to the standard rules of chemical valence known in the chemical arts.

[0010] Where groups of substituents are specified by their conventional chemical formulas, written from left to right, these equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0011] The term "alkyl", either alone or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon (or carbon) chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and may include mono-, di- and multivalent radicals having the designated number of carbon atoms (i.e., C1-C10 means one to ten carbons). Alkyl is a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. An unsaturated alkyl group is one that has one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologues and isomers. An alkoxy is an alkyl attached to the remainder of the molecule through an oxygen (-O-) ligand.

[0012] The term "alkylene", either alone or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term "alkenylene", either alone or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0013] The term "heteroalkyl", alone or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, that includes at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and in which the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any position within the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is a non-cyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2- S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O- CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, - O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O- Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0014] Similarly, the term "heteroalkylene", either by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatoms may also occupy one or both chain termini (e.g., alkylenoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the linking group formula is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and/or -SO2R. Where "heteroalkyl" is mentioned, followed by mentions of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are mentioned for added clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0015] The terms "cycloalkyl" and "heterocycloalkyl", alone or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom may occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene", alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. "Cycloalkyl" is also intended to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0016] The terms "halo" or "halogen", alone or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

[0017] The term "acyl" means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0018] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic hydrocarbon substituent that may be a single ring or multiple rings (preferably 1 to 3 rings) that are fused together (i.e., a fused-ring aryl) or covalently bonded. A fused-ring aryl refers to multiple rings fused together in which at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, in which the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom (or atoms) is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together in which at least one of the fused rings is a heteroaromatic ring). A 5,6-ring fused heteroarylene refers to two rings fused together, where one ring has 5 members and the other ring has 6 members, and where at least one ring is a heteroaryl ring. Similarly, a 6,6-ring fused heteroarylene refers to two rings fused together, where one ring has 6 members and the other ring has 6 members, and where at least one ring is a heteroaryl ring. And a 6,5-ring fused heteroarylene refers to two rings fused together, where one ring has 6 members and the other ring has 5 members, and where at least one ring is a heteroaryl ring. A heteroaryl group may be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. The substituents for each of the aryl and heteroaryl ring systems noted above are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene", alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be attached by -O- to a ring nitrogen heteroatom.

[0019] Spirocyclic rings are two or more rings in which adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. The individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. The possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocyclic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocyclic ring group may be any of the immediately preceding list, which includes having all rings of one type (e.g., all rings being substituted heterocycloalkylene where each ring may be the same or different from substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means spirocyclic rings in which at least one ring is a heterocyclic ring and in which each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means where at least one ring is substituted and each substituent may optionally be different.

[0020] The symbol "^^^" denotes the point of attachment of a chemical moiety to the remainder or to a molecule or chemical formula.

[0021] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0022] The term "alkylarylene" as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene ligand). In embodiments, the alkylarylene group has the formula:

[0023] An alkylarylene moiety can be substituted (e.g., by a substituent group) on the alkylene moiety or on the arylene linker (e.g., on carbons 2, 3, 4, or 6) by halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 -SO3H, -OSO3H, -so2nh2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or unsubstituted or substituted 2- to 5-membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0024] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are given below.

[0025] The substituents for the alkyl and heteroalkyl radicals (which include those groups often called alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR, =N-OR', -NR'R", -SR', -halogen, -SiR''R'", -OC(O)R', -C(O)R, -CO2R, -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'- C(O)NR"R'", -NR"C(O)2R, -NR-C(NR'R"R'")=NR"", -NR- C(NR'R")=NR'", -S(O)R', -S(O)2R, -S(O)2NR'R", -NRSO2R, - NR'NR"R'", -ONR'R", -NR'C(O)NR"NR'"R"", -CN, -NO2, - NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", in a number in the range from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R", R'", and R"" each independently preferably refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. When R and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is intended to include groups that include carbon atoms attached to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0026] Similar to the substituents described for the alkyl radical, the substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR, -NR'R", -SR, -halogen, -SiR'R'R", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R", -NR"C(O)2R', -NR-C(NRR"R")=NR"", -NR'-C(NR'R")=NR", -S(O)R', -S(O)2R', -S(O)2NRR", -NRSO2R', -NR'NR'R", -ONR'R", -NRC(O)NR"NR"R"", -CN, -NO2, -R, -N3, - CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NRSO2R", -NR'C(O)R", -NR'C(O)-OR", -NR’OR", in a number ranging from zero to the total number of open valences in the aromatic ring system; and wherein R', R", R'", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each of the R', R", R" and R"" groups when more than one of these groups is present.

[0027] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific ring atom (commonly called a dangling substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as attached to a member of the fused rings or spirocyclic rings (a dangling substituent on a single ring) may be a substituent on any of the fused rings or spirocyclic rings (a dangling substituent on multiple rings). When a substituent is attached to a ring but not a specific atom (a dangling substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a dangling substituent), the point of attachment may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of either fused ring or spirocyclic ring as long as they obey the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one or more dangling substituents (including, but not limited to, points of attachment to the remainder of the molecule), the dangling substituents may be attached to the heteroatoms. Where ring heteroatoms are shown bonded to one or more hydrogens (e.g., a ring nitrogen with two bonds to the ring atoms and a third bond to a hydrogen) in the structure or formula with the dangling substituent, when the heteroatom is attached to the dangling substituent, it will be understood that the substituent replaces the hydrogen, while obeying the rules of chemical valency.

[0028] Two or more substituents may be optionally joined to form aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0029] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH2)r-B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring or heteroaryl ring may be optionally replaced by a substituent of the formula -(CRR')S-X'-(C"R"R"')d-, where s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0030] As used herein, the terms "heteroatom" or "ring heteroatom" are intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0031] A "substituent group", as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted by at least one substituent selected from: (i) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, - NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted by at least one substituent selected from: a. oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, - NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, - NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and b. alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted by at least one substituent selected from: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0032] A "limited size substituent" or "limited size substituent group", as used herein, means a group selected from all of the substituents described above for a "substituent group", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0033] A "lower substituent" or "lower substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0034] In some embodiments, each substituted group described in the compounds herein is substituted by at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein is substituted by at least one substituent group. In other embodiments, at least one or all of these groups are substituted by at least one substituent group of limited size. In other embodiments, at least one or all of these groups are substituted by at least one lower substituent group.

[0035] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl can be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0036] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0037] Certain compounds of the present invention possess asymmetric carbon atoms (chiral or optical centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms which may be defined, in terms of absolute stoichiometry, as (R)- or (S)- or as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. Compounds of the present invention do not include those which are known in the art to be too unstable to sinter and/or isolate. The present invention is intended to include compounds in optically pure or racemic forms. Optically active (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0038] As used herein, the term "isomers" refers to compounds that have the same number and type of atoms, and therefore the same molecular weight, but differ in the configuration or structural arrangement of the atoms.

[0039] The term "tautomer", as used herein, refers to two or more structural isomers that exist in equilibrium and that are readily converted from one isomeric form to another.

[0040] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

[0041] Unless otherwise stated, the structures presented herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0042] Unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds that have the present structures except for the replacement of a hydrogen by a deuterium or tritium or the replacement of a carbon by a carbon enriched with 13C or 14C are within the scope of this invention.

[0043] The compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0044] It should be noted that throughout the application, alternatives are written in Markush groups, i.e., each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group should not be read as a single unit.

[0045] "Analog" is used according to its simple common meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called "reference" compound), but differs in its composition, for example, in the replacement of an atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of a functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to a reference compound.

[0046] The terms "a" or "an" as used herein mean one or more. In addition, the phrase "substituted by one" as used herein means that the particular group may be substituted by one or more of any or all of the so-called substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted by an unsubstituted C1-C20 alkyl, or unsubstituted 2- to 20-membered heteroalkyl", the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2- to 20-membered heteroalkyls.

[0047] Furthermore, where a moiety is substituted by a substituent R, the group may be referred to as "R-substituted". Where a moiety is R-substituted, the moiety is substituted by at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabet symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13 substituents are present, each R13 substituent may be distinguished as R13A, R13B, R13C, R13D, etc., where each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13 and optionally and differently.

[0048] A “detectable moiety” as used herein refers to a moiety that can be covalently or non-covalently attached to a compound or biomolecule that can be detected, for example, using techniques known in the art. In embodiments, the detectable moiety is covalently attached. The detectable moiety can provide imaging of the compound or biomolecule. The detectable moiety can indicate contact between two compounds. Exemplary detectable moieties are fluorophores, antibodies, reactive matrices, radiolabeled moieties, magnetic contrast agents, and quantum dots. Exemplary fluorophores include fluorescein, rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, and cyanine dyes. Exemplary radionuclides include Fluorine-18, Gallium-68, and Copper-64. Exemplary magnetic contrast agents include gadolinium, iron oxide, and manganese iron platinum.

[0049] Descriptions of compounds of the present invention are limited by principles of chemical bonding known to one of skill in the art. Accordingly, where a group may be replaced by one or more of a number of substituents, such substitutions are selected so as to comply with the principles of chemical bonding and to generate compounds that are not inherently unstable and/or would be known to one of ordinary skill in the art to be prone to being unstable under environmental conditions such as aqueous, neutral, and various known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule through a ring heteroatom in accordance with the principles of chemical bonding known to one of skill in the art, thereby avoiding inherently unstable compounds.

[0050] The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds that are prepared with relatively non-toxic bases or acids, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salt, or a similar salt. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic or phosphorous acid and the like, as well as those salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic and the like. Also included are salts of amino acids, such as arginate and the like, and salts of organic acids such as glucuronic acids or galacturonic acids and the like (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted to acid or base addition salts.

[0051] Thus, the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). Such salts may be prepared by methods known to one of skill in the art.

[0052] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, the compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted to acid or base addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for purposes of the present invention.

[0053] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein can be converted in vivo following administration. Additionally, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an ex vivo environment, such as when contacted with a suitable chemical reagent or enzyme.

[0054] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0055] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids in the delivery of a compound to and absorption by a matter and may be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, Ringer's lactate, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinyl pyrrolidine and colorants, and the like. Such preparations may be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like which do not react deleteriously with the compounds of the invention. One skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0056] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers is surrounded by a carrier which is then in association therewith. Similarly, sachets and dragees are included. Tablets, powders, capsules, pills, sachets and dragees may be used as solid dosage forms suitable for oral administration.

[0057] A “CCR4 inhibitor” refers to a compound (e.g., compounds described herein) that reduces CCR4 activity when compared to a control, such as no compound or a compound with known inactivity.

[0058] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers wherein one or more amino acid residues are an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. In embodiments, the terms “polypeptide,” “peptide,” and “protein,” used interchangeably herein, refer to a polymeric form of amino acids of any length, which may include genetically encoded and genetically non-encoded amino acids, derivatized or chemically modified or biochemically modified amino acids, and polypeptides that have modified polypeptide backbones. The terms include fusion proteins, which include, but are not limited to, fusion proteins with a heterologous amino acid sequence; fusion proteins with homologous and heterologous leader sequences, with or without an N-terminal methionine residue; immunolabeled proteins; and the like.

[0059] A polypeptide or cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered (e.g., non-natural or non-wild type) nucleic acid or protein. For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., into a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not occur in nature, e.g., a variant of a naturally occurring gene, is recombinant.

[0060] “Contact” is used according to its simple common meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, that the resulting reaction product may be produced directly from a reaction between the added reactants or from an intermediate of one or more of the added reactants that may be produced in the reaction mixture.

[0061] The term “contact” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments, contact includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway (e.g., MAP kinase pathway).

[0062] As defined herein, the term “activation,” “turn on,” “activate,” and the like in reference to a protein refers to the conversion of a protein into a biologically active derivative from an initial deactivated or inactive state. The terms refer to activation or that activates or sensitizes or upregulates signal translation or enzymatic activity or the amount of a protein decreased in a disease.

[0063] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist may increase the expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the agonist. In certain examples, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more greater than the expression or activity in the absence of the agonist. In embodiments, an agonist is a molecule that interacts with a target to cause or promote an increase in activation of the target. In embodiments, activators are molecules that enhance, activate, facilitate, enhance activation, sensitize, or upregulate, for example, a gene, protein, ligand, receptor, or cell.

[0064] As defined herein, the term “inhibition,” “inhibit,” “inhibits,” and the like, in reference to a protein-inhibitor interaction means to negatively affect (e.g., decrease) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means to negatively affect (e.g., decrease) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to the reduction of a disease or disease symptoms. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or fully blocking the stimulation, decreasing, preventing, or delaying the activation, deactivation, desensitization, or downregulation of enzymatic activity or signal transduction or the amount of a protein. In embodiments, inhibition refers to a reduction in activity of a target protein that results from a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction in activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing activation of the target protein).

[0065] The terms “inhibitor”, “repressor” or “antagonist” or “downregulator” refer interchangeably to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist may decrease the expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the antagonist. In certain examples, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more lower than the expression or activity in the absence of the antagonist. An antagonist prevents, reduces, inhibits or neutralizes the activity of an agonist, and an antagonist may also prevent, inhibit or reduce the constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist. In embodiments, inhibitors are molecules that decrease, block, prevent, delay the activation of, inactivate, desensitize, or downregulate, for example, a gene, protein, ligand, receptor, or cell. An inhibitor can also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity. An “antagonist” is a molecule that opposes the action (or actions) of an agonist.

[0066] The terms “C-C chemokine receptor type 4” and “CCR4” refer to a protein (which includes homologues, isoforms and functional fragments thereof) and is a high affinity receptor for C-C chemokines (e.g. CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL 17 (TARC) and CCL22 (MDC)). It is referred to by several different names in the scientific literature, which include “CC-CKR-4”, “C-C CKR-4”, “K5-5”, “CD194”, “CMKBR4”, “ChemR13”, “HGCN” and “14099”. The term includes any recombinant or naturally occurring form of CCR4 variants thereof that retain CCR4 activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type CCR4). The term includes any mutant form of CCR4 variants (e.g., reading frame mutations) thereof that retain CCR4 activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type CCR4). In embodiments, the CCR4 protein encoded by the CCR4 gene has the amino acid sequence set forth in or corresponding to Entrez 1233, UniProt P51679, or RefSeq (protein) NP_005499.1. In embodiments, the CCR4 gene has the nucleic acid sequence set forth in RefSeq (mRNA) NM_005508. In embodiments, the amino acid sequence or nucleic acid sequence is the sequence known at the time of filing this application. In embodiments, the sequence corresponds to GI:5031627. In embodiments, the sequence corresponds to NP_005499.1. In embodiments, the sequence corresponds to NM_005508.4. In embodiments, the sequence corresponds to GI:48762930. In embodiments, the CCR4 is a human CCR4, such as a human cancer-causing CCR4. Although frequently found on dendritic cells, macrophages, NK cells, platelets, and basophils, CCR4 is predominantly associated with T cells. It plays a role in the progression of multiple inflammatory-related disorders and, as described herein, has also been implicated in several other conditions. The genomic sequence of CCR4 is present on chromosome 3 (NC_000003.12), and the CCR4 gene is conserved in a number of species, including chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, and zebrafish. The CCR4 polypeptide comprises 360 amino acid residues (NP_005499.1), and like other chemokine receptors, CCR4 is a G protein-coupled receptor found on the surface of leukocytes (see, Horuk (1994) Trends Pharm. Sci. 15:159-165).

[0067] The term "expression" includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0068] The terms “disease” or “condition” refer to a state of being or health status of a patient or individual capable of being treated with the compounds or methods provided herein. The disease may be cancer. The disease may be an autoimmune disease. The disease may be an inflammatory disease. The disease may be an infectious disease. In some additional examples, “cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., which include solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreatic, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophageal, and lung cancers, which include hepatocellular carcinoma, lymphoma, which includes acute B-lymphoblastic lymphoma, non-Hodgkin lymphomas (e.g., Burkitt, Small Cell, and Large Cell lymphomas), Hodgkin lymphoma, leukemia (which includes MDS, AML, ALL, ATLL, and CML), or multiple myeloma.

[0069] As used herein, the term “inflammatory disease” refers to a disease or condition characterized by abnormal inflammation (e.g., an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes, type 1 diabetes mellitus, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma and atopic dermatitis. Such conditions are frequently and inextricably interconnected with other diseases, disorders and conditions. A non-limiting list of related inflammatory conditions, disorders and diseases that may, for example, be caused by inflammatory cytokines, includes arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g. where inflammatory cytokines prevent healing), anemia and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation and multiple sclerosis. Some of the aforementioned diseases, disorders and conditions for which a compound (e.g., CCR4 inhibitor) of the present invention may be particularly effective (due to, for example, limitations of current therapies) are described in more detail below.

[0070] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), which includes leukemia, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer and head cancer. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovarian, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, squamous cell carcinoma of the head and neck, invasive breast carcinoma, lung adenocarcinoma, squamous cell carcinoma of the lung, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, pancreatic malignant insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, cortical cancer adrenal, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0071] The term "leukemia" refers broadly to progressive malignant diseases of the blood organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the acute or chronic disease; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or lack of increase in the number of abnormal cells in the blood leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, allophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross's leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, leukemia lymphogenous, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, granulocytic myeloid leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia or undifferentiated cell leukemia.

[0072] The term "sarcoma" generally refers to a tumor that is composed of a substance such as embryonic connective tissue and is usually composed of highly concentrated cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernetes sarcoma, adipose tissue sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorion carcinoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0073] The term "melanoma" is taken to mean a tumor that originates from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subfungal melanoma, or superficial spreading melanoma.

[0074] The term "carcinoma" refers to a new malignant growth consisting of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, squamous cell carcinoma of the head and neck, invasive breast carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortex carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, carcinoma crifiform carcinoma, carcinoma en cuirasse, cutaneous carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, hard carcinoma, embryonal carcinoma, encephaloid carcinoma, squamous cell carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, ex ulcer carcinoma, fibrous carcinoma, gelatinifome carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellular carcinoma, glandular carcinoma, granulosa cell carcinoma, capillary matrix carcinoma, hematoid carcinoma, hepatic carcinoma cellular, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanotic carcinoma, molle carcinoma, mucinous carcinoma, muciparous carcinoma, mucocellular carcinoma, carcinoma mucoepidermoid, carcinoma mucosum, mucosal carcinoma, myxomatoid carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, inverse cell carcinoma, carcinoma sarcomatodes, carcinoma schneiderian, scirrhous carcinoma, carcinoma scroti, signet ring cell carcinoma, carcinoma simplex, small cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, sponge carcinoma, squamous carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma or carcinoma villosum.

[0075] As used herein, the term “autoimmune disease” refers to a disease or condition in which an individual's immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy individual. Examples of autoimmune diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Acute Disseminated Encephalomyelitis (ADEM), Acute Necrotizing Hemorrhagic Leukoencephalitis, Addison's Disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing Spondylitis, Anti-GBM/anti-TBM Nephritis, Antiphospholipid Syndrome (APS), Autoimmune Angioedema, Autoimmune Aplastic Anemia, Autoimmune Dysautonomia, Autoimmune Hepatitis, Autoimmune Hyperlipidemia, Autoimmune Immunodeficiency, Autoimmune Inner Ear Disease (AIED), Autoimmune Myocarditis, Autoimmune Oophoritis, Autoimmune Pancreatitis, Autoimmune Retinopathy, Autoimmune Thrombocytopenic Purpura (ATP), Autoimmune Thyroid Disease, Autoimmune Urticaria, Axonal Neuropathies or neuronal, Balo's disease, Behcet's disease, Bullous pemphigoid, Cardiomyopathy, Castleman's disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucous membrane pemphigoid, Crohn's disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Large cell myocarditis, Glomerulonephritis, Goodpasture syndrome, Granulomatosis with polyangiitis (GPA) (formally called Wegener's granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroid, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related multiple sclerosis disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Conjunctivitis ligneosa, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic brain degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Autoimmune polyglandular syndromes Types I, II and III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Rainauds phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleroderma, Scleroderma, Sjogren's syndrome, Testicular & sperm autoimmunity, Subacute bacterial endocarditis (SBE), Susac syndrome, Sympathetic ophthalmia, Takayasu arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, Wegener's granulomatosis (i.e., Granulomatosis with polyangiitis (GPA).

[0076] As used herein, the term “inflammatory disease” refers to a disease or condition characterized by abnormal inflammation (e.g., an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes, type 1 diabetes mellitus, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Ankylosing spondylitis, Psoriasis, Sjogren's syndrome, Vasculitis, Glomerulonephritis, Autoimmune thyroiditis, Behçet's disease, Crohn's disease, Ulcerative colitis, Bullous pemphigoid, Sarcoidosis, Ichthyosis, Graves' ophthalmopathy, Inflammatory bowel disease, Addison's disease, Vitiligo, Asthma, Allergic asthma, Acne vulgaris, Celiac disease, Chronic prostatitis, Inflammatory bowel disease, Pelvic inflammatory disease, Reperfusion injury, Sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis and atopic dermatitis.

[0077] The terms “treat” or “treatment” refer to any indication of success in the therapy or amelioration of an injury, disease, pathology or condition, which includes any objective or subjective parameter such as attenuation; remission; lessening of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; improving the mental or physical well-being of a patient. The treatment or amelioration of symptoms may be based on objective or subjective parameters; which include the results of a physical examination, neuropsychiatric examinations and/or a psychiatric evaluation. The term “treat” and conjugations thereof may include the prevention of an injury, pathology, condition or disease. In embodiments, the treatment is preventative. In embodiments, the treatment does not include prevention.

[0078] “Treat” or “treatment” as used herein (and as well understood in the art) also broadly includes any approach to achieving beneficial or desired results in a subject’s condition, which includes clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, lessening the extent of a disease, stabilization (i.e., non-worsening) of the disease state, prevention of the spread or transmission of a disease, delay or retardation of the progression of a disease, amelioration or palliation of the disease state, decrease in disease recurrence, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the occurrence of the disease; inhibit the spread of the disease; relieve symptoms of the disease (e.g., eye pain, halos around lights, red eyes, very high intraocular pressure), completely or partially remove the underlying cause of the disease, shorten the duration of a disease, or do a combination of these.

[0079] "Treat" and "treatment" as used herein include prophylactic treatment. Methods of treatment include administering to a subject a therapeutically effective amount of a compound described herein. The administration step may consist of a single administration or may include a series of administrations. The duration of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for treatment or prophylaxis may increase or decrease the course of a particular treatment or prophylaxis regimen. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.

[0080] The term “prevent” refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur in the absence of treatment. In embodiments, prevent refers to slowing the progression of the disease, disorder, or condition or inhibiting its progression to a harmful or otherwise undesirable state.

[0081] “Patient” or “subject in need thereof” refers to a living organism suffering from or prone to having a disease or condition that can be treated by the administration of a pharmaceutical composition as provided herein. Non-limiting examples include mammals, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.

[0082] An “effective amount” is an amount sufficient for a compound to perform an indicated purpose relative to the absence of the compound (e.g., to achieve the effect for which it is administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signaling pathway, or to reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which may also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of that phrase) means the lessening of the severity or frequency of the symptom (or symptoms) or the elimination of the symptom (or symptoms). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to an individual, will have the intended prophylactic effect of, for example, preventing or delaying the onset (or recurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology or condition or its symptoms. The full prophylactic effect does not necessarily occur by the administration of one dose, and may occur after the administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity-decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function-suppressing amount,” as used herein, refers to the amount of antagonist required to suppress the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment and will be determinable by one of skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be determined by measuring the relevant physiological effects, and can be adjusted in connection with the dosage regimen and diagnostic workup of the individual's condition, and the like. By way of example, measurement of the serum level of a CCR4 inhibitor (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of the possibility that a therapeutically effective amount has been administered.

[0083] For any compound described herein, the therapeutically effective amount may be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0084] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a human dose can be formulated to achieve a concentration that has been found to be effective in animals. The human dosage can be adjusted by monitoring the effectiveness of compounds and adjusting the dosage up and down as described above. Adjusting the dose to achieve maximum efficacy in humans based on the methods described above and other methods is well within the capabilities of the common skill element. Adjusting the dose to achieve maximum therapeutic window toxicity or efficacy in humans based on the methods described above and other methods is well within the capabilities of the common skill element.

[0085] The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 150%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy may also be expressed as a “fold” increase or decrease. For example, a therapeutically effective amount may have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or greater effect over a control.

[0086] Dosages may be varied depending on the requirements of the patient and the compound being employed. The dose administered to a patient in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature and extent of any adverse side effects. Determination of the appropriate dosage for a particular situation is within the scope of the practitioner. In general, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is achieved. Dosage intervals and amounts may be individually adjusted to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0087] As used herein, the term "administer" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is via any route, which includes parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of administration include, but are not limited to, the use of oliposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administration" it is meant that a composition described herein is administered at the same time as, shortly before or shortly after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic agent or treatment for a neurodegenerative disease). The compound of the invention may be administered alone or may be co-administered to the patient. Co-administration is intended to include the simultaneous or sequential administration of the compound individually or in combination with more than one compound or agent. Thus, the preparations may also be combined, where desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention may be applied transdermally, topically, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, sachets, gels, syrups, liquid pastes, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, seals, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, e.g., water or water and propylene glycol solutions. The compositions of the present invention may additionally include components to provide conformal and/or sustained release. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. These components are discussed in greater detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention may also be applied as microspheres for slow release in the body. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J Biomater Sci. Polym. Ed. 7:623-645, 1995; as injectable and biodegradable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eiles, J Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present invention can be delivered using liposomes that fuse with the cell membrane or are endocytosed, i.e., using receptor ligands attached to the liposome, which bind to protein receptors on the cell surface membrane resulting in endocytosis. Using the liposomes, particularly where the liposome surface carries specific receptor ligands for target cells, or is otherwise preferentially targeted to a specific organ, can focus on applying the compositions of the present invention to target cells in vivo. (See, e.g., Al-Muhammed, J Microencapsul 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J Hosp. Pharm. 46:1576-1587, 1989). The compositions of the present invention can also be applied as nanoparticles.

[0088] By “co-administration” it is meant that a composition described herein is administered at the same time as, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention may be administered alone or may be co-administered to the patient. Co-administration is intended to include the simultaneous or sequential administration of the compounds individually or in combination with more than one compound. The compositions of the present invention may be applied transdermally, topically, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0089] For any compound described herein, the therapeutically effective amount may be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0090] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a human dose can be formulated to achieve a concentration that has been found to be effective in animals. The human dosage can be adjusted by monitoring the effectiveness of compounds and adjusting the dosage up and down, as described above. Adjusting the dose to achieve maximum efficacy in humans based on the methods described above and other methods is well within the capabilities of the common skill element.

[0091] Dosages may be varied depending on the requirements of the patient and the compound being employed. The dose administered to a patient in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature and extent of any adverse side effects. Determination of the appropriate dosage for a particular situation is within the scope of the practitioner. In general, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is achieved.

[0092] Dosage intervals and amounts may be individually adjusted to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0093] Using the teachings provided herein, an effective therapeutic or prophylactic treatment regimen can be designed that does not cause substantial toxicity and yet is effective in treating the clinical symptoms demonstrated by the particular patient. Such planning would involve careful selection of the active compound considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.

[0094] The compounds described herein may be used in combination with one another, with other active agents known to be useful in the treatment of cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or disorder.

[0095] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week, or 1 month of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and/or adjuvants can be linked or conjugated together. In some embodiments, the compounds described herein may be combined with treatments for cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, or immune or inflammatory disorder.

[0096] The term “cardiovascular agent” is used in accordance with its simple common meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) used in any manner to treat conditions of the heart or the vascular or circulatory system. In some embodiments, a cardiovascular agent is an agent identified herein that has utility in methods of treating cardiovascular disease or disorder. In some embodiments, a cardiovascular agent is an agent approved by the FDA or similar regulatory agency of a country other than the United States, to treat cardiovascular disease or disorder.

[0097] The term “anti-inflammatory agent” is used in accordance with its simple common meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) used in any manner to reduce inflammation or swelling. In some embodiments, an anti-inflammatory agent is an agent identified herein that has utility in methods of treating an inflammatory disease or disorder. In some embodiments, an anti-inflammatory agent is an agent approved by the FDA or similar regulatory agency of a country other than the United States to reduce swelling and inflammation.

[0098] The compounds described herein can be administered to treat an immune or inflammatory disease or disorder, a cancer or disorder, and/or a cardiovascular or metabolic disease. Accordingly, the compounds disclosed herein can be administered alone to treat such diseases or disorders or can be co-administered with another therapeutic agent to treat such diseases or disorders.

[0099] The compounds disclosed herein may be co-administered with a cytokine or cytokine function agonist or antagonist, (which includes agents that act on cytokine signaling pathways such as modulators of the SOCS system) that includes alpha, beta and gamma interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) that includes IL1 to 17, and interleukin inhibitors or antagonists such as analkinra; tumor necrosis factor alpha (TNF-alpha) inhibitors such as anti-TNF monoclonal antibodies (e.g., infliximab; adalimumab and CDP-870); and TNF receptor antagonists that include immunoglobulin molecules (such as etanercept) and low molecular weight agents such as pentoxifylline.

[0100] The compounds disclosed herein may be co-administered with an anti-inflammatory agent such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol, a non-steroidal anti-inflammatory agent (hereinafter NSAID) that includes non-selective COX-1/COX-2 cyclooxygenase inhibitors whether applied typically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclooxygenase inhibitor nitric oxide donors (CINODs); glucocorticoids (whether administered topically, orally, intramuscularly, intravenously, or intraarticularly); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other oral or parenteral gold preparations; analgesic; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

[0101] The compounds disclosed herein may be co-administered with a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid-lowering agent such as a statin or a fibrate; a blood cell morphology modulator such as pentoxifylline; a thrombolytic or an anticoagulant such as a platelet aggregation inhibitor.

[0102] The term “anticancer agent” is used in accordance with its simple common meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) that has antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, an anticancer agent is a chemotherapeutic. In some embodiments, an anticancer agent is an agent identified herein that has utility in methods of treating cancer. In some embodiments, an anticancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the United States, to treat cancer. Examples of anticancer agents include, but are not limited to, MEK (e.g., MEK 1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meifalan), ethylenimine and methylmelamines (e.g. hexamethylmelamine, thiotepa), alkyl sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomustine, semustine, streptozocin), triazenes (decarbazine)), antimetabolites (e.g. 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, ampicillin acid analogue (e.g. methotrexate) or pyrimidine analogues (e.g. fluorouracil, floxouridine, cytarabine), purine analogues (e.g. mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g. vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), mitogen-activated protein kinase signaling inhibitors (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossypol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; ansaccharin; anagrelide; anastrozole; andrographolide; Angiogenesis inhibitors; D antagonist; G antagonist; antarelix; antidorsalizing morphogenetic protein-I; antiandrogen, prostate carcinoma; antiestrogen; antinaoplaston; antisense oligonucleotides; Aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta-lactamase derivatives; beta-alletin; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropyrimine; budotitan; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canaripox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; chrysnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatin; cypemycin; cytarabine phosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunoruncin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; gallocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfan; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; hydramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladin; isobengazole; isohomohalichondrin B; itasetron; jasplacinolide; cahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lisofylline; lytic peptides; maytansine; manostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; unaligned double-stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor saposin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+myobacterial cell wall sk; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavine; nafterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitruline; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxitriol; panomiphene; parabactin; pazeliptin; pegaspargase; peldesin; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perilyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propylbis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; polyoxyethylene conjugate of pyridoxylated hemoglobin; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated reteliptin; rhenium etidronate Re-186; rhizoxin; ribozymes; RII retinamide; rogletimide; roitucin; romurtide; roquinimex; rubiginone B1; ruboxil; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence-derived inhibitor 1; senso oligonucleotides; signal transduction inhibitors; signal transduction modulators; single-chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin-binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradist; suramin; swainsonine; synthetic glycosaminoglycans; talimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogallan sodium; tegafur; tellurapyrillium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastin; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; timotrinan; thyroid stimulating hormone; stannous ethyl ethiopurpurine; tirapazamine; titanocene bichloride; topsentine; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin estimamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; amethantron acetate; aminoglutethimide; ansaccharin; anastrozole; anthramycin; asparaginase; asperline; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropyrimine; busulfan; cactinomycin; calusterone; characemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomicin; edatrexate; eflomitine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidin; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; ethoprin; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; immofosine; interleukin II (including interleukin II, or recombinant r1L.sub.2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-lb; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexole sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitochromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosphamide; pipobroman; poposulfan; pyroxantrone hydrochloride; plicamycin; plomestane; sodium porfimer; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; rogletimide; safingol; safingol hydrochloride; semustina; simtrazene; sodium sparfosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; Tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesina; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate microtubule formation or stability (e.g., Taxol.TM (i.e., paclitaxel), Taxotere.TM, compounds comprising a taxane skeleton, Erbulozole (i.e., R-55104), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobuline isethionate (i.e., as CI-980), Vincristine, NSC-639829, Discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altoirtins (e.g., Altoirtin A and Altoirtin C), Spongistatins (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), Epothilones (e.g., Epothilone A, Epothilone B, Epothilone C (i.e., deoxyepothilone A or dEpoA), Epothilone D (i.e., KOS-862, dEpoB, and deoxyepothilone B), Epothilone E, Epothilone F, Epothilone N-oxide B, Epothilone oxide A, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., Deoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e., NSC-654663), Soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacy, i.e., LS-4577), LS-4578 (Pharmacy, i.e., LS-477-P), LS-4477 (Pharmacy), LS-4559 (Pharmacy), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-22365I (BASF, i.e. ILX-65I and LU-22365I), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptoficina 52 (i.e. LY-35570 3), AC-7739 (Ajinomoto, i.e. AVE-8063A and CS-39. HC1), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidine (i.e., NSC-I06969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-I (Parker Hughes Institute, i.e., DDE-26I and WHI-26I), HIO (Kansas State University), HI6 (Kansas State University), Oncocidin AI (i.e., BT0-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-I (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Nascapine, D-2485I (Asta Medica), A-I05972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-I9I), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocin (i.e. NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204I97 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR- II578I (Aventis), Eleutherobins (as Desmethyleleutherobin, Desaethyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-6413I (Asta Medica), D-68I44 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Tacalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylhistine (i.e., NSCL-96F037), D-68838 (Asta Medica), D 68836 (Asta Medica), Myoseverin B, D-434II (Zentaris, i.e., D-8I862), A-289099 (Abbott), A-3I83I5 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate salt) (Wyeth), D-823I7 (Zentaris), D-823I8 (Zentaris), SC-I2983 (NCI), Prednisolone sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-2504II (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone (GnRH) agonists such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylestrilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, peseudomonas exotoxin-anti-CD22 monoclonal antibody conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to 1Bln, 90Y, or 131I, etc.), triptolide, homoharingtonin, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutics (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992, Cl-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, W Z3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib or similar.

[0103] “Chemotherapeutic” or “chemotherapeutic agent” is used according to its simple common meaning and refers to a chemical compound or composition that has antineoplastic properties or the ability to inhibit the growth or proliferation of cells.

[0104] Additionally, the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, pseudomonas exotoxin-anti-CD22 monoclonal antibody conjugate, etc.), and radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to 1BIn, 90Y, or 1BI, etc.).

[0105] The compounds disclosed herein may be co-administered with an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, or a nitrosourea); an antimetabolite (e.g., an antifolate, such as a fluoropyrimidine similar to 5-fluorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine, or paclitaxel); an antitumor antibiotic (e.g., an anthracycline, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, or mithramycin); an antimitotic agent (e.g., a vinca alkaloid such as vincristine, vinblastine, vindesine, or vinorelbine or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (e.g., an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan, or camptothecin); (ii) a cytostatic agent such as an antioestrogen (e.g. tamoxifen, toremifene, raloxifene, droloxifene or iodoxifene), an oestrogen receptor downregulator (e.g. fulvestrant), an antiandrogen (e.g. bicalutamide, flutamide, nilutamide or cyproterone acetate), an LHRH antagonist or LHRH agonist (e.g. goserelin, leuprorelin or buserelin), a progestogen (e.g. megestrol acetate), an aromatase inhibitor (e.g. anastrozole, letrozole, vorazole or exemestane) or a 5-alpha-reductase inhibitor such as finasteride; (iii) an agent that inhibits cancer cell invasion (e.g. a metalloproteinase inhibitor similar to marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (e.g. the anti-erbb2 antibody trastuzumab, or the anti-erbb 1 antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (e.g. an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-N-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro-4- (fluorophenyl)-7-(3-morpholinopropoxy)quinazol-n-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family; (v) an antiangiogenic agent, such as one that inhibits the effects of vascular endothelial growth factor (e.g., the antivascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (e.g., linomide, an inhibitor of integrin.alpha.v.beta.3 function or an angiostatin); (vi) a vascular damaging agent, such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) an agent used in a gene therapy approach, for example, approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-targeted enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multidrug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example, ex-vivo and in-vivo approaches to increase the immunogenicity of the patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte macrophage colony-stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

[0106] In embodiments, compounds disclosed herein can be co-administered with an antibody, such as a monoclonal antibody that targets B lymphocytes (such as, CD20 (rituximab), MRA-aiL16R and T lymphocytes, CTLA4-Ig, HuMax 11-15) or antibody that modulates Ig function, such as anti-IgE (e.g., omalizumab).

[0107] In embodiments, treating cancer includes administering an effective amount of at least two of the following: a CCR4 inhibitor, a PD-L1/PD-1 pathway inhibitor, a CTLA-4 inhibitor, a CD137 agonist antibody (4-1BB). In some embodiments, the method may comprise using two or more combinations.

[0108] In embodiments, the cancer treatment includes an effective amount of at least two or more of the following: a CCR4 inhibitor and any combination of agents that may be immune modulators such as, but not limited to, those listed in Table 1. Such immune modulators may be depleting antibodies, neutralizing antibodies, blocking antibodies, agonist antibodies, small molecule modulators (inhibitors or stimulators), or small molecule analogs.

[0109] Table 1.

[0110] In a further embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as 47Sc, 64Cu, 67Cu, 86Y, 87Y, 90Y, losRh, 111Ag, 1B1n, 1171BSn, 149Pm, 153Sm, 166Ho, inLu, 186Re, 188Re, 211At, and 212Bi, optionally conjugated to antibodies directed against tumor antigens.

[0111] In addition, a CCR4 inhibitor may be combined with therapeutic administration of immune cells, sometimes referred to as adoptive cell transfer. These cells may be cells from the patient, an unrelated or genetically related donor, they may be genetically modified (e.g., CAR-T cells, cells, etc.), cell lines, genetically modified cell lines, and living or non-living versions of the above. CCR4 inhibitors may also be combined with vaccines of any type (e.g., protein/peptide, viral, bacterial, cellular) to stimulate immune responses to cancer.

[0112] In embodiments, the treatment is administration of an effective amount of a CCR4 inhibitor in combination with a PD-L1/PD-1 pathway inhibitor, a CTLA-4 inhibitor, a CD137 agonist antibody (4-1BB), or in combination with another immune modulator as listed in Table 1.

[0113] In embodiments, the treatment is therapeutic administration of an effective amount of a CCR4 inhibitor in combination with a PD-L1/PD-1 pathway inhibitor, a CTLA-4 inhibitor, a CD137 agonist antibody (4-1BB), or in combination with another immune modulator as listed in Table 1. Herein, treatment begins when tumors reach a size of 40-70 mm3.

[0114] The CCR4 inhibitors disclosed herein may be administered by any acceptable route, such as oral, intra-adipose, intra-arterial, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravesicular, intravitreal, liposomal, local, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, transbucal, transdermal, vaginal, in creams, in lipid compositions, through a catheter, through a lavage, through continuous infusion, through infusion, through inhalation, through injection, through local application, through localized perfusion, directly from the target cell bath, or any combination thereof.

[0115] The immune modulators disclosed herein may be administered by any acceptable route, such as oral, intra-adipose, intra-arterial, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravesicular, intravitreal, liposomal, local, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, transbucal, transdermal, vaginal, in creams, in lipid compositions, through a catheter, through a lavage, through continuous infusion, through infusion, through inhalation, through injection, through local application, through localized perfusion, directly from the target cell bath, or any combination thereof.

[0116] The CCR4 inhibitors disclosed herein may be administered once daily until the study reaches its trial endpoint. The immune modulator disclosed herein may be administered at least three times, but in some studies, four or more times depending on the length of the study and/or the study design.

[0117] The methods disclosed herein may be used in combination with additional cancer therapy. In some embodiments, the distinct cancer therapy comprises surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy. In some embodiments, the cancer is a radiation therapy-resistant or chemotherapy-resistant cancer.

[0118] A “cell” as used herein refers to a cell that performs metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by methods well known in the art that include, for example, the presence of an intact membrane, staining with a particular dye, the ability to produce progeny or, in the case of a gamete, the ability to combine with a second gamete to produce viable progeny. Cells can include both prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, e.g., mammalian, insect (e.g., spodoptera), and human cells. Cells may be useful when they are naturally nonadherent or have been treated to not adhere to surfaces, e.g., by trypsinization.

[0119] “Control” or “control experiment” is used according to its simple common meaning and refers to an experiment in which the experimental subjects or reagents are treated as in a parallel experiment except for the omission of a procedure, reagent, or variable from the experiment. In some cases, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

[0120] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target molecule. In some embodiments, a CCR4-associated disease modulator is a compound that reduces the severity of one or more symptoms of a CCR4-associated disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease). A CCR4 modulator is a compound that increases or decreases the activity or function or level of activity or level of function of CCR4. A modulator may act alone, or may use a cofactor, e.g., a protein, metal ion, or small molecule. Examples of modulators include small molecule compounds and other bio-organic molecules. Various libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying a modulator. The skilled individual has the ability to develop one or more assays (e.g., cell-based or biochemical assays) in which such compound libraries can be screened in order to identify one or more compounds having desired properties; thereafter, the skilled medicinal chemist has the ability to optimize such one or more compounds, e.g., by sintering and evaluating analogues and derivatives thereof. Molecular modeling and/or synthetic studies may also be used in identifying an activator.

[0121] The term “modulate” is used according to its simple common meaning and refers to the act of altering or varying one or more properties. “Modulation” refers to the process of altering or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to alter by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. In embodiments, the terms “modulate,” “modulation,” and the like refer to the ability of a molecule (e.g., an activator or an inhibitor) to increase or decrease the function or activity of CCR4, directly or indirectly, relative to the absence of the molecule.

[0122] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein-associated disease, a cancer associated with CCR4 activity, CCR4-associated cancer, CCR4-associated disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease)) means that the disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease) is caused (in whole or in part), or a symptom of the disease is caused (in whole or in part), by the substance or substance activity or function. For example, a cancer associated with CCR4 activity or function may be a cancer that results (wholly or in part) from aberrant CCR4 function (e.g., enzyme activity, protein-protein interaction, signaling pathway), or a cancer in which a particular symptom of the disease is caused (wholly or in part) by aberrant CCR4 activity or function. As used herein, that which is described as associated with a disease, if it is a causative agent, could be a target for treatment of the disease. For example, a cancer associated with CCR4 activity or function, or a CCR4-associated disease (e.g., cancer, inflammatory disease, autoimmune disease, infectious disease), can be treated with a compound described herein (e.g., CCR4 modulator or CCR4 inhibitor), in the case where increased CCR4 activity or function (e.g., signaling pathway activity) causes the disease (e.g., cancer, inflammatory disease, autoimmune disease, infectious disease). For example, an inflammatory disease associated with CCR4 activity or function, or an inflammatory disease associated with CCR4, can be treated with a CCR4 modulator or CCR4 inhibitor, in the case where increased CCR4 activity or function (e.g., signaling pathway activity) causes the disease.

[0123] The term “aberrant” as used herein refers to different from normal. When used to describe enzyme activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal, non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein the return of the aberrant activity to an amount associated with non-diseased or normal individuals (e.g., by administration of a compound or by use of a method as described herein), results in the reduction of the disease or one or more symptoms of the disease.

[0124] The term “signaling pathway” as used herein refers to a series of interactions between optionally extracellular and cellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that leads to a change in one component to one or more other components, which in turn may lead to a change to additional components, which is optionally propagated to other signaling pathway components. For example, binding of a CCR4 with a compound as described herein may reduce the level of a CCR4-catalyzed reaction product or the level of a downstream derivative of the product, or the binding may reduce interactions between CCR4 or a reaction product and downstream actuators or signaling pathway components (e.g., MAP kinase pathway), which results in changes in cell growth, proliferation, or survival.

[0125] As used herein, the terms “CCR4 inhibitor,” “CCR4 antagonist,” “C-C chemokine receptor type 4 inhibitor,” “C-C chemokine receptor type 4 antagonist,” and all other related art-accepted terms, many of which are set forth below, refer to a compound capable of modulating, directly or indirectly, the CCR4 receptor in an in vitro assay, an in vivo model, and/or other means indicative of therapeutic efficacy. The terms also refer to a compound that exhibits at least some therapeutic benefit in a human subject.

[0126] The phrase “in an amount sufficient to effect a change” means that there is a detectable difference between a level of an indicator measured before (e.g., a baseline level) and after the administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., an individual’s well-being).

[0127] The “activity” of a molecule may describe or refer to the molecule’s binding to a ligand or receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation, or maturation; antigenic activity; modulation of activities of other molecules; and the like. The term “proliferative activity” encompasses an activity that promotes, is necessary for, or is specifically associated with, for example, normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.

[0128] “Substantially pure” indicates that a component constitutes greater than about 50% of the total content of the composition, and typically greater than about 60% of the total polypeptide content. More typically, “substantially pure” refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide will constitute greater than about 90%, or greater than about 95% of the total content of the composition (percentage on a weight by weight basis).

[0129] The terms “specifically binds” and “selectively binds,” when referring to a ligand/receptor, antibody/antigen, or other binding pair, indicate a binding reaction that is determinative of the presence of the protein in a heterogeneous population of proteins and other biological elements. Thus, under designated conditions, a specific ligand binds to a particular receptor and does not bind in a significant amount to other proteins present in the sample. The antibody, or binding composition derived from the antigen binding site of an antibody, of the contemplated method binds to its antigen, or a variant or mutein thereof, with an affinity that is at least twofold greater, at least 10fold greater, at least 20fold greater, or at least 100fold greater than the affinity for any other antibody, or binding composition derived therefrom. In embodiments, the antibody will have an affinity that is greater than about 109 liters/mole, as determined by, for example, Scatchard analysis (Munsen, et al. (1980) Analyt. Biochem. 107:220-239).

[0130] The terms “DNA”, “nucleic acid”, “nucleic acid molecule”, “polynucleotide” and the like are used interchangeably herein to refer to a polymeric form of nucleotides of any length, deoxyribonucleotides or ribonucleotides, or analogs thereof. Non-limiting examples of polynucleotides include linear and circular nucleic acids, messenger RNA (mRNA), complementary DNA (cDNA), recombinant polynucleotides, vectors, probes, primers and the like.

[0131] As used herein, the terms “variants” and “homologs” are used interchangeably to refer to amino acid or nucleic acid sequences that are similar to reference amino acid or nucleic acid sequences, respectively. The term encompasses both naturally occurring variants and non-naturally occurring variants. Naturally occurring variants include homologs (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence, respectively, from one species to another), and allelic variants (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence, respectively, from one individual to another within a species). Thus, variants and homologs encompass naturally occurring amino acid and nucleic acid sequences encoded thereby and their isoforms, as well as splice variants of a protein or gene. The terms also encompass nucleic acid sequences that vary by one or more bases from a naturally occurring nucleic acid sequence, but still translate into an amino acid sequence that corresponds to the naturally occurring protein due to degeneracy of the genetic code. Non-naturally occurring homologues and variants include polypeptides and nucleic acids that comprise a change in the amino acid or nucleotide sequence, respectively, where the change in sequence is artificially introduced (e.g., muteins); for example, the change is generated in the laboratory by human intervention (“hand of man”). Therefore, naturally occurring homologues and variants may also refer to those that differ from naturally occurring sequences by one or more conservative substitutions and/or tags and/or conjugates.

[0132] The term “muteins” as used herein refers broadly to mutated recombinant proteins. These proteins generally carry single or multiple amino acid substitutions and are often derived from cloned genes that have undergone site-directed or random mutagenesis or from completely synthetic genes.

II. Compounds

[0133] In one aspect provided herein is a compound having the structural formula (I): or a pharmaceutically acceptable salt thereof. X1 is CR8 or N. X2 is CR9 or N. X3 is CR10 or N. The symbols n1, n2, n3, n4, n5, n6, n7, n8, n9, and n10 are independently an integer from 0 to 4. The symbols m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9, and v10 are independently 1 or 2. The symbol z1 is an integer from 0 to 5. The symbol z2 is an integer from 0 to 5. In embodiments, z2 is an integer from 0 to 2. The symbol z3 is an integer from 0 to 11. In embodiments, the symbol z3 is an integer from 0 to 4. The symbol z4 is an integer from 0 to 2. L7 is a bond, -O-, -S-, -NR7.2B-, - C(O)-, -C(O)O-, -S(O)-, -S(O)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R1 is hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -N3, -SOn1R1A, -SOv1NR1BR1C, - NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl. R2 is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -N3, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, - NHC(O)NR2BR2C, -N(O)m2, -nr2Br2C, -C(O)R2D, -C(O)OR2D, - C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, - NR2BOR2D, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl or unsubstituted, or substituted or unsubstituted heteroaryl. R3 is independently hydrogen, halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -N3, -SOn3R3A, - SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, - NHC(O)NR3BR3C, -N(O)m3, -nr3Br3C, -C(O)R3D, -C(O)OR3D, - C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, - NR3BOR3D, -OCX3.13, -OCHX3.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R4 is hydrogen, halogen, -CX4 S, - CHX4.12, -CH2X4.1, -CN, -N3, -SOn4R4A, -SOv4NR4BR4C, -nhnr4Br4C, - ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, - C(O)R4D, -C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, - NR4BC(O)R4D, -NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl. R5 is independently hydrogen, halogen, oxo, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, -SOv5NR5BR5C, -NHNR5BR5C, - onr5Br5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, - C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl substituted, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R6 is independently hydrogen, halogen, oxo, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, -NHNR6BR6C, - ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, - C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R7 is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, - NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, -C(O)R7D, -C(O)OR7D, - C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, -NR7BC(O)R7D, -NR7BC(O)OR7D, - NR7BOR7D, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl. R8 is hydrogen, halogen, -CX8.13, -CHX8.12, -CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, - ONR8BR8C, -NHC(O)NHNR8BR8C, -NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, - C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, - NR8BC(O)R8D, -NR8BC(O)OR8D, -NR8BOR8D, -OCX8.13, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl. R9 is hydrogen, halogen, -CX9.1, -CHX9.12, -CH2X9.1, -CN, -N3, -SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, - NHC(O)NR9BR9C, -N(O)m9, -NR9BR9C, -C(O)R9D, -C(O)OR9D, - C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, -NR9BC(O)R9D, -NR9BC(O)OR9D, - NR9BOR9D, -OCX9.13, -OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl. R10 is hydrogen, halogen, -CX10.13, -CHX10.12, -CH2X10.1, -CN, -SOn10R10A, -SOv10NR10BR10C, -NHNR10BR10C, -ONR10BR10C, -NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, -N(O)m10, - NR10BR10C, -C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, - NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, - OCX10.13, -OCHX10.12, substituted alkyl or unsubstituted, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2B, R8A, R8B, R8C, R9A, R9B, R9C, R9D, R10A, R10B, R10C, and R10D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; the substituents R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B, R9C, R10B, and R10C attached to the same nitrogen atom can optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1, and X10.1 are independently -Cl, -Br, -I, or -F, wherein at least one of X1, X2, and X3 is N.

[0134] In embodiments, X1 is CR8. In embodiments, X2 is CR9. In embodiments, X3 is CR10. In embodiments, X1 is N. In embodiments, X2 is N. In embodiments, X3 is N.

[0135] In embodiments, R1 is halogen, -CX1.1, -CHX1.12, - CH2X1.1, -CN, -N3, -SOn1R1A, -SOv1NR1BR1C, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, - C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, - NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl substituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R1 is hydrogen.

[0136] In embodiments, R1 is hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -N3, -SOn1R1A, -SOv1NR1BR1C, - NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, alkyl substituted or unsubstituted for R11 (e.g., C1-C8 alkyl, C1-C6 alkyl or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R11 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R11 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R11 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R11 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R11 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0137] In embodiments, R1 is alkyl substituted or unsubstituted by R11 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R1 is alkyl substituted by R11 (e.g., C1-C8 alkyl, C1-C8 alkyl, or C1-C4 alkyl). In embodiments, R1 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0138] In embodiments, R1 is heteroalkyl substituted or unsubstituted by R11 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R1 is heteroalkyl substituted by R11 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R1 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0139] In embodiments, R1 is cycloalkyl substituted or unsubstituted by R11 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R1 is cycloalkyl substituted by R11 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R1 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0140] In embodiments, R1 is R11-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R1 is R11-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R1 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0141] In embodiments, R1 is aryl substituted or unsubstituted by R11 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R1 is aryl substituted by R11 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R1 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0142] In embodiments, R1 is heteroaryl substituted or unsubstituted by R11 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R1 is heteroaryl substituted by R11 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R1 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0143] In embodiments, R2 is halogen, -CX2.13, -CHX2.12, - CH2X2.1, -CN, -N3, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, - C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, - NR2BC(O)OR2D, -NR2BOR2D, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted heterocycloalkyl, or unsubstituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R2 is hydrogen.

[0144] In embodiments, R2 is halogen, -CX2.13, -CHX2.12, CH2X2.1, -CN, -N3, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, - C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, - NR2BC(O)OR2D, -NR2BOR2D, -OCX2.13, -OCHX2.12, alkyl substituted or unsubstituted by R14 (e.g., C1-C8 alkyl, C1-C6 alkyl alkyl, or C1-C4 alkyl), R14-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R14-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R14-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R14-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R14-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0145] In embodiments, R2 is alkyl substituted or unsubstituted by R14 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R2 is alkyl substituted by R14 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R2 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R2 is an unsubstituted ethyl. In embodiments, R2 is an unsubstituted C3 alkyl. In embodiments, R2 is an unsubstituted C4 alkyl.

[0146] In embodiments, R2 is heteroalkyl substituted or unsubstituted by R14 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R2 is heteroalkyl substituted by R14 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R2 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0147] In embodiments, R2 is cycloalkyl substituted or unsubstituted by R14 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R2 is cycloalkyl substituted by R14 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R2 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0148] In embodiments, R2 is R14-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R2 is R14-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R2 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0149] In embodiments, R2 is aryl substituted or unsubstituted by R14 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R2 is aryl substituted by R14 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R2 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0150] In embodiments, R2 is heteroaryl substituted or unsubstituted by R14 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R2 is heteroaryl substituted by R14 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R2 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0151] In embodiments, R3 is independently halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -N3, -SOn3R3A, -SOv3NR3BR3C, - NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, -NHC(O)NR3BR3C, -N(O)m3, -NR3BR3C, -C(O)R3D, -C(O)OR3D, -C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, -NR3BOR3D, -OCX3.13, -OCHX3.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, heterocycloalkyl substituted or unsubstituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3 is hydrogen.

[0152] In embodiments, R3 is independently halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -N3, -SOn3R3A, -SOv3NR3BR3C, - NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, -NHC(O)NR3BR3C, -N(O)m3, -NR3BR3C, -C(O)R3D, -C(O)OR3D, -C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, -NR3BOR3D, -OCX3.13, -OCHX3.12, alkyl substituted or unsubstituted by R17 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R17 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R17 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R17 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R17 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R17 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6 members).

[0153] In embodiments, R3 is independently alkyl substituted or unsubstituted by R17 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3 is independently alkyl substituted by R17 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0154] In embodiments, R3 is independently heteroalkyl substituted or unsubstituted by R17 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R3 is independently heteroalkyl substituted by R17 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R3 is independently unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0155] In embodiments, R3 is independently cycloalkyl substituted or unsubstituted by R17 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3 is independently cycloalkyl substituted by R17 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3 is independently an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0156] In embodiments, R3 is independently heterocycloalkyl substituted or unsubstituted by R17 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R3 is independently heterocycloalkyl substituted by R17 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R3 is independently an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0157] In embodiments, R3 is independently aryl substituted or unsubstituted by R17 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is independently aryl substituted by R17 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3 is independently an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0158] In embodiments, R3 is independently heteroaryl substituted or unsubstituted by R17 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R3 is independently heteroaryl substituted by R17 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R3 is independently an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0159] In embodiments, the definition of R3 is assumed by (independently assigned to) R3.1, R3.2, R3.3, R3.4, R3.5.

[0160] In embodiments, R3.2 is halogen, -CX3.23, -CHX3.22, -CH2X3.2, -CN, -N3, -SOn3.2R3.2A, -SOv3.2NR3.2BR3.2C, - NHNR3.2BR3.2C, -ONR3.2BR3.2C, -NHC(O)NHNR3.2BR3.2C, -NHC(O)NR3.2BR3.2C, -N(O)m3.2, -NR3.2BR3.2C , -C(O)R3.2D, -C(O)OR3.2D, -C(O)NR3.2BR3.2C, -OR3.2A, - NR3.2BSO2R3.2A, -NR3.2BC(O)R3 .2D, -NR3.2BC(O)OR3.2D, -NR3.2bOR3.2D, -OCX3.23, -OCHX3.22, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl substituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. X3.2 is halogen. In embodiments, R3.2 is hydrogen. In embodiments, R3.2 is halogen. In embodiments, R3.2 is chlorine.

[0161] In embodiments, R3.2 is hydrogen, halogen, -CX3.23, -CHX3.22, -CH2X3.2, -CN, -N3, -SOn3.2R3.2A, -SOv3.2NR3.2BR3.2C , -NHNR3.2BR3.2C, -ONR3.2BR3.2C, -NHC(O)NHNR3.2BR3.2C, -NHC(O)NR3.2BR3.2C, -N(O)m3.2, -NR3.2BR3 .2C, -C(O)R3.2D, - C(O)OR3.2D, -C(O)NR3.2BR3.2C, -OR3.2A, -NR3.2BSO2R3.2A, - NR3.2BC(O )R3.2D, -NR3.2BC(O)OR3.2D, -NR3.2BOR3.2D, -OCX3.23, -OCHX3.22, alkyl substituted or unsubstituted by R17.2 (e.g., C1-C8 alkyl, C1-C6 alkyl , or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R17.2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R17.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R17.2 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl , or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R17.2 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or heteroaryl 5 to 6 members).

[0162] In embodiments, R3,2 is alkyl substituted or unsubstituted by R17,2 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3.2 is alkyl substituted by R17.2 (e.g., C3-C8 alkyl, C1-6 alkyl, or C1-C4 alkyl). In embodiments, R3,2 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0163] In embodiments, R3,2 is heteroalkyl substituted or unsubstituted by R17,2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R3,2 is heteroalkyl substituted by R17,2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R3,2 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0164] In embodiments, R3.2 is cycloalkyl substituted or unsubstituted by R17.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3.2 is cycloalkyl substituted by R17.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3,2 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0165] In embodiments, R3.2 is R17.2-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R3,2 is R17.2-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R3,2 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0166] In embodiments, R3,2 is aryl substituted or unsubstituted by R17,2 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3,2 is aryl substituted by R17,2 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3,2 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0167] In embodiments, R3,2 is heteroaryl substituted or unsubstituted by R17,2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R3,2 is heteroaryl substituted by R17,2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R3,2 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0168] In embodiments, R3.3 is halogen, -CX3.33, -CHX3.32, -CH2X3.3, -CN, -N3, -SOn3.3R3.3A, -SOv3.3NR3.3BR3.3C, - NHNR3.3BR3.3C, -ONR3.3BR3.3C, -NHC(O)NHNR3.3BR3.3C, -NHC(O)NR3.3BR3.3C, -N(O)m3.3, -NR3.3BR3.3C , -C(O)R3.3D, -C(O)OR3.3D, -C(O)NR3.3BR3.3C, -OR3.3A, - NR3.3BSO2R3.3A, -NR3.3BC(O)R3 .3D, -NR3.3BC(O)OR3.3D, -NR3.3BOR3.3D, -OCX3.33, -OCHX3.32, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl substituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. X3.3 is halogen. In embodiments, R3.3 is hydrogen. In embodiments, R3.3 is halogen. In embodiments, R3.3 is chlorine.

[0169] In embodiments, R3.3 is hydrogen, halogen, -CX3.33, -CHX3.32, -CH2X3.3, -CN, -N3, -SOn3.3R3.3A, -NR3.3BC(O)R3.3D, -NR3.3BC(O)OR3.3D, -NR3.3BOR3.3D, -OCX3.33, -OCHX3.32, alkyl substituted or unsubstituted for R17.3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R17.3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R17.3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R17.3 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R17.3 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0170] In embodiments, R3,3 is alkyl substituted or unsubstituted by R17,3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3,3 is alkyl substituted by R17,3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R3,3 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0171] In embodiments, R3,3 is heteroalkyl substituted or unsubstituted by R17,3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R3,3 is heteroalkyl substituted by R17,3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R3,3 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0172] In embodiments, R3,3 is cycloalkyl substituted or unsubstituted by R17,3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3,3 is cycloalkyl substituted by R17,3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R3,3 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0173] In embodiments, R3.3 is R17.3-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R3,3 is R17.3-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R3,3 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0174] In embodiments, R3,3 is aryl substituted or unsubstituted by R17,3 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3,3 is aryl substituted by R17,3 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R3,3 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0175] In embodiments, R3,3 is heteroaryl substituted or unsubstituted by R17,3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R3,3 is heteroaryl substituted by R17,3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R3,3 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0176] In embodiments, R4 is halogen, -CX4.13, -CHX4.12, - CH2X4.1, -CN, -N3, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, -C(O)R4D, - C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, - NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted heterocycloalkyl, or unsubstituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R4 is hydrogen.

[0177] In embodiments, R4 is halogen, -CX4.13, -CHX4.12, - CH2X4.1, -CN, -N3, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, -C(O)R4D, - C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, - NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, alkyl substituted or unsubstituted for R20 (e.g., C4-C8 alkyl, C1-C6 alkyl alkyl, or C4-C4 alkyl), R20-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R20-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R20-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R20-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R4 is -CN. In embodiments, R4 is -C(O)NH2. In embodiments, R4 is -CF3. In embodiments, R4 is -CH3.

[0178] In embodiments, R4 is alkyl substituted or unsubstituted by R20 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R4 is alkyl substituted by R20 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C4-C4 alkyl). In embodiments, R4 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C4-C4 alkyl). In embodiments, R4 is an unsubstituted ethyl. In embodiments, R4 is an unsubstituted C3 alkyl. In embodiments, R4 is an unsubstituted C4 alkyl.

[0179] In embodiments, R4 is heteroalkyl substituted or unsubstituted by R20 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R4 is heteroalkyl substituted by R20 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R4 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0180] In embodiments, R4 is cycloalkyl substituted or unsubstituted by R20 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R4 is cycloalkyl substituted by R20 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R4 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0181] In embodiments, R4 is R20-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R4 is R20-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R4 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0182] In embodiments, R4 is aryl substituted or unsubstituted by R20 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R4 is aryl substituted by R20 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R4 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0183] In embodiments, R4 is heteroaryl substituted or unsubstituted by R20 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R4 is heteroaryl substituted by R20 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R4 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0184] In embodiments, R5 is independently halogen, oxo, -CX5.13, -CHX5.12, -CH2X55.1, -CN, -N3, -SOn5R5A, - SOv5NR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, - NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, - C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D, - NR5BOR5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R5 is hydrogen.

[0185] In embodiments, R5 is independently halogen, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, -SOv5NR5BR5C, - NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, alkyl substituted or unsubstituted by R23 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R23 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R23 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R23 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R23 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R23 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6 members).

[0186] In embodiments, R5 is independently alkyl substituted or unsubstituted by R23 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R5 is independently alkyl substituted by R23 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R5 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0187] In embodiments, R5 is independently heteroalkyl substituted or unsubstituted by R23 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R5 is independently heteroalkyl substituted by R23 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R5 is independently unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0188] In embodiments, R5 is independently cycloalkyl substituted or unsubstituted by R23 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R5 is independently cycloalkyl substituted by R23 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R5 is independently an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0189] In embodiments, R5 is independently heterocycloalkyl substituted or unsubstituted by R23 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R5 is independently heterocycloalkyl substituted by R23 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R5 is independently an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0190] In embodiments, R5 is independently aryl substituted or unsubstituted by R23 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R5 is independently aryl substituted by R23 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R5 is independently an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0191] In embodiments, R5 is independently heteroaryl substituted or unsubstituted by R23 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R5 is independently heteroaryl substituted by R23 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R5 is independently an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0192] In embodiments, R6 is independently halogen, oxo, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, - NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, - C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, -NR6BC(O)R6D, -NR6BC(O)OR6D, - NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R6 is hydrogen.

[0193] In embodiments, R6 is independently halogen, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, - NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, -NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, alkyl substituted or unsubstituted by R26 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R26-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R26-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R26-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R26-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R26-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6 members).

[0194] In embodiments, R6 is hydrogen. In embodiments, R6 is alkyl substituted or unsubstituted by R26. In embodiments, R6 is unsubstituted phenyl. In embodiments, R6 is -F. In embodiments, R6 is -OH. In embodiments, R6 is - CH2OH. In embodiments, R6 is -(CH2)2OH. In embodiments, R6 is -(CH2)3OH. In embodiments, R6 is -C(CH3)2OH. In embodiments, R6 is -CH2SO2NH2. In embodiments, R6 is -(CH2)2SO2NH2. In embodiments, R6 is -CH2C(O)NH2. In embodiments, R6 is -(CH2)2C(O)NH2. In embodiments, R6 is -(CH2)3C(O)NH2. In embodiments, R6 is -CH2NHSO2CF3. In embodiments, R6 is -(CH2)2NHSO2CF3. In embodiments, R6 is -(CH2)3NHSO2CF3. In embodiments, R6 is -CH2NHSO2CH3. In embodiments, R6 is -(CH2)2NHSO2CH3. In embodiments, R6 is -(CH2)3NHSO2CH3. In embodiments, R6 is -CH2SO2CH3. In embodiments, R6 is -(CH2)2SO2CH3. In embodiments, R6 is -CH2SO2NH2-. In embodiments, R6 is -(CH2)2SO2NH2.

[0195] In embodiments, R6 is independently alkyl substituted or unsubstituted by R26 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R6 is independently alkyl substituted by R26 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R6 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0196] In embodiments, R6 is independently heteroalkyl substituted or unsubstituted by R26 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R6 is independently heteroalkyl substituted by R26 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R6 is independently unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0197] In embodiments, R6 is independently cycloalkyl substituted or unsubstituted by R26 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R6 is independently cycloalkyl substituted by R26 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R6 is independently an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0198] In embodiments, R6 is independently heterocycloalkyl substituted or unsubstituted by R26 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R6 is independently heterocycloalkyl substituted by R26 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R6 is independently an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0199] In embodiments, R6 is independently aryl substituted or unsubstituted by R26 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R6 is independently aryl substituted by R26 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R6 is independently an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0200] In embodiments, R6 is independently heteroaryl substituted or unsubstituted by R26 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R6 is independently heteroaryl substituted by R26 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R6 is independently an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0201] In embodiments, R7 is halogen, -CX7.13, -CHX7.12, - CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, -NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, -C(O)R7D, - C(O)OR7D, -C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, -NR7BC(O)R7D, - NR7BC(O)OR7D, -NR7BOR7D, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted heterocycloalkyl, or unsubstituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R7 is hydrogen. In embodiments, R7 is -C(O)OH. In embodiments, R7 is -OH. In embodiments, R7 is -NH2. In embodiments, R7 is -C(O)NH2.

[0202] In embodiments, R7 is halogen, -CX7.13, -CHX7.12, - CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, -NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, -C(O)R7D, - C(O)OR7D, -C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, -NR7BC(O)R7D , - NR7BC(O)OR7D, -NR7BOR7D, -OCX7.13, -OCHX7.12, alkyl substituted or unsubstituted by R29 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R29 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R29 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R29 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl aryl substituted or unsubstituted by R29 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R29 (e.g., 5- to 10-membered heteroaryl ... 9-membered, or 5- to 6-membered heteroaryl).

[0203] In embodiments, R7 is -(CH2)3COOH. In embodiments, R7 is -(CH2)2COOH. In embodiments, R7 is -(CH2)1COOH. In embodiments, R7 is -(CH2)2CONH2. In embodiments, R7 is -(CH2)3CONH2. In embodiments, R7 is -(CH2)3OH. In embodiments, R7 is substituted cyclobutyl. In embodiments, R7 is -(CH2)2SO2CH3. In embodiments, R7 is -CH2CH(CH3)OH. In embodiments, R7 is -(CH2)2OH. In embodiments, R7 is -(CH2)4OH. In embodiments, R7 is -(CH2)1OH. In embodiments, R7 is - (CH2)2NHSO2CH3. In embodiments, R7 is -(CH2)2NHSO2CH2CH3. In embodiments, R7 is -(CH2)2NHSO2(CH2)2CH3. In embodiments, R7 is -(CH2)2NHSO2CH(CH3)2. In embodiments, R7 is -(CH2)2NHC(O)OCH3. In embodiments, R7 is -(CH2)3SO2CH3. In embodiments, R7 is - (CH2)2NHC(O)CH3. In embodiments, R7 is -(CH2)2NHC(O)H. In embodiments, R7 is -CH2C(O)OCH3. In embodiments, R7 is - CH2C(O)OCH2CH3. In embodiments, R7 is -(CH2)3SO2NH2. In embodiments, R7 is -(CH2)2SO2NH2. In embodiments, R7 is - (CH2)1SO2NH2. In embodiments, R7 is -(CH2)2NHC(O)CH2CH3. In embodiments, R7 is -(CH2)2NHC(O)CH(CH3)2.

[0204] In embodiments, R7 is hydrogen. In embodiments, R7 is alkyl substituted or unsubstituted by R29. In embodiments, R7 is phenyl. In embodiments, R7 is -(CH2)2OH. In embodiments, R7 is -CH2C(CH3)2OH. In embodiments, R7 is -(CH2)3OH. In embodiments, R7 is -(CH2)2CH(CH3)2OH. In embodiments, R7 is -(CH2)2SO2NH2. In embodiments, R7 is -(CH2)3SO2NH2. In embodiments, R7 is -(CH2)2CONH2. In embodiments, R7 is -(CH2)3CONH2. In embodiments, R7 is -(CH2)3CON(H)Me. In embodiments, R7 is -(CH2)3CON(Me)2. In embodiments, R7 is -(CH2)2SO2Me. In embodiments, R7 is -(CH2)3SO2Me. In embodiments, R7 is -CH2CH(OH)Me. In embodiments, R7 is -CH2CO2H. In embodiments, R7 is -(CH2)2CO2H. In embodiments, R7 is -CH(CH3)CH2CO2H. In embodiments, R7 is -(CH2)3CO2H. In embodiments, R7 is -(CH2)2SO2NHCH3. In embodiments, R7 is -(CH2)2SO2N(CH3)2. In embodiments, R7 is - (CH2)2SO2-(N-morpholinyl). In embodiments, R7 is - (CH2)2NHCOCH3. In embodiments, R7 is -(CH2)2NHC(O)OCH3. In embodiments, R7 is -(CH2)3NHCOCH3. In embodiments, R7 is - (CH2)2NHCOCH(CH3)2. In embodiments, R7 is -(CH2)2NHSO2CH3. In embodiments, R7 is -(CH2)2NHSO2CF3. In embodiments, R7 is - (CH2)2NHSO2NHCH(CH3)2. In embodiments, R7 is -CH2CH(CH3)CH2OH (R and S). In embodiments, R7 is -CH(CH3)(CH2)2OH. In embodiments, R7 is -CH2-(2-imidazoyl). In embodiments, R7 is - CH2-(4-imidazoyl). In embodiments, R7 is -CH2-(3-pyrazolyl). In embodiments, R7 is 4-tetrahydropyranyl. In embodiments, R7 is 3-oxetanyl. In embodiments, R7 is -(CH2)2NHCO2Me. In embodiments, R7 is -(CH2)3NHCO2Me.

[0205] In embodiments, R7 is hydrogen, alkyl substituted or unsubstituted with R29, phenyl, -F, -OH, CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, - (CH2)2SO2NH2. -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, - CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, - (CH2)2NHSO2CH3, -(CH2)3NHSO2CH3, -CH2SO2CH3, -(CH2)2SO2CH3, - CH2SO2NH2, or -(CH2)2SO2NH2.

[0206] In embodiments, R7 is alkyl substituted or unsubstituted by R29 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R7 is alkyl substituted by R29 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R7 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R7 is an unsubstituted C1-C4 alkyl. In embodiments, R7 is an unsubstituted C1-C3 alkyl. In embodiments, R7 is an unsubstituted C3-C2 alkyl. In embodiments, R7 is an unsubstituted C4 alkyl. In embodiments, R7 is an unsubstituted C3 alkyl. In embodiments, R7 is an alkyl substituted with R27 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R7 is a C1-C4 alkyl substituted with R27. In embodiments, R7 is a C1-C3 alkyl substituted with R27. In embodiments, R7 is a C1-C2 alkyl substituted with R27. In embodiments, R7 is a C4 alkyl substituted with R27. In embodiments, R7 is a C3 alkyl substituted with R27.

[0207] In embodiments, R7 is heteroalkyl substituted or unsubstituted by R29 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R7 is heteroalkyl substituted by R29 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R7 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0208] In embodiments, R7 is cycloalkyl substituted or unsubstituted by R29 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R7 is cycloalkyl substituted by R29 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R7 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R7 is an unsubstituted C3-C6 cycloalkyl. In embodiments, R7 is an unsubstituted C3-C8 cycloalkyl. In embodiments, R7 is an unsubstituted C3-C4 cycloalkyl. In embodiments, R7 is an unsubstituted C4 cycloalkyl. In embodiments, R7 is a C3-C6 cycloalkyl substituted by R29. In embodiments, R7 is a C3-C5 cycloalkyl substituted by R29. In embodiments, R7 is a C3-C4 cycloalkyl substituted by R29. In embodiments, R7 is a C4 cycloalkyl substituted by R29.

[0209] In embodiments, R7 is R29-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R7 is R29-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R7 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0210] In embodiments, R7 is aryl substituted or unsubstituted by R29 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R7 is aryl substituted for R29 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R7 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0211] In embodiments, R7 is heteroaryl substituted or unsubstituted by R29 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R7 is heteroaryl substituted by R29 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R7 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0212] In embodiments, R8 is halogen, -CX8.13, -CHX8.12, - CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, -ONR8BR8C, -NHC(O)NHNR8BR8C, -NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, -C(O)R8D, - C(O)OR8D, -C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, -NR8BC(O)R8D, - NR8BC(O)OR8D, -NR8BOR8D, -OCX8.13, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted heterocycloalkyl, or unsubstituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R8 is hydrogen.

[0213] In embodiments, R8 is halogen, -CX8.13, -CHX8.12, - CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, -ONR8BR8C, -NHC(O)NHNR8BR8C, -NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, -C(O)R8D, - C(O)OR8D, -C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, -NR8BC(O)R8D, - NR8BC(O)OR8D, -NR8BOR8D, -OCX8.13, -OCHX8.12, alkyl substituted or unsubstituted for R32 (e.g., C1-C8 alkyl, C1-C6 alkyl alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R32 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R32 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R32 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R32 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R32 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0214] In embodiments, R8 is alkyl substituted or unsubstituted by R32 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R8 is alkyl substituted by R32 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R8 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0215] In embodiments, R8 is heteroalkyl substituted or unsubstituted by R32 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R8 is heteroalkyl substituted by R32 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R8 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0216] In embodiments, R8 is cycloalkyl substituted or unsubstituted by R32 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R8 is cycloalkyl substituted by R32 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R8 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0217] In embodiments, R8 is R32-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R8 is R32-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R8 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0218] In embodiments, R8 is aryl substituted or unsubstituted by R32 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R8 is aryl substituted by R32 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R8 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0219] In embodiments, R8 is heteroaryl substituted or unsubstituted by R32 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R8 is heteroaryl substituted by R32 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R8 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0220] In embodiments, R9 is halogen, -CX9.13, -CHX9.12, - CH2X9.1, -CN, -N3, -SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, -NHC(O)NR9BR9C, -N(O)m9, -NR9BR9C, -C(O)R9D, - C(O)OR9D, -C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, -NR9BC(O)R9D, - NR9BC(O)OR9D, -NR9BOR9D, -OCX9.13, -OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted heterocycloalkyl, or unsubstituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R9 is hydrogen.

[0221] In embodiments, R9 is halogen, -CX9.13, -CHX9.12, - CH2X9.1, -CN, -N3, -SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, -NHC(O)NR9BR9C, -N(O)m9, -NR9BR9C, -C(O)R9D, - C(O)OR9D, -C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, -NR9BC(O)R9D, - NR9BC(O)OR9D, -NR9BOR9D, -OCX9.13, -OCHX9.12, alkyl substituted or unsubstituted by R35 (e.g., C1-C8 alkyl, C1-C6 alkyl alkyl, or C1-C4 alkyl), R35-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R35-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R35-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R35-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R35-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0222] In embodiments, R9 is alkyl substituted or unsubstituted by R35 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R9 is alkyl substituted by R35 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R9 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0223] In embodiments, R9 is heteroalkyl substituted or unsubstituted by R35 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R9 is heteroalkyl substituted by R35 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R9 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0224] In embodiments, R9 is cycloalkyl substituted or unsubstituted by R35 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R9 is cycloalkyl substituted by R35 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R9 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0225] In embodiments, R9 is R35-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R9 is R35-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R9 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0226] In embodiments, R9 is aryl substituted or unsubstituted by R35 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R9 is aryl substituted by R35 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R9 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0227] In embodiments, R9 is heteroaryl substituted or unsubstituted by R35 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R9 is heteroaryl substituted by R35 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R9 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0228] In embodiments, R10 is halogen, -CX10.13, -CHX10.12, -CH2X10.1, -CN, -N3, -SOn10R10A, -SOv10NR10BR10C, -nhnr10Br10C, - ONR10BR10C, -NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, -N(O)m10, - NR10BR10C, -C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -or10A, - nr10Bso2r10A, -NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, - OCX10.13, -OCHX10.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R10 is hydrogen.

[0229] In embodiments, R10 is halogen, -CX10.13, -CHX10.12, -CH2X10.1, -CN, -N3, -SOn10R10A, -SOv10NR10BR10C, -NHNR10BR10C, - ONR10BR10C, -NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, -N(O)m10, - NR10BR10C, -C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, - NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, - OCX10.13, -OCHX10.12, R38-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R38-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R38-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R38-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R38-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R38-substituted or unsubstituted heteroaryl (e.g. example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0230] In embodiments, R10 is alkyl substituted or unsubstituted by R38 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R10 is alkyl substituted by R38 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R10 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0231] In embodiments, R10 is heteroalkyl substituted or unsubstituted by R38 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R10 is heteroalkyl substituted by R38 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R10 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0232] In embodiments, R10 is cycloalkyl substituted or unsubstituted by R38 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R10 is cycloalkyl substituted by R38 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R10 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0233] In embodiments, R10 is R38-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R10 is R38-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R10 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0234] In embodiments, R10 is aryl substituted or unsubstituted by R38 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R10 is aryl substituted by R38 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R10 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0235] In embodiments, R10 is heteroaryl substituted or unsubstituted by R38 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R10 is heteroaryl substituted by R38 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R10 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0236] In embodiments, L7 is a bond, -O-, -S-, -NR7.2B-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene), substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene), substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene).

[0237] In embodiments, L7 is a bond, -O-, -S-, -NR7.2B-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, alkylene substituted or unsubstituted for R41 (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), heteroalkylene substituted or unsubstituted for R41 (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene), cycloalkylene substituted or unsubstituted for R41 (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), heterocycloalkylene substituted or unsubstituted for R41 (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or heterocycloalkylene 5- to 6-membered heteroarylene), R41-substituted or unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene), or R41-substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene). In embodiments, L7 is a bond.

[0238] In embodiments, L7 is alkylene substituted or unsubstituted by R41 (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L7 is alkylene substituted by R41 (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In embodiments, L7 is an unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene).

[0239] In embodiments, L7 is heteroalkylene substituted or unsubstituted by R41 (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene). In embodiments, L7 is heteroalkylene substituted by R41 (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene). In embodiments, L7 is an unsubstituted heteroalkylene (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene).

[0240] In embodiments, L7 is cycloalkylene substituted or unsubstituted by R41 (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L7 is cycloalkylene substituted by R41 (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In embodiments, L7 is an unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).

[0241] In embodiments, L7 is heterocycloalkylene substituted or unsubstituted by R41 (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene). In embodiments, L7 is heterocycloalkylene substituted by R41 (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene). In embodiments, L7 is an unsubstituted heterocycloalkylene (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene).

[0242] In embodiments, L7 is arylene substituted or unsubstituted with R41 (e.g., C6-C10 arylene, C10 arylene, or phenylene). In embodiments, L7 is arylene substituted with R41 (e.g., C6-C10 arylene, C10 arylene, or phenylene). In embodiments, L7 is an unsubstituted arylene (e.g., C6-C10 arylene, C10 arylene, or phenylene).

[0243] In embodiments, L7 is R41-substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene). In embodiments, L7 is R41-substituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene). In embodiments, L7 is an unsubstituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene).

[0244] In embodiments, R1A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R11A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R11A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R11A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R11A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R11A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R11A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0245] In embodiments, R2A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R14A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R14A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R14A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R14A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R14A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R14A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0246] In embodiments, R3A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R17A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0247] In embodiments, R3,2A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17,2A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17,2A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17,2A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17,2A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered), R17,2A-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R17,2A-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0248] In embodiments, R3.3A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17.3A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R17.3A (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R17.3A (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R17.3A (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered), aryl substituted or unsubstituted by R17.3A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.3A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0249] In embodiments, R4A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R20A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R20A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R20A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R20A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R20A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0250] In embodiments, R5A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R23A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R23A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R23A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R23A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R23A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0251] In embodiments, R6A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R26A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R26A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R26A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R26A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R26A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R26A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0252] In embodiments, R7A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R29A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R29A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R29A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R29A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R29A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0253] In embodiments, R8A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R32A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R32A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R32A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R32A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R32A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R32A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0254] In embodiments, R9A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R35A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R35A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R35A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R35A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R35A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R35A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0255] In embodiments, R10A is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R38A-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R38A-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R38A-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R38A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R38A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R38A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R38A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl substituted by R38A (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R38A (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0256] In embodiments, R1B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R11B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R11B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R11B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R11B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R11B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R11B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R1B and R1C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R11B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R11B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0257] In embodiments, R2B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R14B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R14B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R14B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R14B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... substituted by R14B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R14B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R2B and R2C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R14B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R14B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0258] In embodiments, R3B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R17B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R3B and R3C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R17B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R17B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0259] In embodiments, R3.2B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17.2B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17.2B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17.2B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17.2B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl), or R17.2B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl). aryl substituted or unsubstituted by R17.2B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.2B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0260] In embodiments, R3.3B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, alkyl substituted or unsubstituted for R17.3B (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R17.3B (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R17.3B (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R17.3B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl), or heterocycloalkyl substituted or unsubstituted for R17.3B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl). aryl substituted or unsubstituted by R17.3B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.3B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0261] In embodiments, R4B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R20B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R20B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R20B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R20B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R20B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R4B and R4C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R20B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R20B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0262] In embodiments, R5B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R23B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R23B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R23B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R23B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R23B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R5B and R5C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R23B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R23B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0263] In embodiments, R6B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R26B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R26B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R26B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R26B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R26B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R26B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R6B and R6C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R26B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R26B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0264] In embodiments, R7B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R29B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R29B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R29B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... substituted by R29B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R29B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R7B and R7C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R29B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R29B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0265] In embodiments, R8B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R32B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R32B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R32B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R32B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... substituted by R32B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R32B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R8B and R8C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R32B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R32B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0266] In embodiments, R9B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R35B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R35B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R35B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R35B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl by R35B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R35B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R9B and R9C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R35B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R35B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0267] In embodiments, R10B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R38B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1C6 alkyl, or C1-C4 alkyl), R38B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R38B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R38B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R38B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R38B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R38B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R38B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R38B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R10B and R10C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R38B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R38B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0268] In embodiments, R1C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R11C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R11C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R11C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R11C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ...), R11C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R11C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl substituted by R11C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R11C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R1B and R1C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R11C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R11C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0269] In embodiments, R2C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R14C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R14C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R14C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R14C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R14C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R14C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R14C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R14C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R14C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R2B and R2C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R14C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R14C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0270] In embodiments, R3C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ...), R17C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R17C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl substituted by R17C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R3B and R3C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R17C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R17C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0271] In embodiments, R3.2C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, alkyl substituted or unsubstituted for R17.2C (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R17.2C (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R17.2C (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R17.2C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl), or heterocycloalkyl substituted or unsubstituted for R17.2C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl). aryl substituted or unsubstituted by R17.2C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.2C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0272] In embodiments, R3.3C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, alkyl substituted or unsubstituted for R17.3C (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R17.3C (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R17.3C (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R17.3C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl), or heterocycloalkyl substituted or unsubstituted for R17.3C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl). aryl substituted or unsubstituted by R17.3C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.3C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0273] In embodiments, R4C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R20C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R20C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R20C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R20C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R20C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R20C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R20C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R20C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R4B and R4C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R20C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R20C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0274] In embodiments, R5C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R23C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R23C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R23C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R23C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R23C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R23C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R23C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R23C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R5B and R5C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R23C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R23C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0275] In embodiments, R6C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R26C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R26C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R26C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R26C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R26C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R26C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R26C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R26C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R26C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R6B and R6C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R26C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R26C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0276] In embodiments, R7C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R29C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R29C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R29C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... substituted by R29C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R29C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R7B and R7C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R29C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R29C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0277] In embodiments, R8C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R32C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R32C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R32C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R32C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R32C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R32C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R32C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R32C (e.g., C3-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R32C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R8B and R8C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R32C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R32C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0278] In embodiments, R9C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R35C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R35C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R35C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R35C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R35C-substituted or unsubstituted aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R35C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3 ... substituted by R35C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R35C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R9B and R9C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R35C (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R35C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0279] In embodiments, R10C is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R38C-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1C6 alkyl, or C1-C4 alkyl), R38C-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R38C-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R38C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R38C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R38C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R38C-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R38C (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R38C (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, the substituents R10B and R10C attached to the same nitrogen atom can optionally be joined to form a heterocycloalkyl substituted or unsubstituted by R38B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or heteroaryl substituted or unsubstituted by R38B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0280] In embodiments, R1D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R11D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R11D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R11D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R11D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R11D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R11D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R11D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R11D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R11D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0281] In embodiments, R2D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R14D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R14D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R14D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R14D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ...), R14D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R14D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl substituted by R14D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R14D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0282] In embodiments, R3D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R17D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R17D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R17D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R17D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0283] In embodiments, R3.2D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17.2D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17.2D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17.2D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17.2D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl), or R17.2D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl). to 6-membered), aryl substituted or unsubstituted by R17.2D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.2D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0284] In embodiments, R3.3D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R17.3D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R17.3D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17.3D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R17.3D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl), or R17.3D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl). to 6-membered), aryl substituted or unsubstituted by R17.3D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R17.3D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0285] In embodiments, R4D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R20D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R20D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R20D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R20D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R20D-substituted or unsubstituted aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R20D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3 ...), substituted by R20D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R20D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0286] In embodiments, R5D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R23D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R23D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R23D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R23D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ...), R23D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R23D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl substituted by R23D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R23D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0287] In embodiments, R6D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R26D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R26D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R26D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R26D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R26D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R26D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R26D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R26D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R26D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0288] In embodiments, R7D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R29D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R29D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R29D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R29D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R29D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R29D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R29D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R29D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R29D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R7D is hydrogen. In embodiments, R7D is -NH2. In embodiments, R7D is -CH3. In embodiments, R7D is unsubstituted C1-C3 alkyl.

[0289] In embodiments, R8d is hydrogen, halogen, -cf3, -ccl3, -cbr3, -cl3, -cooh, -conh2, alkyl substituted or unsubstituted for R32d (e.g., C1-c8 alkyl, C1-c6 alkyl, or C1-c4 alkyl), heteroalkyl substituted or unsubstituted for R32d (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R32d (e.g., C3-c8 cycloalkyl, C3-c6 cycloalkyl, or C5-c6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R32d (e.g., heterocycloalkyl 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R32d-substituted or unsubstituted aryl (for example, C6-c10 aryl, C10 aryl, or phenyl), or R32d-substituted or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0290] In embodiments, R9D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R35D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R35D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R35D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R35D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R35D-substituted or unsubstituted aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R35D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3 ... substituted by R35D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R35D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0291] In embodiments, R10D is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R38D-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1C6 alkyl, or C1-C4 alkyl), R38D-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R38D-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R38D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered hetero ... aryl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R38D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R38D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), R38D-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl), substituted by R38D (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R38D (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0292] In embodiments, R7.2B is hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, R4.12B-substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R4.12B-substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R4.12B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R4.12B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl), or R4.12B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5-membered heterocycloalkyl). aryl substituted or unsubstituted by R4.12B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R4.12B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0293] R11 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H,-NHC(O)OH, -nhoh, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R12 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R12 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R12 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R12 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R12 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R12 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R12 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0294] In embodiments, R11 is alkyl substituted or unsubstituted by R12 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R11 is alkyl substituted by R12 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R11 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0295] In embodiments, R11 is heteroalkyl substituted or unsubstituted by R12 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R11 is heteroalkyl substituted by R12 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R11 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0296] In embodiments, R11 is cycloalkyl substituted or unsubstituted by R12 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R11 is cycloalkyl substituted by R12 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R11 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0297] In embodiments, R11 is R12-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R11 is R12-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R11 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0298] In embodiments, R11 is aryl substituted or unsubstituted by R12 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R11 is aryl substituted by R12 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R11 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0299] In embodiments, R11 is heteroaryl substituted or unsubstituted by R12 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R11 is heteroaryl substituted by R12 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R11 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0300] R12 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R13 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R13 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R13 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R13 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R13 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R13 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R13 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0301] In embodiments, R12 is alkyl substituted or unsubstituted by R13 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R12 is alkyl substituted by R13 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R12 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0302] In embodiments, R12 is heteroalkyl substituted or unsubstituted by R13 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R12 is heteroalkyl substituted by R13 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R12 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0303] In embodiments, R12 is cycloalkyl substituted or unsubstituted by R13 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R12 is cycloalkyl substituted by R13 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R12 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0304] In embodiments, R12 is R13-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R12 is R13-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R12 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0305] In embodiments, R12 is aryl substituted or unsubstituted by R13 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R12 is aryl substituted by R13 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R12 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0306] In embodiments, R12 is heteroaryl substituted or unsubstituted by R13 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R12 is heteroaryl substituted by R13 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R12 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0307] R14 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R15 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R15 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R15 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R15 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R15 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R15 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R15 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0308] In embodiments, R14 is alkyl substituted or unsubstituted by R15 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R14 is alkyl substituted by R15 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R14 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0309] In embodiments, R14 is heteroalkyl substituted or unsubstituted by R15 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R14 is heteroalkyl substituted by R15 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R14 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0310] In embodiments, R14 is cycloalkyl substituted or unsubstituted by R15 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R14 is cycloalkyl substituted by R15 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R14 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0311] In embodiments, R14 is R15-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R14 is R15-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R14 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0312] In embodiments, R14 is aryl substituted or unsubstituted by R15 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R14 is aryl substituted by R15 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R14 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0313] In embodiments, R14 is heteroaryl substituted or unsubstituted by R15 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R14 is heteroaryl substituted by R15 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R14 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0314] R15 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R16 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R16 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R16 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R16 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R16 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R16 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R16 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0315] In embodiments, R15 is alkyl substituted or unsubstituted by R16 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R15 is alkyl substituted by R16 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R15 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0316] In embodiments, R15 is heteroalkyl substituted or unsubstituted by R16 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R15 is heteroalkyl substituted by R16 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R15 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0317] In embodiments, R15 is cycloalkyl substituted or unsubstituted by R16 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R15 is cycloalkyl substituted by R16 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R15 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0318] In embodiments, R15 is R16-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R15 is R16-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R15 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0319] In embodiments, R15 is aryl substituted or unsubstituted by R16 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R15 is aryl substituted by R16 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R15 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0320] In embodiments, R15 is heteroaryl substituted or unsubstituted by R16 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R15 is heteroaryl substituted by R16 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R15 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0321] R17 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -nhoh, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R18 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R18 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R18 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R18 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R18 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R18 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R18 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0322] In embodiments, R17 is alkyl substituted or unsubstituted by R18 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R17 is alkyl substituted by R18 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R17 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0323] In embodiments, R17 is heteroalkyl substituted or unsubstituted by R18 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R17 is heteroalkyl substituted by R18 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R17 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0324] In embodiments, R17 is cycloalkyl substituted or unsubstituted by R18 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R17 is cycloalkyl substituted by R18 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R17 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0325] In embodiments, R17 is R18-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R17 is R18-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R17 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0326] In embodiments, R17 is aryl substituted or unsubstituted by R18 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R17 is aryl substituted by R18 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R17 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0327] In embodiments, R17 is heteroaryl substituted or unsubstituted by R18 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R17 is heteroaryl substituted by R18 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R17 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0328] R18 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -nhoh, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R19 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R19 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R19 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R19 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R19 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R19 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R19 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0329] In embodiments, R18 is alkyl substituted or unsubstituted by R19 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R18 is alkyl substituted by R19 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R18 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0330] In embodiments, R18 is heteroalkyl substituted or unsubstituted by R19 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R18 is heteroalkyl substituted by R19 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R18 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0331] In embodiments, R18 is cycloalkyl substituted or unsubstituted by R19 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R18 is cycloalkyl substituted by R19 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R18 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0332] In embodiments, R18 is R19-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R18 is R19-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R18 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0333] In embodiments, R18 is aryl substituted or unsubstituted by R19 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18 is aryl substituted by R19 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0334] In embodiments, R18 is heteroaryl substituted or unsubstituted by R19 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R18 is heteroaryl substituted by R19 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R18 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0335] R17.2 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R18.2 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R18.2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R18.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R18.2 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R18.2 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R18.2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0336] In embodiments, R17.2 is alkyl substituted or unsubstituted by R18.2 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R17,2 is alkyl substituted by R18,2 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R17,2 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0337] In embodiments, R17,2 is heteroalkyl substituted or unsubstituted by R18,2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R17,2 is heteroalkyl substituted by R18.2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R17,2 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0338] In embodiments, R17.2 is cycloalkyl substituted or unsubstituted by R18.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R17.2 is cycloalkyl substituted by R18.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R17.2 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0339] In embodiments, R17.2 is R18.2-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R17,2 is R18,2-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R17,2 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0340] In embodiments, R17,2 is aryl substituted or unsubstituted by R18,2 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R17,2 is aryl substituted by R18,2 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R17,2 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0341] In embodiments, R17,2 is heteroaryl substituted or unsubstituted by R18,2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R17,2 is heteroaryl substituted by R18,2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R17,2 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0342] R18.2 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R19.2 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R19.2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R19.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R19.2 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R19.2 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R19.2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0343] In embodiments, R18.2 is alkyl substituted or unsubstituted by R19.2 (e.g., C1-C8 alkyl, CpCr, alkyl, or C1-C4 alkyl). In embodiments, R18,2 is alkyl substituted by R19,2 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R18,2 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0344] In embodiments, R18,2 is heteroalkyl substituted or unsubstituted by R19,2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R18,2 is heteroalkyl substituted by R19,2 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R18,2 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0345] In embodiments, R18.2 is cycloalkyl substituted or unsubstituted by R19.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R18.2 is cycloalkyl substituted by R19.2 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R18.2 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0346] In embodiments, R18.2 is R19.2-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R18,2 is R19,2-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R18,2 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0347] In embodiments, R18,2 is aryl substituted or unsubstituted by R19,2 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18,2 is aryl substituted by R19,2 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18,2 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0348] In embodiments, R18,2 is heteroaryl substituted or unsubstituted by R19,2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R18,2 is heteroaryl substituted by R19,2 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R18,2 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0349] R17,3 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted for R18,3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted for R18,3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R18,3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R18,3 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R18,3 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R18,3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0350] In embodiments, R17,3 is alkyl substituted or unsubstituted by R18,3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R17,3 is alkyl substituted by R18,3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R17,3 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0351] In embodiments, R17,3 is heteroalkyl substituted or unsubstituted by R18,3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R17,3 is heteroalkyl substituted by R18,3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R17,3 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0352] In embodiments, R17.3 is cycloalkyl substituted or unsubstituted by R18.3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R17,3 is cycloalkyl substituted by R18,3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R17.3 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0353] In embodiments, R17.3 is R18.3-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R17,3 is R18,3-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R17,3 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0354] In embodiments, R17,3 is aryl substituted or unsubstituted by R18,3 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R17,3 is aryl substituted by R18,3 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R17,3 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0355] In embodiments, R17,3 is heteroaryl substituted or unsubstituted by R18,3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R17,3 is heteroaryl substituted by R18,3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R17,3 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0356] R18.3 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R19.3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R19.3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R19.3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R19.3 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R19.3 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R19.3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0357] In embodiments, R18.3 is alkyl substituted or unsubstituted by R19.3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R18,3 is alkyl substituted by R19,3 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R18,3 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0358] In embodiments, R18,3 is heteroalkyl substituted or unsubstituted by R19,3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R18,3 is heteroalkyl substituted by R19,3 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R18,3 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0359] In embodiments, R18.3 is cycloalkyl substituted or unsubstituted by R19.3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R18.3 is cycloalkyl substituted by R19.3 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R18.3 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0360] In embodiments, R18.3 is R19.3-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R18,3 is R19,3-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R18,3 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0361] In embodiments, R18,3 is aryl substituted or unsubstituted by R19,3 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18,3 is aryl substituted by R19,3 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R18,3 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0362] In embodiments, R18,3 is heteroaryl substituted or unsubstituted by R19,3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R18,3 is heteroaryl substituted by R19,3 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R18,3 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0363] R20 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R21 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R21 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R21 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R21 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R21 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R21 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R21 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0364] In embodiments, R20 is alkyl substituted or unsubstituted by R21 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R20 is alkyl substituted by R21 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R20 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0365] In embodiments, R20 is heteroalkyl substituted or unsubstituted by R21 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R20 is heteroalkyl substituted by R21 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R20 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0366] In embodiments, R20 is cycloalkyl substituted or unsubstituted by R21 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R20 is cycloalkyl substituted by R21 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R20 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0367] In embodiments, R20 is R21-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R20 is R21-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R20 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0368] In embodiments, R20 is aryl substituted or unsubstituted by R21 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R20 is aryl substituted by R21 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R20 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0369] In embodiments, R20 is heteroaryl substituted or unsubstituted by R21 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R20 is heteroaryl substituted by R21 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R20 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0370] R21 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2,-NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R22 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R22 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R22 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R22 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R22 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R22 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R22 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0371] In embodiments, R21 is alkyl substituted or unsubstituted by R22 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R21 is alkyl substituted by R22 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R21 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0372] In embodiments, R21 is heteroalkyl substituted or unsubstituted by R22 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R21 is heteroalkyl substituted by R22 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R21 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0373] In embodiments, R21 is cycloalkyl substituted or unsubstituted by R22 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R21 is cycloalkyl substituted by R22 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R21 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0374] In embodiments, R21 is R22-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R21 is R22-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R21 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0375] In embodiments, R21 is aryl substituted or unsubstituted by R22 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R21 is aryl substituted by R22 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R21 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0376] In embodiments, R21 is heteroaryl substituted or unsubstituted by R22 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R21 is heteroaryl substituted by R22 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R21 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0377] R23 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R24 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R24 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R24 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R24 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R24 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R24 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R24 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0378] In embodiments, R23 is alkyl substituted or unsubstituted by R24 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R23 is alkyl substituted by R24 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R23 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0379] In embodiments, R23 is heteroalkyl substituted or unsubstituted by R24 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R23 is heteroalkyl substituted by R24 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R23 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0380] In embodiments, R23 is cycloalkyl substituted or unsubstituted by R24 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R23 is cycloalkyl substituted by R24 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R23 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0381] In embodiments, R23 is R24-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R23 is R24-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R23 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0382] In embodiments, R23 is aryl substituted or unsubstituted by R24 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R23 is aryl substituted by R24 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R23 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0383] In embodiments, R23 is heteroaryl substituted or unsubstituted by R24 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R23 is heteroaryl substituted by R24 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R23 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0384] R24 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -nhoh, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R25 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R25 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R25 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R25 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R25 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R25 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R25 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0385] In embodiments, R24 is alkyl substituted or unsubstituted by R25 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R24 is alkyl substituted by R25 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R24 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0386] In embodiments, R24 is heteroalkyl substituted or unsubstituted by R25 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R24 is heteroalkyl substituted by R25 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R24 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0387] In embodiments, R24 is cycloalkyl substituted or unsubstituted by R25 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R24 is cycloalkyl substituted by R25 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R24 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0388] In embodiments, R24 is R25-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R24 is R25-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R24 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0389] In embodiments, R24 is aryl substituted or unsubstituted by R25 (e.g., C3-C10 aryl, C10 aryl, or phenyl). In embodiments, R24 is aryl substituted by R25 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R24 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0390] In embodiments, R24 is heteroaryl substituted or unsubstituted by R25 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R24 is heteroaryl substituted by R25 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R24 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0391] R26 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R27 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R27 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R27 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R27 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R27 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R27 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R27 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0392] In embodiments, R26 is alkyl substituted or unsubstituted by R27 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R26 is alkyl substituted by R27 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R26 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0393] In embodiments, R26 is heteroalkyl substituted or unsubstituted by R27 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R26 is heteroalkyl substituted by R27 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R26 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0394] In embodiments, R26 is cycloalkyl substituted or unsubstituted by R27 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R26 is cycloalkyl substituted by R27 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R26 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0395] In embodiments, R26 is R27-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R26 is R27-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R26 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0396] In embodiments, R26 is aryl substituted or unsubstituted by R27 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R26 is aryl substituted by R27 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R26 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0397] In embodiments, R26 is heteroaryl substituted or unsubstituted by R27 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R26 is heteroaryl substituted by R27 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R26 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0398] R27 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R28 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R28 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R28 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R28 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R28 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R28 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R28 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0399] In embodiments, R27 is alkyl substituted or unsubstituted by R28 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R27 is alkyl substituted by R28 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R27 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0400] In embodiments, R27 is heteroalkyl substituted or unsubstituted by R28 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R27 is heteroalkyl substituted by R28 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R27 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0401] In embodiments, R27 is cycloalkyl substituted or unsubstituted by R28 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R27 is cycloalkyl substituted by R28 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R27 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0402] In embodiments, R27 is R28-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R27 is R28-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R27 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0403] In embodiments, R27 is aryl substituted or unsubstituted by R28 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R27 is aryl substituted by R28 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R27 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0404] In embodiments, R27 is heteroaryl substituted or unsubstituted by R28 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R27 is heteroaryl substituted by R28 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R27 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0405] R29 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R30 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R30 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R30 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R30-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R30-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R30-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R30-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R29 is oxo. In embodiments, R29 is -CH3. In embodiments, R29 is -COOH. In embodiments, R29 is -NHC(O)NH2. In embodiments, R29 is -OH. In embodiments, R29 is -NH2. In embodiments, R29 is -CONH2. In embodiments, R29 is -NHC(O)OH. In embodiments, R29 is -SO2CH3. In embodiments, R29 is -NHSO2CH3. In embodiments, R29 is -SO2CH2CH3. In embodiments, R29 is -SO2R30. In embodiments, R29 is -SO2CH(CH3)2.

[0406] In embodiments, R29 is alkyl substituted or unsubstituted by R30 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R29 is alkyl substituted by R30 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R29 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0407] In embodiments, R29 is heteroalkyl substituted or unsubstituted by R30 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R29 is heteroalkyl substituted by R30 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R29 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0408] In embodiments, R29 is cycloalkyl substituted or unsubstituted by R30 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R29 is cycloalkyl substituted by R30 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R29 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0409] In embodiments, R29 is R30-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R29 is R30-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R29 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0410] In embodiments, R29 is aryl substituted or unsubstituted by R30 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R29 is aryl substituted by R30 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R29 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0411] In embodiments, R29 is heteroaryl substituted or unsubstituted by R30 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R29 is heteroaryl substituted by R30 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R29 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0412] R30 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R31 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R31 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R31 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted by R31 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted by R31 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted by R31 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted by R31 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0413] In embodiments, R30 is alkyl substituted or unsubstituted by R31 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R30 is alkyl substituted by R31 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R30 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0414] In embodiments, R30 is heteroalkyl substituted or unsubstituted by R31 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R30 is heteroalkyl substituted by R31 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R30 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0415] In embodiments, R30 is cycloalkyl substituted or unsubstituted by R31 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R30 is cycloalkyl substituted by R31 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R30 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0416] In embodiments, R30 is R31-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R30 is R31-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R30 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0417] In embodiments, R30 is aryl substituted or unsubstituted by R31 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R30 is aryl substituted by R31 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R30 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0418] In embodiments, R30 is heteroaryl substituted or unsubstituted by R31 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R30 is heteroaryl substituted by R31 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R30 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0419] R32 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R33 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R33 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R33 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R33 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R33 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R33 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R33 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0420] In embodiments, R32 is alkyl substituted or unsubstituted by R33 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R32 is alkyl substituted by R33 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R32 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0421] In embodiments, R32 is heteroalkyl substituted or unsubstituted by R33 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R32 is heteroalkyl substituted by R33 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R32 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0422] In embodiments, R32 is cycloalkyl substituted or unsubstituted by R33 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R32 is cycloalkyl substituted by R33 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R32 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0423] In embodiments, R32 is R33-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R32 is R33-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R32 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0424] In embodiments, R32 is aryl substituted or unsubstituted by R33 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R32 is aryl substituted by R33 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R32 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0425] In embodiments, R32 is heteroaryl substituted or unsubstituted by R33 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R32 is heteroaryl substituted by R33 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R32 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0426] R33 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R34 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R34 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R34 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R34 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R34 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R34 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R34 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0427] In embodiments, R33 is alkyl substituted or unsubstituted by R34 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R33 is alkyl substituted by R34 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R33 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0428] In embodiments, R33 is heteroalkyl substituted or unsubstituted by R34 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R33 is heteroalkyl substituted by R34 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R33 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0429] In embodiments, R33 is cycloalkyl substituted or unsubstituted by R34 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R33 is cycloalkyl substituted by R34 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R33 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0430] In embodiments, R33 is R34-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R33 is R34-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R33 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0431] In embodiments, R33 is aryl substituted or unsubstituted by R34 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R33 is aryl substituted by R34 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R33 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0432] In embodiments, R33 is heteroaryl substituted or unsubstituted by R34 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R33 is heteroaryl substituted by R34 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R33 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0433] R35 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -nhoh, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R36 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R36 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R36 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R36 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R36 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R36 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R36 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0434] In embodiments, R35 is alkyl substituted or unsubstituted by R36 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R35 is alkyl substituted by R36 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R35 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0435] In embodiments, R35 is heteroalkyl substituted or unsubstituted by R36 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R35 is heteroalkyl substituted by R36 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R35 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0436] In embodiments, R35 is cycloalkyl substituted or unsubstituted by R36 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R35 is cycloalkyl substituted by R36 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R35 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0437] In embodiments, R35 is R36-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R35 is R36-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R35 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0438] In embodiments, R35 is aryl substituted or unsubstituted by R36 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R35 is aryl substituted by R36 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R35 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0439] In embodiments, R35 is heteroaryl substituted or unsubstituted by R36 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R35 is heteroaryl substituted by R36 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R35 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0440] R36 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R37 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R37 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R37 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R37 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R37 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R37 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R37 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0441] In embodiments, R36 is alkyl substituted or unsubstituted by R37 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R36 is alkyl substituted by R37 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R36 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0442] In embodiments, R36 is heteroalkyl substituted or unsubstituted by R37 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R36 is heteroalkyl substituted by R37 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R36 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0443] In embodiments, R36 is cycloalkyl substituted or unsubstituted by R37 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R36 is cycloalkyl substituted by R37 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R36 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0444] In embodiments, R36 is R37-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R36 is R37-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R36 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0445] In embodiments, R36 is aryl substituted or unsubstituted by R37 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R36 is aryl substituted by R37 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R36 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0446] In embodiments, R36 is heteroaryl substituted or unsubstituted by R37 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R36 is heteroaryl substituted by R37 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R36 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0447] R38 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R39 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R39 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R39 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R39 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R39 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R39 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R39 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0448] In embodiments, R38 is alkyl substituted or unsubstituted by R39 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R38 is alkyl substituted by R39 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R38 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0449] In embodiments, R38 is heteroalkyl substituted or unsubstituted by R39 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R38 is heteroalkyl substituted by R39 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R38 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0450] In embodiments, R38 is cycloalkyl substituted or unsubstituted by R39 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R38 is cycloalkyl substituted by R39 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R38 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0451] In embodiments, R38 is R39-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R38 is R39-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R38 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0452] In embodiments, R38 is aryl substituted or unsubstituted by R39 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R38 is aryl substituted by R39 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R38 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0453] In embodiments, R38 is heteroaryl substituted or unsubstituted by R39 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R38 is heteroaryl substituted by R39 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R38 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0454] R39 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R40 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R40 (e.g., 2- to 3-hydroxyalkyl), or heteroalkyl substituted or unsubstituted by R40 (e.g., 2- to 3-hydroxyalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R40 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R40 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R40 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R40 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0455] In embodiments, R39 is alkyl substituted or unsubstituted by R40 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R39 is alkyl substituted by R40 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R39 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0456] In embodiments, R39 is heteroalkyl substituted or unsubstituted by R40 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R39 is heteroalkyl substituted by R40 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R39 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0457] In embodiments, R39 is cycloalkyl substituted or unsubstituted by R40 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R39 is cycloalkyl substituted by R40 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R39 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0458] In embodiments, R39 is R40-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R39 is R40-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R39 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0459] In embodiments, R39 is aryl substituted or unsubstituted by R40 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R39 is aryl substituted by R40 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R39 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0460] In embodiments, R39 is heteroaryl substituted or unsubstituted by R40 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R39 is heteroaryl substituted by R40 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R39 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0461] R41 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R42 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R42 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R42 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R42 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R42 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R42 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R42 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0462] In embodiments, R41 is alkyl substituted or unsubstituted by R42 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R41 is alkyl substituted by R42 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R41 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0463] In embodiments, R41 is heteroalkyl substituted or unsubstituted by R42 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R41 is heteroalkyl substituted by R42 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R41 is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0464] In embodiments, R41 is cycloalkyl substituted or unsubstituted by R42 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R41 is cycloalkyl substituted by R42 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R41 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0465] In embodiments, R41 is R42-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R41 is R42-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R41 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0466] In embodiments, R41 is aryl substituted or unsubstituted by R42 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R41 is aryl substituted by R42 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R41 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0467] In embodiments, R41 is heteroaryl substituted or unsubstituted by R42 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R41 is heteroaryl substituted by R42 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R41 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0468] R42 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R43 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R43 (e.g., 2- to 3-hydroxyheteroalkyl), or a heteroalkyl substituted or unsubstituted by R43 (e.g., 2- to 3-hydroxyheteroalkyl). 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R43 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R43 (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R43 (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R43 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0469] In embodiments, R42 is alkyl substituted or unsubstituted by R43 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R42 is alkyl substituted by R43 (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R42 is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0470] In embodiments, R42 is heteroalkyl substituted or unsubstituted by R43 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R42 is heteroalkyl substituted by R43 (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R42 is an unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0471] In embodiments, R42 is cycloalkyl substituted or unsubstituted by R43 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R42 is cycloalkyl substituted by R43 (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R42 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0472] In embodiments, R42 is R43-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R42 is R43-substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R42 is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0473] In embodiments, R42 is aryl substituted or unsubstituted by R43 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R42 is aryl substituted by R43 (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R42 is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0474] In embodiments, R42 is heteroaryl substituted or unsubstituted by R43 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R42 is heteroaryl substituted by R43 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R42 is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0475] R41.2B is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl substituted or unsubstituted by R42.2B (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R42.2B (e.g. English: example, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl substituted or unsubstituted for R42.2B (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl substituted or unsubstituted for R42.2B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl substituted or unsubstituted for R42.2B (e.g., C6-C10 aryl, C10 aryl, or phenyl), or heteroaryl substituted or unsubstituted for R42.2B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0476] In embodiments, R41.2B is alkyl substituted or unsubstituted by R42.2B (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R41.2B is alkyl substituted by R42.2B (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R41.2B is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0477] In embodiments, R41.2B is heteroalkyl substituted or unsubstituted with R42.2B (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R41.2B is heteroalkyl substituted with R42.2B (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R41.2B is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0478] In embodiments, R41.2B is cycloalkyl substituted or unsubstituted by R42.2B (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R41.2B is cycloalkyl substituted by R42.2B (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R41.2B is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0479] In embodiments, R41.2B is heterocycloalkyl substituted or unsubstituted by R42.2B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R41.2B is heterocycloalkyl substituted by R42.2B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R41.2B is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0480] In embodiments, R41.2B is aryl substituted or unsubstituted by R42.2B (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R41.2B is aryl substituted by R42.2B (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R41.2B is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0481] In embodiments, R41.2B is heteroaryl substituted or unsubstituted by R42.2B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R41.2B is heteroaryl substituted by R42.2B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R41.2B is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0482] R42.2B is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3, -OCHCl2, -OCHBr2, -OCHB, -OCHF2, alkyl substituted or unsubstituted by R43.2B (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl substituted or unsubstituted by R43.2B (e.g. (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R43.2B-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R43.2B-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R43.2B-substituted or unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or R43.2B-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0483] In embodiments, R42.2B is alkyl substituted or unsubstituted by R43.2B (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R42.2B is alkyl substituted by R43.2B (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R42.2B is an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0484] In embodiments, R42.2B is heteroalkyl substituted or unsubstituted with R43.2B (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R42.2B is heteroalkyl substituted with R43.2B (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R42.2B is unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0485] In embodiments, R42.2B is cycloalkyl substituted or unsubstituted by R43.2B (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R42.2B is cycloalkyl substituted by R43.2B (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R42.2B is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0486] In embodiments, R42.2B is heterocycloalkyl substituted or unsubstituted by R43.2B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R42.2B is heterocycloalkyl substituted by R43.2B (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R42.2B is an unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0487] In embodiments, R42.2B is aryl substituted or unsubstituted by R43.2B (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R42.2B is aryl substituted by R43.2B (e.g., C6-C10 aryl, C10 aryl, or phenyl). In embodiments, R42.2B is an unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl).

[0488] In embodiments, R42.2B is heteroaryl substituted or unsubstituted by R43.2B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R42.2B is heteroaryl substituted by R43.2B (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R42.2B is an unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0489] R13, R16, R19, R19.2, R19.3, R22, R25, R28, R31, R34, R37, R40, R43, and R43.2B are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, - NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, alkyl unsubstituted (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0490] R11A, R11B, R11C, R11D, R14, R14B, R14C, R14d, R17A, R17b, R17C, R17d, R17.2A, R17.2B, R17.2C, R17.2D, R17.3A, R17.3B , R17.3C, R17.3D, R20A, R20B, R20C, R20D, R23A, R23B, R23A, R23B, R23C, R23D, R26A, R26B, R26C, R26D, R29A, R29B, R29C, R29D, R32A, R32B, R32C , R32D, R35A, R35B, R35C, R35D, R38A, R38B, R38C, and R38D are independently hydrogen, oxo, halogen -CF3, -Cl3, -CN, -OH, -nh2, -cooh, -CONH2, -no2 -so4h, -SO2NH2, - NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCl3 , -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl , heteroalkyl from 2 to 6 membered, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, heterocycloalkyl 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, heteroaryl 5- to 9-membered, or 5- to 6-membered heteroaryl).

[0491] In embodiments, X1.1 is -Cl. In embodiments X1.1 is -F. In embodiments, X1.1 is -Br. In embodiments, X1.1 is -I. In embodiments, X2.1 is -Cl. In embodiments, X2.1 is -F. In embodiments, X2.1 is -Br. In embodiments, X2.1 is -I. In embodiments, X3.1 is -Cl. In embodiments, X3.1 is -F. In embodiments, X3.1 is -Br. In embodiments, X3.1 is -I. In embodiments, X3.2 is -Cl. In embodiments, X3.2 is -F. In embodiments, X3.2 is -Br. In embodiments, X3.2 is -I. In embodiments, X3.3 is -Cl. In embodiments, X3.3 is -F. In embodiments, X3.3 is -Br. In modalities, X3.3 is -I. In modalities, X4.1 is -Cl. In modalities, X4.1 is -F. In modalities, X4.1 is -Br. In modalities, X4.1 is -I. In modalities, X5.1 is -Cl. In modalities, X5.1 is -F. In modalities, X5.1 is -Br. In modalities, X5.1 is -I. In modalities, X6.1 is -Cl. In modalities, X6.1 is -F. In modalities, X6.1 is -Br. In modalities, X6.1 is -I. In modalities, X7.1 is -Cl. In modalities, X7.1 is -F. In modalities, X7.1 is -Br. In modalities, X7.1 is -I. In modalities, X8.1 is -Cl. In modalities, X8.1 is -F. In modalities, X8.1 is -Br. In modalities, X8.1 is -I. In modalities, X9.1 is -Cl. In modalities, X9.1 is -F. In modalities, X9.1 is -Br. In modalities, X9.1 is -I. In modalities, X10.1 is -Cl. In modalities, X10.1 is -F. In modalities, X10.1 is -Br. In modalities, X10.1 is -I.

[0492] In embodiments, X1.1 is -Cl, and X1 is N. In embodiments, X1.1 is -F, and X1 is N. In embodiments, X1.1 is -Br, and X1 is N. In embodiments, X1.1 is -I, and X1 is N. In embodiments, X2.1 is -Cl, and X1 is N. In embodiments, X2.1 is -F, and X1 is N. In embodiments, X2.1 is -Br, and X1 is N. In embodiments, X2.1 is -I, and X1 is N. In embodiments, X3.1 is -Cl, and X1 is N. In embodiments, X3.1 is -F, and X1 is N. In embodiments, X3.1 is -Br, and X1 is N. In embodiments, X3.1 is -I, and X1 is N. In embodiments, X4.1 is -Cl, and X1 is N. In embodiments, X4.1 is -F, and X1 is N. In embodiments, X4.1 is -Br, and X1 is N. In embodiments, X4.1 is -I, and X1 is N. In embodiments, X5.1 is -Cl, and X1 is N. In embodiments, X5.1 is -F, and X1 is N. In embodiments, X5.1 is -Br, and X1 is N. In embodiments, X5.1 is -I, and X1 is N. In embodiments, X6.1 is -Cl, and X1 is N. In embodiments, X6.1 is -F, and X1 is N. In embodiments, X6.1 is -Br, and X1 is N. In embodiments, X6.1 is -I, and X1 is N. In embodiments, X7.1 is -Cl, and X1 is N. In embodiments, X7.1 is -F, and X1 is N. In embodiments, X7.1 is -Br, and X1 is N. In embodiments, X7.1 is -I, and X1 is N. In embodiments, X8.1 is -Cl, and X1 is N. In embodiments, X8.1 is -F, and X1 is N. In embodiments, X8.1 is -Br, and X1 is N. In embodiments, X8.1 is -I, and X1 is N. In embodiments, X9.1 is -Cl, and X1 is N. In embodiments, X9.1 is -F, and X1 is N. In embodiments, X9.1 is -Br, and X1 is N. In embodiments, X9.1 is -I, and X1 is N. In embodiments, X10.1 is -Cl, and X1 is N. In embodiments, X10.1 is -F, and X1 is N. In embodiments, X10.1 is -Br, and X1 is N. In embodiments, X10.1 is -I, and X1 is N.

[0493] In embodiments, X1.1 is -Cl, and X2 is N. In embodiments, X1.1 is -F, and X2 is N. In embodiments, X1.1 is -Br, and X2 is N. In embodiments, X1.1 is -I, and X2 is N. In embodiments, X2.1 is -Cl, and X2 is N. In embodiments, X2.1 is -F, and X2 is N. In embodiments, X2.1 is -Br, and X2 is N. In embodiments, X2.1 is -I, and X2 is N. In embodiments, X3.1 is -Cl, and X2 is N. In embodiments, X3.1 is -F, and X2 is N. In embodiments, X3.1 is -Br, and X2 is N. In embodiments, X3.1 is -I, and X2 is N. In embodiments, X4.1 is -Cl, and X2 is N. In embodiments, X4.1 is -F, and X2 is N. In embodiments, X4.1 is -Br, and X2 is N. In embodiments, X4.1 is -I, and X2 is N. In embodiments, X5.1 is -Cl, and X2 is N. In embodiments, X5.1 is -F, and X2 is N. In embodiments, X5.1 is -Br, and X2 is N. In embodiments, X5.1 is -I, and X2 is N. In embodiments, X6.1 is -Cl, and X2 is N. In embodiments, X6.1 is -F, and X2 is N. In embodiments, X6.1 is -Br, and X2 is N. In embodiments, X6.1 is -I, and X2 is N. In embodiments, X7.1 is -Cl, and X2 is N. In embodiments, X7.1 is -F, and X2 is N. In embodiments, X7.1 is -Br, and X2 is N. In embodiments, X7.1 is -I, and X2 is N. In embodiments, X8.1 is -Cl, and X2 is N. In embodiments, X8.1 is -F, and X2 is N. In embodiments, X8.1 is -Br, and X2 is N. In embodiments, X8.1 is -I, and X2 is N. In embodiments, X9.1 is -Cl, and X2 is N. In embodiments, X9.1 is -F, and X2 is N. In embodiments, X9.1 is -Br, and X2 is N. In embodiments, X9.1 is -I, and X2 is N. In embodiments, X10.1 is -Cl, and X2 is N. In embodiments, X10.1 is -F, and X2 is N. In embodiments, X10.1 is -Br, and X2 is N. In embodiments, X10.1 is -I, and X2 is N.

[0494] In embodiments, X1.1 is -Cl, and X3 is N. In embodiments, X1.1 is -F, and X3 is N. In embodiments, X1.1 is -Br, and X3 is N. In embodiments, X1.1 is -I, and X3 is N. In embodiments, X2.1 is -Cl, and X3 is N. In embodiments, X2.1 is -F, and X3 is N. In embodiments, X2.1 is -Br, and X3 is N. In embodiments, X2.1 is -I, and X3 is N. In embodiments, X3.1 is -Cl, and X3 is N. In embodiments, X3.1 is -F, and X3 is N. In embodiments, X3.1 is -Br, and X3 is N. In embodiments, X3.1 is -I, and X3 is N. In embodiments, X4.1 is -Cl, and X3 is N. In embodiments, X4.1 is -F, and X3 is N. In embodiments, X4.1 is -Br, and X3 is N. In embodiments, X4.1 is -I, and X3 is N. In embodiments, X5.1 is -Cl, and X3 is N. In embodiments, X5.1 is -F, and X3 is N. In embodiments, X5.1 is -Br, and X3 is N. In embodiments, X5.1 is -I, and X3 is N. In embodiments, X6.1 is -Cl, and X3 is N. In embodiments, X6.1 is -F, and X3 is N. In embodiments, X6.1 is -Br, and X3 is N. In embodiments, X6.1 is -I, and X3 is N. In embodiments, X7.1 is -Cl, and X3 is N. In embodiments, X7.1 is -F, and X3 is N. In embodiments, X7.1 is -Br, and X3 is N. In embodiments, X7.1 is -I, and X3 is N. In embodiments, X8.1 is -Cl, and X3 is N. In embodiments, X8.1 is -F, and X3 is N. In embodiments, X8.1 is -Br, and X3 is N. In embodiments, X8.1 is -I, and X3 is N. In embodiments, X9.1 is -Cl, and X3 is N. In embodiments, X9.1 is -F, and X3 is N. In embodiments, X9.1 is -Br, and X3 is N. In embodiments, X9.1 is -I, and X3 is N. In embodiments, X10.1 is -Cl, and X3 is N. In embodiments, X10.1 is -F, and X3 is N. In embodiments, X10.1 is -Br, and X3 is N. In embodiments, X10.1 is -I, and X3 is N.

[0495] In embodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is 2. In embodiments, n1 is 3. In embodiments, n1 is 4. In embodiments, n2 is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3. In embodiments, n2 is 4. In embodiments, n3 is 0. In embodiments, n3 is 1. In embodiments, n3 is 2. In embodiments, n3 is 3. In embodiments, n3 is 4. In embodiments, n3.2 is 0. In embodiments, n3.2 is 1. In embodiments, n3.2 is 2. In embodiments, n3.2 is 3. In embodiments, n3.2 is 4. In embodiments, n3.3 is 0. In embodiments, n3.3 is 1. In modalities, n3. 3 is 2. In modalities, n3.3 is 3. In modalities, n3. 3 is 4. In modalities, n4 is 0. In modalities, n4 is 1. In modalities, n4 is 2. In modalities, n4 is 3. In modalities, n4 is 4. In modalities, n5 is 0. In modalities, n5 is 1. In modalities, n5 is 2. In modalities, n5 is 3. In modalities, n5 is 4. In modalities, n6 is 0. In modalities, n6 is 1. In modalities, n6 is 2. In modalities, n6 is 3. In modalities, n6 is 4. In modalities, n7 is 0. In modalities, n7 is 1. In modalities, n7 is 2. In modalities, n7 is 3. In modalities, n7 is 4. In modalities, n8 is 0. In modalities, n8 is 1. In modalities, n8 is 2. In modalities, n8 is 3. In modalities, n8 is 4. In modalities, n8 is 0. In modalities, n8 is 1. In modalities, n8 is 2. In modalities, n8 is 3. In modalities, n8 is 4. In modalities, n9 is 0. In modalities, n9 is 1. In modalities, n9 is 2. In modalities, n9 is 3. In modalities, n9 is 4. In modalities, n10 is 0. In modalities, n10 is 1. In modalities, n10 is 2. In modalities, n10 is 3. In modalities, n10 is 4.

[0496] In embodiments, m1 is 1. In embodiments , m1 is 2. In embodiments, v1 is 1. In embodiments , v1 is 2. In embodiments, m2 is 1. In embodiments, m2 is 2. In embodiments, v2 is 1. In embodiments, v2 is 2. In embodiments, m3 is 1. In embodiments, m3 is 2. In embodiments, v3 is 1. In embodiments, v3 is 2. In embodiments, m3.2 is 1. In embodiments, m3.2 is 2. In embodiments, v3. 2 is 1. In modalities, v3.2 is 2. In modalities, m3.3 is 1. In modalities, m3.3 is 2. In modalities, v3.3 is 1. In modalities, v3.3 is 2. In modalities, m4 is 1. In modalities, m4 is 2. In modalities, v4 is 1. In modalities, v4 is 2. In modalities, m5 is 1. In modalities, m5 is 2. In modalities, v5 is 1. In modalities, v5 is 2. In modalities, m6 is 1. In modalities, m6 is 2. In modalities, v6 is 1. In modalities, v6 is 2. In modalities, m7 is 1. In modalities, m7 is 2. In modalities, v7 is 1. In modalities, v7 is 2. In modalities, m8 is 1. In modalities, m8 is 2. In modalities, v8 is 1. In modalities, v8 is 2. In modalities, m9 is 1. In modalities, m9 is 2. In modalities, v9 is 1. In modalities, v9 is 2. In modalities, m10 is 1. In modalities, m10 is 2. In modalities, v10 is 1. In modalities, v10 is 2.

[0497] In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5.

[0498] In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5.

[0499] In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6. In embodiments, z3 is 7. In embodiments, z3 is 8. In embodiments, z3 is 9. In embodiments, z3 is 10. In embodiments, z3 is 11.

[0500] In modalities, z4 is 0. In modalities, z4 is 1. In modalities, z4 is 2.

[0501] In embodiments, z1 is 2, z2 is 0, z4 is 1, and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -F, -OH, -CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SO2NH2, -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, - ch2nhso2cf3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, - (CH2)2NHSO2CH3, -(CH2)3NHSO2CH3, -CH2SO2CH3, -(CH2)2SO2CH3, - CH2SO2NH2, or -(CH2)2SO2NH2.

[0502] In embodiments, R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R1 and R2 are independently hydrogen, R11-substituted or unsubstituted alkyl, or R11-substituted or unsubstituted heteroalkyl. In embodiments, R1 and R2 are hydrogen.

[0503] In embodiments, the compound has the structural formula (II): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, X2, X3, z4, L7, and R7 are as described herein, including embodiments. R3.2 and R3.3 may be substituents encompassed by the definitions of R3. In embodiments, R3.2 is hydrogen, halogen, -CX3.23, -CHX3.22, -CH2X3.2, -CN, -N3, -SOn32R3.2A, -SOv3.2NR3.2BR3.2C, -NHNR3.2BR3.2C, -ONR3.2BR3.2C, -NHC(O)NHNR3.2BR3.2C, -NHC(O)NR3. 2BR3.2C, -N(O)m3.2, -NR3.2bR3.2C, -C(O)R3.2D, -C(O)OR3.2D, -C(O)NR3.2BR3.2C, -OR3.2A, - NR3.2BSO2R3.2A, -NR3.2BC(O)R3.2D, -NR3.2BC(O)OR3.2D, -NR3.2BOR3.2D, -OCX3.23, -OCHX3.22, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R3.3 is hydrogen, halogen, -CX3.33, -CHX3.32, -CH2X3.3, -CN, -N3, -SOn3.3R3.3A, -SOv3.3NR3.3BR3.3C, -NHNR3.3BR3.3C, -ONR3.3BR3.3C, -NHC(O)NHNR3.3BR3.3C, -NHC(O)NR3.3BR3 .3C, -N(O)m3.3, -NR3.3BR3.3C, - C(O)R3.3D, -C(O)OR3.3D, -C(O)NR3.3BR3.3C, -OR3.3A, -NR3.3BSO2R3.3A, -NR3.3BC(O)R3.3D, -NR3.3BC(O)OR3.3D, -NR3.3BOR3.3D, -OCX3.33, -OCHX3.32, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The symbols n3.2, and n3.3 are independently an integer from 0 to 4. The symbols m3.2, m3.3, v3.2, and v3.3 are independently 1 or 2. In embodiments, R4 is hydrogen, -CX4.13, -CN, -C(O)NR4BR4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0504] R3.2A, R3.2B, R3.2C, R3.2D, R3.3A, R3.3B, R3.3C, and R3.3D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The substituents R3.2B, R3.2C, R3.2B, and R3.2C attached to the same nitrogen atom can optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X3.3 and X3.3 are independently -Cl, -Br, -I, or -F.

[0505] In embodiments, the compound has the structural formula (IIa): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, X3, z4, L7, and R7 are as described herein, including embodiments.

[0506] In embodiments, wherein the compound has structural Formula (IIb): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, X2, z4, L7, and R7 are as described herein, including embodiments.

[0507] In embodiments, the compound has the structural formula (IIc): or a pharmaceutically acceptable salt thereof wherein R1, R2, R4, z4, L7, and R7 are as described herein, including embodiments. In embodiments, z4 is 1. In embodiments, R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R1 is hydrogen. In embodiments, R2 is substituted or unsubstituted alkyl. In embodiments, R4 is hydrogen, -CN, -C(O)NH2, -CX4.13, or substituted or unsubstituted alkyl. In embodiments, R3.2 and R3.3 are independently halogen. In embodiments, R3.2 and R3.3 are independently chlorine. In embodiments, R7 is -OR7A, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -SOn1R7A, -SOv1NR7BR7C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, L7 is a bond or substituted or unsubstituted alkylene. In embodiments, L7 is a bond. In embodiments, L7 is a bond; and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -(CH2)2OH, - CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH, -(CH2)2SO2NH2, - (CH2)3SO2NH2, -(CH2)2CONH2, -(CH2)3CONH2 -(CH2)3CON(H)Me, - (CH2)3CON(Me)2, -(CH2)2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, - CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, (CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, (CH2)2NHCOCH3, -(CH2)3NHCOCH3, (CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, CH2CH(CH3)CH2OH (R and S), imidazoyl), -CH2-(4-imidazoyl), -CH2-(3-pyrazoyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me.

[0508] In embodiments, the compound has the structural formula (IId): or a pharmaceutically acceptable salt thereof, wherein R1, L7, and R7 as described herein, embodiments. In embodiments, z4 is 1. In embodiments, R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R1 is hydrogen. In embodiments, R2 is substituted or unsubstituted alkyl. In embodiments, R4 is hydrogen, -CN, -C(O)NH2, -CX4.13, or substituted or unsubstituted alkyl. In embodiments, R4 is -CN, -C(O)NH2 -CF3, or -CH3. In embodiments, R3.2 and R3.3 are independently halogen. In embodiments, R3.2 and R3.3 are independently chlorine. In embodiments, R7 is -OR7A, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -SOn1R7A, -SOv1NR7BR7C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, L7 is a bond or substituted or unsubstituted alkylene. In embodiments, L7 is a bond. In embodiments, L7 is a bond; and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -(CH2)2OH, - CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH, -(CH2)2SO2NH2, - (CH2)3SO2NH2, -(CH2)2CONH2, -(CH2)3CONH2 -(CH2)3CON(H)Me, - (CH2)3CON(Me)2, -(CH2)2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, - CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, (CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, (CH2)2NHCOCH3, -(CH2)3NHCOCH3, (CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, CH2CH(CH3)CH2OH (R and S), imidazoyl), -CH2-(4-imidazoyl), -CH2-(3-pyrazoyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me.

[0509] In embodiments, the compound has the Formula [0509] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R3, z1, X1, X2, X3, R5, z2, R6, z3, z4, L7, and R7 as described herein, including embodiments. In embodiments, R2 is hydrogen. In embodiments, R1 is hydrogen. In embodiments, R1 is -CH3.

[0510] In embodiments, the compound has the structural formula (IV): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R3.2, R3.3, X2, X3, z4, L7, and R7 are as described herein, including embodiments. In embodiments, R2 is hydrogen. In embodiments, R1 is -CH3.

[0511] In embodiments, the structural compound (V): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R3.2, R3.3, X2, X3, z4, L7, and R7 are as described herein, including embodiments. In embodiments, R2 is hydrogen. In embodiments, R1 is hydrogen. In embodiments, R1 is -CH3.

[0512] In embodiments, the compound has the structural formula (VI): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, X2, X3, L7, and R7 are as described herein, including embodiments.

[0513] In embodiments, the compound has the structural formula (VII): or a pharmaceutically acceptable salt thereof, wherein R4, R3.2, R3.3, X2, X3, L7, and R7 are as described herein, including embodiments.

[0514] In embodiments, the compound has the structure: or a pharmaceutically acceptable salt thereof.

[0515] In embodiments, the compound has the structure: or a pharmaceutically acceptable salt thereof.

[0516] In embodiments, the compound has the structure: or a pharmaceutically acceptable salt thereof.

[0517] In embodiments, the compound has the structure: or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, a compound as described herein may include multiple instances of a substituent (e.g., R3, R5, or R6 and/or other variables). In such embodiments, each variable may optionally be different and be appropriately identified to distinguish each group for clarity. For example, where each R3, R5, R6 is different, they may be referred to, for example, as R3.1, R3.2, R3.3, R3.4, R3.5, R5.1, R5.2, R5.3, R5.4, or R6.1, R6.2, R6.3, R6.4, R6.5, R6.6, R6.7, R6.8, R6.9, or R6.10, respectively, wherein the definition of R3 is assumed by (independently assigned to) R3.1, R3.2, R3.3, R3.4, R3.5; R5 is assumed by (independently assigned to) R5.1, R5.2, R5.3, R5.4; or R6 is assumed by (independently assigned to) R6.1, R6.2, R6.3, R6.4, R6.5, R6.6, R6.7, R6.8, R6.9, or R6.10. Variables used within a definition of R3, R5, or R6, and/or other variables that appear in multiple cases and are different may be similarly identified in an appropriate manner to distinguish each group for clarity.

[0519] In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all stereoisomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of all enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite stereoisomers. In embodiments, unless otherwise indicated, a compound described herein is a racemic mixture of two opposite enantiomers. In embodiments, unless otherwise indicated, a compound described herein is a single stereoisomer. In embodiments, unless otherwise indicated, a compound described herein is a single enantiomer. In embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, figure, table, schematic, or claim).

III. Pharmaceutical compositions

[0520] In one aspect, a pharmaceutical composition is provided, which includes a compound as described herein, including embodiments, or structural Formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII), and a pharmaceutically acceptable excipient.

[0521] The compounds (e.g., CCR4 inhibitors) of the present invention can be in the form of compositions suitable for administration to a subject. In general, such compositions are “pharmaceutical compositions” that comprise a compound (e.g., CCR4 inhibitor(s)) and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers, or excipients. In certain embodiments, the compound (e.g., CCR4 inhibitor) is present in a therapeutically acceptable amount. The pharmaceutical compositions can be used in the methods of the present invention; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.

[0522] The pharmaceutical compositions of the present invention may be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.

[0523] Pharmaceutical compositions containing the active ingredient (e.g., an inhibitor of CCR4 function) may be in a form suitable for oral use, for example, as tablets, capsules, lozenges, dragees, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microspheres or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets, capsules and the like contain the active ingredient in admixture by addition with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture thereof. Such excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; disintegrating and granulating agents, for example cornstarch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[0524] Tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene vinyl acetate, methyl cellulose, carboxymethyl cellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylene vinyl acetate copolymers in order to control the delivery of an administered composition. For example, the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, using hydroxymethyl cellulose or gelatin microcapsules or poly(methyl methacrylate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microspheres, and lipid-based systems, which include oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the aforementioned formulations will be apparent to those skilled in the art.

[0525] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0526] Aqueous suspensions contain the active materials in admixture by addition with excipients suitable for their manufacture. Such excipients may be suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents in some cases are a naturally occurring phosphatide (e.g., lecithin) or condensation products of an alkylene oxide with fatty acids (e.g., polyoxyethylene stearate) or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyl-eneoxycetanol) or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate) or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0527] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, ginger oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set out above, and flavoring agents may be added to provide a palatable oral preparation.

[0528] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture by addition with a dispersing or wetting agent, and optionally one or more suspending agents and/or preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0529] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums, e.g., gum acacia or gum tragacanth; naturally occurring phosphatides, e.g., soybean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, e.g., sorbitan monooleate; and condensation products of partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate.

[0530] Pharmaceutical compositions typically comprise a therapeutically effective amount of a CCR4 inhibitor contemplated by the present invention and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically or physiologically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants. For example, a suitable carrier may be physiological saline or citrate-buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral saline or saline mixed with serum albumin are additional exemplary carriers. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, weak acids, pharmaceutically acceptable weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Suitable buffering agents include, for example, a Tris buffer; N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-morpholino)ethanesulfonic acid (MES); 2-(N-Morpholino)ethanesulfonic acid (MES) sodium salt; 3-(N-morpholino)propanesulfonic acid (MOPS); and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0531] After a pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in a ready-to-use form, a lyophilized form that requires reconstitution prior to use, a liquid form that requires dilution prior to use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, for example, an EpiPen®)), while a multiple-use container (e.g., a multi-use vial) is provided in other embodiments.

[0532] The formulations may also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, which includes liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed. Any drug delivery device may be used to deliver a CCR4 inhibitor, which includes implants (e.g., implantable pumps) and catheter systems, pumps, and slow injection devices, all of which are well known to the skilled artisan.

[0533] Depot injections, which are generally administered subcutaneously or intramuscularly, can also be used to release the compound (e.g., CCR4 inhibitor) disclosed herein over a defined period of time. Depot injections are usually solid or oil based and generally comprise at least one of the formulation components disclosed herein. One of ordinary skill in the art is familiar with possible formulations and uses of depot injections.

[0534] The pharmaceutical compositions may be in the form of a sterile aqueous or oleaginous injectable suspension. Such a suspension may be formulated in accordance with the known art, using those suitable dispersing or wetting agents and suspending agents mentioned herein. The sterile injectable preparation may also be a sterile injectable suspension or solution in a non-toxic parenterally acceptable solvent or diluent, for example, as a solution in 1,3-butane diol. Suitable diluents, solvents and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution, Cremophor® EL (BASF, Parsippany, NJ, USA) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium; for this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid have utility in the preparation of injectable products. Prolonged absorption of particular injectable formulations may be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).

[0535] The present invention contemplates administration of the compound (e.g., CCR4 inhibitor) in the form of suppositories for rectal administration. The suppositories may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycols.

[0536] The compound (e.g., CCR4 inhibitor) contemplated by the present invention may be in the form of any other suitable pharmaceutical composition (e.g., nasal or inhalation sprays) currently known or developed in the future.

IV. Methods of use

[0537] In another aspect, a method of inhibiting C-C chemokine receptor type 4 (CCR4) is provided, wherein the method comprises contacting CCR4 with a compound as described herein, including embodiments, or structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof.

[0538] In one aspect, a method of treating or preventing a CCR4-mediated disease or disorder is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, including embodiments, or structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof.

[0539] In embodiments, the method further includes administering a therapeutically effective amount of a compound as described herein, including embodiments, or structural formulas (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof.

[0540] In embodiments, the method further includes administering a therapeutically effective amount of a compound as described herein, including embodiments, or structural formulas (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof.

[0541] In embodiments, the disease or disorder is an immune or inflammatory disease or disorder. In embodiments, the methods of treating an immune or inflammatory disease or disorder disclosed herein further include co-administering an anti-inflammatory agent in combination with a compound of structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof. In embodiments, the anti-inflammatory is thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol, a nonsteroidal anti-inflammatory agent (NSAID), nitric oxide donor inhibitor of cyclooxygenases (CINODs), glucocorticoids, methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, analgesic; diacerein, hyaluronic acid derivatives, or nutritional supplements.

[0542] In embodiments, the disease or disorder is a cardiovascular or metabolic disease or disorder. In embodiments, the methods of treating a cardiovascular or metabolic disease or disorder disclosed herein further include co-administering a cardiovascular agent or a metabolic disorder agent in combination with a compound of structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof. In embodiments, the cardiovascular agent is a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a lipid-lowering agent, a blood cell morphology modulator, a thrombolytic, or an anticoagulant.

[0543] In embodiments, the disease or disorder is cancer. In embodiments, the methods of treating cancer disclosed herein further include co-administering a chemotherapeutic agent or anti-cancer agent in combination with a compound of structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof. In embodiments, the chemotherapeutic agent or anticancer agent is an antiproliferative/antineoplastic drug, an antimetabolite, an antitumor antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, a 5-alpha-reductase inhibitor, an agent that inhibits cancer cell invasion, a growth factor function inhibitor, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor, an epidermal growth factor family inhibitor, a platelet-derived growth factor family inhibitor, a hepatocyte growth factor family inhibitor; an anti-angiogenic agent, a vascular damaging agent, an agent used in antisense therapy, an anti-ras antisense, an agent used in a gene therapy, an immunotherapeutic agent, or an antibody. In embodiments, the methods of treating cancer disclosed herein further include co-administering a chemotherapeutic agent or anticancer agent in combination with a compound of structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least two of: a CCR4 inhibitor, a PD-L1/PD-1 pathway inhibitor, a CTLA-4 inhibitor, or a CD137 agonist antibody (4-1BB). In embodiments, the methods of treating cancer disclosed herein further include co-administering a chemotherapeutic agent or anti-cancer agent in combination with a compound of structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least two of: a CCR4 inhibitor, an immunomodulatory agent, or a Schedule 1 agent, or any combination thereof.

[0544] In embodiments, the disease or disorder is inflammatory bowel disease. In embodiments, the disease or disorder is rheumatoid arthritis. In embodiments, the disease or disorder is psoriasis. In embodiments, the disease or disorder includes allergy-related disorders (e.g., hypersensitivity and anaphylactic responses); gastrointestinal disorders (e.g., Crohn's disease, ulcerative colitis, ileitis, and enteritis); psoriasis and inflammatory dermatoses (e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, and pruritus); vasculitis; scleroderma; asthma, COPD, and respiratory allergic diseases (e.g., allergic rhinitis and hypersensitivity lung diseases); autoimmune diseases, which include arthritis (e.g., rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, type I diabetes, and glomerulonephritis; graft rejection (e.g., allograft rejection); transplant rejection (e.g., solid organ); cancers, such as leukemias, lymphomas, and metastatic cancers, particularly solid tumors (e.g., gastric cancers); and other diseases in which inhibition of unwanted inflammatory and/or immune responses is desired, such as atherosclerosis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis media, and sinusitis. In particular embodiments, the disease, disorder, or condition mediated by CCR4 is asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis, and contact dermatitis. In embodiments, the disease or disorder includes pulmonary fibrosis, liver inflammation, asthma, atopic dermatitis, cancer (e.g., thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, invasive breast carcinoma, lung adenocarcinoma, lung squamous cell carcinoma), or granuloma development.

[0545] In embodiments, the method further includes administering a therapeutically effective amount of a compound as described herein, including embodiments, or structural formulas (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII) or a pharmaceutically acceptable salt thereof.

[0546] In embodiments, administration of the compounds disclosed herein is for the treatment or prevention of immune, inflammatory, or cancer-related diseases, disorders, and conditions. Such diseases, disorders, and conditions are described in detail elsewhere, as are other conditions that may be treated or prevented with compounds (e.g., CCR4 inhibitor) described herein.

[0547] It is often beneficial to improve one or more of the physical properties of the treatment modalities disclosed herein and/or the manner in which they are administered. Physical property improvements include, for example, methods of increasing water solubility, bioavailability, serum half-life, and/or therapeutic half-life; and/or modulating biological activity. Modifications known in the art include pegylation, Fc fusion, and albumin fusion. While generally associated with large molecule agents (e.g., polypeptides), such modifications have recently been evaluated with particular small molecules. By way of example, Chiang, M. et al. (J. Am. Chern. Soc., 2014, 136(9):3370-73) describe a small molecule adenosine 2a receptor agonist conjugated to the Fc domain of immunoglobulin. The small molecule-Fc conjugate retained potent Fc receptor and adenosine receptor 2a interactions and showed superior properties compared to the unconjugated small molecule. Covalent attachment of PEG molecules to small molecule therapeutics has also been described (Li, W. et al., Progress in Polymer Science, 2013 38:421-44).

[0548] In embodiments, the compounds of the present invention are effective in treating and preventing IBD (e.g., Crohn's disease and ulcerative colitis, both of which are chronic idiopathic diseases that can affect any part of the gastrointestinal tract, and are associated with many untoward effects, and patients with prolonged ulcerative colitis are at an increased risk of developing colon cancer). Current IBD treatments are focused on controlling inflammatory symptoms, and although certain agents (e.g., corticosteroids, aminosalicylates, and standard immunosuppressive agents (e.g., cyclosporine, azathioprine, and methotrexate)) have met with limited success, long-term therapy can lead to liver damage (e.g., fibrosis or cirrhosis) and bone marrow suppression, and patients often become refractory to such treatments.

[0549] The compounds of the present invention can be used to enhance or improve an immune response; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. Immunodeficiencies associated with immunodeficiency diseases, immunosuppressive medical treatment, acute and/or chronic infection, and aging can be treated using the compounds disclosed herein. The compounds described herein can also be used to stimulate the immune system of patients suffering from iatrogenically induced immunosuppression, including those who have undergone bone marrow transplants, chemotherapy, or radiation therapy.

[0550] According to the present invention, a compound or pharmaceutical salt thereof can be used to treat or prevent a proliferative condition or disorder, including a cancer, for example, cancer of the uterus, cervix, breast, prostate, testis, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, large or small intestines, colon or rectum), kidney, renal cell, bladder, bone, bone marrow, skin, head or neck, liver, gallbladder, heart, lungs, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., gliomas), ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic system and the immune system (e.g., spleen or thymus). The present invention also provides methods of treating or preventing other cancer-related diseases, disorders or conditions, including, for example, immunogenic tumors, immunogenic tumors, dormant tumors, virally induced cancers (e.g., epithelial cell cancers, endothelial cell cancers, squamous cell carcinomas and papillomaviruses), adenocarcinomas, lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas, teratocarcinomas, chemically induced cancers, metastasis, and angiogenesis. The invention contemplates reducing tolerance to a tumor cell or cancer cell antigen, for example, by modulating the activity of a regulatory T cell and/or a CD8+ T cell (see, e.g., Ramirez-Montagut, et al. (2003) Oncogene 22:3180-87; and Sawaya, et al. (2003) New Engl. J. Med. 349:1501-09). In some embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. In particular embodiments, the cancer is gastric cancer. The use of the term(s) cancer-related diseases, disorders, and conditions is intended to refer broadly to conditions that are associated, directly or indirectly, with cancer, and includes, for example, angiogenesis and precancerous conditions such as dysplasia. In modalities, the cancer is thyroid carcinoma, cholangiocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, cutaneous melanoma, colon cancer, colon adenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, invasive breast carcinoma, lung adenocarcinoma, lung squamous cell carcinoma.

[0551] In embodiments, a cancer may be metastatic or at risk of becoming metastatic, or may occur in a diffuse tissue, including cancers of the blood or bone marrow (e.g., leukemia). In some additional embodiments, compounds of the invention may be used to achieve T-cell tolerance.

[0552] In some embodiments, the present invention provides methods for treating a proliferative condition, cancer, tumor, or precancerous condition with a compound described herein and at least one additional therapeutic or diagnostic agent, examples of which are provided elsewhere herein.

[0553] The present invention provides methods for treating and/or preventing a proliferative condition, cancer, tumor or precancerous disease, disorder or condition with a compound described herein.

[0554] In embodiments outlined for methods of treating cancer, administration of a therapeutically effective amount of a compound described herein results in a cancer survival rate greater than the cancer survival rate observed by administration of the agent alone. In additional embodiments outlined for methods of treating cancer, administration of a therapeutically effective amount of a compound described herein (e.g., CCR4 inhibitor) results in a reduction in tumor size or a slowing of tumor growth greater than the reduction in tumor size or tumor growth observed following administration of the agent alone. In embodiments, methods of treating cancer disclosed herein further include administering a chemotherapeutic agent or anticancer agent in combination with a compound of structural formula (I), (II), (IIa), (IIb), (IIe), (IId), (III), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof. In embodiments, the chemotherapeutic agent or anticancer agent is an antiproliferative/antineoplastic drug, an antimetabolite, an antitumor antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, a 5-alpha-reductase inhibitor, an agent that inhibits cancer cell invasion, a growth factor function inhibitor, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor, an epidermal growth factor family inhibitor, a platelet-derived growth factor family inhibitor, a hepatocyte growth factor family inhibitor; an anti-angiogenic agent, a vascular damage agent, an agent used in antisense therapy, an anti-ras antisense, an agent used in a gene therapy, an immunotherapeutic agent, or an antibody. In embodiments, the methods of treating cancer disclosed herein further include co-administering a therapeutically effective amount of at least two of: a CCR4 inhibitor, a PD-L1/PD-1 pathway inhibitor, a CTLA-4 inhibitor, or a CD137 agonist antibody (4-1BB). In embodiments, the methods of treating cancer disclosed herein further include co-administering a therapeutically effective amount of at least two of: a CCR4 inhibitor, an agent that may be an immune modulator, or an agent from Table 1.

[0555] Inhibition of CCR4 activity may also represent an important strategy for the treatment or prevention of neurological, neuropsychiatric, neurodegenerative or other diseases, disorders and conditions that have some association with the central nervous system, including disorders associated with impairment of cognitive function and/or motor function. Many of these diseases, disorders and conditions comprise an immune and/or inflammatory component. In embodiments, the disease or disorder is Parkinson's disease, extrapyramidal syndrome (EPS), dystonia, akathisia, tardive dyskinesia, restless legs syndrome, epilepsy, periodic limb movement in sleep, attention deficit disorder, depression, anxiety, dementia, Alzheimer's disease, Huntington's disease, multiple sclerosis, cerebral ischemia, hemorrhagic stroke, subarachnoid hemorrhage or traumatic brain injury.

[0556] Embodiments of the present invention contemplate administration of the compounds described herein to a subject for the treatment or prevention of any other disorder that may benefit from at least some level of CCR4 modulation. Such diseases, disorders, and conditions may include, for example, asthma, chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema, idiopathic pulmonary fibrosis, atopic or contact dermatitis, urticaria, allergic rhinitis, nasal polyps, allergic conjunctivitis, thrombosis, myocardial and brain reperfusion injury, chronic glomerulonephritis, sepsis, adult respiratory distress syndrome, and pain. Additional diseases, disorders, and conditions include allergic bronchopulmonary aspergillosis, allergic fungal sinusitis, severe asthma with fungal sensitization, and diseases involving a pathogenic role for fungi including invasion or colonization (such as invasive aspergillosis, aspergilloma, or candidiasis).

[0557] In embodiments, the disease or disorder includes cardiovascular (e.g., cardiac ischemia), metabolic (e.g., development of diabetes insulitis), hepatic (e.g., liver fibrosis, NASH, and NAFLD), ophthalmologic (e.g., diabetic retinopathy), and renal (e.g., renal failure) disorders.

[0558] The present invention contemplates administration of the compounds described herein, and compositions (e.g., pharmaceutical salts, pharmaceutical composition) thereof, in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal), and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Depot injections, which are generally administered subcutaneously or intramuscularly, can also be used to deliver the compounds disclosed herein over a defined period of time. In embodiments, the administration is oral administration.

[0559] The present invention provides methods for treating and/or preventing certain cardiovascular and/or metabolic diseases, disorders and conditions, as well as disorders associated therewith, with a compound described herein.

[0560] The compounds of the present invention can be administered to a subject in an amount that is dependent on, for example, the purpose of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to whom the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition, or symptom thereof. The dosage regimen can also take into account the existence, nature, and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can be readily determined, for example, from safety and dose escalation trials, in vivo studies (e.g., animal models), and other methods known to one of skill in the art.

[0561] In general, dosage parameters dictate that the dosage amount is less than an amount that could be irreversibly toxic to the individual (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect in the individual. Such amounts are determined, for example, by the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into account the route of administration and other factors.

[0562] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the individuals taking it. The “median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is commonly used as a measure of the reasonable expectation of an agent's effect, it is not necessarily the dose that a physician would consider appropriate taking into account all relevant factors. Thus, in some situations, the effective amount is more than the calculated ED50, in other situations, the effective amount is less than the calculated ED50, and in still other situations, the effective amount is equal to the calculated ED50.

[0563] Furthermore, an effective dose of the compounds of the present invention can be an amount that, when administered in one or more doses to an individual, produces a desired result relative to a healthy individual. For example, for an individual suffering from a particular disorder, an effective dose can be one that enhances a parameter, measure, diagnostic marker, and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the parameter, measure, diagnostic marker, and the like exhibited by a normal individual.

[0564] In embodiments, compounds contemplated by the present invention can be administered (e.g., orally) at dosage levels of about 0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of the subject's body weight per day, one, two, three, four, or more times per day, to achieve the desired therapeutic effect. For administration of an oral agent, the compositions may be provided in the form of tablets, capsules and the like containing from 0.05 to 1000 milligrams of the active ingredient, particularly 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0, 175.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient. A pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s) may be present in an amount of from about 0.1 g to about 2.0 g.

[0565] In embodiments, the dosage of the desired compound is contained in a “unit dosage form.” The phrase “unit dosage form” refers to physically distinct units, wherein each unit includes a predetermined amount of the compound (e.g., CCR4 inhibitor) sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.

V. Kits

[0566] In another aspect, provided herein is a kit that includes a compound described herein (e.g., a CCR4 inhibitor) or pharmaceutical compositions thereof, wherein the kits are generally in the form of a physical structure that houses various components, as described below, and can be used, for example, in practicing the methods described above.

[0567] A kit may include one or more of the compounds disclosed herein (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to an individual. The compounds described herein (e.g., CCR4 inhibitor) may be provided in a form that is ready for use (e.g., a tablet or capsule) or in a form that requires, for example, reconstitution or dilution (e.g., a powder) prior to administration. When the compound (e.g., CCR4 inhibitor) is in a form that needs to be reconstituted or diluted by a user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from the compound. Each component of the kit may be packaged in an individual container, and all of the multiple containers may be contained within a single package. A kit of the present invention can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing).

[0568] A kit may contain a label or package insert that includes identifying information for the components therein and instructions for their use (e.g., dosage parameters, clinical pharmacology of the active ingredient(s) including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The labels or inserts may include manufacturer information such as lot numbers and expiration dates. The label or package insert may be, for example, integrated into the physical structure housing the components, contained separately within the physical structure, or attached to a component of the kit (e.g., an ampoule, tube, or vial).

[0569] The labels or inserts may additionally include, or be incorporated into, a computer-readable medium such as a disk (e.g., hard drive, card, memory stick), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as e-ROM or hybrids thereof such as magnetic/optical storage media, FLASH media, or memory-type cards. In some embodiments, the actual instructions are not present in the kit, but the means for obtaining the instructions from a remote source, e.g., via the internet, are provided.

[0570] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are intended to be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

[0571] Additional Modalities

[0572] Embodiments include the following embodiments P1 through P41.

[0573] Embodiment P1. A compound having the structural formula (I): or a pharmaceutically acceptable salt thereof, wherein: X1 is CR8 or N; X2 is CR9 or N; X3 is CR10 or N; n1 and z3 are independently an integer from 0 to 4; m1 and v1 are independently 1 or 2; z1 is an integer from 0 to 5; z2 is an integer from 0 to 2; z4 is an integer from 0 to 2; L7 is a bond, -O-, -S-, -NR7.2B-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -SOn1R1A, -SOv1NR1BR1C, - NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -SOn1R2A, -SOv1NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, - NHC(O)NR2BR2C, -N(O)m1, -NR2BR2C, -C(O)R2D, -C(O)OR2D, - C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, - NR2BOR2D, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -SOn1R3A, -SOv1NR3BR3C, -NHNR3BR3C, - ONR3BR3C, -NHC(O)NHNR3BR3C, -NHC(O)NR3BR3C, -N(O)m1, -NR3BR3C, - C(O)R3D, -C(O)OR3D, -C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, - NR3BC(O)R3D, -NR3BC(O)OR3D, -NR3BOR3D, -OCX3.13, -OCHX3.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R4 is hydrogen, halogen, -CX4.13, -CHX4.12, -CH2X4.1, -CN, -SOn1R4A, -SOv1NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(O)NHNR4BR4C, - NHC(O)NR4BR4C, -N(O)m1, -NR4BR4C, -C(O)R4D, -C(O)OR4D, - C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, -NR4BC(O)OR4D, - nr4Bor4D, -OCX4.13, -OCHX4.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R5 is hydrogen, halogen, oxo, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -SOn1R5A, -SOv1NR5BR5C, - NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m1, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R6 is hydrogen, halogen, oxo, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -SOn1R6A, -SOv1NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, - NHC(O)NR6BR6C, -N(O)m1, -NR6BR6C, -C(O)R6D, -C(O)OR6D, - C(O)NR6BR6C, -or6A, -NR6BSO2R6A, -NR6BC(O)R6D, -NR6BC(O)OR6D, - NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -SOn1R7A, -SOv1NR7BR7C, -NHNR7BR7C, - ONR7BR7C, -NHC(O)NHNR7BR7C, -NHC(O)NR7BR7C, -N(O)m1, -NR7BR7C, - C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, - NR7BC(O)R7D, -NR7BC(O)OR7D, -NR7BOR7D, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R8 is hydrogen, halogen, -CX8.13, -CHX8.12, -CH2X8.1, -CN, -SOn1R8A, -SOv1NR8BR8C, -NHNR8BR8C, -ONR8BR8C, -NHC(O)NHNR8BR8C, - NHC(O)NR8BR8C, -N(O)m1, -NR8BR8C, -C(O)R8D, -C(O)OR8D, - C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, -NR8BC(O)R8D, -NR8BC(O)OR8D, - NR8BOR8D, -OCX8.13, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -CX9.13, -CHX9.12, -CH2X9.1, -CN, -SOn1R9A, -SOv1NR9BR9C, -NHNR9BR9C, - ONR9BR9C, -NHC(O)NHNR9BR9C, -NHC(O)NR9BR9C, -N(O)m1, -NR9BR9C, - C(O)R9D, -C(O)OR9D, -C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, - NR9BC(O)R9D, -NR9BC(O)OR9D, -NR9BOR9D, -OCX9.13, -OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10 is hydrogen, halogen, -CX10.13, -CHX10.12, -CH2X10.1, -CN, - SOn1R10A, -SOv1NR10BR10C, -NHNR10BR10C, -ONR10BR10C, - NHC(O)NHNR10BR10C, -NHC(O)NR10BR10c, -N(O)m1, -NR10BR10C, - C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, -NR10BSO2R10A, - NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, -OCX10.13, -OCHX10.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2D, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D. R10A, R10B, R10C, and R10D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; the substituents R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B, R9C, R10B, R10C attached to the same nitrogen atom can optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1, and X10.1 are independently -Cl, -Br, -I, or -F, where at least one of X1, X2, and X3 is N.

[0574] Embodiment P2. The compound of embodiment P1, wherein: z1 is 2; z2 is 0; z4 is 1; and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -F, -OH, CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SO2NH2. - CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, - (CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH3 -CH2SO2CH3, -(CH2)2SO2CH3, -CH2SO2NH2 or- (CH2)2SO2NH2.

[0575] Embodiment P3. The compound of embodiment P2, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0576] Embodiment P4. The compound of embodiment P1, wherein the compound has structural formula (II): or a pharmaceutically acceptable salt thereof, wherein: R4 is -CN, -C(O)NR4BR4C, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.2 is hydrogen, halogen, -CX3.23, -CHX3.22, -CH2X3.2, -CN, -SOn1R3.2A, -SOv1NR3.2BR3.2C, -NHNR3.2BR3.2C, -ONR3.2BR3.2C, -NHC(O)NHNR3.2BR3.2C, -NHC(O)NR3.2BR3.2C, -N(O) )m1, - NR3.2BR3.2C, -C(O)R3.2D, -C(O)OR3.2D, -C(O)NR3.2BR3.2C, -OR3.2A, - NR3.2BSO2R3.2A, -NR3.2BC(O)R3.2D, -NR3.2BC(O)OR3.2D, -NR3.2BOR3.2D, - OCX3.23, -OCHX3.22, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.3 is hydrogen, halogen, -CX3.33, -CHX3.32, -CH2X3.3, -CN, -SOn1R3.3A, -SOv1NR3.3BR3.3C, -NHNR3.3BR3.3C, -ONR3.3BR3.3C, -NHC(O)NHNR3.3BR3.3C, -NHC(O)NR3.3BR3.3C, -N(O) )m1, -NR3.3BR3.3C, - C(O)R3.3D, -C(O)OR3.3D, -C(O)NR3.3BR3.3C, -OR3.3A, -NR3.3BSO2R3.3A, -NR3.3BC(O)R3.3D, -NR3.3BC(O)OR3.3D, -NR3.3BOR3.3D, -OCX3.33, -OCHX3.32, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.2A, R3.2B, R3.2C, R3.2D, R3.3A, R3.3B, R3.3C and R3.3D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; The substituents R3.2B, R3.2C, R3.2B, and R3.2C attached to the same nitrogen atom may be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X3.2 and X3.3 are independently -Cl, -Br, -I, or -F.

[0577] Embodiment P5. The compound of embodiment P4, wherein the compound has structural formula (IIa): or a pharmaceutically acceptable salt thereof.

[0578] Embodiment P6. The compound of embodiment P4, wherein the compound has structural formula (IIb): or a pharmaceutically acceptable salt thereof.

[0579] Embodiment P7. The compound of embodiment P5, wherein the compound has structural formula (IIc): or a pharmaceutically acceptable salt thereof.

[0580] Embodiment P8. The compound of embodiment P6, wherein the compound has structural formula (IId): or a pharmaceutically acceptable salt thereof.

[0581] Mode P9. The compound of mode P7 or P8, wherein z4 is 1.

[0582] Embodiment P10. The compound of embodiment P7 or P8, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0583] Embodiment P11. The compound of embodiment P10, wherein R1 is hydrogen.

[0584] Embodiment P12. The compound of embodiment P10, wherein R2 is substituted or unsubstituted alkyl.

[0585] Embodiment P13. The compound of embodiment P7 or P8, wherein R4 is hydrogen, -CN, -C(O)NH2, -CX4.13, or substituted or unsubstituted alkyl.

[0586] Embodiment P14. The compound of embodiment P13, wherein R4 is -CN, -C(O)NH2. -CF3, or -CH3.

[0587] Embodiment P15. The compound of embodiment P7 or P8, wherein R3.2 and R3.3 are independently halogen.

[0588] Embodiment P16. The compound of embodiment P15, wherein R3.2 and R3.3 are independently chlorine.

[0589] Embodiment P17. The compound of embodiment P7 or P8, wherein R7 is -OR7A, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -SOn1R7A, -SOv1NR7BR7C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0590] Embodiment P18. The compound of embodiment P17, wherein L7 is a substituted or unsubstituted alkylene or bond.

[0591] Embodiment P19. The compound of embodiment P7 or P8, wherein: L7 is a bond; and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -(CH2)2OH, - CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH, -(CH2)2SO2NH2, - (CH2)3SO2NH2, -(CH2)2CONH2, -(CH2)3CONH2, -(CH2)3CON(H)Me, - (CH2)3CON(Me)2, -(CH2)2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, - CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, (CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, (CH2)2NHCOCH3, -(CH2)3NHCOCH3, (CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, CH2CH(CH3)CH2OH (R and S), imidazoyl), -CH2-(4-imidazoyl), hydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me.

[0592] Embodiment P20. The compound of embodiment P1, wherein the compound has structural formula (III): or a pharmaceutically acceptable salt thereof.

[0593] Embodiment P21. The compound of embodiment P1, wherein the compound has structural formula (IV): or a pharmaceutically acceptable salt thereof.

[0594] Embodiment P22. The compound of embodiment P1, wherein the compound has structural formula (V): or a pharmaceutically acceptable salt thereof.

[0595] Embodiment P23. The compound of any one of embodiments P20 through P22, wherein R2 is hydrogen.

[0596] Embodiment P24. The compound of any one of embodiments P20 through P22, wherein R1 is hydrogen.

[0597] Embodiment P25. The compound of any one of embodiments P20 through P22, wherein R1 is -CH3.

[0598] Embodiment P26. The compound of embodiment P1, wherein the compound has the structure:

[0599] Embodiment P27. A pharmaceutical composition comprising a compound of structural Formula (I) of embodiment P1 and a pharmaceutically acceptable excipient.

[0600] Embodiment P28. A method of inhibiting C-C chemokine receptor type 4 (CCR4), wherein the method comprises contacting CCR4 with a compound of structural formula (I) of embodiment P1.

[0601] Embodiment P29. A method of treating or preventing a CCR4-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural Formula (I) of embodiment P1 or a pharmaceutically acceptable salt thereof.

[0602] Embodiment P30. The method of embodiment P29, wherein the disease or disorder is an immune or inflammatory disease or disorder.

[0603] Embodiment P31. The method of embodiment P30, further comprising co-administering an anti-inflammatory agent in combination with a compound of structural Formula (I).

[0604] Embodiment P32. The method of embodiment P31, wherein the anti-inflammatory is thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol, a nonsteroidal anti-inflammatory agent (NSAID), cyclooxygenase inhibitor nitric oxide donor (CINODs), glucocorticoids, methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, analgesic; diacerein, hyaluronic acid derivatives or nutritional supplements.

[0605] Embodiment P33. The method of embodiment P29, wherein the disease or disorder is a cardiovascular or metabolic disease or disorder.

[0606] Embodiment P34. The method of embodiment P33, further comprising co-administering a cardiovascular agent or a metabolic disorder agent in combination with a compound of structural Formula (I).

[0607] Embodiment P35. The method of embodiment P31, wherein the cardiovascular agent is a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a lipid-lowering agent, a blood cell morphology modulator, a thrombolytic, or an anticoagulant.

[0608] Mode P36. The method of mode P29, wherein the disease or disorder is cancer.

[0609] Embodiment P37. The method of embodiment P36, further comprising co-administering a chemotherapeutic agent or anticancer agent in combination with a compound of structural Formula (I).

[0610] Embodiment P38. The method of embodiment P37, wherein the chemotherapeutic agent or anticancer agent is an antiproliferative/antineoplastic drug, an antimetabolite, an antitumor antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, a 5.alpha.-reductase inhibitor, an agent that inhibits cancer cell invasion, a growth factor function inhibitor, a famyl transferase inhibitor, a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor, an epidermal growth factor family inhibitor, a platelet-derived growth factor family inhibitor, a hepatocyte growth factor family inhibitor; an antiangiogenic agent, a vascular damaging agent, an agent used in antisense therapy, an anti-ras antisense, an agent used in gene therapy, an immunotherapeutic agent, or an antibody.

[0611] Embodiment P39. The method of embodiment P36, further comprising co-administering a therapeutically effective amount of at least two of: a CCR4 inhibitor, a PD-L1/PD-1 pathway inhibitor, a CTLA-4 inhibitor, or a CD137 agonist antibody (4-1BB).

[0612] Embodiment P40. The method of embodiment P36, further comprising co-administering a therapeutically effective amount of at least two of: a CCR4 inhibitor, an agent that may be an immune modulator, or an agent from Table 1.

[0613] Embodiment P41. The method of any of embodiments P37 through P40, wherein the cancer is colon cancer or pancreatic cancer.

[0614] Additional embodiments include embodiments 1 through 68 below.

[0615] Embodiment 1. A compound having the structural formula (I): or a pharmaceutically acceptable salt thereof, wherein: X1 is CR8 or N; X2 is CR9 or N; X3 is CR10 or N; n1, n2, n3, n4, n5, n6, n7, n8, n9, and n10 are independently an integer from 0 to 4; m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9, and v10 are independently 1 or 2; z1 is an integer from 0 to 5; z2 is an integer from 0 to 2; z3 is an integer from 0 to 11; z4 is an integer from 0 to 2; L7 is a bond, -O-, -S-, -NR7.2B-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -N3, -SOn1R1A, -SOv1NR1BR1C, - NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R2 is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -N3, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, - NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D, - C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, - NR2BOR2D, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -N3, -SOn3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, - NHC(O)NR3BR3C, -N(O)m3, -nr3Br3C, -C(O)R3D, -C(O)OR3D, - C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, - NR3BOR3D, -OCX3.13, -OCHX3.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, aryl substituted or unsubstituted or substituted or unsubstituted heteroaryl; R4 is hydrogen, halogen, -CX4.13, -COX4.12, -CH2X4.1, -CN, -N3, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, - ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, - C(O)R4D, -C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, - NR4BC(O)R4D, -NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl; R5 is independently hydrogen, halogen, oxo, -CX5.13, - CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, -SOv5NR5BR5C, -NHNR5BR5C, - ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, - C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R6 is independently hydrogen, halogen, oxo, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, -NHNR6BR6C, - ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, - C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, - NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, -C(O)R7D, -C(O)OR7D, - C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, -NR7BC(O)R7D, -NR7BC(O)OR7D, - NR7BOR7D, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl; R8 is hydrogen, halogen, -CX8.13, -CHX8.12, -CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, - ONR8BR8C, -NHC(O)NHNR8BR8C, -NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, - C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, - NR8BC(O)R8D, -NR8BC(O)OR8D, -NR8BOR8D, -OCX8.13, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -CX9.13, -CHX9.12, -CH2X9.1, -CN, -N3, -SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, - NHC(O)NR9BR9C, -N(O)m9, -NR9BR9C, -C(O)R9D, -C(O)OR9D, - C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, -NR9BC(O)R9D, -NR9BC(O)OR9D, - NR9BOR9D, -OCX9.13, -OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R10 is hydrogen, halogen, -CX10.13, - CHX10.12, -CH2X10.1, -CN, -N3, -SOn10R10A, -SOv10NR10BR10C, - NHNR10BR10C, -ONR10BR10C, -NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, - N(O)m10, -NR10BR10C, -C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, - OCX10.13, -OCHX10.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2B, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D, R10A, R10B, R10C, and R10D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; the substituents R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B, R9C, R10B, and R10C attached to the same nitrogen atom can optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1, and X10.1 are independently -Cl, -Br, -I, or -F, wherein at least one of X1, X2, and X3 is N.

[0616] Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein: z1 is 2; z2 is 0; z4 is 1; and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -F, -OH, CH2OH, -(CH2)2OH, - (CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SO2NH2, -CH2C(O)NH2, - (CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, - (CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH3, -CH2SO2CH3, -(CH2)2SO2CH3, -CH2SO2NH2 or -(CH2)2SO2NH2.

[0617] Embodiment 3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0618] Embodiment 4. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (II): wherein: n3.2, and n3.3 are independently an integer from 0 to 4; m3.2, m3.3, v3.2, and v3.3 are independently 1 or 2; -CX4.13, -CN, -C(O)NR4BR4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.2 is hydrogen, halogen, -CX3.23, -CHX3.22, -CH2X3.2, -CN, -N3, -SON3.2R3.2A, -sOv3.2NR3.2bR3.2C, -NHNR3.2Br3.2C, -ONR32BR32C, -NHC(O)NHNR3.2BR3.2C, -NHC(O)NR3.2BR3 .2C, -N(O)m3.2, -NR3.2BR3.2C, -C(O)R3.2D, -C(O)OR3.2D, -C(O)NR3.2BR3.2C, -OR3.2A, -NR3.2BSO2R3.2A, -NR3.2BC(O)R3.2D, -NR3.2BC(O)OR3.2D, - NR3.2BOR3.2D, -OCX3.23, -OCHX3.22, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.3 is hydrogen, halogen, -CX3.33, - CHX3.32, -CH2X3.3, -CN, -N3, -SOn3.3R3.3A, -SOv3.3NR3.3BR3.3C, - NHNR3.3BR3.3C, -ONR3.3BR3.3C, -NHC(O)NHNR3.3BR3.3C, - NHC(O)NR3.3BR3 .3C, -N(O)m3.3, -NR3.3BR3.3C, -C(O)R3.3D, -C(O)OR3.3D, -C(O)NR3.3BR3.3C, -OR3.3A, -NR3.3BSO2R3.3A, -NR3.3BC(O)R3.3D, - NR33BC(O)OR33D, -NR33BOR33D, -OCX3.33, -OCHX3.32, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.2A, R3.2B, R3.2C, R3.2D, R3.3A, R3.3B, R3.3C, and R3.3D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; The substituents R3.2B, R3.2C, R3.2B, and R3.2C attached to the same nitrogen atom may be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X3.2 and X3.3 are independently -Cl, -Br, -I, or -F.

[0619] Embodiment 5. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (IIa):

[0620] Embodiment 6. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (IIb):

[0621] Embodiment 7. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (IIc):

[0622] Embodiment 8. The compound of embodiment 6, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (IId):

[0623] Embodiment 9. The compound of embodiment 7 or 8, or a pharmaceutically acceptable salt thereof, wherein z4 is 1.

[0624] Embodiment 10. The compound of embodiment 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0625] Embodiment 11. The compound of embodiment 10, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

[0626] Embodiment 12. The compound of embodiment 10, or a pharmaceutically acceptable salt thereof, wherein R2 is substituted or unsubstituted alkyl.

[0627] Embodiment 13. The compound of embodiment 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, -CN, -C(O)NH2, -CX4.13, or substituted or unsubstituted alkyl.

[0628] Embodiment 14. The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, wherein R4 is -CN, -C(O)NH2. -CF3, or -CH3.

[0629] Embodiment 15. The compound of embodiment 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently halogen.

[0630] Embodiment 16. The compound of embodiment 15, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently chlorine.

[0631] Embodiment 17. The compound of embodiment 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R7 is -OR7A, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -SOn7R7A, -SOv7NR7BR7C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0632] Embodiment 18. The compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein L7 is a substituted or unsubstituted alkylene or bond.

[0633] Embodiment 19. The compound of embodiment 7 or 8, or a pharmaceutically acceptable salt thereof, wherein: L7 is a bond; and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -(CH2)2OH, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH, -(CH2)2SO2NH2, -(CH2)3SO2NH2 -(CH2)2CONH2, - (CH2)3CONH2 -(CH2)3CON(H)Me, -(CH2)3CON(Me)2, -(CH2)2SO2Me, - (CH2)3SO2Me, -CH2CH(OH)Me, -CH2CO2H, -(CH2)2CO2H, - CH(CH3)CH2CO2H, -(CH2)3CO2H, -(CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, - (CH2)2NHCOCH(CH3)2, -(CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, - (CH2)2NHSO2NHCH(CH3)2, -CH2CH(CH3)CH2OH (R and S), - CH(CH3)(CH2)2OH, -CH2-(2-imidazoyl), -CH2-( 4-imidazoyl), -CH2- (3-pyrazoyl), 4-tetrahydropyranyl, 3-oxetanyl, - (CH2)2NHCO2Me, -(CH2)3NHCO2Me.

[0634] Embodiment 20. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (III):

[0635] Embodiment 21. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (IV):

[0636] Embodiment 22. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (V):

[0637] Embodiment 23. The compound of any one of embodiments 20 to 22, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[0638] Embodiment 24. The compound of any one of embodiments 20 to 22, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

[0639] Embodiment 25. The compound of any one of embodiments 20 to 22, or a pharmaceutically acceptable salt thereof, wherein R1 is -CH3.

[0640] Embodiment 26. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

[0641] Embodiment 27. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

[0642] Embodiment 28. A pharmaceutical composition comprising a compound having structural Formula (I) and a pharmaceutically acceptable excipient: or a pharmaceutically acceptable salt thereof, wherein: N; X2 is CR9 or N; X3 is CR10 or N; n1, n2, n3, n7, n8, n9 and n10 are independently an integer from 0 to 4; m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 are independently 1 or 2; z1 is an integer from 0 to 5; z2 is an integer from 0 to 2; z3 is an integer from 0 to 11; z4 is an integer from 0 to 2; L7 is a bond, -O-, -S-, -NR7.2B-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -N3, -SOn1R1A, -SOv1NR1BR1C, - NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R2 is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -N3, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, - NHC(O)NR2BR2C, -N(O)m2, -nr2Br2C, -C(O)R2D, -C(O)OR2D, - C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, - NR2BOR2D, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl or unsubstituted, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -N3, -SOn3R3A, - SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, - NHC(O)NR3BR3C, -N(O)m3, -nr3Br3C, -C(O)R3D, -C(O)OR3D, - C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, - NR3BOR3D, -OCX3.13, -OCHX3.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R4 is hydrogen, halogen, -CX4.13, -CHX4.12, -CH2X4.1, -CN, -N3, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, - ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, - C(O)R4D, -C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, - NR4BC(O)R4D, -NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl; R5 is independently hydrogen, halogen, oxo, -CX5.13, - CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, -SOv5NR5BR5C, -NHNR5BR5C, - ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, - C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R6 is independently hydrogen, halogen, oxo, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, -NHNR6BR6C, - ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, - C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, - NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, -C(O)R7D, -C(O)OR7D, - C(O)NR7BR7C, -or7A, -NR7BSO2R7A, -NR7BC(O)R7D, -NR7BC(O)OR7D, - NR7BOR7D, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl; R8 is hydrogen, halogen, -CX8.13, -CHX8.12, -CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, - ONR8BR8C, -NHC(O)NHNR8BR8C, -NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, - C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, - NR8BC(O)R8D, -NR8BC(O)OR8D, -NR8BOR8D, -OCX8.13, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -CX9.13, -CHX9.12, -CH2X9.1, -CN, -N3, -SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, - NHC(O)NR9BR9C, -N(O)m9, -nr9Br9C, -C(O)R9D, -C(O)OR9D, - C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, -NR9BC(O)R9D, -NR9BC(O)OR9D, - NR9BOR9D, -OCX9.13, -OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or unsubstituted, or substituted or unsubstituted heteroaryl; R10 is hydrogen, halogen, -CX10.13, - CHX10.12, -CH2X10.1, -CN, -N3, -SOn10R10A, -SOv10NR10BR10C, - NHNR10BR10C, -ONR10BR10C, -NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, - N(O)m10, -NR10BR10C, -C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, - OCX10.13, -OCHX10.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or unsubstituted cycloalkyl; and X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1, and X10.1 are independently -Cl, -Br, -I, or -F, wherein at least one of X1, X2, and X3 is N.

[0643] Embodiment 29. A method of treating or preventing a CCR4-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of embodiment 28.

[0644] Embodiment 30. A method of inhibiting CC chemokine receptor type 4 (CCR4), comprising contacting CCR4 with a compound of structural formula (I): or a pharmaceutically acceptable salt thereof, N; X2 is CR9 or N; X3 is CR10 or N; n1, n7, n8, n9, and n10 are independently an integer from 0 to 4; m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9, and v10 are independently 1 or 2; z1 is an integer from 0 to 5; z2 is an integer from 0 to 2; z3 is an integer from 0 to 11; z4 is an integer from 0 to 2; L7 is a bond, -O-, -S-, -NR7.2B-, -C(O)-, -C(O)O-, -S(O)-S(O)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -N3, -SOn1R1A, -SOv1NR1BR1C, - NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R2 is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -N3, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, - NHC(O)NR2BR2C, -N(O)m2, -nr2Br2C, -C(O)R2D, -C(O)OR2D, - C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, - NR2BOR2D, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl or unsubstituted, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -N3, -SOn3R3A, - SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, - NHC(O)NR3BR3C, -N(O)m3, -nr3Br3C, -C(O)R3D, -C(O)OR3D, - C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, - NR3BOR3D, -OCX3.13, -OCHX3.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R4 is hydrogen, halogen, -CX4.13, -chx4.12, -CH2X4.1, -CN, -N3, -SOn4R4A, -SOv4NR4BR4C, -nhnr4Br4C, - ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, - C(O)R4D, -C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, - NR4BC(O)R4D, -NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, aryl substituted or unsubstituted or substituted or unsubstituted heteroaryl; R5 is independently hydrogen, halogen, oxo, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, -SOv5NR5BR5C, -NHNR5BR5C, - ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, - C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -nr5Bor5D, -OCX5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl substituted, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R6 is independently hydrogen, halogen, oxo, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, -NHNR6BR6C, - ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, - C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, - NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, -C(O)R7D, -C(O)OR7D, - C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, -NR7BC(O)R7D, -NR7BC(O)OR7D, - NR7BOR7D, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl; R8 is hydrogen, halogen, -CX8.13, -CHX8.12, -CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, - ONR8BR8C, -NHC(O)NHNR8BR8C, -NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, - C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, - NR8BC(O)R8D, -NR8BC(O)OR8D, -NR8BOR8D, -OCX8.13, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -CX9.13, -CHX9.12, -CH2X9.1, -CN, -N3, -SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, - NHC(O)NR9BR9C, -N(O)m9, -nr9Br9C, -C(O)R9D, -C(O)OR9D, - C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, -NR9BC(O)R9D, -NR9BC(O)OR9D, - NR9BOR9D, -OCX9.13, -OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or unsubstituted, or substituted or unsubstituted heteroaryl; R10 is hydrogen, halogen, -CX10.13, - CHX10.12, -CH2X10.1, -CN, -N3, -SOn10R10A, -SOv10NR10BR10C, - NHNR10BR10C, -ONR10BR10C, -NHC(O)NHNR10BR10c, -NHC(O)NR10BR10C, - N(O)m10, -NR10BR10C, -C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, - OCX10.13, -OCHX10.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2B, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D, R10A, R10B, R10C, and R10D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; the substituents R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B, R9C, R10B, and R10C attached to the same nitrogen atom can optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1, and X10.1 are independently -Cl, -Br, -I, or -F, wherein at least one of X1, X2, and X3 is N.

[0645] Embodiment 31. A method of treating or preventing a CCR4-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having structural formula (I): or a pharmaceutically acceptable salt thereof, wherein: X1 is CR8 or N; X2 is CR9 or N; X3 is CR10 or N; n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 are independently an integer from 0 to 4; m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 are independently 1 or 2; z1 is an integer from 0 to 5; z2 is an integer from 0 to 2; z3 is an integer from 0 to 11; z4 is an integer from 0 to 2; L7 is a bond, -O-, -S-, -NR7.2B-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1 is hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -N3, -SOn1R1A, -SOv1NR1BR1C, - NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R2 is hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -N3, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, - NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D, - C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, - NR2BOR2D, -OCX2.13, -OCHX2.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -N3, -SOn3R3A, - SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, - NHC(O)NR3BR3C, -N(O)m3, -nr3Br3C, -C(O)R3D, -C(O)OR3D, - C(O)NR3BR3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, - NR3BOR3D, -OCX3.13, -OCHX3.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R4 is hydrogen, halogen, -CX4.13, -CHX4.12, -CH2X4.1, -CN, -N3, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, - ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, - C(O)R4D, -C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, - NR4BC(O)R4D, -NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl; R5 is independently hydrogen, halogen, oxo, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, -SOv5NR5BR5C, -NHNR5BR5C, - ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, - C(O)R5D, -C(O)OR5D, -C(O)NR5BR5C, -OR5A, -NR5BSO2R5A, - NR5BC(O)R5D, -NR5BC(O)OR5D, -nr5Bor5D, -ocx5.13, -OCHX5.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl substituted, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R6 is independently hydrogen, halogen, oxo, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, -NHNR6BR6C, - ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, - C(O)R6D, -C(O)OR6D, -C(O)NR6BR6C, -OR6A, -NR6BSO2R6A, - NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, halogen, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, - NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, -C(O)R7D, -C(O)OR7D, - C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, -NR7BC(O)R7D, -NR7BC(O)OR7D, - NR7BOR7D, -OCX7.13, -OCHX7.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or substituted or unsubstituted heteroaryl; R8 is hydrogen, halogen, -CX8.13, -CHX8.12, -CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, - ONR8BR8C, -NHC(O)NHNR8BR8C, -NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, - C(O)R8D, -C(O)OR8D, -C(O)NR8BR8C, -OR8A, -NR8BSO2R8A, - NR8BC(O)R8D, -NR8BC(O)OR8D, -NR8BOR8D, -OCX8.13, -OCHX8.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -CX9.13, -CHX9.12, -CH2X9.1, -CN, -N3, -SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, - NHC(O)NR9BR9C, -N(O)m9, -nr9Br9C, -C(O)R9D, -C(O)OR9D, - C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, -NR9BC(O)R9D, -NR9BC(O)OR9D, - NR9BOR9D, -OCX9.13, -OCHX9.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl or unsubstituted, or substituted or unsubstituted heteroaryl; R10 is hydrogen, halogen, -CX10.13, - CHX10.12, -CH2X10.1, -CN, -N3, -SOn10R10A, -SOv10NR10BR10C, - NHNR10BR10C, -ONR10BR10C, -NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, - N(O)m10, -NR10BR10C, -C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D, -NR10BOR10D, - OCX10.13, -OCHX10.12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2B, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D, R10A, R10B, R10C, and R10D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted, or substituted or unsubstituted heteroaryl; the substituents R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B, R9C, R10B, and R10C attached to the same nitrogen atom can optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1, and X10.1 are independently -Cl, -Br, -I, or -F, wherein at least one of X1, X2, and X3 is N.

[0646] Embodiment 32. The method of embodiment 31, wherein: z1 is 2; z4 is 1; and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -F, -OH, CH2OH, -(CH2)2OH, - (CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SO2NH2, -CH2C(O)NH2, - (CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, - (CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH3, -CH2SO2CH3, -(CH2)2SO2CH3, -CH2SO2NH2 or -(CH2)2SO2NH2.

[0647] Embodiment 33. The method of embodiment 32, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0648] Embodiment 34. The method of embodiment 31, wherein the compound has structural formula (II): , or a pharmaceutically acceptable salt thereof, wherein: n3.2, and n3.3 are independently an integer from 0 to 4; m3.2, m3.3, v3.2, and v3.3 are independently 1 or 2; R4 is hydrogen, -CX4.13, -CN, -C(O)NR4BR4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.2 is hydrogen, halogen, -CX3.23, - CHX3.22, -CH2X3.2, -CN, -N3, -SOn3.2R3.2A, -SOv3.2NR3.2BR3.2C, - NHNR3.2BR3.2C, -ONR3.2BR3.2C, -NHC(O)NHNR3.2BR3.2C, - NHC(O)NR3.2BR3 .2C, -N(O)m3.2, -NR3.2BR3.2C, -C(O)R3.2D, -C(O)OR3.2D, -C(O)NR3.2BR3.2C, -OR3.2A, -NR3.2BSO2R32A, -NR3.2BC(O)R3.2D, - NR3.2BC(O)OR3.2D, -NR3.2BOR3.2D, -OCX3.23, -OCHX3.22, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.3 is hydrogen, halogen, -CX3.33, -CHX3.32, -CH2X3.3, -CN, -N3, - SOn3 3R3.3A, -SOv3.3NR3.3BR3.3C, -NHNR3.3BR3.3C, -ONR3.3BR3.3C, - NHC(O)NHNR3.3BR3.3C, -NHC(O)NR3.3BR3 .3C, -N(O)m3.3, -NR3.3BR3.3C, - C(O)R3.3D, -C(O)OR3.3D, -C(O)NR3.3BR3.3C, -OR3.3A, -NR3.3BSO2R3.3A, -NR3.3BC(O)R3.3D, -NR3.3BC(O)OR3.3D, -NR3.3BOR3.3D, -OCX3.33, -OCHX3.32, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.2A, R3.2B, R3.2C, R3.2D, R3.3A, R3.3B, R3.3C, and R3.3D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -Cl3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; The substituents R3.2B, R3.2C, R3.2B, and R3.2C attached to the same nitrogen atom may be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X3.2 and X3.3 are independently -Br, -I, or -F.

[0649] Embodiment 35. The method of embodiment 34, wherein the compound has structural formula (IIa): or a pharmaceutically acceptable salt thereof.

[0650] Embodiment 36. The method of embodiment 34, wherein the compound has structural formula (IIb): or a pharmaceutically acceptable salt thereof.

[0651] Embodiment 37. The method of embodiment 35, wherein the compound has structural formula (IIc): or a pharmaceutically acceptable salt thereof.

[0652] Embodiment 38. The method of embodiment 36, wherein the compound has structural formula (IId): or a pharmaceutically acceptable salt thereof.

[0653] Embodiment 39. The method of embodiment 37 or 38, wherein z4 is 1.

[0654] Embodiment 40. The method of embodiment 37 or 38, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0655] Embodiment 41. The method of embodiment 40, wherein R1 is hydrogen.

[0656] Embodiment 42. The method of embodiment 40, wherein R2 is substituted or unsubstituted alkyl.

[0657] Embodiment 43. The method of embodiment 37 or 38, wherein R4 is hydrogen, -CN, -C(O)NH2, -CX4.13, or substituted or unsubstituted alkyl.

[0658] Embodiment 44. The method of embodiment 43, wherein R4 is -CN, -C(O)NH2, -CF3, or -CH3.

[0659] Embodiment 45. The method of embodiment 37 or 38, wherein R3.2 and R3.3 are independently halogen.

[0660] Embodiment 46. The method of embodiment 45, wherein R3.2 and R3.3 are independently chlorine.

[0661] Embodiment 47. The method of embodiment 37 or 38, wherein R7 is -OR7A, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR7C, -SOn7R7A, -SOv7NR7BR7C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0662] Embodiment 48. The method of embodiment 47, wherein L7 is a substituted or unsubstituted alkylene or bond.

[0663] Embodiment 49. The method of embodiment 37 or 38, wherein: L7 is a bond; and R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -(CH2)2OH, - CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH, -(CH2)2SO2NH2, - (CH2)3SO2NH2, -(CH2)2CONH2, -(CH2)3CONH2, -(CH2)3CON(H)Me, - (CH2)3CON(Me)2, -(CH2)2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, - CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, - (CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), - (CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH(CH3)2, - (CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, -(CH2)2NHSO2NHCH(CH3)2, CH2CH(CH3)CH2OH (R and S), -CH(CH3)(CH2)2OH, -CH2-(2- imidazoyl), -CH2-(4- imidazoyl), -CH2-(3-pyrazoyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me.

[0664] Embodiment 50. The method of embodiment 31, wherein the compound has structural formula (III): or a pharmaceutically acceptable salt thereof.

[0665] Embodiment 51. The method of embodiment 31, wherein the compound has structural formula (IV): or a pharmaceutically acceptable salt thereof.

[0666] Embodiment 52. The method of embodiment 31, wherein the compound has structural formula (V): or a pharmaceutically acceptable salt thereof.

[0667] Embodiment 53. The method of any one of embodiments 50 to 52, wherein R2 is hydrogen.

[0668] Embodiment 54. The method of any one of embodiments 50 to 52, wherein R1 is hydrogen.

[0669] Embodiment 55. The method of any one of embodiments 50 to 52, wherein R1 is -CH3.

[0670] Embodiment 56. The method of embodiment 31, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

[0671] Embodiment 57. The method of embodiment 31, wherein the disease or disorder is an immune or inflammatory disease or disorder.

[0672] Embodiment 58. The method of embodiment 57, further comprising co-administering an anti-inflammatory agent in combination with a compound of structural Formula (I) or a pharmaceutically acceptable salt thereof.

[0673] Embodiment 59. The method of embodiment 58, wherein the anti-inflammatory is thalidomide or a derivative thereof, a retinoid, dithranol, calcipotriol, a nonsteroidal anti-inflammatory agent (NSAID), a cyclooxygenase inhibitor nitric oxide donor (CINOD), a glucocorticoid, methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, an analgesic, a diacerein, a hyaluronic acid derivative, or a nutritional supplement.

[0674] Embodiment 60. The method of embodiment 31, wherein the disease or disorder is a cardiovascular or metabolic disease or disorder.

[0675] Embodiment 61. The method of embodiment 60, further comprising co-administering a cardiovascular agent or a metabolic disorder agent in combination with a compound of structural Formula (I).

[0676] Embodiment 62. The method of embodiment 61, wherein the cardiovascular agent is a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a lipid lowering agent, a blood cell morphology modulator, a thrombolytic, or an anticoagulant.

[0677] Mode 63. The method of mode 31, wherein the disease or disorder is cancer.

[0678] Embodiment 64. The method of embodiment 63, further comprising co-administering a chemotherapeutic agent or anti-cancer agent in combination with a compound of structural Formula (I).

[0679] Embodiment 65. The method of embodiment 64, wherein the chemotherapeutic agent or anticancer agent is an antiproliferative/antineoplastic drug, an antimetabolite, an antitumor antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, a 5.alpha.-reductase inhibitor, an agent that inhibits cancer cell invasion, a growth factor function inhibitor, a famyl transferase inhibitor, a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor, an epidermal growth factor family inhibitor, a platelet-derived growth factor family inhibitor, a hepatocyte growth factor family inhibitor; an antiangiogenic agent, a vascular damaging agent, an agent used in antisense therapy, an anti-ras antisense, an agent used in gene therapy, an immunotherapeutic agent, or an antibody.

[0680] Embodiment 66. The method of embodiment 65, further comprising co-administering a therapeutically effective amount of at least two of: a CCR4 inhibitor, a PD-L1/PD-1 pathway inhibitor, a CTLA-4 inhibitor, or a CD137 agonist antibody (4-1BB).

[0681] Embodiment 67. The method of embodiment 65, further comprising co-administering a therapeutically effective amount of at least two of: a CCR4 inhibitor, an immunomodulatory agent, or a Schedule 1 agent, or any combination thereof.

[0682] Embodiment 68. The method of any of embodiments 63 to 67, wherein the cancer is colon cancer or pancreatic cancer.

EXAMPLES

[0683] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are intended to be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

[0684] The successful operation of the host defense system is the result of several processes that work together to eliminate exogenous pathogens. Coordinated innate and adaptive immune responses are required, and many cell-associated and secreted factors have been identified as important mediators that coordinate and regulate these two arms of host defense (see, e.g., Ness, T. et al. (2006) J Immunol 177:7531-39).

[0685] Chemokines are a family of cytokines that act as chemoattractants to guide leukocyte migration. They are secreted by a wide variety of cells and can be functionally divided into two groups, hemostatic chemokines and inflammatory chemokines. Hemostatic chemokines are constitutively produced in certain tissues and control cells of the immune system during immune inspection processes, such as homing of lymphocytes to lymph nodes to allow them to screen for invading pathogens. Inflammatory chemokines are released from cells in response to a pathological event (e.g., proinflammatory stimuli such as IL-1 or viruses). They function primarily as chemoattractants as part of the inflammatory response and serve to guide cells of both the innate and adaptive immune systems to the site of inflammation. [See, for example, Le, Y. et al. (2004) Cellular & Molec Immuno 1(2):95-104,]

[0686] Structurally, there are four subgroups of chemokines, classified according to the spacing of the first two cysteine residues: i) CC chemokines (β-chemokines) have adjacent cysteines; ii) CXC chemokines (α-chemokines) have a single amino acid residue between the first two cysteines; iii) C chemokines (γ-chemokines) have only a single N-terminal cysteine residue; and iv) CX3C chemokines (δ-chemokines) have three amino acid residues between the first two cysteines. CC chemokines, examples of which include monocyte chemoattractant protein-1 (MCP-1 or CCL2) and CCL5 (RANTES), induce the migration of monocytes and other cell types; at least 27 members have been identified. The CXC chemokines (some 17 in number) can be subdivided into two groups, both of which have unique structural and functional features; the CXC chemokines bind to CXC chemokine receptors, of which 7 are known (designated CXCR1-7). Only two members of the C chemokine subgroup have been identified, XCL1 and XCL2 (lymphotactin-α and -β, respectively). Finally, the CX3C chemokine subgroup has only one member, CX3CL1, which is both secreted and associated with the surface of cells expressing it, resulting in both chemoattractant and adhesion properties. [See Sokol, C. and Luster, A. (2015) Cold Spring Harb Prospect Biol. doi: 10.1101/cshperspect. a016303,]

[0687] Chemokines bind to specific G-protein-coupled receptors (“chemokine receptors”), which are characterized by containing seven transmembrane domains, found on the surface of leukocytes (see Horuk (1994) Trends Pharm. Sci. 15:159-165). Approximately 20 human chemokine receptors have been identified, which are divided into four subgroups depending on the type of chemokine they bind: CXCR binds CXC chemokines; CCR binds CC chemokines; CX3CR1 binds CX3CL1, the single CXC3 chemokine; and XCR1 binds XCL1 and XCL2, the two XC chemokines. Binding of a chemokine ligand to its cognate receptor triggers the receptor, resulting in dissociation of an intracellular heterotrimeric G-protein complex into Ga and GβY subunits. These second messengers play an integral role in activating several signaling cascades (e.g., the MAP kinase pathway), resulting in responses that include chemotaxis, inflammatory mediator release, degranulation, and changes in cell shape. Chemokine receptors have been implicated as important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. [See, for example, Comerford, I. and McColl, S. (2011) Immunol Cell Biol 89:183–84.]

[0688] C-C chemokine receptor type 4 (CCR4), first identified by Power et al. (J. Biol. Chern. 270: 19495-500 (1995)), plays a vital role in the progression of a number of inflammation-related and other disorders (Gadhe, C. G. (February 2015) Mol Biosyst 11(2):618-34). CCR4 is a high-affinity receptor for the C-C chemokines CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC). Increased expression of CCR4 and its ligands is associated with the pathogenesis of a diverse array of diseases, including pulmonary fibrosis, liver inflammation, granuloma development, certain cancers, and diabetes, each of which is characterized by infiltration of CCR4+ T cells into affected sites. The identification of compounds that modulate CCR4 function provides an opportunity for the development of therapeutic agents for the treatment of a diverse array of diseases and disorders associated with CCR4 activation.

[0689] The present invention relates to compounds that inhibit the activity of C-C chemokine receptor type 4 (CCR4), and compositions (e.g., pharmaceutical compositions) comprising the compounds. Such compounds, including methods of their synthesis, and compositions are described in detail herein. The present invention also relates to the use of such compounds and compositions for the treatment and/or prevention of diseases, disorders and conditions mediated, in whole or in part, by CCR4.

[0690] Many individuals suffer from the debilitating effects of inflammatory and/or immune system disorders such as asthma and rheumatoid arthritis. Recently generated data support the role of inhibitors of CCR4 function to modulate such inflammatory and/or immune system activity in a therapeutically beneficial manner. Furthermore, the number of individuals diagnosed with cancer and the number of deaths attributable to cancer continue to rise, both in the United States and abroad. Traditional treatment approaches comprising chemotherapy and radiation therapy are often difficult for patients to tolerate and become less effective as cancers (e.g., tumors) evolve to evade such treatments.

Identification of CCR4 inhibitors

[0691] In embodiments, the compounds described herein possess at least one property or characteristic that is of therapeutic relevance. Candidate inhibitors can be identified using, for example, a art-accepted assay or model. The Example section described assay(s) that were used to determine the CCR4γ inhibitory activity of the compounds described herein, as well as assays that could be used to evaluate one or more characteristics of the compounds; One of skill in the art is aware of other procedures, assay formats, and the like that can be employed to generate data and information useful for evaluating the CCR4 inhibitors described herein.

[0692] Following identification, candidate inhibitors can be further evaluated using techniques that provide data regarding inhibitor characteristics (e.g., pharmacokinetic parameters). Comparisons of candidate inhibitors to a reference standard (which may be the current “best in class” of inhibitors) are indicative of the potential viability of such candidates. CCR4 inhibitors that may serve as reference or focus compounds include those that have demonstrated the desired activity and characteristics as described, for example, in US Patent Publication 2012/0015932 and PCT Publication 2013/082490. Other means of analyzing candidate inhibitors will be apparent to one of skill in the art.

Summary details

[0693] The following general schemes represent synthetic methods that can be used in the preparation of the compounds of the present invention, as well as common chemical intermediates generated in the preparation thereof. One of ordinary skill in the art will recognize that these schemes are representative only, and that in many cases alternative synthetic means may be employed.

[0694] The following examples are presented for the purpose of providing those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope to which the inventors refer in their invention, nor are they intended to represent that the experiments below have been performed or that they may be all of the experiments that may be performed. It is understood that the exemplary descriptions written herein have not necessarily been performed, but rather that the descriptions may be performed to generate data and the like of the nature described therein. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, temperature, etc.), but some experimental errors and deviations should be allowed for.

[0695] Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (°C), and pressure is or near atmospheric. Standard abbreviations are used, including the following: wt = wild type; bp = base pair(s); kb = kilobase(s); nt = nucleotide(s); aa = amino acid(s); s or sec = second(s); min = minute(s); h or hr = hour(s); ng = nanogram; μg = microgram; mg = milligram; g = gram; kg = kilogram; dl or dl = deciliter; μl or μl = microliter; m1 or ml = milliliter; 1 or l = liter; μM = micromolar; mM = millimolar; M = molar; kDa = kilodalton; i.m. = intramuscular(ly); i.p. = intraperitoneal(ly); SC or SQ = subcutaneous(ly); QD = daily; BID = twice daily; QW = weekly; QM = monthly; psi = pounds per square inch; HPLC = high-performance liquid chromatography; BW = body weight; U = unit; ns = not statistically significant; HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate); TFA = trifluoroacetic acid; MBTE = methyl t-butyl ether; DCM = dichloromethane; PBS = phosphate buffered saline; IHC = immunohistochemistry; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; EtOH = ethanol; DMEM = Dulbeco's modification of Eagle's medium; EDTA = ethylenediaminetetraacetic acid; Me = methyl; Et = ethyl; S - singlet; D - doublet; dd - doublet doublet; m - multiplet.

[0696] General preparation of hydrazine starting material:

[0697] A substituted aminomethyl benzene of general structure 1 may be reacted with an alkali metal cyanate such as potassium cyanate in an acidified solvent such as concentrated HCl. The resulting urea of general structure 2 may be isolated by standard methods such as filtration. After suitable purification, the urea of general structure 2 may be dissolved in a mixture of organic solvents such as toluene and tert-butanol and treated with t-butyl hypochlorite under a nitrogen atmosphere and the mixture is cooled to a temperature between -40 and 0 °C preferably around -20 °C. The mixture is then warmed to 0 °C and the resulting solution is transferred to a flask containing a solution of an alkoxide base such as potassium t-butoxide in a mixture of organic solvents such as toluene and t-butanol which has been maintained at a temperature between -40 and 0 °C preferably at -20 °C. After the addition, the reaction is stirred for 15 min at 0 °C and then poured into ice-water. The mixture is allowed to warm to room temperature over 20 min and is then extracted with an organic solvent such as ethyl acetate. The organic extract is washed with water, an aqueous solution of sodium thiosulfate, and brine. The mixture is then concentrated to give the desired tert-butyl carboxylate intermediate which can be immediately hydrolyzed in an acidic organic mixture such as HCl in dioxane for 8–24 h. Concentration of the solution followed by titration of the resulting residue with an organic solvent such as ethyl acetate to give the desired hydrazine hydrochloride 3.

[0698] General synthesis of pyrazolopyrazine and pyridines:

[0699] A solution of hydrazine hydrochloride of general structure 3 in a protic organic solvent such as ethanol is treated with the ketone of general structure 4. The mixture was stirred for 8 h at room temperature. The reaction is concentrated under reduced pressure to give a residue. The residue was suspended in the mixture of organic solvents such as ethyl acetate and hexanes and then filtered through a plug of silica gel and eluted with a similar solvent mixture. The filtrate is concentrated to give the crude hydrazone of general structure 5 as a mixture of E and Z isomers. The mixture of E and Z hydrazine isomers of general structure 5 is dissolved in a polar aprotic solvent such as N-methyl-2-pyrrolidinone and treated with excess of a Lewis base, e.g., 2,6-lutidine. The mixture is degassed with nitrogen and stirred under a nitrogen atmosphere at an elevated temperature, e.g., 100 °C, for 8 h. The reaction mixture is cooled to room temperature and then poured into an acidic aqueous solution such as 1 M HCl, and the resulting mixture is extracted with an organic solvent such as ethyl acetate. The layers are separated, and the organic layer is washed with an acidic aqueous solution such as 1 M HCl, dried over a drying agent such as magnesium sulfate, and concentrated under reduced pressure. The resulting residue can optionally be purified by recrystallization or chromatography on silica gel using a mixture of organic solvents, e.g., a mixture of MBTE and DCM, to give compounds of general formula 6.

[0700] In certain cases, where ketone 4 is not commercially available, it can be prepared as follows:

[0701] A solution of halide of general structure 4a and an acetate source in polar aprotic solvent such as THF is treated with a strong alkali complex base such as LiTMP at low temperature -78 °C to produce 4 which is used in the very next step described in the previous procedure to produce compounds of general formula 6.

[0702] A solution of halide of general structure 6 in an organic solvent such as dioxane is treated with ammonia source such as ammonium hydroxide (29% in water). The mixture is stirred at room temperature for 3 d. The reaction is diluted with a solvent such as ethyl acetate and washed with a weak aqueous base such as aqueous sodium carbonate. The organic layer is separated and dried over a drying agent such as magnesium sulfate. The organic layer is concentrated under reduced pressure to give the compounds of general formula 7. A solution of primary amide of general structure 7 in a polar aprotic organic solvent such as DCM at room temperature under inert atmosphere is added as a dehydrating agent such as Burgess reagent. The mixture was stirred at room temperature for about 2 d. The resulting mixture can be purified by chromatography on silica gel using a mixture of organic solvents, for example, a mixture of EtOAc and Hexanes to give the compounds of general formula 8.

[0703] General synthesis of azetidine derivatives:

[0704] To a solution of the protected ketone of general structure 10 in an organic solvent such as dichloroethane is added amine 9 and an imine reducing agent such as sodium triacetoxyborohydride and the mixture is stirred for between 4 and 18 h. The reaction is treated with a weak aqueous base such as aqueous sodium carbonate and the mixture is extracted with an organic solvent such as ethyl acetate. The organic solvent is separated, treated with a drying agent such as sodium sulfate and the dried solution is evaporated to give amine of general structure 11. The protecting group on the compound of general structure 11 may be exposed to an acidic organic solution, for example HCl in dioxane or trifluoroacetic acid in DCM or may be removed using catalytic Pd. The mixture is stirred at room temperature for between 1 and 16 h. The reaction mixture can be concentrated or filtered through a pad of celite and then concentrated under reduced pressure to give an amine salt of general structure 12 that can be used in subsequent reactions without further purification.

[0705] Alternatively, piperidine 9 may be reacted with an alkyl halide optionally in the presence of sodium iodide, in the presence of a base such as sodium carbonate in a solvent such as DMF. After stirring for 4 to 18 h, the reaction is diluted with water, and the mixture is extracted with an organic solvent such as ethyl acetate. The organic solvent is separated, treated with a drying agent such as sodium sulfate, and the dried solution is evaporated to give the amine of general structure 11. The protecting group on the compound of general structure 11 may be exposed to an acidic organic solution, for example, HCl in dioxane or trifluoroacetic acid in DCM, or may be removed using catalytic Pd. The mixture is stirred at room temperature for 1 to 16 h. The reaction mixture can be concentrated or filtered through a pad of celite and then concentrated under reduced pressure to give an amine salt of general structure 12 that can be used in subsequent reactions without further purification.

[0706] For cases where R8 contains electron withdrawing groups (EWG):

[0707] To a solution of amine of general structure 9 in dry organic solvent such as DCM is added Michael acceptor 13. The reaction mixture was stirred at room temperature or at 50 °C until complete conversion which can be monitored using TLC or LCMS. Upon completion, the solvent is removed. The resulting residue can be purified by chromatography on silica gel using a mixture of organic solvents, for example, a mixture of MeOH and DCM to give the compounds of general formula 14. The protecting group on the compound of general structure 14 can be exposed to an acidic organic solution, for example, HCl in dioxane or trifluoroacetic acid in DCM or can be removed using catalytic Pd. The mixture is stirred at room temperature for a time between one and 16 h. The reaction mixture can be concentrated or filtered through a pad of celite and then concentrated under reduced pressure to give an amine salt of general structure 12 that can be used in subsequent reactions without further purification.

[0708] The compounds of general formulae 12 and 6 in an organic solvent such as DMF are heated in the presence of a base such as diisopropyl ethyl amine to a temperature in the range of 70 to 100 °C for 1 hour. The reaction mixture can be partitioned between ethyl acetate and water containing TFA. The aqueous layer is evaporated and the resulting residue can be purified by preparative reversed phase HPLC using a stationary phase such as C-18 and a solvent system such as varying amounts of water and acetonitrile containing 0.1% TFA. The resulting mixture of stereoisomers can be converted to the free base by passage over amberlite resin and the basified amines purified using a chiral HPLC column such as Chiracel OZ-H and the like using a mixture of organic solvents such as ethanol and heptanes containing 0.1% diethyl amine as the solvent. The purified stereoisomers could be dissolved in ethanol and treated with HCl in ether and the solvents were removed under reduced pressure to give the desired compound 15 as HCl salt.

[0709] In certain cases where R8 = -(CH2)nCO2Et compound 15 is dissolved in an organic solvent such as MeOH and then treated with an alkali metal hydroxide such as LiOH and the resulting mixture is stirred for 3 h. An aqueous acid such as 3M HCl is then added to the reaction. The mixture is concentrated under reduced pressure and the resulting residue is purified by preparative reversed phase HPLC using a stationary phase such as C-18 and a solvent system such as varying amounts of water and acetonitrile containing 0.1% TFA to afford a compound of general structure 16.

[0710] Precursor I. Preparation of (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine.

[0711] Step 1. Preparation of (R)-1-(2,4-dichlorophenyl)ethan-1-ol.

[0712] To a solution of 2',4'-dichloroacetophenone (10.9 g, 77.0 mmol) in anhydrous THF (80 mL) at -78 °C under nitrogen was slowly added a solution of (+)-B-chlorodiisopinocampheylborane ((+)-Ipc2BCl, 27.2, 85.0 mmol) in THF (15 mL). After the addition was complete, the reaction mixture was slowly warmed to -25 °C and stirred at that temperature for 2 h (monitored by TLC and LCMS). The reaction mixture was then quenched with diethanolamine (17.9 g, 170 mmol), and stirred for 10 min. During this time, a solid formed and was removed by filtration. The filtrate was dried over NaCl, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in hexanes) to give (R)-1-(2,4-dichlorophenyl)ethanol. Yield 12.0 g, 63.3 mmol, 82%. Enantiomeric purity was determined on a CHIRALPAK ID column using 5% isopropanol in heptanes (98% ee, retention time 5.3 min). 1H NMR (400 MHz, CDCl3) δ ppm 7.55 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 2.2 Hz, 1H), 7.29 (ddd, J = 8.4, 2.1, 0.5 Hz, 1H), 5.26 (q, J = 6.4 Hz, 1H), 1.47 (d , J = 6.4 Hz, 3H).

[0713] Step 2. Preparation of (S)-2,4-dichloro-1-(1-chloroethyl)benzene.

[0714] To a stirred solution of N-chlorosuccinimide (11.0 g, 82.4 mmol) in THF at 0 °C (240 mL) was added triphenylphosphine (21.6 g, 82.4 mmol). The reaction mixture was stirred at 0 °C for 10 min and then stirred at room temperature for 30 min. The mixture was cooled to 0 °C and then (R)-1-(2,4-dichlorophenyl)ethanol (12.0 g, 63.4 mmol) was added (dissolved in 25 mL of THF). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for an additional 3 h. The reaction mixture was concentrated in vacuo and suspended in hexanes. The solid was removed by filtration and discarded. The filtrate was then concentrated in vacuo and the resulting residue was taken up in hexanes. The solid was removed by filtration and discarded. The filtrate was then concentrated in vacuo and the crude material was used without further purification. Yield 12.1 g, 58 mmol, 91 %. Enantiomeric purity was determined on a CEQRALPAK IC-3 column using 100 % heptanes (96 % ee, retention time 4.5 min). 1H NMR (400 MHz, CDCl) Hz, 1H).

[0715] Step 3. Alkylation of 6-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine with (S)-2,4-dichloro-1-(1-chloroethyl)benzene.

[0716] 6-Chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.97 mmol) was dissolved in 10 mL of anhydrous DMF. Anhydrous Cs2CO3 (2.42 g, 7.43 mmol) was added to the solution immediately followed by 1.74 g (8.91 mmol) of (S)-2,4-dichloro-1-(1-chloroethyl)benzene (96% ee). The reaction mixture was allowed to stir at room temperature for 24 h and the progress was monitored by LCMS. Upon completion, the reaction mixture was diluted with 20 mL of water and extracted 3 times with 20 mL of ethyl acetate. The combined organic fraction was dried over MgSO4, filtered, and purified by silica gel chromatography using ethyl acetate and hexanes (gradient 0 to 100%). Yield 500 mg, 49%. Enantiomeric purity was determined by chiral HPLC using 5% isopropanol on a CHIRACEL OZ-H column in heptanes (retention time 6.9 min, 94% ee). 1H NMR (400 MHz, DMSO-d6): δ ppm 9.27 (s, 1H), 7.63-7.65 (m, 1H), 7.41-7.49 (m, 2H), 6.31 (q, J = 7.0Hz, 1H), 2.56 (s, 3H), 1.83 (d, J = 7.0Hz, 3H). [M+H] 341.0.

[0717] Precursor II. Preparation of (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazine.

[0718] Step 1. Preparation of (R)-1-(1-(2,4-dichlorophenyl)ethyl)urea.

[0719] To a 6 L flask equipped with an overhead stirrer were added (R)-1-(2,4-dichlorophenyl)ethan-1-amine (211 g, 1.11 mol) [reference WO 2013082490], water (3.4 L) and concentrated HCl (92.5 ml, 1.11 mol). The mixture was an aqueous slurry. Then, solid KOCN (90 g, 1.11 mol) was added in one portion at rt. All of the solids went into solution and a white precipitate began to form after 1 h. The white precipitate was isolated by filtration. The filtrate was allowed to stand at room temperature and more precipitate formed. The precipitate was isolated by filtration. This was repeated several times until no additional precipitate formed in the filtrate upon standing at room temperature for 1 d. All solids were combined and dried under high vacuum.

[0720] Step 2. Preparation of (R)-(1-(2,4-dichlorophenyl)ethyl)hydrazine hydrochloride.

[0721] (R)-1-(1-(2,4-dichlorophenyl)ethyl)urea (Example 5, Step 1, 50 g, 214.6 mmol) was ground to a fine powder and placed in a 2 L flask. The 2 L flask was purged with nitrogen gas and a degassed mixture of 1000 mL of toluene and 375 mL of tBuOH was added via cannula under nitrogen gas. KOtBu (240.3 g, 2146 mmol) was ground to a fine powder and added to a separate 5 L 3-neck flask. The 5 L flask was purged with nitrogen and a degassed mixture of 1000 mL of toluene and 650 mL of tBuOH was added via cannula under nitrogen gas. The 2 L and 5 L mixtures were aqueous slurries and were cooled to -20 °C. The lights in the oven were turned off. tBuOCl (23.18 g, 24 mL, 214.6 mmol) was added to the 2 L flask at −20 °C. It was then removed from the −20 °C bath, and the mixture was placed in a 0 °C bath. Once the aqueous slurry had completely turned into solution, the mixture was transferred to the 5 L flask via cannula under nitrogen at −20 °C. The lights in the oven were turned on. The flask was removed from the −20 °C bath, and the mixture was placed in the 0 °C bath. The mixture was stirred at 0 °C for 10 min and then warmed to rt. The mixture was poured onto ice. The mixture was extracted with EtOAc (2×). The combined organic layers were washed with 1 L of water, 500 mL of saturated sodium thiosulfate, and 1 L of brine. The mixture was concentrated under reduced pressure to give tert-butyl (R)-2-(1-(2,4-dichlorophenyl)ethyl)hydrazine-1-carboxylate in 98.9% enantiomeric excess. The enantiomeric excess was determined by HPLC using a Chiralpak® IF-3 column and eluting with 5% isopropanol in heptanes (retention time 5.3 min).

[0722] The residue was dissolved in 250 mL of 1,4-dioxane and 1,4-dioxane HCl (4 M, 161 mL, 643.8 mmol) was added at room temperature. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was titrated from 25% EtOAc in hexanes (1 mL of solvent per 1 g of residue) to give (R)-(1-(2,4-dichlorophenyl)ethyl)hydrazine hydrochloride in 99.2% enantiomeric excess. The enantiomeric excess was determined by HPLC using a Chiralpak® IF-3 column and eluting with 20% isopropanol in heptanes (retention time 4.7 min). 1H NMR (400 MHz, CDCl3, HCl salt) H), 1.64 (d, J = 6.8 Hz, 3H). [M+H] 205.2.

[0723] Step 3. Preparation of 3,5-dichloropyrazine-2-carboxamide.

[0724] 2,6-Dichloropyrazine (55 g, 0.37 mol) and formamide were combined and heated to 90 °C. Sodium persulfate (86.7 g, 0.36 mol) was added to the mixture at 90 °C in portions (~1 g) at 20-30 s intervals. An exotherm was observed and the color of the mixture changed from yellow to dark red/brown. The mixture was stirred at 90 °C for 2 h and then cooled to room temperature. The mixture was diluted with water (500 mL) and filtered. The filtered layers were separated. The aqueous layer was extracted with IPA/chloroform (1/3, 3 x 750 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to yield a viscous oil. The oil was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to afford the title product as a colorless solid (25 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.87 (s, 1H), 8.18 (s l, 1H), 8.01 (s l, 1H).

[0725] Step 4. Preparation of 3,5-dichloropyrazine-2-carbonitrile.

[0726] To a solution of 3,5-dichloropyrazine-2-carboxamide (Example 12, Step 2, 52 g, 0.27 mol) in acetonitrile (1 L) was added POCl3 (146 g, 89 mL, 0.95 mol) at room temperature. The mixture was heated to 90-100 °C for 4 h. The mixture was cooled to room temperature and slowly poured into a vigorously stirred solution of saturated aqueous NaHCO3. Evolution of gas was observed. The mixture was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate then concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.64 (s, 1H): 13C NMR (101 MHz, CDCl3) δ ppm 150.8, 150.43, 143.24, 128.06, 113.06.

[0727] Step 5. Preparation of 1-(3,5-dichloropyrazin-2-yl)ethan-1-one.

[0728] 3,5-Dichloropyrazine-2-carbonitrile (Example 12, Step 2, 31.0 g, 178.18 mmol) was dissolved in anhydrous diethyl ether (890 mL, 0.2 M) and cooled to -78 °C. Then, MeMgBr in diethyl ether (3.0 M, 65.3 mL, 190 mmol) was added slowly to keep the temperature down. After the addition was complete, the mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. The mixture was poured into a beaker containing a mixture of HCl in water (1.0 M, 1 L) and ice (1 kg). The mixture was stirred vigorously for 10 min. The mixture was extracted with diethyl ether (3 X 1 L). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an orange oil (34 g, 99% yield). The mixture was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ ppm 8.56 (s, 1H), 2.71 (s, 3H).

[0729] Step 6. Preparation of (R,Z)-3,5-dichloro-2-(1-(2- (1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine and (R,E )- 3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine.

[0730] (R)-(1-(2,4-Dichlorophenyl)ethyl)hydrazine hydrochloride (Example 5, Step 2, 47.3 g, 196 mmol) was dissolved in ethanol (356 mL, 0.5 M) at room temperature, and then 1-(3,5-dichloropyrazin-2-yl)ethan-1-one (34.0 g, 178 mmol) was added. The mixture was stirred at room temperature for 8 h. The mixture was concentrated under reduced pressure to give a residue. The residue was suspended in 20% EtOAc in hexanes (200 mL) and then filtered through a plug of silica gel and eluted using 20% EtOAc in hexanes. The filtrate was concentrated under reduced pressure to give the title products as a viscous orange oil.

[0731] Step 7. Cyclization of (R,Z)-3,5-dichloro-2-(1-(2- (1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine and (R,E )- 3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine.

[0732] A mixture of (R,Z)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine and (R,E)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)ethyl)pyrazine (9:1) (33 g, 87 mmol) was dissolved in N-methyl-2-pyrrolidone (218 mL) at room temperature. 2,6-Lutidine (30.3 mL, 262 mmol) was added. The mixture was degassed with nitrogen and then heated to 100 °C under nitrogen for 8 h. The reaction mixture was cooled to room temperature and then poured into a separatory funnel containing 500 ml of HCl in water (1 M) and 500 ml of ethyl acetate. The layers were separated, and the organic layer was washed with 500 ml of HCl in water (1 M), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% (1:1 MTBE:CH2Cl2) in hexanes) to afford the title compound as an off-white solid (67% yield). Enantiomeric purity was determined by HPLC using CHIRALPAK IA-3 and eluting with 5% isopropanol in heptanes. 1H NMR (400 MHz, CDCl3): δ ppm 8.46 (s, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 8.5, 2.2 Hz, 1H), 6.49 (q, J = 7.1 Hz, 1H), 2.67 (s, 3H), 1.94 (d, J = 7.1 Hz, 3H); [M+H] 341.0.

[0733] Precursor III. Preparation of (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide.

[0734] Step 1. Preparation of ethyl 2-(3,5-dichloropyrazin-2-yl)-2-oxoacetate.

[0735] To a solution of 2,4,6-trimethylpyridine (67 mL, 0.40 mol) in THF (600 mL) at -78 °C was added nBuLi (2.5 M in hexanes, 208 mL, 0.52 mol). The mixture was stirred at -78 °C for 20 min and then warmed to 0 °C. In a separate flask, diethyl oxalate (65 mL, 0.48 mol) and 2,6-dichloropyrazine (60 g, 0.40 mol) were dissolved in THF (600 mL) and cooled to -78 °C. The lithium 2,4,6-trimethylpyridine solution was added to the 2,6-dichloropyrazine solution via cannula over 1 h at -78 °C. The mixture was stirred at -78 °C for 20 min, and then the mixture was poured into a mixture of saturated NH4Cl (300 ml) and water (300 ml). The mixture was diluted with EtOAc (300 ml), and the layers were separated. The aqueous layer was extracted with EtOAc (300 ml), and the combined organic layers were dried over MgSO4. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5 to 20% EtOAc in hexanes) to afford the title compound (32 g, 32% yield). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.87 (s, 1H), 8.18 (s l, 1H), 8.01 (s l, 1H).

[0736] Step 2. Preparation of ethyl (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxylate.

[0737] To a solution of ethyl 2-(3,5-dichloropyrazin-2-yl)-2-oxoacetate (14.5 g, 58.4 mmol) in THF (97 mL) was added (R)-(1-(2,4-dichlorophenyl)ethyl)hydrazine hydrochloride (Example 5, Step 2, 11.7 g, 48.7 mmol). The mixture was heated to 80 °C for 2 h and then cooled to room temperature. The mixture was allowed to stand at room temperature under argon for 12 h. The mixture was diluted with brine and the layers were separated. The aqueous layer was extracted with EtOAc 2x. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give a red oil.

[0738] The red oil was dissolved in THF (240 mL) and cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 3.9 g, 97 mmol) was added, and the mixture was stirred at room temperature for 15 h. The mixture was diluted with saturated NH4Cl (200 mL), water (200 mL), and EtOAc (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10 to 20% EtOAc in hexanes) to afford the title compound (9.0 g, 46% yield) in >99% enantiomeric excess. The enantiomeric excess was determined by HPLC using a CHIRALPAK IF-3 column and eluting with 5% isopropanol in heptanes (retention time 7.2 min).

[0739] Step 3. Reaction of ammonia with (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-ethyl carboxylate.

[0740] To a solution of ethyl (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxylate (4.0 g, 10 mmol) in dioxane (40 mL) at room temperature was added ammonium hydroxide (29% in water, 40 mL). The mixture was stirred in a sealed tube at room temperature for 3 d. The mixture was diluted with saturated NaHCO3. The mixture was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound (3.4 g, 92% yield) as a light yellow solid. *H NMR (400 MHz, DMSO-dd): δ ppm 8.87 (s, 1H), 7.93 (bs, 1H), 7.84 (bs, 1H), 7.65-7.68 (m, 1H), 7.46-7.50 (m, 1H), 7.51-7.45 (m, 1H), 6.49 (q, J = 6.9Hz , 1H), 1.91 (d, J = 7.0Hz, 3H); [M+H] 370.0.

[0741] Precursor IV. (R)-6-Chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.

[0742] To a solution of (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide (4.5 g, 12.2 mmol) in dichloromethane (30 mL) at room temperature under argon was added methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent, 4.3 g, 18.1 mmol). The mixture was stirred at room temperature for 2 d. The mixture was preabsorbed onto silica gel and purified by chromatography (5% to 20% EtOAc in hexanes) to give the title compound (3.68 g, 88% yield) as a sticky colorless solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.69 (s, 1H), 7.40-7.45 (m, 2H), 7.25-7.29 (m, 1H), 6.68 (q, J = 7.0Hz, 1H), 1.98 (d, J = 7.1Hz, 3H); [M+H] 351.9.

[0743] Precursor V. (R)-6-Chloro-1-(1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine.

[0744] Step 1. (E)-3,5-Dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)-2,2,2-trifluoroethyl)pyrazine and ( Z)-3,5-dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)-2,2,2-trifluoroethyl)pyrazine.

[0745] To a solution of 2,2,6,6-tetramethylpiperidine (13.71 mL, 80.55 mmol) in THF (200 mL) at -40 °C was added n-BuLi (2.5 M in hexanes, 34.91 mL, 87.26 mmol). The mixture was stirred at -40 °C for 30 min. In a separate flask, ethyl 2,2,2-trifluoroacetate (10.38 mL, 87.26 mmol) and 2,6-dichloropyrazine (10.00 g, 67.13 mmol) were dissolved in THF (200 mL) and cooled to -90 °C. The 2,2,6,6-tetramethylpiperidine lithium solution was added to the 2,6-dichloropyrazine solution via cannula over 30 min at -90 °C. The mixture was stirred at -90 °C for 30 min and (R)-(1-(2,4-dichlorophenyl)ethyl)hydrazine hydrochloride (Example 5, Step 2, 11.7 g, 9.73 g, 40.28 mmol) was added, and then the mixture was allowed to warm to room temperature. The mixture was concentrated under reduced pressure, then ethanol (200 mL) was added, and the mixture was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to afford the title compounds as a viscous orange oil.

[0746] Step 2. (R)-6-Chloro-1-(1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine.

[0747] (E/Z mixture of (R))-3,5-Dichloro-2-(1-(2-(1-(2,4-dichlorophenyl)ethyl)hydrazono)-2,2,2-trifluoroethyl)pyrazine (2.5 g, 5.8 mmol) was dissolved in THF (58 mL) and then the solution was cooled to 0 °C. Then, 1,8-diazabicyclo[5,4,0]undec-7-ene (1.73 mL, 11.8 mmol) was then added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 10 h. The mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (0 to 20% EtOAc in hexanes) to afford the title compound as a light orange oil.

[0748] General procedure A: Alkylation of tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate by reductive amination.

[0749] Commercially available tert-butyl 3-(Piperidin-3-yl)azetidine-1-carboxylate (240 mg, 1 mmol) was dissolved in 6 mL of dry 1,2-dichloromethane and carbonyl compound (1 mmol) was added all at once. The mixture was allowed to stir at room temperature for 5 min and then NaBH(OAc)3 (2 mmol) was added and the reaction mixture was stirred for 1-18 h at room temperature. The conversion was monitored by LCMS. Upon completion, saturated sodium bicarbonate solution was added and the reaction mixture was allowed to stir for an additional 30 min. The mixture was extracted 3 times with dichloromethane, the combined organic phase was dried over MgSO4, filtered, and the residue was purified on silica using methanol-dichloromethane as eluent.

[0750] General procedure B: Alkylation of tert-butyl 3-(pipedin-3-yl)azetidine-1-carboxylate.

[0751] tert-Butyl 3-(Piperidin-3-yl)azetidine-1-carboxylate (240 mg, 1 mmol) was dissolved in 5 mL of dry solvent and (a) Michael acceptor (1 mmol) was added to the solution all at once and the reaction mixture was stirred at room temperature or at 50 °C until complete conversion was achieved (followed by LCMS); upon completion, the solvent was removed in vacuo and the product purified by silica gel chromatography using methanol and dichloromethane as eluent, or (b) 1 mmol of alkyl halide, 10 mol % sodium iodide, and sodium carbonate (2 mmol) were added to the solution all at once and the reaction mixture was heated to 75 °C under a nitrogen atmosphere and monitored by LCMS; Upon completion, the reaction mixture was diluted with 20 ml of water, extracted 3 times with ethyl acetate, the combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure; the residue was purified on silica using methanol and dichloromethane as the eluent.

[0752] General procedure C: Deprotection of 1-alkyl tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate.

[0753] 1-Alkyl tert-butyl 3-(Pipe ridin-3-yl)azetidine-1-carboxylate (0.7 mmol) was dissolved in 3 ml of dichloromethane and 2 ml of 4 M HCl solution in 1,4-dioxane was added thereto. The resulting mixture was stirred at room temperature until complete conversion was achieved (1-3 h). After that, the solvents were removed in vacuo and the residue was dried under high vacuum for 12 h. The product was used in the next step without purification.

[0754] General procedure D: Nucleophilic aromatic substitution by 1-alkyl 3-(azetidin-3-yl)piperidine.

[0755] 1-Alkyl 3-(azetidin-3-yl)piperidine (0.55 mmol) and appropriate heteroaryl precursor I, II, III, IV or V (0.5 mmol) were dissolved in 2 ml of dry DMF or DMSO. Diisopropylethylamine (2.5 mmol) was added and the mixture was stirred at room temperature (Y=CH, X=N, R2=CN) or at 80 °C (Y=N, X=CH, R2=Me and Y=CH, X=N, R2=Me). The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was (a) diluted with 2 ml of acetonitrile and injected directly onto reversed-phase HPLC for purification or (b) concentrated in vacuo and purified by normal-phase silica gel chromatography using dichloromethane and methanol as eluent.

[0756] Precursors VI and VII. Chiral resolution of tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate.

[0757] tert-Butyl 3-(3-Pipe ridyl)azetidine-1-carboxylate (77.02 g, 320 mmol) was dissolved in tert-butyl methyl ether (1700 mL) in a 5 L three-neck flask equipped with a mechanical stirrer and a water condenser. When the mixture was stirred at reflux, L-(+)-mandelic acid (24.38 g, 160 mmol) was added. The resulting mixture was allowed to stir at reflux for 15 min and then cooled to rt overnight. The white solid was collected by filtration, rinsing with tert-butyl methyl ether (500 mL). The white solid was stirred at reflux in tert-butyl methyl ether (1700 mL) for 30 min. The salt was collected by filtration and washed with tert-butyl methyl ether (500 ml). The process was repeated again to yield a white solid (95% ee).

[0758] The white salt (~62.8 g) was further purified by recrystallization from chloroform/tert-butyl methyl ether (900 mL/900 mL). The salt was dissolved in chloroform (900 mL) on a hot plate bringing it to a gentle boil, then tert-butyl methyl ether (900 mL) was slowly added. This formed a clear solution when hot. The solution was cooled to room temperature overnight, and crystals appeared. The crystals were isolated by filtration and further dried under high vacuum for 4 h to yield 64.85 g of the mandelate salt with 1 equiv of chloroform by 1H nuclear magnetic resonance ("NMR") in methanol (>99% ee).

[0759] Method for determination of %ee: Chiral high performance liquid chromatography ("HPLC"), 210nm, IC-3 column (4.6 x 250 mm, 3 μM), 50% heptane, 50% isopropanol, 1 ml/min, 210 nM, (R-3-(piperidin-3-yl)azetidine-1-carboxylate tert-butyl (precursor VI) Rt = 8.8-9 min, (S)-3-(piperidin-3-yl)azetidine-1-carboxylate tert-butyl (precursor VII) Rt = 8.5 min.

[0760] Precursor VIII. 1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl) -1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile.

[0761] Step 1: (R)-1-(4-Chloro-2-fluorophenyl)ethan-1-ol.

[0762] To a solution of 1-(4-chloro-2-fluorophenyl)ethan-1-one (10 g, 58 mmol) in tetrahydrofuran (100 mL) at -78 °C under a nitrogen atmosphere was added (+)-B-Chlorodiisopinocampheylborane (50 to 60 wt % in hexanes, 9.2 mL, 64 mmol) slowly. The resulting mixture was slowly warmed to -25 °C and stirred at that temperature for 2 h. 1-(4-Chloro-2-fluorophenyl)ethan-1-one was detected by LCMS and HPLC, and the mixture was cooled back to -78 °C. (+)-B-Chlorodiisopinocampheylborane (50 to 65 wt % in hexanes, 5.4 mL, 38 mmol) was added to the mixture at -78 °C. The resulting mixture was slowly warmed to -25 °C and stirred at that temperature for 5 h. Diethanolamine (18 mL, 191 mmol) was added to the reaction mixture, which was then stirred at room temperature for 3 d. The reaction was filtered, and the filtrate was concentrated and purified by silica gel chromatography (0 to 30% ethyl acetate in hexanes) to afford 18.8 g of crude (R)-1-(chloro-2-fluorophenyl)ethan-1-ol.

[0763] Step 2: 4-Chloro-1-(1-chloroethyl)-2-fluorobenzene.

[0764] To a flask containing (R)-1-(4-chloro-2-fluorophenyl)ethan-1-ol (18.8 g, 108 mmol) in dichloromethane ("DCM") (1 L) were added triphenylphosphine (113 g, 432 mmol) and carbon tetrachloride (41.7 mL, 432 mmol). The mixture was stirred at room temperature for 3 d, then silica gel (400 g) was added to the mixture. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% hexanes) to afford 4-chloro-1-(1-chloroethyl)-2-fluorobenzene (8 g) as a colorless oil.

[0765] Step 3: (1-(4-chloro-2-fluorophenyl)ethyl)hydrazine hydrochloride.

[0766] To a solution of 4-chloro-1-(1-chloroethyl)-2-fluorobenzene (4.0 g, 41 mmol) in ethanol (120 ml) was added hydrazine hydrate (excess). The mixture was stirred at 35 °C for 3 d. The reaction was concentrated, and diethyl was added to the mixture. The bottom hydrazine layer was removed, and about 5 ml of 4 M HCl in 1,4-dioxane was added to the mixture at 0 °C. The mixture was kept at 0 °C until all of the hydrazine HCl salt had precipitated. The mixture was filtered, washed with cold diethyl ether, and concentrated in vacuo to afford the title compound as the hydrochloride salt (3.95 g), which was used without further purification.

[0767] Step 4. (R)-6-chloro-1-(1-(4-chloro-2-fluorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazine.

[0768] The title compound was synthesized according to the procedures outlined in Precursor III, Steps 1-3 and Precursor VI. The crude product was purified using an alumina column (eluting with 25% to 50% DCM in hexanes) to afford impure 6-chloro-1-(1-(4-chloro-2-fluorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazine (2.2 g). This material was repurified by alumina column to afford the title compound (1.94 g) as a light yellow oil which was purified by SFC (Lux-amylose 4 (two 2 × 15 cm columns), eluting with 10% methanol with 0.1% DEA and CO2 at 10 MPa (100 bar), 60 ml/min) to afford the pure product as a mixture of enantiomers. The enantiomers were separated by preparative chiral SFC (OJ-H (2 × 25 cm), eluting with 10% isopropanol with 0.1% DEA and CO2 at 10 MPa (100 bar), 70 ml/min) to afford the desired enantiomer as the first eluting enantiomer (485 mg) at 2.67 min.

Exemplary compounds

[0769] EXAMPLE 1

[0770] 2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin Ethyl -6-yl)azetidin-3-yl)piperidin-1-yl)acetate 2,2,2-trifluoroacetate and 2-((S)-3-(1-(1-((R)-1- (2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl acetate 2,2,2 -trifluoroacetate. Prepared as a mixture of the above two diastereomers using general procedure A with 50% toluene solution of ethyl 2-oxoacetate, followed by procedure C. The resulting diastereomeric mixture product was condensed with Precursor II using procedure D(a). 1HRMN (400 MHz, CDCl3, trifluoroacetic acid salt): δ ppm 10.43 (bs, 1H), 7.66 (s, 1H), 7.37-7.39 (m, 2H), 7.12- 7.17 (m, 1H), 6.26-6.35 (m, 1H), 4.16-4.29 (m, 4H), 3.88-3.96 (m, 4H), 3, 54-3.68 (m, 2H), 3.07-3.20 (m, 1H), 2.80-2.94 (m, 1H), 2.54-2.68 (m, 4H), 2.30-2.43 (m, 1H), 1.92-2.10 (m, 3H), 1.88 (d, J = 7.1Hz, 3H), 1.29 (t, J = 7.1Hz, 3H), 1.08-1.23 (m, 1H). [M+H] 531.3.

[0771] EXAMPLE 2

[0772] 2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)acetic acid. The diastereomers of Example 1 were separated using 5% isopropanol in heptanes (0.1% diethylamine) on CHIRALPAK IF SFC 20 x 250 mm (5 μM), followed by treatment of the first eluting diastereomer with 5 equiv of LiOH in MeOH at room temperature for 12 h, and repurification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluent. 1H NMR (400 MHz, CDCl3, trifluoroacetic acid salt): δ ppm 7.68 (m, 1H), 7.35-7.40 (m, 1H), 7.31-7.33 (m, 1H), 7.12-7.16 (m, 1H), 6.29 (q, J = 7.0Hz, 1H), 4.16-4.26 ( m, 2H), 3.86-3.98 (m, 4H), 3.64-3.78 (m, 2H), 2.75-2.88 (m, 1H), 2.48-2.65 (m, 5H), 2.28-2.41 (m, 1H), 1.84-2.10 (m, 6H), 1.00-1.18 (m, 1H); [M+H] 503.3.

[0773] EXAMPLE 3

[0774] 2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b] acid pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)acetic acid. The diastereomers of Example 1 were separated at the ester stage using 5% isopropanol in heptanes (0.1% diethylamine) on CHIRALPAK IF SFC 20 x 250 mm (5 μM), followed by treatment of the eluting second diastereomer with 5 equiv of LiOH in MeOH at room temperature for 12 h, and repurification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluent. 1H NMR (400 MHz, CDCl3, trifluoroacetic acid salt): δ ppm 11.42 (bs, 2H), 7.68 (s, 1H), 7.36-7.40 (m, 1H), 7.32 -7.34 (m, 1H), 7.12-.716 (m, 1H), 6.31 (q, J = 7.0Hz, 1H), 4.18 4.26 (m, 2H), 3 .85-3.98 (m, 4H), 3.65-3.78 (m, 2H), 2.74 2.88 (m, 1H), 2.48-2.60 (m, 5H), 2.28-2.40 (m, 1H), 1.85 2.08 (m, 6H), 1.00-1.15 (m, 1H). [M+H] 503.3.

[0775] EXAMPLE 4

[0776] 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin -6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide and 2-((S)-3-(1-(1- ((R)-1-(2,4- dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide. Prepared as a mixture of the above two diastereomers using general procedure B (a) with ethenesulfonyl fluoride and treating the resulting mixture with aqueous ammonia at 70 °C for 30 min followed by procedure C and the resulting diastereomeric mixture product was condensed with Precursor II using procedure D (a). [M+H] 552.2.

[0777] EXAMPLE 5

[0778] 2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide. The diastereomers of Example 4 were separated using 45% isopropanol in heptanes (0.1% diethylamine) on CHIRALPAK IF SFC 20 x 250 mm (5 μM). The first eluting diastereomer had the structure indicated above, 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.71 (s, 1H), 7.29–7.44 (m, 1H), 7.35–7.39 (m, 1H), 7.23–7.27 (m, 1H), 6.28 (q, J = 7.1Hz, 1H), 4.21 (dt, J = 2.6Hz, J = 8.5Hz, 2H), 3.89–3.95 (m, 2H), 3.28–3.33 (m, 1H), 2.83–2.94 (m, 4H), 2.52–2.64 (m, 1H), 2.49 (s, 3H), 2.03-2.13 (m, 1H), 1.72-1.89 (m, 7H), 1.52-1.65 (m, 1H), 1.15 (d, J = 6.2Hz, 3H), 0.88-1.02 (m, 1H). [M+H] 552.2.

[0779] EXAMPLE 6

[0780] 2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide. The diastereomers of Example 4 were separated using 45% isopropanol in heptanes (0.1% diethylamine) on CHIRALPAK IF SFC 20 x 250 mm (5 μM). The second eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.71 (s, 1H), 7.42-7.45 (m. 1H), 7.35-7.39 (m, 1H), 7.23-7.27 (m, 1H), 6.28 (q, J = 7.0Hz, 1H), 4.21 (dt, J = 5.6Hz, J = 8.4Hz, 2H) ppm 3.91 (dt, J = 5.9Hz, J = 9.4Hz, 2H), 3.27-3.33 (m, 1H), 2.83- 2.94 (m, 4H), 2.53-2.63 (m, 1H), 2.49 (s, 3H), 2.02-2.12 (m, 1H), 1.70-1.90 (m, 7H), 1.52-1.64 (m, 1H), 1.15 (d, J = 6.2Hz, 1H), 0.87-1.00 (m, 1H). [M+H] 552.3.

[0781] EXAMPLE 7

[0782] 3-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b] acid pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanoic acid and 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl) ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanoic acid. Prepared as a mixture of the above two diastereomers using general procedure B (a) with methyl acrylate, followed by procedure C and the resulting diastereomeric mixture product was condensed with Precursor II using procedure D (a), followed by treatment of the diastereomeric mixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, and repurification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA). as eluent. [M+H] 517.3.

[0783] EXAMPLE 8

[0784] 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanoic acid. The example was prepared using general procedure B(a) with methyl acrylate, followed by procedure C, and the resulting product was condensed with Precursor II using procedure D(a), followed by treatment of the diastereomeric mixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, and purification by reversed-phase HPLC using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as the eluent. The diastereomers were separated using 40% isopropanol (0.1% diethylamine) and 10 MPa (100 bar) CO2 in AD-H SFC 20 x 250 mm (5 μM). The first eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.74 (s, 1H), 7.44-7.46 (m, 1H), 7.34-7.38 (m, 1H), 7.24-7.28 (m, 1H), 6.29 (q, J = 7.1 Hz, 1H), (m, 2H), 3.98-4.01 (m, 2H), 3.33-3.43 (m, 2H), 3.11-3.19 (m, 2H), 2.62-2.75 (m, 2H), 2.54 (t, J = 6.9Hz, 2H), 2.42-2.52 (m, 4H), 1.68-2.12(m, 7H), 1.10-1.23 (m, 1H). [M+H] 517.3.

[0785] EXAMPLE 9

[0786] 3-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanoic acid. The example was prepared using general procedure B(a) with methyl acrylate, followed by procedure C, and the resulting product was condensed with Precursor II using procedure D(a), followed by treatment of the diastereomeric mixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, and purification by reversed-phase HPLC using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as the eluent. The diastereomers were separated using 40% isopropanol (0.1% diethylamine) and 10 MPa (100 bar) CO2 in AD-H SFC 20 x 250 mm (5 μM). The second eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.73 (s, 1H), 7.43-7.45 (m, 1H), 7.34-7.38 (m, 1H), 7.23-7.28 (m, 1H), 6.28 (q, J = 7.1 Hz, 1H), (m, 2H), 3.93-4.01 (m, 2H), 3.30-3.40 (m, 2H), 3.10-3.17 (m, 2H), 2.62-2.72 (m, 2H), 2.50-2.56 (m, 2H), 2.50 (s, 3H), 2.36-2.50 (m, 1H), 1.99-2.10 (m, 1H), 1.84-1.99 (m, 5H), 1.68-1.80 (m, 1H), 1.09-1.22 (m, 1H). [M+H] 517.3.

[0787] EXAMPLE 10

[0788] 4-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. Example was prepared using general Procedure A with methyl 4-oxobutanoate followed by Procedure C and the resulting product was condensed with Precursor II using Procedure D(a). The diastereomers were separated at the ester stage using 25% ethanol in heptanes (0.1% diethylamine) on CHIRACEL OZ-H 20 × 250 mm (5 μM), followed by treatment of the first eluting diastereomer with 5 equiv of LiOH in MeOH at room temperature for 12 h, and purification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluent. 1H NMR (400 MHz, ACN-d3, trifluoroacetic acid salt): δ ppm 8.03 (bs, 1H), 7.73 (s, 1H), 7.46-7.48 (m, 1H), 7.39-7.43 (m, 1H), 7.24-7.28 (m, 1H), 6.25 (q, J = 7.1Hz, 1H), 4.14-4.24 (m, 2H), 3.86-3.94 (m, 2H), 3.44-3.58 (m, 2H), 3.04-3.12 (m, 2H), 2.73-2.85 (m, 1H), 2.48-2.65 (m, 2H), 2.41-2.47 (m, 5H), 1.68-2.16 (m, 8H), 1.06-1.20 (m, 1H). [M+H] 531.2.

[0789] EXAMPLE 11

[0790] 4-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. Prepared using general Procedure A with methyl 4-oxobutanoate, followed by Procedure C and the resulting product was condensed with Precursor II using Procedure D(a). The diastereomers were separated at the ester stage using 25% ethanol in heptanes (0.1% diethylamine) on a CHIRACEL OZ-H 20 × 250 mm (5 μ), followed by treatment of the second diastereomer by elution with 5 eq of LiOH in MeOH at room temperature for 12 h, and repurification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluent. 1H NMR (400 MHz, ACN-d3, trifluoroacetic acid salt): δ ppm 8.27 (bs, 1H), 7.73 (s, 1H), 7.46-7.48 (m, 1H), 7.40-7.44 (m, 1H), 7.24-7.28 (m, 1H), 6.24 (q, J = 7.1Hz, 1H), 4,154.23 (m, 2H), 3.85-3.95 (m, 2H), 3.43-3.58 (m, 2H), 3,033.13 (m, 2H), 2.72-2.84 (m, 1H), 2.47-2.65 (m, 2H), 2,412.46 (m, 5H), 2.05-2.18 (m, 1H), 1.92-2.02 (m, 3H), 1.691.92 (m, 5H), 1.06-1.19 (m, 1H). [M+H] 531.2.

[0791] EXAMPLE 12

[0792] 3-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide. Prepared using general procedure B (a) using acrylamide, followed by procedure C and the resulting product was condensed with precursor II using procedure D (a). The diastereomers were separated using 20% ethanol in heptanes (0.1% diethylamine) on CHIRALPAK ID 20 x 250 mm (5 μM). The first eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 8.08 (bs, 1H), 7.64 (s, 1H), 7.35-7.38 (m, 1H), 7.32-7.35 (m, 1H), 7.10-7.15 (m, 1H), 6.30 (q, J = 7.1Hz, 5.8), 0 (bs, 1H), 4.14-4.22 (m, 2H), 3.83-3.90 (m, 2H), 2.85-2.98 (m, 2H), 2.63-2.72 (m, 2H), 2.52-2.62 (m, 4H), 2.40-2.48 (m, 2H), 2.00-2.10 (m, 1H), 1.73-1.91 (m, 7H), 1.52-1.64 (m, 1H), 0.90-1.14 (m, 1H). [M+H] 516.3.

[0793] EXAMPLE 13

[0794] 3-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide. The example was prepared using general procedure B (a) using acrylamide followed by procedure C and the resulting product was condensed with Precursor II using procedure D (a). The diastereomers were separated using 20% ethanol in heptanes (0.1% diethylamine) on CHIRALPAK ID 20 x 250 mm (5 μM). The second eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 8.09 (bs, 1H), 7.64 (s, 1H), 7.35-7.39 (m, 1H), 7.33-7.35 (m, 1H), 7.11-7.15 (m, 1H), 6.31 (q, J = 7.1Hz, 5.5), 4 (bs, 1H), 4.15-4.24 (m, 2H), 3.82-3.90 (m, 2H), 2.83-2.96 (m, 2H), 2.60-2.66 (m, 2H), 2.55-2.60 (m, 4H), 2.40-2.46 (m, 2H), 1.97-2.07 (m, 1H), 1.70-1.90 (m, 7H), 1.50-1.63 (m, 1H), 0.90-1.03 (m, 1H). [M+H] 516.3.

[0795] EXAMPLE 14

[0796] 3-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-1-ol. The example was prepared using general procedure A with methyl 4-oxobutanoate, followed by ester reduction with 5 equiv of LiBH4 in THF/MeOH at room temperature, then application of general procedure C and the resulting product was coupled to precursor II using procedure D (a). The diastereomers were separated using 20% ethanol in heptanes (0.1% diethylamine) on CHIRACEL OZ-H 20 x 250 mm (5 μM). The first eluting diastereomer had the structure indicated above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 7.64 (s, 1H), 7.36-7.40 (m, 1H), 7.33-7.36 (m, 1H), 7.12-7.16 (m, 1H), 6.31 (q, J = 7.1Hz, 1H), 4.154.23 (m, 2H), 3.88-3.94 (m, 1H), 3.83-3.88 (m, 1H), 3,773.82 (m, 2H), 2.92-3.06 (m, 2H), 2.53-2.65 (m, 6H), 1,502.06 (m, 11H), 0.88-1.02 (m, 1H). [M+H] 503.0.

[0797] EXAMPLE 15

[0798] 3-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-1-ol. The example was prepared using general procedure A with methyl 4-oxobutanoate, followed by ester reduction with 5 equiv of LiBH4 in THF/MeOH at room temperature, then application of general procedure C and the resulting product was coupled to precursor II using procedure D (a). The diastereomers were separated using 20% ethanol in heptanes (0.1% diethylamine) on CHIRACEL OZ-H 20 x 250 mm (5 μM). The second eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 7.63 (s, 1H), 7.34–7.39 (m, 2H), 7.11–7.15 (m, 1H), 6.30 (q, J = 7.1 Hz, 1H), 4.14–4.22 (m, 2H), 3,843.94 (m, 2H), 3.77–3.82 (m, 2H), 2.89–3.03 (m, 2H), 2,522.64 (m, 6H), 1.65–2.05 (m, 10H), 1.49–1.63 (m, 1H), 0.881.02 (m, 1H). [M+H] 503.0.

[0799] EXAMPLE 16

[0800] Cis-3-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid; Trans-3-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)- 3-methyl-1H-pyrazolo[3,4-b]pyrazin acid -6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid; CA-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin acid -6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid; and trans-3-((R)-3-(1-(1- ((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b] acid pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic. Prepared as a mixture of the above four diastereomers using general procedure A using 3-oxocyclobutane-1-carboxylic acid, followed by procedure C and the resulting diastereomeric mixture product was coupled to Precursor II using procedure D (a). [M+H] 543.2.

[0801] EXAMPLE 17

[0802] 4-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b] acid pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid and 4-((R)-3- (1-(1-((R)-1-(2,4-dichlorophenyl) ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. Prepared as a mixture of the above two diastereomers using general procedure A with methyl 4-oxobutanoate, followed by procedure C and the resulting diastereomeric mixture product was coupled to Precursor II using procedure D(a), followed by treatment of the diastereomeric mixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, and purification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as the eluent. [M+H] 542.2.

[0803] EXAMPLE 18

[0804] 4-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. The diastereomers of Example 17 were separated on a 20 x 250 mm AD-H column using 40% isopropanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The first eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 7.82 (s, 1H), 6.34-7.38 (m, 2H), 7.17-7.21 (m, 1H), 6.45 (q, J = 7.1Hz, 1H), 4.20-4.30 (m, 2H), 3.88-4.00 (m, 2H ), 3.02-3.14 (m, 2H), 2.57-2.70 (m, 3H), 2.45-2.55 (m, 2H), 2.18-2.30 (m, 1H), 1.68-2.10 (m, 10H), 0.93-1.07 (m, 1H). [M+H] 542.2.

[0805] EXAMPLE 19

[0806] 4-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b] acid pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid and 4-((R)-3- (1-(1-((R)-1-(2,4-dichlorophenyl) ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. The example was prepared using general procedure A with methyl 4-oxobutanoate, C and D (a), followed by treatment of the diastereomeric mixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, and purification by HPLC of reverse phase using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluent. The diastereomers were separated on a 20 x 250 mm AD-H column using 40% isopropanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The second eluting diastereomer had the structure indicated above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 7.82 (s, 1H), 7.34-7.38 (m, 2H), 7,177.21 (m, 1H), 6.44 (q , J = 7.1 Hz, 1H), 4.19-4.29 (m, 2H), 3.90-4.02 (m, 2H), 3.04-3.16 (m, 2H), 2.48-2.74 (m, 5H), 2.23-2.33 (m, 1H), 1.95-2.20 (m, 2H), 1.70-1.91 (m, 8H ), 0.96-1.09 (m, 1H). [M+H] 542.2.

[0807] EXAMPLE 20

[0808] 4-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d] acid pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid and 4-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl) ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. Prepared as a mixture of the above two diastereomers using general procedure A with methyl 4-oxobutanoate, followed by procedure C and the resulting diastereomeric mixture product was condensed with Precursor I using procedure D(a), followed by treating the diastereomeric mixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, and purified by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluent. [M+H] 531.3.

[0809] EXAMPLE 21

[0810] 4-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. The example was prepared using general procedure A with methyl 4-oxobutanoate, followed by procedure C and condensation of the product with precursor I using procedure D(a), followed by treatment of the diastereomeric mixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, and purification by reversed-phase HPLC using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluent. The diastereomers were separated on a 20 x 250 mm AD-H column using 30% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The first diastereomer in elution had the structure indicated above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 8.61 (s, 1H), 7.39-7.43 (m, 1H), 7.33-7.36 (m, 1H), 7.13-7.17 (m, 1H), 6.29 (q, J = 7.1Hz, 1H), 4.12-4.23 (m, 2H ), 3.82-3.94 (m, 2H), 3.06-3.21 (m, 2H), 2.66-2.76 (m, 2H), 2.53-2.63 (m, 2H), 2.42-2.52 (m, 4H), 2.22-2.35 (m, 1H), 1.95-22.10 (m, 2H), 1.75-1.94 (m, 7H), 1.22-1.32 (m, 1H), 0.94-1.06 (m, 1H). [M+H] 531.3.

[0811] EXAMPLE 22

[0812] 4-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. The example was prepared using general procedure A with methyl 4-oxobutanoate, followed by procedure C and condensation of the product with precursor I using procedure D(a), followed by treatment of the diastereomeric mixture with 5 equiv of LiOH in MeOH at room temperature for 12 h, and purification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as the eluent. The diastereomers were separated on a 20 x 250 mm AD-H column using 30% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The structure was assigned to the second eluting diastereomer. 1H NMR (400 MHz, CDCl3, free base): δ ppm 8.61 (s, 1H), 7.40-7.44 (m, 1H), 7.34-7.36 (m, 1H), 7.13-7.17 (m, 1H), 6.28 (q, J = 7.1Hz, 1H), 4.13-4.23 (m, 2H ), 3.85-3.93 (m, 2H), 3.03-3.17 (m, 2H), 2.65-2.76 (m, 2H), 2.57-2.62 (m, 2H), 2.45-2.55 (m, 4H), 2.21-2.32 (m, 1H), 1.94-2.10 (m, 2H), 1.73-1.92 (m, 8H), 0.95-1.18 (m, 1H). [M+H] 531.3.

[0813] EXAMPLE 23

[0814] 1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)azetidin- 1-yl)-1H- pyrazolo[3,4-b]pyrazine-3-carbonitrile and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)- 1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. Prepared as a mixture of the above two diastereomers using general procedure B (a) with methylvinyl sulfone, procedure C and condensation of the resulting diastereomeric mixture product with Precursor IV using procedure D (a). 1H NMR (400 MHz, CDCl3; trifluoroacetic acid salt): δ ppm 9.76 (bs, 1H), 7.85 (s, 1H), 7.39 -7.34 (m, 2H), 7.20 (dd, J = 8.5, 2.1 Hz, 1H), 6.45 (qd, J = 7.0, 3.2 Hz, 1H), 4.35 - 4.23 (m, 2H), 4.06 - 3.94 (m, 2H), 3.78 - 3.52 (m, 5H), 3.04 (s, 3H), 2.92 - 2.78 (m, 1H), 2, 74 - 2.59 (m, 1H), 2.60 - 2.47 (m, 1H), 2.36 - 2.21 (m, 1H), 2.14 - 1.93 (m, 4H), 1.90 (d, J = 7.1 Hz, 3H), 1.28 - 1 .11 (m, 1H). [M+H] 562.0.

[0815] EXAMPLE 24

[0816] 3-((S)-3-(1-(3-Cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide and 3-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide. Prepared as a mixture of the above two diastereomers using general Procedure B (a) using acrylamide, followed by Procedure C and condensation of the resulting diastereomeric mixture product with Precursor IV using Procedure D (a). [M+H] 527.2.

[0817] EXAMPLE 25

[0818] 3-((S)-3-(1-(3-Cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide. The diastereomers prepared in Example 24 were separated on a 20 x 250 AD-H column using 30% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The first eluting isomer was assigned to the structure. 1H NMR (400 MHz, DMSOd6, free base): δ ppm 8.04 (s, 1H), 7.64-7.66 (m, 1H), 7.41-7.49 (m, 2H), 7.36 (bs, 1H), 7.76 (bs, 1H), 6.32 (q, J=7.0Hz, 1H), 4.08-4.3 6 (bm, 2H), 3.30-4.08 (bm, 2H), 2.67- 2.75 (m, 2H), 2.54-2.64 (m, 1H), 2.43-2.53 (m, 2H), 2.17- 2.24 (m, 2H), 1.80.1-96 (m, 4H), 1.56-1.80 (m, 4H), 1.34- 1.48 (m, 1H), 0.78-0.92 (m, 1H). [M+H] 527.2.

[0819] EXAMPLE 26

[0820] 3-((R)-3-(1-(3-Cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propanamide. The diastereomers prepared in Example 24 were separated on a 20 x 250 AD-H column using 30% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The second eluting isomer was assigned the structure given above. 1H NMR (400 MHz, DMSO-d6, free base): δ ppm 8.05 (s, 1H), 7.65-7.67 (m, 1H), 7.41-7.48 (m, 2H), 7.36 (bs, 1H), 6.76 (bs, 1H), 6.32 (q, J=7.1Hz, 1H), 4.06-4, 36 (bm, 2H), 3.80-4.06 (bm, 2H), 2.67-2.77 (m, 2H), 2.52- 2.63 (m, 1H), 2.46-2.53 (m, 2H), 2.17-2.23 (m, 2H), 1.82-1.95 (m, 4H), 1.57-1.79 (m, 4H), 1.35- 1.49 (m, 1H), 0.78-0.92 (m, 1H). [M+H] 527.2.

[0821] EXAMPLE 27

[0822] 1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1- ((S)-2-hydroxypropyl)piperidin-3-yl)azetidin -1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile; 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(S)-1-((R)-2-hydroxypropyl)piperidin-3-yl)azetidin-1-yl )-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile; 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)azetidin-1- yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile; and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1 -((R)-2-hydroxypropyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. Prepared as a mixture of the above four diastereomers using of the general procedure A hydroxyacetone, followed by procedure C, and condensation of the resulting diastereomeric mixture product with Precursor IV using procedure D (a). LCMS: [M+H] 514.3. Diastereomers separated on a 20 x 250 mm AD-H column using 40% isopropanol (0.2% n-propylamine) and 10 MPa (100 bar) CO2.

[0823] EXAMPLE 28

[0824] First isomer eluting from the mixture of Example 27. 1H NMR (400 MHz, CDCl3, free base): δ ppm 7.82 (s, 1H), 7.33-7.43 (bm, 2H), 7.16-7.23 (m, 1H), 6.40-6.50 (bq, 1H), 4.18-4.30 (m, 2H), 3.87-3.97 (m, 2H), 3.24-3.45 (m, 2H), 2.46-2.90 (m, 5H), 1.50-1.96 (m, 10H), 0.85-1.04 (2H). [M+H] 514.3.

[0825] EXAMPLE 29

[0826] Second isomer eluting from the mixture of Example 27. 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.96 (s, 1H), 7.47-7.49 (m, 1H), 7.29-7.38 (m, 2H), 6.45 (q, J = 7.1 Hz, 1H), 4.28-4.38 (m, 2H), 3.96-4.10 (m, 2H), 3.84-3.90 (m, 1H), 3.66-3.74 (m, 1H), 3.38-3.59 (m, 3H), 3.95-4.05 (m, 1H), 2.82-2.92 (m, 1H), 2.64-2.76 (m, 1H), 2.15-2.29 (m, 1H), 2.74-2.10 (m, 6H), 1.33 (d, J = 6.8Hz, 3H), 1.15-1.28 (m, 1H). [M+H] 514.3.

[0827] EXAMPLE 30

[0828] Third isomer eluting from the mixture of Example 27. 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.97 (s, 1H), 7.48-7.50 (m, 1H), 7.35-7.39 (m, 1H), 7.30-7.34 (m, 1H), 6.46 (q, J = 7.1 Hz, 1H), 4.27-4.39 (m, 2H), 3.98-4.08 (m, 2H), 3.85-3.92 (m, 1H), 3.69-3.76 (m, 1H), 3.43-3.51 (m, 3H), 3.07-3.18 (m, 1H), 2.74-2.84 (m, 1H), 2.65-2.74 (m, 1H), 1.82-2.20 (m, 7H), 1.35 (d, J = 6.8Hz, 3H), 1.15-1.28 (m, 1H). [M+H] 514.3.

[0829] EXAMPLE 31

[0830] Fourth isomer eluting from the mixture of Example 27. 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.96 (s, 1H), 7.46-7.48 (m, 1H), 7.34-7.39 (m, 1H), 7.29-7.33 (m, 1H), 6.45 (q, J = 7.0Hz, 1H), 4.26-4.38 (m, 2H), 4.00-4.08 (m, 2H), 3.84-3.90 (m, 1H), 3.66-3.73 (m, 1H), 3.39-3.59 (m, 3H), 2.95-3.05 (m, 1H), 2.82-2.92 (m, 1H), 2.65-2.75 (m, 1H), 2.16-2.28 (m, 1H), 1.75-2.10 (m, 6H), 1.34 (d, J = 6.8Hz, 3H), 1.14-1.27 (m, 1H). [M+H] 514.3.

[0831] EXAMPLE 32

[0832] 4-((S)-3-(1-(3-carbamoyl-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. The example was prepared using general procedure A with methyl 4-oxobutanoate, then application of procedure C and condensation of the product with precursor III using procedure D(a). The diastereomers were separated in the ester stage on a 20 × 250 mm OJ-H column using 25% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2, followed by treatment of the first elution peak with 5 equiv of LiOH in MeOH at room temperature for 12 h, and repurification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as the eluent. 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.74 (s, 1H), 7.43-7.45 (m, 1H), 7.38-7.42 (m, 1H), 7.23-7.28 (m, 1H), 6.41 (q, J = 7.1Hz, 1H), 4.19-4.29 ( m, 2H), 3.90-4.00 (m, 2H), 3.54-3.68 (m, 2H), 3.17-3.24 (m, 2H), 2.86-2.96 (m, 1H), 2.60-2.73 (m, 2H), 2.44-2.50 (m, 2H), 1.76-2.22 (m, 9H), 1.14-1.27 (m, 1H). [M+H] 560.2.

[0833] EXAMPLE 33

[0834] 4-((R)-3-(1-(3-carbamoyl-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b] acid pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid. The example was prepared using general procedure A with methyl 4-oxobutanoate, C and D (a). The diastereomers were separated in the ester stage on a 20 x 250 mm OJ-H column using 25% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2, followed by treatment of the second elution peak. with 5 equiv of LiOH in MeOH at room temperature for 12 h and repurification by reversed-phase HPLC using water (0.1% TFA) and acetonitrile (0.1% TFA) as the eluent. 1H NMR (400 MHz, CD3OD, trifluoroacetic acid salt): δ ppm 7.80 (s, 1H), 7.44-7.46 (m, 1H), 7.39-7.43 (m, 1H) , 7.24-7.28 (m, 1H), 6.43 (q, J = 7.0Hz, 1H), 4.21-4.32 (m, 2H), 3.94-4.02 ( m, 2H), 3.54-3.68 (m, 2H), 3.16-3.25 (m, 2H), 2.86-2.96 (m, 1H), 2.61-2, 73 (m, 2H), 2.44-2.50 (m, 2H), 1.77-2.20 (m, 9H), 1.14-1.28 (m, 1H). [M+H] 560.2.

[0835] EXAMPLE 34

[0836] 1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl )-1H-pyrazolo[3,4- b]pyrazine-3-carbonitrile and 1-(S)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(2 -hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. Prepared as a mixture of the above two diastereomers using general procedure A with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followed by procedure C and condensation of the resulting diastereomeric mixture product with Precursor IV using procedure D (b). [M+H] 500.3.

[0837] EXAMPLE 35

[0838] 1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-(S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4- b ]pyrazine-3-carbonitrile. The diastereomers prepared in Example 34 were separated on a CHIRALPAK IF SFC 210 x 50 mm column using 40% ethanol (0.1% diethylamine) in heptanes. The first eluting isomer had the structure shown above. 1H NMR (400 MHz, CD3OD, HCl salt): δ ppm 7.93 (s, 1H), 7.51-7.53 (m, 1H), 7.41-7.45 (m, 1H), 7.31-7.35 (m, 1H), 6.42 (q, J = 7.1 Hz, 1H), 4.19-4.33 (m, 2H), 3.97-4.07 (m, 2H), 3.86-3.91 (m, 2H), 3.51-3.64 (m, 2H), 3.11-3.17 (m, 2H), 2.90-3.00 (m, 2H), 2.72-2.84 (m, 1H), 2.58-2.68 (m, 1H), 2.48-2.56 (m, 2H), 2.05-2.40 (m, 2H), 1.88-1.93 (m, 3H), 1.08-1.20 (m, 1H). [M+H] 500.3.

[0839] EXAMPLE 36

[0840] 1-((S)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4- b ]pyrazine-3-carbonitrile. The diastereomers prepared in Example 34 were separated on a CHIRALPAK IF SFC 210 x 50 mm column using 40% ethanol (0.1% diethylamine) in heptanes. The second eluting isomer had the structure shown above. 1H NMR (400 MHz, CD3OD, free base): δ ppm 7.92 (s, 1H), 7.43-7.46 (m, 1H), 7.33-7.38 (m, 1H), 7.26-7.32 (m, 1H), 6.43 (q, J = 6.9Hz, 1H), 4.27- 4.37 (m, 2 H), 3.98-4.09 (m, 2H), 3.88-3.94 (m, 2H), 3.57- 3.70 (m, 2H), 3.24-3.30 (m, 2H), 2.90-3.00 (m, 1H), 2.65- 2.78 (m, 2H), 2.13-2.26 (m, 1H), 1.80-2.08 (m, 6H), 1.15- 1.28 (m, 1H). [M+H] 500.3.

[0841] EXAMPLE 37

[0842] 2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin -6-yl)azetidin-3- yl)piperidin-1-yl)ethan-1-ol and 2-((R)-3-(1-(1-((R)-1-(2,4- dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. Prepared as a mixture of the above two diastereomers using general procedure A with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followed by procedure C and condensation of the resulting diastereomeric mixture product with Precursor I using procedure D (b). [M+H] 489.1.

[0843] EXAMPLE 38

[0844] 2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. The diastereomers prepared in Example 37 were separated on a 20 x 250 mm AD-H column using 25% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The first eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 8.61 (s, 1H), 7.40-7.44 (m, 1H), 7.34-7.36 (m, 1H), 7.13-7.17 (m, 1H), 6.30 (q, J = 7.1Hz, 1H), 4.134.23 (m, 1H), 3.82-3.92 (m, 2H), 3.61-3.66 (m, 2H), 2,852.95 (m, 2H), 2.54-2.60 (m, 2H), 2.42-2.52 (m, 4H), 2,042.14 (m, 1H), 1.55-1.94 (m, 9H), 0.87-1.00 (m, 1H). [M+H] 489.1.

[0845] EXAMPLE 39

[0846] 2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. The diastereomers prepared in Example 37 were separated on a 20 x 250 mm AD-H column using 25% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The second eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 8.61 (s, 1H), 7.41-7.45 (m, 1H), 7.35-7.37 (m, 1H), 7.13-7.17 (m, 1H), 6.29 (q, J = 7.1 Hz, 1H), 4.14-4.22 (m, 2 H), 3.84-3.92 (m, 2H), 3.58-3.63 (m, 2H), 2.79-2.89 (m, 2H), 2.43-2.56 (m, 6H), 2.00-2.10 (m, 2H), 1.68-1.88 (m, 8H), 1.50-1.63 (m, 1H), 0.86-1.00 (m, 1H). [M+H] 489.1.

[0847] EXAMPLE 40

[0848] 2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin -6-yl)azetidin-3- yl)piperidin-1-yl)ethan-1-ol and 2-((R)-3-(1-(1-((R)-1-(2,4- dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. Prepared as a mixture of the above two diastereomers using general procedure A with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followed by procedure C and condensation of the resulting diastereomeric mixture product with Precursor II using procedure D (b). [M+H] 489.3.

[0849] EXAMPLE 41

[0850] 1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl )-1H-pyrazolo[3,4- b]pyrazine-3-carboxamide and 1-(S)-1-(2,4-dichlorophenyl)ethyl)- 6-(3-((R)-1-(2 -hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carboxamide. Prepared as a mixture of the above two diastereomers using general procedure A with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde, followed by procedure C and condensation of the resulting diastereomeric mixture product with Precursor III using procedure D (b). [M+H] 518.3.

[0851] EXAMPLE 42

[0852] 2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b ]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol and 2-((S)-3-(1-(1-((R)-1-(2, 4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. Prepared as a mixture of the above two diastereomers using general procedure A with 2-(tert-butyldimethylsilyl)oxy)acetaldehyde, followed by procedure C and condensation of the resulting diastereomeric mixture product with Precursor V using procedure D ( b). LCMS [M+H]: 543.0.

[0853] EXAMPLE 43

[0854] 2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. The diastereomers prepared in Example 42 were separated on a CHIRACEL IF column using 5% ethanol and heptanes (0.1% diethylamine). The first eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CDCl3, free base): δ ppm 7.83 (s, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.19 (dd, J = 8.5, 2.1 Hz, 1H), 6.46 (q, J = 7.0 Hz, 1 H), 4.24 (q, J = 8.8 Hz, 2H), 3.97 -3.86 (m, 2H), 3.62 (t, J = 5.4 Hz, 2H), 2.84 (t, J = 9.9 Hz, 2H), 2.68 -2.59 (m, 1H), 2.56 - 2.52 (m, 2H), 2.08 (t, J = 10.3 Hz, 1H), 1.93 (d, J = 7.1 Hz, 3H), 1.88 - 1.70 (m, 4H), 1.63 - 1.53 (m, 1H), 1.01 - 0.92 (m, 1H). LCMS [M+H]: 543.0.

[0855] EXAMPLE 44

[0856] 2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol. The diastereomers prepared in Example 42 were separated on a CHIRACEL IF column using 5% ethanol and heptanes (0.1% diethylamine). The second eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CDCl3; free base) δ 7.83 (s, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.1 Hz, 1H), 6.45 (q, J = 7.1 Hz, 1H), 4.24 - 1.96 (m, 2H), 1.93 (d, J = 7.1 Hz, 3H), 1.89 - 1.73 (m, 3H), 1.06 - 0.97 (m, 1H). LCMS [M+H]: 543.0.

[0857] EXAMPLE 45

[0858] N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)- 3-(trifluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)azetidin- 3-yl)piperidin-1-yl)ethyl)acetamide and N-(2-((S)-3-(1-(1- ((R)-1 -(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. Prepared as a mixture of the above two diastereomers according to general procedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotection with 5 equiv of hydrazine hydrate in methanol for 5 h, and acylation with 1.2 equiv of acetic anhydride in dichloromethane with 2 equiv of trimethyl amine, followed by procedure C and condensation of the resulting diastereomeric mixture product with Precursor V using procedure D (a). [M+H] 584, 0.

[0859] EXAMPLE 46

[0860] N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)- 3-(trifluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide and A-(2-((S)-3- (1-(1-((R)-1 -(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide. Prepared as a mixture of the above two diastereomers using general procedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotection with 5 equiv of hydrazine hydrate in methanol for 5 h, and reaction with 1.2 equiv of mesyl chloride in dichloromethane with 2 equiv of trimethylamine, followed by procedure C and the resulting diastereomeric mixture product was condensed with Precursor V using procedure D (a). [M+H] 620 ,1.

[0861] EXAMPLE 47

[0862] N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)- 3-(trifluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)azetidin- 3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide and N-(2-(S)- 3-(1-(1-((R )-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl) propane-2-sulfonamide. Prepared as a mixture of the above two diastereomers by employing general procedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotection with 5 equiv of hydrazine hydrate in methanol for 5 h, and reaction with 1.2 equiv of isopropylsulfonyl chloride in dichloromethane with 2 equiv of trimethylamine, followed by procedure C. The resulting diastereomeric mixture product was condensed with Precursor V using procedure D(a). [M+H] 648 ,1.

[0863] EXAMPLE 48

[0864] N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)- 3-(trifluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)azetidin- 3-yl)piperidin-1-yl)ethyl)isobutyramide and N-(2-((S)-3-(1-(1- ((R)-1 -(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide. Prepared as a mixture of the above two diastereomers using general procedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotection with 5 equiv of hydrazine hydrate in methanol for 5 h, and reaction with 1.2 equiv of 2-methylpropionyl chloride in dichloromethane with 2 equiv of trimethylamine, followed by procedure C. The resulting diastereomeric mixture was condensed with Precursor V using procedure D(a). [M+H ] 612.2.

[0865] EXAMPLE 49

[0866] (2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4- b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methyl carbamate and (2-((S)-3-(1- (1-((R)-1-( Methyl 2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamate. Prepared as a mixture of the above two diastereomers using general procedure A using 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde, deprotection with 5 equiv of hydrazine hydrate in methanol for 5 h, and reaction with 1.2 equiv of methyl chloroform in dichloromethane with 2 equiv of trimethylamine, followed by procedure C. The resulting diastereomeric mixture product was condensed with Precursor V using procedure D(a). [M+H] 600 ,1.

[0867] EXAMPLE 50

[0868] 1-((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((R)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin- 1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S )-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine. Prepared as a mixture of the above two diastereomers by employing general procedure B (b) using 1-bromo-3-(methylsulfonyl)propane, followed by procedure C and the resulting diastereomeric mixture product was condensed with Precursor V using procedure D (a). [M+H] 619.0.

[0869] EXAMPLE 51

[0870] N-(2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide. The diastereomers prepared in Example 48 were separated on a 20 x 250 mm AD-H column using 25% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The first eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CD3OD, HCl salt): δ ppm 7.93 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.5, 2.0 Hz, 1H), 6.43 (q, J = 7.1 Hz, 1H), 4.31 (t, J = 8.7 Hz, 2H), 4.09 - 3.98 (m, 2H), 3.57 (d, J = 5.8 Hz, 3H), 3.21 (d, J = 2.8 Hz, 2H), 2.92 (s, 1H), 2.69 (s, 2H), 2.48 (dt, J = 13.8, 6.9 Hz, 1H), 2.21-2.07 (m, 1H), 2.07 - 1.92 (m, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.87- 1.75 (m, 1H), 1.34- 1.18 (m, 2H), 1.16-1.09 (m, 6H). [M+H] 612.2.

[0871] EXAMPLE 52

[0872] N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide. The diastereomers prepared in Example 48 were separated on a 20 x 250 mm AD-H column using 25% ethanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The second eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CD3OD, HCl salt) δ ppm 7.93 (d, J = 0.6 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.1 Hz, 1H), 6.44 (q, J = 6.9 Hz, 1H), 4.39 - 4.22 (m, 2H), 4.07 - 3.97 (m, 2H), 3.60 - 3.38 (m, 3H), 3.09 (br s, 2H), 2.87 - 2.41 (m, 4H), 2.47 (dt, J = 13.7, 6.8 Hz, 1H), 2.16-2.02 (m, 1H), 2.02 - 1.93 (m, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.85-1.71 (m, 1H), 1.37-1.15 (m, 1H), 1.13 (d, J = 6.9 Hz, 6H). [M+H] 612.2.

[0873] EXAMPLE 53

[0874] N-(2-((S)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. The diastereomers prepared in Example 45 were separated on a 20 x 250 mm AD-H column using 20% methanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The first eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CD3OD, HCl salt): δ ppm 7.93 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.5, 1.9 Hz, 1H), 6.43 (q, J = 7.0 Hz, 1H), 4.31 (t, J = 8.7 Hz, 2H), 4.10 - 3.99 (m, 2H), 3.77 - 3.49 (m, 4H), 3.25 (t, J = 5.8 Hz, 2H), 2.92 (t, J = 11.3 Hz, 1H), 2.67 (t, J = 12.0 Hz, 2H), 2.14 (d, J = 9.8 Hz, 1H), 2.08-1.92 (m, 2H), 1.99 (s, 3H), 1.90 (d, J = 7.1 Hz, 3H), 1,881.77 (m, 1H), 1.27-1.16 (m, 1H). [M+H] 584.0.

[0875] EXAMPLE 54

[0876] N-(2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. The diastereomers prepared in Example 45 were separated on a 20 x 250 mm AD-H column using 20% methanol (0.1% diethylamine) and 10 MPa (100 bar) CO2. The second eluting diastereomer had the structure shown above. 1H NMR (400 MHz, CD3OD, HCl salt): δ ppm 7.93 (s, 1H), 7.48 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.0 Hz, 1H), 6.44 (q, J = 7.1 Hz, 1H), - 4.25 (m, 2H), 4.08 - 3.96 (m, 2H), 3.65 - 3.42 (m, 4H), 3.15 - 3.06 (m, 2H), 2.84 - 2.62 (m, 2H), 2.60 - 2.44 (m, 1H), 2.05 (s, 1H), 1.98 (s, 3H), 2.02 - 1.93 (m, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.86-1.71 (m, 1H), 1.25 - 1.10 (m, 1H). [M+H] 584.0.

[0877] EXAMPLE 55

[0878] 1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxyethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. The title compound was prepared using general Procedure B with Precursor VI and 2-bromoethan-1-ol, followed by Procedure C. The resulting product was condensed with Precursor VIII using Procedure D and converted to the corresponding HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M HCl in EtOH. 1H NMR (300 MHz, Methanol-d4; HCl Salt) δ 7.92 (s, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.22 - 7.17 (m, 2H), 6.34 (q, J = 6.9 Hz, 1H), 4.32 (q, J = 9.0 Hz, 2H), 3 (t, J = 7.2 Hz, 2H), 3.87 (t, J = 5.1 Hz, 2H), 3,553.41 (m, 2H), 3.17-3.08 (m, 2H), 2.78-2.52 (m, 2H), 2,182.06 (m, 1H), 1.98 - 1.75 (m, 4H), 1.92 (d, J = 7.2 Hz, 3H), 1.24-1.12 (m, 1H). LCMS [M+H] 484.1.

[0879] EXAMPLE 56

[0880] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(4-hydroxy-4-methylpentyl)piperidin-3-yl)azetidin -1-yl)-1H- pyrazolo[3,4-b]pyrazine-3-carbonitrile and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R) -1-(4-hydroxy-4-methylpentyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. Tert-butyl oxobutyl)piperidin-3-yl)azetidine-1-carboxylate was prepared using general procedure A with methyl 4-oxobutanoate. tert-Butyl 3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate (251 mg, 0.737 mmol) was dissolved in tetrahydrofuran ("THF") (7 ml ) and treated with a 3 M solution of methyl magnesium bromide in diethyl ether (0.61 ml, 1.84 mmol, 2.5 eq) at -78 °C. The solution was stirred for 1 h, then warmed to room temperature and quenched with saturated aqueous ammonium chloride (25 ml) and extracted with ethyl acetate (3 x 25 ml). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, tert-butyl 3-(1-(4-hydroxy-4-methylpentyl)piperidin-3-yl)azetidine-1-carboxylate was isolated by flash chromatography flash column (silica gel, 0-10% 7N NH3 in methanol in DCM) (176 mg, 70% yield). The title compound as a mixture of the two diastereomers was prepared from 3-(1-( tert-butyl 4-hydroxy-4-methylpentyl)piperidin-3-yl)azetidine-1-carboxylate using general procedures C and D using Precursor IV. 1H NMR (400 MHz, Methanol-d4, trifluoroacetic acid salt): δ 7.96 (s, 1H), 7.51 - 7.45 (m, 1H), 7.38 -7.33 (m, 1H ), 7.31 (dd, 7=8.5, 2.1 Hz, 1H), 6.45 (q, J = 7.0Hz, 1H), 4.40- 4.23 (m, 2H), 4.12 - 3.94 (m, 2H), 3.57 (dd, J = 23.3, 12.2 Hz, 2H), 3.16 - 3.07 (m, 2H), 2.95 - 2.80 (m, 1H), 2.77-2.57 (m, 2H), 2.15 - 1.70 (m, 9H), 1.59 - 1.47 (m, 2H), 1.34 - 1.08 (m, 7H). LCMS [M+H] 557.1.

[0881] EXAMPLE 57

[0882] 2-((S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin -6-yl)azetidin- 3-yl)piperidin-1-yl)-N-methylethane-1-sulfonamide and 2-((R)-3- (1-(3-cyano-1-((R)- 1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylethane-1-sulfonamide. tert-Butyl 3-[1-(2-fluorosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate was prepared from vinyl sulfonyl fluoride according to General Procedure B. The 3-[1-(2- tert-Butyl fluorosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate (231 mg, 0.66 mmol) in THF (3 ml) was added a 33% solution of methylamine in ethanol (0.6 ml, 6. 6 mmol, 10 equiv.). The mixture was heated in a sealed tube at 70 °C for 2.5 h. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0- 10% 7N NH3 in methanol in DCM) (133 mg, 56% yield). The title compound as a mixture of the two diastereomers was prepared from tert-butyl 3-[1-[2-(methylsulfamoyl)ethyl]-3-piperidyl]azetidine-1-carboxylate according to general procedures C and D with the use of Precursor IV. 1H NMR (400 MHz, Methanol-d4, free base): δ 7.95 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.38 (dd, 7= 8, 6, 1.2 Hz, 1H), 7.31 (dd, 7= 8.5, 2.2 Hz, 1H), 6.45 (q, J = 7.1 Hz, 1H), 4.33 - 4.19 (m, 2H), 4.04 - 3.88 (m, 2H), 3.29 - 3.21 (m, 2H), 2.94-2.86 (m, 2H), 2, 86-2.75 (m, 2H), 2.71 (s, 3H), 2.68 - 2.55 (m, 1H), 2.08 (s, 1H), 1.90 (d, J = 7.1 Hz, 3H), 1.87 - 1.69 (m, 4H) , 1.66 - 1.52 (m, 1H), 1.03 - 0.87 (m, 1H). LCMS [M+H] 577.0.

[0883] EXAMPLE 58

[0884] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(2-(morpholinosulfonyl)ethyl)piperidin-3-yl)azetidin- 1-yl)-1H- pyrazolo[3,4-b]pyrazine-3-carbonitrile and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)- 1-(2-(morpholinosulfonyl)ethyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. tert-Butyl 3-[1-(2-fluorosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate was prepared from vinyl sulfonyl fluoride according to General Procedure B. The 3-[1-(2- tert-butyl fluorosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate (230 mg, 0.53 mmol) and N,N-diisopropyl-N-ethylamine (85 mg, 0.66 mmol, 1.0 equiv .) in THF (3 ml) is added morpholine (69 mg, 0.79 mmol, 1.2 equiv.). The mixture was heated in a sealed tube at 70 °C for 2.5 h and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% 7N NH3 in methanol in DCM) to yield 3-[1-(2-morpholinosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate tert-butyl (230 mg, 83 % yield). The title compound as a mixture of the two diastereomers was prepared from 3-[1-(2-morpholinosulfonylethyl)-3-piperidyl]azetidine-1-carboxylate tert-butyl according to general procedures C and D using Precursor IV. 1H NMR (400 MHz, Methanol-d4, trifluoroacetic acid salt): δ 7.97 (s, 1H), 7.48 (dd, J = 2.1, 0.4 Hz, 1H), 7.35 ( dd, J = 8.5, 2.8 Hz, 1H), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 6.45 (q, J = 7.1 Hz, 1H ), 4.88 - 4.87 (m, 4H), 4.40 - 4.25 (m, 2H), 4.13 - 3.95 (m, 2H), 3.79 - 3.50 (m , 8H), 3.33 -3.29 (m, 2H), 3.05 -2.88 (m, 1H), 2.85 -2.62 (m, 2H), 2.17 - 1.94 (m, 3H), 1.90 (d, J =7.1 Hz, 3H), 1, 88- 1.34- 1.12 (m, 1H). LCMS [M+H] 633.1.

[0885] EXAMPLE 59

[0886] 6-(3-((S)-1-((1H-pyrazol-3-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-( 2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile and 6-(3-((R)-1-((1H-pyrazol-3-yl)methyl)piperidin -3-yl)azetidin-1-yl)-1-((R)-1- (2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. The title compound as a mixture of the two diastereomers was prepared using General Procedure A using 1H-pyrazole-3-carbaldehyde and 4:2:1 1,2-dichloroethane/dimethylformamide ("DMF")/trifluoroethanol as the solvent, followed by procedure C. The resulting product was condensed with Precursor IV using procedure D. 1H NMR (400 MHz, Methanol-d4, free base): δ 7.93 (s, 1H), 7 ,63 (s, 1H), 7.48 (dd, J = 2.1, 1.3 Hz, 1H), 7.38 (dd, J = 8.5, 1.1 Hz, 1H), 7, 31 (dd, J = 8.5, 2.1 Hz, 1H), 6.45 (q, J = 7.1 Hz, 1H), 6.32 (s, 1H), 4.32 - 4.14 (m, 2H), 4.04 - 3.81 (m, 2H), 3.70 - 3.53 (m, 2H) , 3.02 - 2.72 (m, 2H), 2.71 - 2.47 (m, 1H), 2.12 - 1.98 (m, 1H), 1.90 (d, J =7, 1 Hz, 3H), 1.86- 1.68 (m, 4H), 1.68- 1.43 (m, 1H), 1.07-0.76 (m, 1H). LCMS [M+H] 536.0.

[0887] EXAMPLE 60

[0888] 6-(3-((S)-1-((1H-imidazol-4-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-( 2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile and 6-(3-((R)-1-((1H-imidazol-4-yl)methyl)piperidin -3-yl)azetidin-1-yl)-1-((R)-1- (2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. The title compound as a mixture of the two diastereomers was prepared using general procedure A starting from 1H-imidazole-5-carbaldehyde using 2:1 1,2-dichloroethane/DMF as the solvent, followed by the procedure C. The resulting product was condensed with Precursor IV using procedure D. 1H NMR (400 MHz, Methanol-d4, free base): δ 7.94 (s, 1H), 7.71 (dd, J = 2.0, 1.2 Hz, 1H), 7.48 (dd, J = 2.1, 1.6 Hz, 1H), 7.37 (dd, J = 8.5, 1.4 Hz, 1H ), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 7.13 (s, 1H), 6.45 (q, J = 7.0 Hz, 1H), 4.34 - 4.16 (m, 2H), 4.06 - 3.84 (m, 2H), 3.80 (s, 2H) , 3.16 - 3.01 (m, 2H), 2.69-2.55 (m, 1H), 2.42 - 2.25 (m, 1H), 2.12 - 1.97 (m, 1H), 1,991.76 (m, 6H), 1.73 - 1.57 (m, 1H), 1.06 - 0.92 (m, 1H). LCMS [M+H] 536.0.

[0889] EXAMPLE 61

[0890] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl )piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6 -(3-((S)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b ]pyrazine-3-carbonitrile. The title compound as a mixture of the two diastereomers was prepared from tetrahydro-4H-thiopyran-4-one 1,1-dioxide by general procedure A using 2:1 1,2-dichloroethane/DMF as the solvent, followed by procedure C. The resulting product was treated with Precursor IV using general procedure D. 1H NMR (400 MHz, Methanol-d4, free base): δ 7.94 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.6, 1.2 Hz, 1H), 7.31 (dd, J = 8.5, 2, 1 Hz, 1H), 6.45 (q, J = 7.1 Hz, 1H), 4.36 - 4.18 (m, 2H), 4.03 - 3.86 (m, 2H), 3.19 - 3.02 (m, 4H), 2.87 - 2.79 (m, 2H), 2.75 - 2.58 ( m, 2H), 2.27 (t, J = 10.9 Hz, 1H), 2.22 - 2.04 (m, 5H), 2.03 - 1.94 (m, 1H), 1.90 (d, J = 7.0 Hz, 3H), 1.87 - 1.70 (m, 2H), 1.66 - 1.45 (m, 1H), 1.03 - 0.87 (m, 1H ). LCMS [M+H] 588.0.

[0891] EXAMPLE 62

[0892] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3 -yl)azetidin-1-yl)- 1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3- ((S)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. The title compound as a mixture of the two diastereomers was prepared from tetrahydro-4H-pyran-4-one by general procedure A, followed by procedure C. The resulting product was treated with Precursor IV using procedure general D. 1H NMR (400 MHz, Methanol-d4, free base): δ 7.95 (s, 1H), 7.48 (dd, J = 2.2, 1.0 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 6.45 (q, J = 7.1 Hz, 1H), 4.34 - 4.20 (m, 2H), 4.04 - 3.90 (m, 4H), 3.40 (t, J = 11.8 Hz, 2H), 3.05 -2.90 (m, 2H), 2.68 - 2.46 (m, 2H), 2.25 - 2.12 (m, 1H), 1.90 (d, J = 7.1Hz, 3H), 1.88- 1.71 (m, 5H), 1.68- 1.48 (m, 4H), 1.02-0.86 (m, 1H). LCMS [M+H] 540.0.

[0893] EXAMPLE 63

[0894] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)- 3-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)azetidin-3- yl)piperidin-1-yl)ethyl)acetamide and N-(2-((S)-3-(1-(1-((R)- 1-( 2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. The title compound as a mixture of the two diastereomers was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of the phthaloyl group with hydrazine hydrate (4 equiv. ) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. 3-[1- Crude tert-butyl (2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv .) and acetyl chloride (40.0 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to to produce tert-butyl 3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate. The title compound as a mixture of the two diastereomers was prepared from 3-(1-(2- tert-butyl acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate according to general procedures C and D using Precursor II. 1H NMR (400 MHz, Methanol-d4, trifluoroacetic acid salt): δ 7.75 (s, 1H), 7.44 (dd, 7=2.2, 1.3 Hz, 1H), 7.35 ( dd, J = 8.5, 2.4 Hz, 2H), 7.27-7.21 (m, 1H), 6.31-6.25 (m, 1H), 4.34 - 4.19 ( m, 2H), 4.04 - 3.93 (m, 2H), 3.81 - 3.42 (m, 4H), 3.23 (t, J = 5.9 Hz, 2H), 2.98 - 2.83 (m, 1H), 2.71 - 2.59 (m, 2H), 2.50 (s, 3H), 2.12 - 1.93 (m, 5H), 1.88 - 1.74 (m, 4H), 1.30 - 1.16 (m, 1H). LCMS [M+H] 530.0.

[0895] EXAMPLE 64

[0896] N-[2-[(R)-3-[1-[1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-3-methyl-pyrazolo[3,4-b] pyrazin-6-yl]azetidin-3-yl]-1-piperidyl]ethyl]methanesulfonamide and N-[2-[(S)-3-[1-[1-[(1R)-1-(2,4 -dichlorophenyl)ethyl]-3-methyl-pyrazolo[3,4-b]pyrazin-6-yl]azetidin-3-yl]-1-piperidyl]ethyl]methanesulfonamide. The title compound as a mixture of the two diastereomers was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of the phthaloyl group with hydrazine hydrate (4 equiv. ) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. 3-[1-( Crude tert-butyl 2-aminoethyl]-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv. ) and methanesulfonyl chloride (58 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to to produce tert-butyl 3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate. The title compound as a mixture of the two diastereomers was prepared from 3-(1- (2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-tert-butyl carboxylate according to general procedures C and D using Precursor II. 1H NMR (400 MHz, Methanol-d4, trifluoroacetic acid salt): δ 7.73 (s, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.37 (dd, J = 8.5, 2.2 Hz, 1H), 7.30 - 7.21 (m, 1H), 6.33 - 6.23 (m, 1H), 4.33 - 4.20 (m, 2H) , 4.03 - 3.91 (m, 2H), 3.77 - 3.59 (m, 2H), 3.59 - 3.40 (m, 2H), 3.30 - 3.25 (m, 2H), 3.02 (s, 3H), 3.00 - 2.87 (m, 1H), 2.75 - 2.57 (m, 2H), 2.50 (s, 3H), 2.21 - 1.93 (m, 3H), 1.93 - 1.74 (m, 4H) , 1.30 - 1.09 (m, 1H). [M+H] 566.0.

[0897] EXAMPLE 65

[0898] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)- 3-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide and N-(2-((S)-3- (1-(1-((R) -1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2 -sulfonamide. The title compound as a mixture of the two diastereomers was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of the phthaloyl group with hydrazine hydrate (4 equiv. ) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. 3-[1-( tert-Butyl 2-aminoethyl]-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv.) and 2-propanesulfonyl chloride (73 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to to produce tert-butyl 3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate. The title compound as a mixture of the two diastereomers was prepared from tert-Butyl 3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate according to general procedures C and D using Precursor II. 1H NMR (400 MHz, Methanol-d4, trifluoroacetic acid salt): δ 7.74 (s, 1H), 7.46 - 7.42 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.5, 2.1 Hz, 1H), 6.34 - 6.21 (m, 1H), 4.33 - 4.18 (m, 2H) , 4.05 - 3.94 (m, 2H), 3.78 - 3.59 (m, 2H), 3.59 - 3.41 (m, 2H), 3.36 - 3.19 (m, 4H), 3.03 - 2.92 (m, 1H), 2.75 - 2.57 (m, 2H), 2.50 (s, 3H), 2.21 - 1.93 (m, 2H), 1.93 - 1.76 (m, 4H), 1.41 - 1, 32 (m, 6H), 1.28-1.12 (m, 1H). LCMS [M+H] 594.0.

[0899] EXAMPLE 66

[0900] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)- 3-(trifluoromethyl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)azetidin- 3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide and N-(2-((S)- 3-(1-(1-(( R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl )propane-2-sulfonamide. The title compound as a mixture of the two diastereomers was prepared from tert-butyl 3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate (see the preparation in the previous example) according to general procedures C and D using Precursor V. 1H NMR (400 MHz, Methanol-d4, trifluoroacetic acid salt): δ 7.75 (s, 1H), 7, 45 - 7.40 (m, 1H), 7.35 (dd, J = 8.5, 4.3 Hz, 1H), 7.26 (dd, J = 8.5, 2.2 Hz, 1H) , 6.33 - 6.24 (m, 1H), 4.34 - 4.20 (m, 2H), 4.06 - 3.92 (m, 2H), 3.73 - 3.49 (m, 4H), 3.24 (t, J = 6.2 Hz, 2H), 2.93 (t , J = 12.7 Hz, 1H), 2.75 -2.58 (m, 2H), 2.54-2.40 (m, 4H), 2.17-1.90 (m, 3H), 1.90- 1.84 (m, 3H), 1.84- 1.72 (m, 1H), 1.30-1.17 (m, 1H), 1.17 - 1.09 (m, 6H) ). LCMS [M+H] 558.1.

[0901] EXAMPLE 67

[0902] (2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methyl carbamate and (2-((S)-3-(1- (1-((R)-1-(2, Methyl 4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamate. The title compound as a mixture of the two diastereomers was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of the phthaloyl group with hydrazine hydrate (4 equiv. ) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. 3-[1-( Crude tert-butyl 2-aminoethyl]-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv. ) and methyl chloroformate (48 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to to produce tert-butyl 3-(1-(2-((methoxycarbonyl)amino)ethyl)piperidin-3-yl)azetidine-1-carboxylate. The title compound as a mixture of the two diastereomers was prepared from 3- tert-Butyl (1-(2-((methoxycarbonyl)amino)ethyl)piperidin-3-yl)azetidine-1-carboxylate using general procedures C and D using Precursor II. 1H NMR (400 MHz, Methanol-d4, trifluoroacetic acid salt): δ 7.74 (s, 1H), 7.48 - 7.40 (m, 1H), 7.35 (dd, J = 8.5 , 2.2 Hz, 1H), 7.26 (dd, J = 8.5, 2.2 Hz, 1H), 6.34 - 6.23 (m, 1H), 4.35 - 4.22 ( m, 2H), 4.05 - 3.91 (m, 2H), 3.76 - 3.61 (m, 5H), 3.60 - 3.42 (m, 2H), 3.24 (t, J = 5.9 Hz, 2H), 2.98 - 2.84 (m, 1H), 2.71 - 2.59 (m, 2H), 2.50 (s, 3H), 2.16 - 1.93 (m, 3H), 1.93 - 1.72 (m, 4H), 1, 30-1.12 (m, 1H). LCMS [M+H] 546.0.

[0903] EXAMPLE 68

[0904] 4-((S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin -6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylbutanamide. Tert-butyl 3-[1-(4-Methoxy-4-oxo-butyl)-3-piperidyl]azetidine-1-carboxylate was prepared from methyl 4-oxobutanoate according to general procedure A. 3- Tert-butyl (1-(4-Methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate was hydrolyzed with 4 equiv. of lithium hydroxide in a methanol/water mixture (3:1 by volume) at room temperature for 18 hours, followed by removal of methanol in vacuo, acidification of the reaction mixture with concentrated HCl to pH 7, and extraction with DCM. Drying with sodium sulfate, filtration and removal of solvent in vacuo afforded the corresponding acid as a white solid. 4-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)butanoic acid (288 mg, 0.88 mmol) in DMF (5 mL) was treated with HATU (402 mg, 1.06 mmol, 1.2 equiv.). The mixture was stirred for 5 min, then N,N-diisopropyl -N-ethylamine (0.46 ml, 2.65 mmol, 3.0 equiv.) was added. After 10 min, a 33% solution of methylamine in ethanol (0.15 ml, 4.4 mmol, 5.0 equiv.) was added and the reaction was allowed to stir overnight. The reaction was quenched with 1 M aqueous sodium carbonate (5 ml), diluted with ethyl acetate (10 ml), and the organic layer was washed with water (3 x 5 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuum to produce 3-[1-[4-(methylamino)-4-oxo-butyl]-3-pipeddyljazetidine-1- tert-butyl carboxylate. 4-(3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin- 3-yl)piperidin-1-yl)-N-methylbutanamide was prepared from tert-butyl 3-[1-[4-(methylamino)-4-oxo-butyl]-3-piperidylazetidine-1-carboxylate with the use of general procedures C and D with the use of Precursor IV. The title compound was isolated by chiral supercritical fluid chromatography ("SFC") (OD-H, 30% methanol (0.1% diethylamine)/CO2 10 MPa (100 bar) as the first eluting peak. 1H NMR (400 MHz, Methanol-d4, free base): δ 7.92 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.1 Hz, 1H), 6.44 (q, J = 7.0 Hz, 1H), 4.25 (t, J = 8 ,1 Hz, 2H), 4.02 - 3.86 (m, 2H), 2.99 - 2.83 (m, 2H), 2.83 - 2.51 (m, 2H), 2.71 (s, 3H), 2.40 - 2.30 (m, 2H), 2.19 (t, J = 7.4 Hz, 2H), 2.04 - 1.92 (m, 1H), 1.90 (d, J =7.1 Hz, 3H), 1.87 - 1.50 (m, 5H ), 1.23 - 1.12 (m, 1H), 1.01-0.81 (m, 1H). LCMS [M+H] 555.1.

[0905] EXAMPLE 69

[0906] 4-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin -6-yl)azetidin-3-yl)piperidin-1-yl)-N-methylbutanamide. Tert-butyl 3-[1-(4-Methoxy-4-oxo-butyl)-3-piperidyl]azetidine-1-carboxylate was prepared from methyl 4-oxobutanoate according to general procedure A. 3- Tert-butyl (1-(4-Methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate was hydrolyzed with 4 equiv. of lithium hydroxide in a methanol/water mixture (3:1 by volume) at room temperature for 18 hours, followed by removal of methanol in vacuo, acidification of the reaction mixture with concentrated HCl to pH 7, and extraction with DCM. Drying with sodium sulfate, filtration and removal of solvent in vacuo afforded the corresponding acid as a white solid. 4-(3-(1-{tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)butanoic acid (288 mg, 0.88 mmol) in DMF (5 mL) was treated with HATU (402 mg, 1.06 mmol, 1.2 equiv.). The mixture was stirred for 5 min, then N,N-diisopropyl -N-ethylamine (0.46 ml, 2.65 mmol, 3.0 equiv.) was added. After 10 min, a 33% solution of methylamine in ethanol (0.15 ml, 4.4 mmol, 5.0 equiv.) was added and the reaction was allowed to stir overnight. The reaction was quenched with 1 M aqueous sodium carbonate (5 ml), diluted with ethyl acetate (10 ml), and the organic layer was washed with water (3 x 5 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuum to produce tert-butyl 3-[1-[4-(methylamino)-4-oxo-butyl]-3-pipeddyl]azetidine-1-carboxylate. 4-(3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin- 3-yl)piperidin-1-yl)-N-methylbutanamide was prepared from tert-3-[1-[4-(methylamino)-4-oxo-butyl]-3-piperidyl]azetidine-1-carboxylate butyl using general procedures C and D using Precursor IV. The title compound was isolated by chiral SFC chromatography (OD-H, 30% methanol (0.1% diethylamine)/CO2 10 MPa (100 bar) as the second eluting peak. 1H NMR (400 MHz, Methanol- 74, free base): δ 7.92 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7, 30 (dd, J = 8.5, 2.1 Hz, 1H), 6.44 (q, J = 7.0 Hz, 1H), 4.31–4.18 (m, 2H), 4.02 - 3.86 (m, 2H), 2.96 - 2.83 (m, 2H), 2.70 (s, 3H), 2.75 - 2.52 (m, 2H), 2.41 - 2.30 (m, 2H), 2.19 (t, J = 7.4 Hz, 2H) , 2.01 - 1.92 (m, 1H), 1.90 (d, J = 7.0 Hz, 3H), 1.86 - 1.50 (m, 5H), 1.15 (t, J = 7.2 Hz, 1H), 1.00 - 0.84 (m, 1H). LCMS [M+H] 555.1.

[0907] EXAMPLE 70

[0908] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidin -1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. tert-Butyl 3-[1-(2-ethoxy-2-oxo-ethyl)-3-piperidyl]azetidine-1-carboxylate was prepared from diethyl glyoxylate according to General Procedure A. 3-[1- tert-Butyl (2-ethoxy-2-oxo-ethyl)-3-piperidyl]azetidine-1-carboxylate (240 mg, 0.74 mmol) in anhydrous THF (7 ml) was cooled to -78 °C and MeMgBr was added as a 3 M solution in diethyl ether (0.52 ml, 1.54 mmol, 2.1 equiv.). The mixture was warmed to 0 °C and allowed to stir for 1 h before being quenched with chloride of saturated ammonium (5 ml) and extracted with DCM (10 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0–10% methanol in DCM) to yield 3-(1-(2-hydroxy tert-butyl (2-methylpropyl)piperidin-3-yl)azetidine-1-carboxylate (100 mg, 43% yield). 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidin-1-yl)-1H -pyrazolo[3,4- b]pyrazine-3-carbonitrile was prepared from tert-butyl 3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidine-1-carboxylate with the use of general procedures C and D with the use of Precursor IV. The title compound was isolated by chiral SFC (AD-H, 40% isopropanol (0.1% diethylamine)/CO2 10 MPa (100 bar) as the first eluting peak. 1H NMR (400 MHz, Methanol- d4 , free base): 5 7.94 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 8.5, 2.2 Hz, 1H), 6.50 - 6.40 (m, 1H), 4.30 - 4.20 (m, 2H), 3.98 - 3.85 (m, 2H), 3.40 - 3.21 (m, 2H), 2.95 - 2.75 (m, 2H), 2.75-2.62 (m, 1H), 2.34-2.11 (m, 2H), 2.06 - 1.80 (m, 4H), 1 .80- 1.47 (m, 3H), 1.18 (d, J = 3.9 Hz, 3H), 1.15 (d, J =6.1 Hz, 3H), 1.06-0, 81 (m, 1H). LCMS [M+H] 528.1.

[0909] EXAMPLE 71

[0910] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidin -1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. tert-Butyl 3-[1-(2-ethoxy-2-oxo-ethyl)-3-piperidyl]azetidine-1-carboxylate was prepared from diethyl glyoxylate according to General Procedure A. 3-[1- tert-Butyl (2-ethoxy-2-oxo-ethyl)-3-piperidyl]azetidine-1-carboxylate (240 mg, 0.74 mmol) in THF (7 ml) was cooled to -78 °C and MeMgBr was added as a 3 M solution in diethyl ether (0.52 ml, 1.54 mmol, 2.1 equiv.). The mixture was warmed to 0 °C and allowed to stir for 1 h before being quenched with sodium chloride saturated ammonium chloride (5 ml) and extracted with DCM (10 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% methanol in DCM) to yield 3-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)azetidine-1-carboxylate tert-butyl (100 mg, 43% yield). 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(1-(2-hydroxy-2-methylpropyl) piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4- b ]pyrazine-3-carbonitrile was prepared from 3-(1-(2-hydroxy-2-methylpropyl)piperidin-3 -yl)azetidine-1- tert-butyl carboxylate using general procedures C and D using Precursor IV. The title compound was isolated from its diastereomer by chiral SFC (AD-H, 40% isopropanol (0.1% diethylamine)/CO2 10 MPa (100 bar) as the second eluting peak, 1H NMR (400 MHz, Methanol-d4, free base): δ 7.94 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 6.44 (q, J = 7.1 Hz, 1H), 4.33–4.19 (m, 2H), 4.003 ,85 (m, 2H), 3.33 - 3.28 (m, 2H), 2.98-2.78 (m, 2H), 2.73 -2.61 (m, 1H), 2.36-2.11 (m, 2H), 2.04 - 1.81 ( m, 4H), 1.79- 1.55 (m, 3H), 1.18 (d, J =3.9 Hz, 3H), 1.15 (d, J =6.2 Hz, 3H), 1.04-0.84 (m, 1H). LCMS [M+H] 528.1.

[0911] EXAMPLE 72

[0912] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-propylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazole [3,4- b]pyrazine-3-carbonitrile. Tert-butyl 3-(1-Propylpiperidin-3-yl)azetidine-1-carboxylate was prepared according to general procedure B(b) with the use of 1-iodopropane. 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(1-propylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b] Pyrazine-3-carbonitrile was prepared from tert-butyl 3-(1-propylpiperidin-3-yl)azetidine-1-carboxylate using general procedures C and D using Precursor IV. The title compound was isolated from its diastereomer by chiral SFC (AD-H, 40% isopropanol (0.1% diethylamine)/CO2 10 MPa (100 bar) as the first eluting peak. 1HRMN (400 MHz, Methanol -d4) δ 7.95 (s, 1H), 7.51 - 7.46 (m, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.35 - 7.28 ( m, 1H), 6.45 (q, J = 7.1 Hz, 1H), 4.32 - 4.22 (m, 2H), 4.02 - 3.86 (m, 2H), 3.30 - 3.23 (m, 2H), 3.03 - 2.87 (m, 2H), 2.67 - 2.55 (m, 1H), 2.42 - 2.28 (m, 2H), 2.06 - 1.94 (m, 1H), 1, 90 (d, J = 7.1 Hz, 3H), 1.88 - 1.65 (m, 3H), 1.65 - 1.49 (m, 2H), 1.03 - 0.88 (m, 4H). LCMS [M+H] 498.0.

[0913] EXAMPLE 73

[0914] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-propylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazole [3,4- b]pyrazine-3-carbonitrile. Tert-butyl 3-(1-propylpiperidin-3-yl)azetidine-1-carboxylate was prepared according to general procedure B(b) using 1-iodopropane. 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-(1-propylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b] Pyrazine-3-carbonitrile was prepared from tert-butyl 3-(1-propylpiperidin-3-yl)azetidine-1-carboxylate using general procedures C and D using Precursor IV. The title compound was isolated from its diastereomer by chiral SFC (AD-H, 40% isopropanol (0.1% diethylamine)/CO2 10 MPa (100 bar) as the second eluting peak. 1H NMR (400 MHz, Methanol-d4, free base): δ 7.95 (s, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.35 - 7.24 (m, 1H), 6.45 (q, J = 7.0 Hz, 1H), 4.33 - 4.20 (m, 2H), 4.02 - 3.84 ( m, 2H), 3.39 - 3.19 (m, 2H), 3.02 - 2.89 (m, 2H), 2.67 - 2.55 (m, 1H), 2.48 - 2.26 (m, 2H), 2.07 - 1.95 (m, 1H ), 1.90 (d, J = 7.1 Hz, 3H), 1.88 - 1.65 (m, 2H), 1.65 - 1.45 (m, 3H), 0.98 - 0, 87 (m, 4H). [LCMS M+H] 498.0.

[0915] EXAMPLE 74

[0916] 4-((S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N,N-dimethylbutanamide. The diastereomeric mixture was prepared starting with general procedure A and methyl 4-oxobutanoate. tert-Butyl 3-(1-(4-Methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate was hydrolyzed with 4 equiv. of lithium hydroxide in methanol/water mixture (3:1 by volume) at room temperature for 18 h, followed by removal of methanol in vacuo, acidification of reaction mixture with concentrated HCl to pH 7, and extraction with DCM. Drying over sodium sulfate, filtration, and removal of solvent in vacuo afforded the corresponding acid as a white solid. 4-(3-(1-(tert-Butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)butanoic acid was mixed with HATU (1.2 equiv.) in anhydrous DMF (0.2 M) and stirred for 5 min, followed by the addition of diisopropylethylamine (3 equiv.) and an additional 10 min of stirring at room temperature. A 2 M solution of dimethylamine in THF was then added to the reaction mixture (5 equiv.), the reaction was stirred at room temperature for 18 h, quenched with 1 M sodium carbonate, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was deprotected using general procedure C, and final coupling to precursor IV using general procedure D. The title compound was separated from its diastereomer on an AD-H column using 35% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.93 (s, 1H), 7.47 (d, J = 2.1Hz, 1H), 7.38 (d, J = 8.51Hz, 1H), 7.31 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.45 (q, J = 7.0Hz, 1 H), 4.21-4.31 (m, 2H), 3.92-4.02 (m, 2H), 3.07 (m, 3H), 2.88-2.96 (m, 5H), 2.55-2.66 (m, 1H), 2.37-2.46 (m, 4H), 1.94-2.04 (m, 1H), 1.90 (d, J = 7.1Hz, 3H), 152-1.88 (m, 7H), 0.87-1.01 (m, 1H). LCMS [M+H]: 569.1.

[0917] EXAMPLE 75 4-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)- N,N-dimethylbutanamide. A mixture of the title compound and its diastereomer was prepared as described in the previous example. The title compound was separated from its diastereomer on an AD-H column using 35% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second elution peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.92 (s, 1H), 7.47 (d, J = 2.1Hz, 1H), 7.38 (d, J = 8.5Hz, 1H), 7.31 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.45 (q, J = 7.1Hz, 1H, ), 4.21-4.31 (m, 2H), 3.92-4.02 (m, 2H), 3.06 (s, 3H), 2.88-2.96 (m, 5H), 2.55-2.66 (m, 1H), 2.37-2.45 (m, 4H), 1.94-2.04 (m, 1H), 1.91 (d, J = 7.1Hz, 3H), 1.53-1.88 (m, 7H), 0.87-1.00 (m, 1H). LCMS [M+H]: 569.1.

[0918] EXAMPLE 76 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-isopropylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4- b ]pyrazine-3-carbonitrile. A mixture of the title compound and its diastereomer was prepared according to general procedure A with acetone, general procedure C, and general procedure D with precursor IV. The title compound was separated from its diastereomer on an AD-H column using 30% isopropanol (0.1% diethylamine)/10 MPa (100 bar) CO2 as the first eluting peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.94 (s, 1H), 7.47 (d, J = 2.1Hz, 1H), 7.38 (d, J = 8.5Hz, 1H), 7.31 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.45 (q, J = 7.0Hz, 1H, ), 4.23-4.33 (m, 2H), 3.92-4.02 (m, 2H), 2.84-2.94 (m, 2H), 2.74-2.84 (m, 1H), 2.55-2.65 (m, 1H), 2.13-2.23 (m, 1H), 1.72-1.94 (m, 7H), 1.52-1.66 (m, 1H), 1.07-1.20 (m, 7H), 0.85-0.98 (m, 1H). LCMS [M+H]: 498.2.

[0919] EXAMPLE 77

[0920] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-isopropylpiperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4- b ]pyrazine-3-carbonitrile. A mixture of the title compound and its diastereomer was prepared according to general procedure A with acetone, general procedure C, and general procedure D with precursor IV. The title compound was separated from its diastereomer on an AD-H column using 30% isopropanol (0.1% diethylamine)/10 MPa (100 bar) CO2 as the second elution peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.94 (s, 1H), 7.48 (d, J = 2.1Hz, 1H), 7.39 (d, J = 8.5Hz, 1H), 7.31 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.45 (q, J = 7.1Hz, 1H, ), 4.22-4.32 (m, 2H), 3.92-4.02 (m, 2H), 2.84-2.94 (m, 2H), 2.73-2.83 (m, 1H), 2.55-2.66 (m, 1H), 2.12-2.22 (m, 1H), 1.72-1.94 (m, 7H), 1.52-1.66 (m, 1H), 1.07-1.21 (m, 7H), 0.85-0.98 (m, 1H). LCMS [M+H]: 498.2.

[0921] EXAMPLE 78

[0922] 4-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanamide. A mixture of the title compound and its diastereomer was prepared starting with general procedure A and methyl 4-oxobutanoate. tert-Butyl 3-(1-(4-Methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate was hydrolyzed with 4 equiv. of lithium hydroxide in methanol/water mixture (3:1 by volume) at room temperature for 18 h, followed by removal of methanol in vacuo, acidification of the reaction mixture with concentrated HCl to pH 7, and extraction with DCM. Drying over sodium sulfate, filtration, and removal of solvent in vacuo afforded the corresponding acid as a white solid. 4-(3-(1-(tert-Butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)butanoic acid was mixed with HATU (1.2 equiv.) in anhydrous DMF (0.2 M) and stirred for 5 min, followed by the addition of diisopropylethylamine (3 equiv.) and an additional 10 min of stirring at room temperature. A 2 M solution of dimethylamine in THF was then added to the reaction mixture (5 equiv.), the reaction was stirred at room temperature for 18 h, quenched with 1 M sodium carbonate, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was deprotected using procedure C, and final coupling to precursor IV using general procedure D. The title compound was separated from its diastereomer on an AD-H column using 30% ethanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second elution peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.92 (s, 1H), 7.47 (d, J = 2.1Hz, 1H), 7.38 (d, J = 8.5Hz, 1H), 7.30 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.44 (q, J = 7.1Hz, 1H, ), 4.21-4.31 (m, 2H), 3.92-4.02 (m, 2H), 2.87-2.96 (m, 2H), 2.55-2.68 (m, 1H), 2.37-2.44 (m, 2H), 2.23 (t, J = 7.4Hz, 2H), 1.94-2.06 (m, 1H), 1.90 (d, J = 7.1Hz, 3H), 1.53-1.89 (m, 7H), 0.87-1.00 (m, 1H). LCMS [M+H]: 541.2.

[0923] EXAMPLE 79

[0924] 4-((S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)butanamide. A mixture of the title compound and its diastereomer was prepared as shown in the previous example. The title compound was separated from its diastereomer on an AD-H column using 30% ethanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first eluting peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.93 (s, 1H), 7.47 (d, J = 2.1Hz, 1H), 7.38 (d, J = 8.5Hz, 1H), 7.31 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.45 (q, J = 7.1Hz, 1H, ), 4.22-4.32 (m, 2H), 3.92-4.02 (m, 2H), 2.88-2.98 (m, 2H), 2.55-2.68 (m, 1H), 2.37-2.45 (m, 2H), 2.23 (t, J = 7.4Hz, 2H), 1.95-2.06 (m, 1H), 1.90 (d, J = 7.1Hz, 3H), 1.53-1.99 (m, 7H), 0.84-1.01 (m, 1H). LCMS [M+H]: 541.2.

[0925] EXAMPLE 80

[0926] 6-(3-((R)-1-((1H-imidazol-2-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. A mixture of the title compound and its diastereomer was prepared starting with general procedure A and 1H-imidazol-2-carbaldehyde, followed by general procedure C, and final coupling to precursor IV using general procedure D. The title compound was separated from its diastereomer on an AD-H column using 20% ethanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second elution peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.89 (s, 1H), 7.46 (d, J = 2.1Hz, 1H), 7.37 (d, J = 8.5Hz, 1H), 7.29 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 7.00 (bs, 2H), 6.43 (q , J = 7.0Hz, 1H), 4.16-4.30 (m, 2H), 3.85-3.98 (m, 2H), 3.62 (bs, 2H), 2.76-2.88 (m, 2H), 2.58-2.70 (m, 1H), 2.06-2.16 (m, 1H), 1.52-1.94 (m, 8H), 0.85- LOO (m, 1H). LCMS [M+H]: 536.0.

[0927] EXAMPLE 81

[0928] 6-(3-((S)-1-((1H-imidazol-2-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. A mixture of the title compound and its diastereomer was prepared starting with general procedure A and 1H-imidazol-2-carbaldehyde, followed by general procedure C, and final coupling to precursor IV using general procedure D. The title compound was separated from its diastereomer on an AD-H column using 20% ethanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first eluting peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.92 (s, 1H), 7.47 (d, J = 2.1Hz, 1H), 7.37 (d, J = 8.5Hz, 1H), 7.30 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 7.00 (bs, 2H), 6.44 (q , J = 7.1Hz, 1H), 4.18-4.32 (m, 2H), 3.82-4.00 (m, 2H), 3.63 (bs, 2H), 2.77-2.89 (m, 2H), 2.58-2.70 (m, 1H), 2.04-2.14 (m, 1H), 1.53-1.94 (m, 8H), 0.861.00 (m, 1H). LCMS [M+H]: 536.0.

[0929] EXAMPLE 82

[0930] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1- ((R)-4-hydroxybutan-2-yl)piperidin-3 -yl)azetidin-1-yl)-1H- pyrazolo[3,4-b]pyrazine-3-carbonitrile and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3- ((R)-1-((S)-4-hydroxybutan-2-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. A mixture of the two title compounds and their respective diastereomers (four diastereomers) was prepared using general procedure A with 4-hydroxybutan-2-one, followed by general procedure C, and coupling using general procedure D and precursor IV. The single diastereomers were separated on an AD-H column using 35% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) and the compounds corresponding to peaks 1 and 2 were then , further purified on an OJ-H column using 20% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar). The first eluting isomer had the following 1H NMR (400 MHz, CDCl3; free base): δ ppm 7.61 (s, 1H), 7.37 (s, 1H), 7.36 (d, J = 5, 9Hz, 1H), 7.20 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.46 (q, J = 7.1Hz, 1H), 4.20-4.30 (m , 2H), 3.76-4.03 (m, 4H), 2.86-3.02 (m, 2H), 2.70-2.80 (m, 1H), 2.47-2.68 (m, 2H), 1.87-1.98 (m, 4H), 1.70-1.84 (m, 4H), 1.54-1.70 (m, 1H), 1.29-1.38 (m, 1H), 0.87-1.04 (m, 4H). LCMS [M+H]: 528.2. The second eluting isomer had the following 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.82 (s, 1H), 7.37 (s, 1H), 7.36 (d, J = 6, Hz, 1H), 7.20 (dd, J = 2.2Hz, J = 8.5Hz, 1H), 6.46 (q, J = 7.0Hz, 1H), 4.19-4.29 (m , 2H), 3.72-4.00 (m, 4H), 2.87-3.00 (m, 2H), 2.70-2.80 (m, 1H), 2.52-2.64 (m, 1H), 2.14-2.24 (m, 1H), 1.98-2.10 (m, 1H), 1.72-1.97 (m, 8H), 1.41-1.54 (m, 1H), 1.27-1.37 (m, 1H), 0.84-1.02 ( m, 4H). LCMS [M+H]: 528.2.

[0931] EXAMPLE 83

[0932] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1- ((R)-4-hydroxybutan-2-yl)piperidin-3 -yl)azetidin-1-yl)-1H- pyrazolo[3,4-b]pyrazine-3-carbonitrile and 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3- ((S)-1-((S)-4-hydroxybutan-2-yl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. A mixture of the two title compounds and their respective diastereomers (four diastereomers) was prepared using general procedure A with 4-hydroxybutan-2-one, followed by general procedure C, and coupling using general procedure D and precursor IV. The single diastereomers were separated on an AD-H column using 35% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar). The third eluting isomer had the following 1H NMR (400 MHz, CDCl3; free base): δ ppm 7.82 (s, 1H), 7.34-7.37 (m, 2H), 7.19 (dd, J = 2.2Hz, J = 8.5Hz, 1H), 6.45 (q, J = 7.0Hz, 1H), 4.19-4.27 (m, 2H), 3.73-4.06 (m, 4H), 2.88-3.00 (m, 2H), 2.70-2.78 (m, 1H), 2.53- 2.66 (m, 1H), 2.15-2 ,25 (m, 1H), 2.00-2.10 (m, 1H), 1.72-1.98 (m, 8H), 1.40-1.54 (m, 1H), 1.28- 1.37 (m, 1H), 0.84-1.01 (m, 4H ). LCMS [M+H]: 528.2. The fourth eluting isomer had the following 1H NMR (400 MHz, CDCl3; free base): δ ppm 7.81 (s, 1H), 7.38 (d, J = 2.1Hz, 1H), 7.35 ( d, J = 8.4Hz, 1H), 7.19 (dd, J = 2.2Hz, J = 8.4Hz, 1H), 6.44 (q, J = 7.2Hz, 1H), 4.18 -4.29 (m, 2H), 3.68-4.08 (m, 4H), 2.86-3.00 (m, 2H), 2.46-2.78 (m, 3H), 1 ,54-1.98 (m, 10H), 1.28-1.41 (m, 1H), 0.87-1.04 (m, 4H). LCMS [M+H]: 528.2.

[0933] EXAMPLE 84

[0934] Methyl (2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamate. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DCM (0.26 M) and 3 equiv. Triethylamine was added, followed by methylchloroformate (1.2 equiv.) dropwise at room temperature. The reaction mixture was stirred for 70 min, quenched with 1 M sodium carbonate, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The crude material was deprotected using general procedure C and coupled to precursor II using general procedure D. The title compound was separated from its diastereomer on an AD-H column using 35% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first eluting peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.75 (s, 1H), 7.45 (d, J = 2.1Hz, 1H), 7.36 (d, J = 8.5Hz, 1H), 7.26 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.29 (q, J = 7.2Hz, 1H, ), 4.22-4.32 (m, 2H), 3.94-4.04 (m, 2H), 3.43-3.69 (m, 7H), 3.12-3.22 (m, 2H), 2.80-2.92 (m, 1H), 2.56-2.72 (m, 2H), 2.50 (s, 3H), 1.75-2.16 (m, 7H), 1.12-1.30 (m, 1H). LCMS [M+H]: 546.1.

[0935] EXAMPLE 85

[0936] Methyl (2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)carbamate. A mixture of the title compound and its diastereomer was prepared as shown in the previous example. The title compound was separated from its diastereomer on an AD-H column using 35% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second elution peak. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.75 (s, 1H), 7.44 (d, J = 2.1Hz, 1H), 7.36 (d, J = 8.5Hz, 1H), 7.26 (dd, J = 2.2Hz, J = 8.5Hz, 1H), 6.29 (q, J = 7.0Hz, 1H, ), 4.24-4.32 (m, 2H), 3.95-4.05 (m, 2H), 3.61-3.77 (m, 5H), 3.44-3.60 (m, 2H), 3.21-3.29 (m, 2H), 2.88-2.98 (m, 1H), 2.62-2.73 (m, 2H), 2.50 (s, 3H), 1.92-2.18 (m, 3H), 1.76-1.92 (m, 4H), 1.141.30 (m, 1H). LCMS [M+H]: 546.1.

[0937] EXAMPLE 86

[0938] N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DCM (0.23 M) and 3 equiv. of triethylamine was added, followed by acetic anhydride (1.1 equiv.) dropwise at room temperature. The reaction mixture was stirred for 12 h, quenched with water, and extracted with DCM, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was deprotected using general procedure C, and coupled to precursor V using general procedure D. The title compound was separated from its diastereomer on an OD-H column using 20% methanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first eluting isomer. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.94 (s, 1H), 7.47 (d, J = 2.0Hz, 1H), 7.27-7.37 (m, 2H), 6.44 (m, 2H), 4.00-4.10 (m, 2H), (m, 2H), 2.87- 2.98 (m, 1H), (m, 10H), 1.14-1.30 (m, 1H).

[0939] EXAMPLE 87

[0940] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. A mixture of the title compound and its diastereomer was prepared as shown in the previous example. The title compound was separated from its diastereomer on an OD-H column using 20% methanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second eluting isomer. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.93 (s, 1H), 7.48 (d, J = 2.1Hz, 1H), 7.287.38 (m, 2H), 6.44 (q, J = 7.1Hz, 1H), 4.26-4.37 (m, 2H), 3.98-4.08 (m, 2H), 3.44-3.64 (m, 4H), 3.06-3.16 (m, 2H), 2.63-2.88 (m, 2H), 2.46-2.60 (m, 1H), 1.72-2.16 (m, 9H), 1.12-1.26 (m, 1H). LCMS [M+H]: 584.0.

[0941] EXAMPLE 88

[0942] N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanol, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM (3 x 10 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DMF (0.5 M), and 3 equiv. of triethylamine and 1.2 equiv. of HATU were added and stirred for 15 min. Isobutyric acid solution in DCM was added, and the reaction mixture was stirred at room temperature. Upon completion of the reaction, it was quenched with 1 M sodium carbonate, extracted 3 times with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was deprotected using general procedure C and coupled to precursor V using general procedure D. The title compound was separated from its diastereomer on an AS-H column using 25% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second eluting isomer. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.93 (s, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.28-7.36 (m, 2H), 6.44 (q, J = 7.1Hz, 1H), 4.28-4.38 (m, 2H), 3.99-4.10 (m, 2H), 3.50-3.68 (m, 4H), 3.17-3.27 (m, 2H), 2.84-3.00 (bm, 1H), 2.62-2.78 (bm, 2H), 2.43-2.55 (m, 1H), 1.76-2.22 (m, 7H), 1.11-1.34 (m, 7H). LCMS [M+H]: 612.2.

[0943] EXAMPLE 89

[0944] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide. A mixture of the title compound and its diastereomer was prepared as shown in the previous example. The title compound was separated from its diastereomer on an AS-H column using 25% isopropanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first eluting isomer. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.93 (s, 1H) ppm 7.48 (d, J = 2.1Hz, 1H), 7.28-7.37 (m, 2H), 6.44 (q, J = 7.1Hz, 1H), 4.24-4.37 (m, 2H), 3.98-4.08 ( m, 2H), 3.40-3.60 (m, 4H), 3.03-3.16 (m, 2H), 2.63-2.87 (bm, 2H), 2.41-2.60 (m, 2H), 1.72-2.15 (m, 7H), 1.11-1.25 (m, 7H). LCMS [M+H]: 612.2.

[0945] EXAMPLE 90

[0946] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanol, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM (3 x 10 mL), the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DMF (0.5 M), and 3 equiv. of triethylamine and 1.2 equiv. of HATU were added and stirred for 15 min. Isobutyric acid solution in DCM was added, and the reaction mixture was stirred at room temperature. Upon completion of the reaction, it was quenched with 1 M sodium carbonate, extracted 3 times with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was deprotected using general procedure C and coupled to precursor II using general procedure D. The title compound was separated from its diastereomer on an AD-H column using 25% ethanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first eluting isomer. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.75 (s, 1H), 7.45 (d, J = 2.1Hz, 1H), 7.36 (d, J = 8.5Hz, 1H), 7.26 (dd, J = 2.2Hz, J = 8.5Hz, 1H), 6.29 (q, J = 7.1Hz, 1H, ), 4.22-4.33 (m, 2H), 3.95-4.05 (m, 2H), 3.53-3.73 (m, 4H), 3.21-3.31 (m, 2H), 2.89-3.00 (m, 1H), 2.62-2.78 (m, 2H), 2.45-2.52 (m, 4H), 1.80-2.20 (m, 7H), 1.09-1.16 (m, 7H). LCMS [M+H]: 558.1.

[0947] EXAMPLE 91

[0948] N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)isobutyramide. A mixture of the title compound and its diastereomer was prepared as shown in the previous example. The title compound was separated from its diastereomer on an AD-H column using 25% ethanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second eluting isomer. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.76 (s, 1H), 7.44 (d, J = 2.1Hz, 1H), 7.35 (d, J = 8.5Hz, 1H), 7.26 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.29 (q, J = 7.1Hz, 1H, ), 4.23- 4.33 (m, 2H), 3.96-4.05 (m, 2H), 3.50-3.70 (m, 5H), 3.22-3.28 (m, 2H), 2.90-3.00 (m, 1H), 2.62- 2.72 (m, 1H), 2.43-2.53 (m, 4H), 1.77-2.20 (m, 7H), 1.08-1.30 (m, 7H). LCMS [M+H]: 558.1.

[0949] EXAMPLE 92

[0950] N-(2-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanol, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DCM (0.23 M) and 3 equiv. of triethylamine was added, followed by acetic anhydride (1.1 equiv.) dropwise at room temperature. The reaction mixture was stirred for 12 h, quenched with water, and extracted with DCM, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was deprotected using general procedure C, and coupled to precursor IV using general procedure D. The title compound was separated from its diastereomer on an AD-H column using 40% ethanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first eluting isomer. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.91 (s, 1H), 7.46 (d, J = 2.1Hz, 1H), 7.37 (d, J = 8.5Hz, 1H), 7.30 (dd, J = 2.1Hz, J = 8.4Hz, 1H), 6.44 (q, J = 7.1Hz, 1H, ), 4.20-4.30 (m, 2H), 3.92-4.02 (m, 2H), 3.34 (t, J = 7.0Hz, 2H), 2.88-2.98 (m, 2H), 2.55-2.67 (m, 1H), 2.45-2.53 (m, 2H), 1.53-2.08 (m, 12H), 0.87-1.01 (m, 1H). LCMS [M+H] 541.1.

[0951] EXAMPLE 93

[0952] N-(2-((S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DCM (0.23 M) and 3 equiv. of triethylamine was added, followed by acetic anhydride (1.1 equiv.) dropwise at room temperature. The reaction mixture was stirred for 12 h, quenched with water, and extracted with DCM, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was deprotected using general procedure C, and coupled to precursor IV using general procedure D. The title compound was separated from its diastereomer on an AD-H column using 40% ethanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second eluting isomer. 1H NMR (400 MHz, CD3OD; free base): δ ppm 7.92 (s, 1H), 7.46 (d, J = 2.1Hz, 1H), 7.37 (d, J = 8.5Hz, 1H), 7.30 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.44 (q, J = 7.1Hz, 1H, ), 4.20-4.30 (m, 2H), 3.91-4.02 (m, 2H), 3.30-3.38 (m, 2H), 2.87-3.87 (m, 2H), 2.55-2.67 (m, 1H), 2.45-2.53 (m, 2H), 1.52-2.10 (m, 12H), 0.86-1.00 (m, 1H). LCMS [M+H] 541.1.

[0953] EXAMPLE 94

[0954] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(3-hydroxypropyl)pyrrolidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. A mixture of the title compound and its diastereomer was prepared using commercially available 3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)azetidine-1-tert-butyl carboxylate instead of tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate in general procedure A. Followed by deprotection using general procedure C and coupling with precursor IV according to general procedure D. In all these general procedures, the corresponding pyrrolidine analogue was used. The title compound was separated from its diastereomer on an OJ-H column with 20% methanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the first eluting isomer. 1H NMR (400 MHz, CDCl3; free base): δ ppm 7.81 (s, 1H), 7.34-7.38 (m, 2H), 7.19 (dd, J = 2.2Hz, J = 8.5Hz, 1H), 6.45 (q, J = 7.1Hz, 1H), 4.22-4.30 (m, 2H), -3.87 (m, 4H), 2.72-2.88 (m, 5H), 2.60-2.70 (m, 1H), 2.49-2.60 (m, 1H), 2.42-2.49 (m, 1H), 2.03-2.13 (m, 1H), 1.89 (d, J = 7.1Hz, 3H), 1.70-1.79 (m, 2H), 1,421.53 (m, 1H). LCMS [M+H] 500.0.

[0955] EXAMPLE 95

[0956] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(3-hydroxypropyl)pyrrolidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. A mixture of the title compound and its diastereomer was prepared using commercially available 3-(1-(2-hydroxyethyl)pyrrolidin-3-yl)azetidine-1-tert-butyl carboxylate instead of tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate in general procedure A. Followed by deprotection using general procedure C and coupling with precursor IV according to general procedure D. In all these general procedures, the corresponding pyrrolidine analogue was used. The title compound was separated from its diastereomer on an OJ-H column with 20% methanol (0.1% diethylamine)/CO2, 10 MPa (100 bar) as the second eluting isomer. 1H NMR (400 MHz, CDCl3; free base): δ ppm 7.81 (s, 1H), 7.34-7.38 (m, 2H), 7.19 (dd, J = 2.1Hz, J = 8.5Hz, 1H), 6.45 (q, J = 7.1Hz, 1H), 4.20-4.30 (m, 2H), -3.88 (m, 4H), 2.72-2.88 (m, 5H), 2.60-2.70 (m, 1H), 2.48-2.60 (m, 1H), 2.41-2.48 (m, 1H), 2.02-2.13 (m, 1H), 1.89 (d, J = 7.1Hz, 3H), 1.70-1.78 (m, 2H), 1.42-1.53 (m, 1H). LCMS [M+H] 500.0.

[0957] EXAMPLE 96

[0958] N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Crude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv) and 2-propanesulfonyl chloride (73 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate. tert-Butyl 3-(1-(2-((1-Methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate was then condensed with Precursor II according to general procedures C and D to afford a mixture of diastereomers. The title compound was separated from its diastereomer by SFC using a 20 × 250 mm AS-H column and eluting with 25% isopropanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the first eluting isomer and converted to the corresponding HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M HCl in EtOH. 1H NMR (400 MHz, Methanol- d4; HCl Salt) δ 7.74 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.5, 2.2 Hz, 1H), 6.28 (q, J = 7.1 Hz, 1H), 4.26 (q, J = 8.6 Hz, 2H), 4.04 - 3.94 (m, 2H), 3.77 - 3.69 (m, 1H), 3.68 - 3.61 (m, 1H), 3.57 - 3.46 (m, 2H), 3.37 - 3.32 (m, 1H), 3.29 - 3.21 (m, 2H), 3.02 - 2.92 (m, 1H), 2.75 - 2.61 (m, 2H), 2.50 (s, 3H), 2.20 - 2.09 (m, 1H), 2.07 - 1.88 (m, 3H), 1.86 (d, J = 7.1 Hz, 1.37 (d, J = 6.8, Hz, 3H), 1.36 (d, J = 6.8, Hz, 3H), 1.27 - 1.20 (m, 1H). LCMS [M+H] 594.1.

[0959] EXAMPLE 97

[0960] N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Crude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv) and 2-propanesulfonyl chloride (73 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 3-(1-(2-((1-methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate. tert-Butyl 3-(1-(2-((1-Methylethyl)sulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate was then condensed with Precursor II according to general procedures C and D to afford a mixture of diastereomers. The title compound was separated from its diastereomer by SFC using a 20 × 250 mm AS-H column and eluting with 25% isopropanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the second eluting isomer and converted to the corresponding HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M HCl in EtOH. 1H NMR (400 MHz, Methanol-d4; HCl salt) 1H), 4.33 -4.22 (m, 2H), 4.04-3.96 (m, 2H), 3.77-3.70 (m, 1H), 3.68 - 3.59 (m, 1H), 3.56 - 3.45 (m, 2H), 3.37 - 3.32 (m, 1H), 3.27 - 3.23 (m, 2H), 3.01 - 2.91 (m, 2H), 2.74-2.62 (m, 2H), 2.50 (s, 3H), 2.19-2.10 (m, 1H), 2.08 - 1.88 (m, 2H), 1.86 (d, J = 7.1 Hz, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.24 - 1.18 (m, 1H). LCMS [M+H] 594.0.

[0961] EXAMPLE 98

[0962] N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Crude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv) and methanesulfonyl chloride (58 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate. tert-Butyl 3-(1-(2-(Methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate was then condensed with Precursor II according to general procedures C and D to afford a mixture of diastereomers. The title compound was separated from its diastereomer by SFC using an AS-H column and eluting with 30% ethanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the first eluting isomer and converted to the corresponding HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M HCl in EtOH. 1H NMR (400 MHz, Methanol-d4, HCl Salt) δ 7.73 (s, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.5, 2.1 Hz, 1H), 6.29 (q, J = 7.1 56 6.0 (M+H+).

[0963] EXAMPLE 99

[0964] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Crude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv) and methanesulfonyl chloride (58 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate. tert-Butyl 3-(1-(2-(Methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate was then condensed with Precursor II according to general procedures C and D to afford a mixture of diastereomers. The title compound was separated from its diastereomer by SFC using an AS-H column and eluting with 30% ethanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the second eluting isomer and converted to the corresponding HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M HCl in EtOH. 1H NMR (400MHz, Methanol-d4; HCl salt) 1H), 4.34-4.21 (m, 2H), 4.04-3.96 (m, 2H), 3.82-3.41 (m, 4H), 3.29-3.26 (m, 1H), 3.03 (s, 3H), 3.02 - 2.92 (m, 2H), 2.76 - 2.60 (m, 2H), 2.50 (s, 3H), 2.23 - 2.10 (m, 1H), 2.08 - 1.89 (m, 3H), 1.87 (d, J = 7.1 Hz, 3H), 1.25 - 1.18 (m, 1H). LCMS [M+H] 566.0.

[0965] EXAMPLE 100

[0966] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Crude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv) and acetyl chloride (40.0 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate. tert-Butyl 3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate was then condensed with Precursor II according to general procedures C and D to afford a mixture of diastereomers. The title compound was separated from its diastereomer by SFC using an AD-H column and eluting with 25% ethanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the first eluting isomer and converted to the corresponding HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M HCl in EtOH. 1H NMR (400 MHz, Methanol-d4; HCl Salt) δ 7.75 (s, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.5, 2.1 Hz, 1H), 6.29 (q, J = 7.1 Hz, 1H), 4.27 (q, J = 8.9 Hz, 2H), 4.00 (ddd, 7= 11.6, 8.9, 5.6 Hz, 2H), 3.78 - 3.63 (m, 2H), 3.58 - 3.46 (m, 1H), 3.25 (t, J = 5.8 Hz, 2H), 2.98 - 2.86 (m, 1H), 2.73 - 2.62 (m, 2H), 2.50 (s, 3H), 2.14 - 1.94 (m, 4H), 1.99 (s, 3H), 1.86 (d, J = 7.1 Hz, 3H), 1.86 - 1.77 (m, 1H), 1.21 ( d, J = 17.3 Hz, 1H). LCMS [M+H] 530.1.

[0967] EXAMPLE 101

[0968] N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)acetamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Crude tert-butyl 3-[1-(2-aminoethyl)-3-piperidyl]azetidine-1-carboxylate (120 mg, 0.423 mmol) in DCM (2 ml) was treated with triethylamine (129 mg, 1.27 mmol, 3.0 equiv) and acetyl chloride (40.0 mg, 0.51 mmol, 1.2 equiv). After 30 min, the mixture was quenched with 1 M aqueous sodium carbonate (10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate. tert-Butyl 3-(1-(2-acetamidoethyl)piperidin-3-yl)azetidine-1-carboxylate was then condensed with Precursor II according to general procedures C and D to afford a mixture of diastereomers. The title compound was separated from its diastereomer by SFC using an AD-H column and eluting with 25% ethanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the second eluting isomer and converted to the corresponding HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M HCl in EtOH. 1H NMR (400MHz, Methanol-d4; HCl salt) 1H), 4.27 (t, J = 8.3 Hz, 2H), 3.99 (ddd, J = 8.5, 5.6, 2.2 Hz, 2H), 3.75 - 3.44 (m, 3H), 3.21 (t, J = 5.8 Hz, 2H), 2.99 - 2.81 (m, 1H), 2.77 - 2.57 (m, 2H), 2.50 (s, 3H), 2.18 - 2.00 (m, 3H), 2.00 (s, 3H), 1.99 - 1.92 (m, 1H), 1.87 (d, J =7.1 Hz, 3H), 1.81 (s, 1H), 1.27-1.18 (m, 1H). LCMS [M+H] 530.1.

[0969] EXAMPLE 102

[0970] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-isopropylpiperidin-3-yl)azetidin-1-yl)-3-( trifluoromethyl)- 1H-pyrazolo[3,4-b]pyrazine. The title compound was prepared using general procedure A with Precursor VI and acetone, followed by procedure C. The resulting product was condensed with Precursor V using procedure D. 1H NMR (400 MHz, Methanol-d4 ; HCl salt) δ 7.94 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 6.44 (q, J = 7.0 Hz, 1H), 4.38 - 4.26 (m, 2H), 4.08 - 3.98 (m, 2H), 3.49 - 3.34 (m, 2H), 3.03 - 2.90 (m, 1H), 2.82-2.63 (m, 2H), 2.212.13 (m, 2H), 2.11-2.03 (m, 1H), 2.02- 1.95 (m , 1H), 1.91 (d, J =7.1 Hz, 3H), 1.88 - 1.80 (m, 1H), 1.38 (d, J = 4.5 Hz, 6H), 1 .26 - 1.20 (m, 1H). LCMS [M+H] 541.0.

[0971] EXAMPLE 103

[0972] (R)-1-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3 ,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol. Precursor VI (270 mg, 1.30 mmol) was condensed with (2R)-2-hydroxypropanoic acid (152 mg, 1.69 mmol) in DMF (5 mL) using 1H-benzo[d][1 ,2,3]triazol-1-ol (258 mg, 1.69 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (324 mg, 1.69 mmol) for 30 min and then poured into ethyl acetate (50 ml), washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by flash chromatography using of silica gel and a gradient of methanol (0 to 20%) in DCM to produce 3- tert-butyl [(3R)-1-[(2R)-2-hydroxypropanoyl]-3-piperidyl]azetidine-1-carboxylate (350 mg, 1.12 mmol). 3-[(3R)-1-[(2R)-2-hydroxypropanoyl]-3-piperidyl]azetidine-1-carboxylate (350 mg, 1.12 mmol) was dissolved in tetrahydrofuran (6 ml) and treated with borane-tetrahydrofuran complex (3.36 ml, 3.36 mmol, 1 M in tetrahydrofuran) and stirred for 12 hours, quenched with methanol and concentrated under reduced pressure, the residue was purified by flash chromatography using silica gel and a methanol gradient (0 to 20%) in DCM to produce tert-3-[(3R)-1-[(2R)-2-hydroxypropyl]-3-piperidyl]azetidine-1-carboxylate butyl (193 mg, 0.6500 mmol), 3-[(3R)- tert-Butyl 1-[(2R)-2-hydroxypropyl]-3-piperidyl]azetidine-1-carboxylate was then condensed with Precursor V using general procedures C and D to afford the title compound.1H NMR (400 MHz, Methanol-d4; HCl Salt) δ 7.93 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8, 5 Hz, 1H), 7.30 (dd, J = 8.5, 2.0 Hz, 1H), 6.44 (q, J = 7.1 Hz, 1H), 4.38 - 4.26 ( m, 2H), 4.26 - 4.17 (m, 1H), 4.07 - 3.96 (m, 2H), 3.76 - 3.70 (m, 1H), 3.70 - 3, 65 (m, 1H), 3.58 - 3.54 (m, 1H), 3.15-3.00 (m, 2H), 2.93 - 2.81 (m, 1H), 2.79 - 2.58 (m, 2H), 2.28 - 2.12 (m, 1H ), 2.11-1.92 (m, 2H), 1.91 (d, J = 7.1 Hz, 3H), 1.89- 1.75 (m, 1H), 1.24 (d, J =6.2 Hz, 3H), 1.22- 1.18 (m, 1H). LCMS [M+H] 557.0.

[0973] EXAMPLE 104

[0974] (S)-1-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3 ,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol. Precursor VI (270 mg, 1.30 mmol) was condensed with (2S)-2-hydroxypropanoic acid (152 mg, 1.69 mmol) in DMF (5 mL) using 1H-benzo[d][1 ,2,3]triazol-1-ol (258 mg, 1.69 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (324 mg, 1.69 mmol) for 30 min and then poured into ethyl acetate (50 ml), washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by flash chromatography using of silica gel and a gradient of methanol (0 to 20%) in DCM to produce 3- tert-butyl [(3R)-1-[(2S)-2-hydroxypropanoyl]-3-piperidyl]azetidine-1-carboxylate (350 mg, 1.12 mmol). 3-[(3R)-1-[(2S)-2-hydroxypropanoyl]-3-piperidyl]azetidine-1-carboxylate (350 mg, 1.12 mmol) was dissolved in tetrahydrofuran (6 ml) and treated with borane-tetrahydrofuran complex (3.36 ml, 3.36 mmol, 1 M in tetrahydrofuran) and stirred for 12 hours, quenched with methanol and concentrated under reduced pressure, the residue was purified by flash chromatography using silica gel and a methanol gradient (0 to 20%) in DCM to produce tert-3-[(3R)-1-[(2S)-2-hydroxypropyl]-3-piperidyl]azetidine-1-carboxylate butyl (90 mg, 0.3016 mmol), 3-[(3R)-1- tert-Butyl [(2S)-2-hydroxypropyl]-3-piperidyl]azetidine-1-carboxylate was then condensed with Precursor V using general procedures C and D to afford the title compound. 1H NMR (400 MHz, Methanol-d4; HCl Salt) δ 7.93 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8, 5 Hz, 1H), 7.30 (dd, J = 8.5, 2.1 Hz, 1H), 6.44 (q, J = 7.1 Hz, 1H), 4.37 - 4.25 ( m, 2H), 4.23-4.10 (m, 1H), 4.073.97 (m, 2H), 3.77-3.56 (m, 2H), 3.55 -3.39 (m, 1H), 3,072.76 (m, 3H), 2.19-2.03 (m, 1H), 1.98- 1.92 (m, 2H), 1.91 (d, J = 7.1 Hz, 3H), 1.90- 1.80 (m, 2H), 1.22 (d , J = 6.2 Hz, 3H), 1.20- 1.17 (m, 1H). LCMS [M+H] 557.0.

[0975] EXAMPLE 105

[0976] N-((R)-1-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-2-yl)acetamide. Precursor VI (270 mg, 1.13 mmol) was condensed with (2R)-2-(benzyloxycarbonylamino)propanoic acid (376.7 mg, 1.69 mmol) in DMF (3 mL) using 2-(benzyloxycarbonylamino)propanoic acid (376.7 mg, 1.69 mmol) in DMF (3 mL). -(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium(V) (642 mg, 1.69 mmol) and N, N-Diisopropylethylamine (0.587 ml, 3.38 mmol) for 12 hours and then poured into ethyl acetate (50 ml), washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated under pressure reduced, the residue was purified by flash chromatography using silica gel and an ethyl acetate gradient (10 to 100%) in hexanes to yield tert-butyl 3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propanoyl]-3-piperidyl]azetidine-1-carboxylate (306 mg, 0.687 mmol). tert-Butyl 3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propanoyl]-3-piperidyl]azetidine-1-carboxylate (306 mg, 0.687 mmol) was dissolved in tetrahydrofuran (6 ml) and treated with borane-tetrahydrofuran complex (2.06 ml, 2.06 mmol, 1 M in tetrahydrofuran) and stirred for 12 hours, quenched with methanol and concentrated under reduced pressure, the residue was purified by flash chromatography using silica gel and a methanol gradient (0 to 20%) in DCM to produce 3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propyl]-3-piperidyl] tert-butyl azetidine-1-carboxylate (296 mg, 0.687 mmol), tert-butyl 3-[(3R)-1-[(2R)-2-(benzyloxycarbonylamino)propyl]-3-piperidyl]azetidine-1-carboxylate (296 mg, 0.687 mmol) was dissolved in methanol ( 5 ml) and 10 wt% palladium on carbon (89.4 mg) was added, the mixture was then placed under a hydrogen atmosphere (balloon) and stirred for 15 minutes, filtered through celite, concentrated under pressure reduced, diluted with DCM (5 ml), treated with triethylamine (0.29 ml, 2.07 mmol) and acetyl chloride (0.15 ml, 2.07 mmol), stirred for 30 minutes, quenched with sodium carbonate at 1 M, extracted with ethyl acetate (2 x 5 ml), dried over sodium sulfate, concentrated in vacuo to yield tert-Butyl 3-[(3R)-1-[(2R)-2-acetamidopropyl]-3-piperidyl]azetidine-1-carboxylate (220 mg, 0.648 mmol), 3-[(3R)-1-[ (2R)-2-acetamidopropyl]-3-piperidyl]azetidine-1-carboxylate tert-butyl was then condensed with Precursor V using general procedures C and D to afford the title compound. 1H NMR (400 MHz, Methanol-d4; HCl Salt) δ 7.93 (s, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8, 5 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 6.44 (q, J = 7.2 Hz, 1H), 4.39 - 4.24 ( m, 3H), 4.08 - 3.93 (m, 2H), 3.58 - 3.47 (m, 1H), 3.44 - 3.34 (m, 1H), 3.17-2, 94 (m, 2H), 2.86-2.49 (m, 2H), 2.19-2.00 (m, 1H), 2.00 (s, 3H), 1.98 - 1.94 (m, 3H), 1.91 (d, J = 7.1 Hz, 3H) , 1.83 - 1.68 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), 1.20-1.17 (m, 1H). LCMS [M+H] 598.1.

[0977] EXAMPLE 106

[0978] N-((S)-1-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propan-2-yl)acetamide. Precursor VI (270 mg, 1.13 mmol) was condensed with (2S)-2-(benzyloxycarbonylamino)propanoic acid (376.7 mg, 1.69 mmol) in DMF (3 mL) using 2-(benzyloxycarbonylamino)propanoic acid (376.7 mg, 1.69 mmol) in DMF (3 mL). -(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium(V) (642 mg, 1.69 mmol) and N, N-Diisopropylethylamine (0.587 ml, 3.38 mmol) for 12 hours and then poured into ethyl acetate (50 ml), washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated under pressure reduced, the residue was purified by flash chromatography using silica gel and an ethyl acetate gradient (10 to 100%) in hexanes to yield tert-butyl 3-[(3R)-1-[(2S)-2-(benzyloxycarbonylamino)propanoyl]-3-piperidyl]azetidine-1-carboxylate (501 mg, 1.13 mmol). tert-Butyl 3-[(3R)-1-[(2S)-2-(benzyloxycarbonylamino)propanoyl]-3-piperidyl]azetidine-1-carboxylate (501 mg, 1.13 mmol) was dissolved in tetrahydrofuran (6 ml) and treated with borane-tetrahydrofuran complex (3.37 ml, 3.37 mmol, 1 M in tetrahydrofuran) and stirred for 12 hours, quenched with methanol and concentrated under reduced pressure, the residue was purified by flash chromatography using silica gel and a methanol gradient (0 to 20%) in DCM to yield 3-[(3R)-1-[(2S)-2-(benzyloxycarbonylamino)propyl]-3- tert-butyl piperidyl]azetidine-1-carboxylate (485 mg, 1.13 mmol), tert-Butyl 3-[(3R)-1-[(2S)-2-(benzyloxycarbonylamino)propyl]-3-piperidyl]azetidine-1-carboxylate (485 mg, 1.13 mmol) was dissolved in methanol (5 ml) and 10 wt% palladium on carbon (89.4 mg) was added, the mixture was then placed under a hydrogen atmosphere (balloon) and stirred for 15 minutes, filtered through celite, concentrated under reduced pressure , diluted with DCM (5 ml), treated with triethylamine (0.468 ml, 3.38 mmol) and acetyl chloride (0.245 ml, 3.38 mmol), stirred for 30 minutes, quenched with 1 M sodium carbonate, extracted with ethyl acetate (2 x 5 ml), dried over sodium sulfate, concentrated in vacuo to yield tert-Butyl 3-[(3R)-1-[(2S)-2-acetamidopropyl]-3-piperidyl]azetidine-1-carboxylate (230 mg, 0.678 mmol), 3-[(3R)-1-[ tert-Butyl (2S)-2-acetamidopropyl]-3-piperidyl]azetidine-1-carboxylate was then condensed with Precursor V using general procedures C and D to afford the title compound. 1H NMR (400 MHz, Methanol-d4; HCl Salt) δ 7.95 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8, 5 Hz, 1H), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 6.45 (q, J = 7.0 Hz, 1H), 4.50 - 4.39 ( m, 1H), 4.37 - 4.26 (m, 2H), 4.18-3.97 (m, 4H), 3.52 - 3.42 (m, 1H), 3.23 - 3, 06 (m, 2H), 3.06 - 2.90 (m, 1H), 2.76 - 2.62 (m, 1H), 2.61 - 2.48 (m, 1H), 2.06-2.00 (m, 1H), 2.00 (s, 3H), 2.00 - 1, 93 (m, 1H), 1.91 (d, J = 7.1 Hz, 3H), 1.89- 1.82 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H ), 1.23 - 1.14 (m, 1H). LCMS [M+H] 598.2.

[0979] EXAMPLE 107

[0980] 3-((R)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propane-1-sulfonamide. A mixture of the title compound and its diastereomer was prepared using general procedure B (b) and 3-chloropropane-1-sulfonamide followed by general procedures C and D with precursor IV. The title compound was separated from its diastereomer by SFC using an AD-H column and eluting with 30% isopropanol (0.1% diethylamine) in CO2 to give the title compound as the first eluting isomer. 1H NMR (400 MHz, CDCl3, HCl Salt) δ 7.83 (s, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.5, 2.1Hz, 1H), 6.46 (q, J = 7.0 Hz, 1H, ), 4.29 - 4.17 (m, 2H), 4.02 - 3.96 (m, 1H), 3.95 - 3.87 (m, 1H), 3.26 - 3.15 (m, 2H), 3.04 - 2.85 (m, 2H), 2.65 - 2.49 (m, 3H), 2.23 - 1.94 (m, 3H), 1.90 (d, J = 7.1 Hz, 3H), 1.84 - 1.50 (m, 5H), 1.02 - 0.88 (m, 1H). LCMS [M+H] 577.1.

[0981] EXAMPLE 108

[0982] 3-((S)-3-(1-(3-cyano-1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)propane-1-sulfonamide. A mixture of the title compound and its diastereomer was prepared as described in the previous example. The title compound was separated from its diastereomer by SFC using an AD-H column and eluting with 30% isopropanol (0.1% diethylamine) in CO2 to give the title compound as the second eluting isomer. 1H NMR (400 MHz, CDCl, HCl Salt) H), 4.29 - 4.17 (m, 2H), 4.04 - 3.89 (m, 2H), 3.26 - 3.16 (m, 2H), 3.00 - 2.85 (m, 2H), 2.68 - 2.48 (m, 3H), 2.25 - 1.92 (m, 4H), 1.90 (d, J = 7.1 Hz, 3H), 1.85 - 1.67 (m, 3H), 1.64 - 1.49 (m, 1H), 1.03 - 0.89 (m, 1H). LCMS [M+H] 577.0.

[0983] EXAMPLE 109

[0984] N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DCM and 3 equiv. of triethylamine was added to the reaction mixture followed by 1.2 equiv. of 2-propanesulfonyl chloride. The reaction mixture was stirred at room temperature until complete conversion (by LCMS) was achieved. The reaction was quenched with 1 M sodium carbonate, extracted with ethyl acetate, the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was then used in general procedure C and coupled to precursor V using general procedure D. The title compound was separated from its diastereomer by SFC using an AD-H column and eluting with 20% isopropanol (0.1% diethylamine) in CO2 to give the free base as the first eluting isomer. 1H NMR (400 MHz, Methanol-d4, HCl Salt) δ 7.93 (s, 1H), 7.50 - 7.46 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 6.45 (q, J = 7.1 Hz, 1H, ), 4.40 - 4.25 (m, 2H), 4.14- 3.93 (m, 2H), 3,813.70 (m, 1H), 3.69 - 3.61 (m, 1H), 3.61 - 3.43 (m, 2H), 3.39 - 3.32 (m, 1H), 3.30-3.22 (m, 1H), 3.06-2.88 (m, 1H), 2.78-2.57 (m, 2H), 2.23-2.11 (m, 1H), 2.10-1.93 (m, 4H), 1.91 (d, J = 7.0 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H), 1.36 ( d, J = 6.8 Hz, 3H), 1.28-1.17 (m, 1H). LCMS [M+H] 648.1.

[0985] EXAMPLE 110

[0986] N-(2-((S)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)propane-2-sulfonamide. A mixture of the title compound and its diastereomer was prepared using general procedure A with 3-(1,3-dioxoisoindolin-2-yl)propanal, followed by removal of phthaloyl group with hydrazine hydrate (4 equiv.) in methanol (0.4 M) at room temperature for 18 h. The reaction mixture was diluted with water, extracted with DCM, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DCM and 3 equiv. of triethylamine was added to the reaction mixture followed by 1.2 equiv. of 2-propanesulfonyl chloride. The reaction mixture was stirred at room temperature until complete conversion (by LCMS) was achieved. The reaction was quenched with 1 M sodium carbonate, extracted with ethyl acetate, the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was then used in general procedure C and coupled to precursor V using general procedure D. The title compound was separated from its diastereomer by SFC using an AD-H column and eluting with 20% isopropanol (0.1% diethylamine) in CO2 to give the free base as the second eluting isomer. 1H NMR (400MHz, Methanol-d4, HCl Salt) 1H NMR (400MHz, Methanol-d4) ), 6.44 (q, J = 7.1 Hz, 1H), 4.38 - 4.25 (m, 2H), 4.11 - 3.97 (m, 2H), 3.80 - 3.71 (m, 1H), 3.69 - 3.60 (m, 1H), 3.61 - 3.45 (m, 2H), 3.40-3.33 (m, 1H), 3.29-3.21 (m, 1H), 3.03 -2.93 (m, 1H), 2.77-2.63 (m, 2H), 2.23-2.10 (m, 1H), 2.09 - 1.92 (m, 3H), 1.91 (d, J = 7.1 Hz, ), 1.89 - 1.81 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.28 - 1.14 (m, 1H). LCMS [M+H] 648.1.

[0987] EXAMPLE 111

[0988] 6-(3-((S)-1-((1H-imidazol-5-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-( 2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. A mixture of the title compound and its diastereomer was prepared using general procedure A starting from 1H-imidazole-5-carbaldehyde using 2:1 1,2-dichloroethane/DMF as the solvent, followed by procedure C . The resulting product was condensed with Precursor IV using procedure D. The title compound was separated from its diastereomer by SFC using a 20 x 250 mm AD-H column and eluting with 30% isopropanol (0 ,1% diethylamine) in CO2 to give the free base of the title compound as the first eluting isomer and converted to the HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M of HCl in EtOH. 1H NMR (400 MHz, Methanol-d4, HCl Salt) δ 7.94 (s, 1H), 7.64 (d, J = 1.1 Hz, 1H), 7.48 (d, J =2, 1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.31 (dd, 7= 8.5, 2.1 Hz, 1H), 7.01 (s, 1H) , 6.45 (q, J = 7.0 Hz, 1H), 4.33 - 4.18 (m, 2H), 4.03 - 3.93 (m, 1H), 3.93 - 3.84 (m, 1H), 3.58 (s, 2H), 3.34 -3.32 (m, 1H), 2.98-2.85 (m, 2H), 2.68-2.54 (m, 1H), 2.12-2.01 (m, 1H), 1.90 (d, J = 7.0 Hz, 3H), 1.87 - 1.70 (m, 4H), 0.98 - 0.84 (m, 1H). LCMS [M+H] 536.0.

[0989] EXAMPLE 112

[0990] 6-(3-((R)-1-((1H-imidazol-5-yl)methyl)piperidin-3-yl)azetidin-1-yl)-1-((R)-1-( 2,4-dichlorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile. A mixture of the title compound and its diastereomer was prepared using general procedure A starting from 1H-imidazole-5-carbaldehyde using 2:1 1,2-dichloroethane/DMF as the solvent, followed by procedure C . The resulting product was condensed with Precursor IV using procedure D. The title compound was separated from its diastereomer by SFC using a 20 x 250 mm AD-H column and eluting with 30% isopropanol (0 ,1% diethylamine) in CO2 to give the free base of the title compound as the second eluting isomer and converted to the HCl salt by dissolving in EtOH, cooling to 0 °C, and adding 1 equiv. of 0.01 M of HCl in EtOH. 1H NMR (400 MHz, Methanol-d4, HCl Salt) δ 7.94 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.49 (d, J =2, 1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.31 (dd, 7= 8.5, 2.1 Hz, 1H), 7.01 (s, 1H) , 6.45 (q, J = 7.0 Hz, 1H), 4.34 - 4.16 (m, 2H), 4.03 - 3.86 (m, 2H), 3.58 (s, 2H ), 3.34 - 3.32 (m, 1H), 2.97 - 2.84 (m, 2H), 2.67-2.56 (m, 1H), 2.13 - 2.01 (m, 1H), 1.90 (d, J = 7.0 Hz, 3H), 1.88- 1 .70 (m, 3H), 1.72 - 1.53 (m, 1H), 0.97 - 0.83 (m, 1H). LCMS [M+H] 536.0.

[0991] EXAMPLE 113

[0992] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-6-(3-((S)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine. A mixture of the title compound and its diastereomer was prepared using procedure B (b) using 1-bromo-3-(methylsulfonyl)propane followed by general procedure C and coupling with precursor II using general procedure D. The title compound was separated from its diastereomer by SFC using a 20 x 250 mm IC column and eluting with 40% ethanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the first eluting isomer. 1H NMR (400 MHz, Methanol-d4, HCl Salt) δ 7.74 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.26 (dd, 7= 8.5, 2.1 Hz, 1H), 6.29 (q, J = 7.0 Hz , 1H), 4.32 - 4.22 (m, 2H), 4.01 - 3.94 (m, 2H), 3.51-3.45 (m, 1H), 3.35 (s, 2H), 3.34 - 3.32 (m, 1H), 3.28 - 3.23 (m, 3H), 3.17 - 3.10 (m, 1H), 3.03 (s, 3H), 2.75 - 2.63 (m, 1H), 2.50 (s, 3H), 2.28-2.20 (m, 2H), 2.10 - 1.91 (m, 3H), 1.87 (d, J = 7.1 Hz, 3H), 1.82- 1.70 (m, 1H), 1.23-1.14 (m, 1H). LCMS [M+H] 565.0.

[0993] EXAMPLE 114

[0994] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-3-methyl-6-(3-((R)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-1H-pyrazolo[3,4-b]pyrazine. A mixture of the title compound and its diastereomer was prepared using procedure B(b) using 1-bromo-3-(methylsulfonyl)propane followed by general procedure C and coupling with precursor II using general procedure D. The title compound was separated from its diastereomer by SFC using a 20 x 250 mm IC column and eluting with 40% ethanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the second eluting isomer. 1H NMR (400MHz, Methanol-d4, HCl salt) 1H), 4.32 - 4.22 (m, 2H), 4.02 - 3.94 (m, 2H), 3.51 - 3.38 (m, 1H), 3.35 (s, 2H), 3.26 (t, J = 7.3 Hz, 2H), 3.21 - 3.11 (m, 2H), 3.03 (s, 3H), 2.84 - 2.73 (m, 1H), 2.73 - 2.59 (m, 1H), 2.50 (s, 3H), 2.31-2.20 (m, 2H), 2.13 - 1.91 (m, 3H), 1.87 (d, J = 7.1 Hz, 3H), 1.84 - 1.69 (m, 1H), 1.25 - 1.11 (m, 1H). LCMS [M+H] 565.0.

[0995] EXAMPLE 115

[0996] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((S)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine. A mixture of the title compound and its diastereomer was prepared using procedure B (b) using 1-bromo-3-(methylsulfonyl)propane followed by general procedure C and coupling with precursor V using general procedure D. The title compound was separated from its diastereomer by SFC using a 20 x 250 mm IC column and eluting with 35% ethanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the first eluting isomer. 1H NMR (400MHz, Methanol-d4, HCl salt) 1H), 4.35 - 4.28 (m, 2H), 4.06 - 3.97 (m, 2H), 3.50-3.47 (m, 1H), 3.42 - 3.34 (m, 3H), 3.28 - 3.20 (m, 2H), 3.153.10 (m, 1H), 3.03 (s, 3H), 2.76-2.64 (m, 2H), 2.30-2.16 (m, 2H), 2.10-1.93 (m, 3H), 1.91 (d,J = 7.1 Hz, 3H), 1.82 - 1.67 (m, 1H), 1.25-1.12 (m, 1H). LCMS [M+H] 619.1.

[0997] EXAMPLE 116

[0998] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(3-(methylsulfonyl)propyl)piperidin-3-yl)azetidin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyrazine. A mixture of the title compound and its diastereomer was prepared using procedure B(b) using 1-bromo-3-(methylsulfonyl)propane followed by general procedure C and coupling with precursor V using general procedure D. The title compound was separated from its diastereomer by SFC using a 20 x 250 mm IC column and eluting with 35% ethanol (0.1% diethylamine) in CO2 to give the free base of the title compound as the second eluting isomer. 1H NMR (400MHz, Methanol-d4, HCl salt) 1H), 4.37- 4.26 (m, 2H), 4.08 - 3.96 (m, 2H), 3.54 - 3.44 (m, 1H), 3.26 (t, J = 7.4 Hz, 2H), 3.22 - 3.15 (m, 3H), 3.14-3.12 (m, 1H), 3.03 (s, 3H), 2.75 -2.64 (m, 2H), 2,312.20 (m, 2H), 2.13 - 1.91 (m, 3H), 1.91 (d, J = 7.1 Hz, 3H), 1.82 - 1.69 (m, 1H), 1.25-1.12 (m, 1H). LCMS [M+H] 619.1.

Biological Samples and Tests

[0999] The following general materials and methods were used, where indicated, or may be used in the Examples. Standard methods in molecular biology are described in the scientific literature (see, e.g., Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA; and Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, N.Y., USA, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian and yeast cells (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4)).

[1000] The scientific literature describes methods for protein purification, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, as well as chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and protein glycosylation (see, for example, Coligan, et al. (2000) Current Protocols in Protein Science, Vols. 1-2, John Wiley and Sons, Inc., NY, USA).

[1001] Software packages and databases for determining, for example, antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, for example, GCG Wisconsin Package (Accelrys, Inc., San Diego, CA, USA); and DeCypher™ (TimeLogic Corp., Crystal Bay, NV, USA).

[1002] Multiple assays that can be used to evaluate the compounds of the present invention are known to one of skill in the art and/or are described in the patent and scientific literature (see, e.g., US 2006/0004010; US 2002/0173524; Imai et al. (1997) J. Biol. Chern. 272:15036-15042; Imai et al. (1998) J. Biol. Chern. 273:1764-1768, each of which is incorporated by reference). The following procedures are representative of the types of experiments that can be used to demonstrate, e.g., the CCR4 antagonist activity of compounds, inhibitory activity for effector cell functions, TNFα regulatory activity, and efficacy in animal disease models.

[1003] Calcium Flux Assay. Compounds were evaluated in a calcium flux assay substantially performed as follows. Chem5-hCCR4 cells (EMD Millipore, Hayward, CA; HTS009C) were cultured under standard conditions and frozen in aliquots of 10x106 cells/ml. The day before compound testing, one vial was rapidly chilled and pipetted into 20 ml media (DMEM + 10% FBS + 1% Pen-Strep + 1% L-glutamine). Cells were harvested by centrifugation and resuspended in fresh culture media. 25 μl of cell suspension was seeded into 384-well plates (Corning, Tewksbury, MA, USA; CellBind black wall/clear bottom). Plates were centrifuged at 300 g for 10 s and incubated overnight at 37 °C and 5% CO2. On the day of compound testing, media were removed from the plates and 25 μl of serum-free media was added to each well. Plates were returned to the incubator for 2 h. 25 μl of assay buffer (Hank's balanced salt solution + 20 mM HEPES pH 7.4) containing FLIPR Calcium 6 dye (Molecular Devices, Sunnyvale, CA, USA; #R8191) and probenecid (2.5 mM) was added to each well and incubated at 37 °C and 5% CO2 for 2 h. Compounds in DMSO were added to the plates using an HP D300e digital dispenser, and all wells were normalized to contain 0.25 μL (0.5%) DMSO. Plates were incubated for 1 h at 37 °C and 5% CO2. CCL22 (Peprotech; Rockyhill, NJ, USA) was diluted in assay buffer containing 0.1% BSA at 7.5 nM (corresponding to 5 × EC80 of 1.5 nM).

[1004] Assay plates and CCL22 working solution were transferred to the FlexStation plate reader (Molecular Devices) at 37 °C for 5 min equilibration. Fluorescence recordings at 485 excitation/525 emission were taken at 2.5 s intervals. At t = 16 s, 12.5 μL of CCL22 solution was added to each well and readings continued for 30 s at 2.5 s intervals. Minimum fluorescence (Fmin) was calculated by weighting the readings before ligand addition and the change in fluorescence (LlF) was calculated by subtracting Fmin from the mean of the readings after ligand addition. The LlF/Fmin response was plotted as a function of compound concentration, and IC50 values were determined by nonlinear regression analysis using a 4-parameter fit in PRISM software (GraphPad; La Jolla, CA) or Dotmatics Browser.

[1005] Using the calcium flux assay described herein, activity for several compounds described herein was determined.

[1006] The potency levels are presented in Table 2, where IC50: A < 0.1 μM; B = 0.1-0.5 μM; and C > 0.5 μM. Table 2.

[1007] Potent and Selective Antitumor Immune Responses of C-C Motif Chemokine Receptor (CCR4) Antagonists to Inhibit Regulatory T (Treg) Cells

[1008] Naturally occurring CD4+ Foxp3+ suppressor Treg are essential for immune tolerance. Although Treg-mediated suppression of effector cells is important for controlling inflammatory responses and preventing autoimmune diseases, the presence of Treg in the tumor microenvironment (TME) has been shown to attenuate antitumor immune responses. Human Treg express CCR4, the receptor for the chemokines CCL17 and CCL22. These chemokines are produced by tumor cells or tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff). Preclinical and clinical data in several cancer types support a role for CCR4-mediated recruitment and accumulation of Treg in the TME that may be associated with poor prognosis. Additionally, recent longitudinal studies in patients receiving IO agents demonstrate an influx of Treg into responders that may attenuate optimal antitumor responses. Therefore, CCR4 is an ideal target to selectively block Treg recruitment into the TME.

[1009] Multiple structurally unique series of selective small molecule CCR4 antagonists have been developed. These antagonists have cellular potencies in multiple assays (including in a functional chemotaxis assay with primary human Treg in 100% serum) in the low double digit nM range. Representative compounds are selective for other chemokine receptors, GPCRs, and ion channels, including the hERG channel, and lack inhibition of common human CYP450 enzymes. Furthermore, the compounds have excellent in vitro and in vivo ADME properties, consistent with convenient oral dosing. In preclinical syngeneic tumor models, the present CCR4 antagonists block Treg migration and sustain the expansion of activated Teff. In contrast to the nonselective anti-CCR4 antibody depletion approach, the present compounds reduce Treg in the tumor but not in peripheral tissues such as blood, spleen, or skin. In preclinical efficacy studies, CCR4 antagonists potentiate the antitumor effects of several checkpoint inhibitors and immune stimulators such as anti-PD-L1 and anti-CD137 antibodies. Enhanced tumor growth inhibition and increases in the percentage of tumor-free mice when these agents are combined with CCR4 antagonists, without any gross toxicity, have been observed.

[1010] Chemotaxis Assays. In general terms, chemotaxis assays can be performed using 5 μm filter plates (Neuroprobe) with the chemoattractant (MDC, TARC, or SDF) placed in the lower chamber, and a cell suspension of 100,000 CEM cells in the upper chamber. The assays can be incubated 1-2 h at 37 °C, and the number of cells in the lower chamber quantified by the CyQUANT assay (Molecular Probes).

[1011] The following serum chemotaxis assay was used to determine the extent to which compounds of the present invention block CCR4-mediated cell migration. The assay was performed using the ChemoTX migration system (Gaithersburg, MD, USA) with a 5 μm pore size polycarbonate etched (PCTE) membrane. CCR4-expressing CCRF-CEM cells were harvested by centrifugation at 400 x g at room temperature, then suspended at 2 million cells/ml in human serum. Compounds (or an equivalent volume of solvent (DMSO)) were then added to the cell/serum mixture to a final DMSO concentration of 0.25% (v/v), followed by a 30 minute compound pre-incubation period. Separately, recombinant human MDC was diluted to 0.9 nM in 1x HBSS with 0.1% BSA, and 29 μl of diluted MDC was placed in the lower wells of the ChemoTX plate. A polycarbonate (or PCTE) membrane (5 μm pore size) was placed on top of the plate, and 50 μl of the cell/compound mixture was transferred to each well of the membrane. The plates were incubated at 37 °C for 60 min, after which the polycarbonate membranes were removed, and 10 μl of the CyQUANT DNA intercalating agent was added to the lower wells. The amount of fluorescence, which corresponds to the number of migrated cells, was measured using an Envision plate reader (PerkinElmer; Waltham, MA, USA).

[1012] Detection of radiolabeled TARC and/or MDC binding to CCR4 - Protocol A. Chemical library source plates can be obtained from commercial suppliers and can contain individual compounds at 5 mg/ml in DMSO. From this, multiple compound plates containing 10 compounds in each well can be prepared and then diluted in 20% DMSO to a concentration of 50 μg/ml. A 20 μl aliquot of each mixture can be spotted onto the test plates and stored frozen until use.

[1013] A stable transfectant cell line expressing CCR4 can be prepared using current standard molecular biology methods. CCR4 transfectants can be cultured in IMDM-5% FBS, and harvested when the concentration is between 0.5 - 1.0 x 106 cells/ml. The cells can be centrifuged and resuspended in assay buffer (20 mM HEPES, pH 7.1, 140 mM NaCl, 1 mM CaCl2, 5 mM MgCl2, and 0.20% BSA) to a concentration of 5.6 x 106 cells/ml. To set up screening assays, 0.09 ml of cells can be added to assay plates containing compounds (yielding a final compound concentration of 1–5 μg/ml each (~2–10 μM)), and then 0.09 ml of 125I-TARC or 125I-MDC diluted in assay buffer (final concentration ~50 pM, with ~30,000 cpm per well) can be added. Plates can then be sealed and incubated for approximately 3 h at 4 °C on a shaking platform. Assay plates can be harvested using Packard filter plates, pre-soaked in 0.3% PEI (polyethyleneimine) solution, in a Packard vacuum cell harvester. Scintillation fluid (50 μl) was added to all wells and the plates could be sealed and counted in a Top Count scintillation counter. Control wells containing diluent alone (for total counts) or excess MDC or TARC (1 μg/ml, for non-specific binding) could be used to calculate the percent total inhibition for each set of compounds. IC50 values are those concentrations required to reduce the binding of identified MDC or TARC to the receptor by 50%.

[1014] Detection of radiolabeled TARC and/or MDC binding to CCR4 - Protocol B. 125I-labeled TARC and MDC are available from commercial sources (e.g., Perkin Elmer Life Sciences). All buffers and materials are available from commercial sources (e.g., Sigma).

[1015] To measure the binding of 125I-TARC or 125I-MDC to CCR4-expressing cells (e.g., CEM cells (e.g., ATCC HB-12624)), 125I-TARC or 125I-MDC is diluted to a concentration of approximately 200 pM in a buffered saline solution (e.g., RPMI supplemented with 0.5% BSA), and added to an equal volume of a cell suspension (e.g., CEM cells at 5 x 106 cells/ml). The resulting mixture is incubated for a period of time (e.g., 2 h), and unbound 125I-TARC or 125I-MDC is separated from the cells by filtration, e.g., by passage through a GF/B filter plate (Packard Biosciences) pretreated with 0.3% polyethyleneimine (Sigma) using a Packard Filtermate 96 (Packard Biosciences). The amount of 125I-TARC or 125I-MDC retained by the cells on the filter plate is measured by adding a small amount of scintillation fluid (e.g., 50 μl of Microscint-20 Packard Biosciences) and reading the scintillation on appropriate detection equipment, e.g., a Packard TopCount 383 (Packard Biosciences).

[1016] Nonspecific binding of125I-TARC or 125I-MDC can be estimated by measuring the amount of 125I-TARC or 125I-MDC retained with the cells on the filter plate when the assay is performed in the presence of a large excess of unidentified TARC or MDC. Inhibition of 125I-TARC or 125I-MDC binding to CCR4 is defined as a decrease in the retention of 125I-TARC or 125I-MDC to the cells on the filter plate.

[1017] Calcium Mobilization Assay. Calcium mobilization experiments can be performed by staining the human T cell line CEM with ND0-1 dye (45 min at room temperature), washing with PBS, and resuspending in flow buffer (HBSS with 1% FBS). For each experiment, 1x106 cells can be incubated at 37 °C in the cuvette of a PTI spectrometer, and the ratio of 410/490 nm emission plotted over time (typically 2-3 min), with compounds added at 5 s, followed by MDC, TARC, or other chemokines.

[1018] TNFα Production. The present invention contemplates the use of a murine model of TNFα production by LPS stimulation. A CCR4 antagonist compound (or compounds) can be suspended in a medium, orally administered to a mouse (male, C57BL/6), and after 0.5 hour LPS (055:B5, Sigma) peritoneally administered to the mouse at a dose of 60 mg/kg. To the control groups, only the medium can be administered. Sixty min after LPS treatment, blood collection with added heparin can be conducted from the abdominal vena cava under ether anesthesia, and centrifuged (12,000 rpm) at 4 °C for 3 min to provide plasma (which can be stored at -80 °C prior to use). TNFα in plasma can be quantified using an ELISA kit (R&D systems; Minneapolis, MN, USA).

[1019] Efficacy of CCR4 Antagonists for Therapeutic Indications. A representative procedure for evaluating the efficacy of CCR4 antagonists for the treatment of septic shock is described herein. An animal model of endotoxic shock can be induced by injecting mice with LPS. Three groups (15 mice per group) can be treated with an i.p. injection of a dose of LPS that produces 90% mortality in mice. One group of mice can also receive PBS and 0.5% Tween i.p. 30 min prior to LPS administration. A second group of mice can also receive different doses of the CCR4 antagonist(s) i.p., IV, SC, IM, PO, or via any other route of administration 30 min prior to, or concomitantly with, LPS administration. A third group of mice can serve as a positive control and consist of mice treated with mouse IL-10 i.p. or anti-TNF antibodies i.p. 30 min before LPS administration. Mice are monitored for death for 72 h after LPS injection.

[1020] Asthma. Representative procedures for evaluating the efficacy of CCR4 antagonists for the treatment of asthma are as described herein. Procedure A: An animal model of asthma can be induced by sensitizing mice to an experimental antigen (e.g., OVA) by standard immunization techniques and subsequently introducing some of that antigen into the lungs of the mice by aerosolization. Three groups of mice (10 mice per group) can be actively sensitized on Day 0 by a single i.p. injection with 100 μg of OVA in PBS, together with an IgE-selective adjuvant (e.g., aluminum hydroxide). Eleven days post-sensitization, at the peak of their IgE response, mice can be placed in a Plexiglas chamber and challenged with aerosolized OVA (1%) for 30 min using an ultrasonic nebulizer (e.g., De Vilbliss; Ingersoll Rand; Dublin, Ireland). One group of mice may additionally receive PBS and 0.5% Tween i.p. at initial sensitization, and at different dosing schedules thereafter, until challenge with aerosolized OVA. A second group of mice may receive different doses of the CCR4 antagonist(s) given i.p., IV, SC, IM, PO, or via any other route of administration at initial sensitization, and at different dosing schedules thereafter, until challenge with aerosolized OVA. A third group of mice, serving as a positive control, may be treated with mouse IE-10 i.p., anti-IE-4 antibodies i.p., or anti-IE5 antibodies i.p. at initial sensitization, and at different dosing schedules thereafter, until challenge with aerosolized OVA.

[1021] Following challenge with aerosolized OVA, mice can be analyzed at different time points for lung function, cellular infiltrates in bronchoalveolar lavage (BAL), histological examination of lungs, and measurement of serum OVA-specific IgE titers.

[1022] Procedure B. Ovalbumin (OVA, 0.2 mg/ml) and Alum (8 mg/ml) prepared in physiological saline can be intraperitoneally administered (500 μl) to mice (male, C57BL/6) on Day 1 (test starting on day ) and Day 8 (1 week later) to sensitize the mice. On Days 15 to 21, the mice can be placed in an inhalation chamber (W: 240 mm × W: 240 mm × H: 120 mm), and a 2% OVA solution can be sprayed with an ultrasonic wave-type nebulizer (NE-U12; Omron, San Ramon, CA, USA) for 20 min to conduct induction. A CCR4 antagonist(s) can be suspended in medium and administered orally 30 min before OVA sensitization on Day 8 and 30 min before OVA induction on Days 15 to 21. A control group can be administered medium alone. Three h post-OVA inhalation on Day 21, mice can be exsanguinated, catheter tubes inserted into their trachea, and lungs lavaged with physiological saline containing heparin (10 U/ml) to provide bronchoalveolar lavage fluid (BALF). The number of leukocytes in BALF can be counted using a hemocyte counter (SF-3000; Sysmex, Kobe, JP).

[1023] Dermatitis. Representative procedures for evaluating the efficacy of CCR4 antagonists for the treatment of dermatitis are as described herein. Mouse DTH Model. Mice (male, Balb/c) can be shaved on the abdomen with hair clips, and a 7% (w/v) 2,4,6-trinitrochlorobenzene (TNCB) ethanol solution (100 μL) can be applied to the abdomen to sensitize the mice. Seven days post-sensitization, a 1% (w/v) TNCB solution in olive oil (20 μL) can be applied to the auricle of the mice (both sides of the right ear) to conduct induction. A CCR4 antagonist can be dissolved in a medium and applied to both sides of the right ear (20 μL) 2 h prior to TNCB application. For control groups, only the medium can be applied. Immediately after compound(s) administration and 24 h after TNCB application, the thickness of the mice's auricles can be measured with a Dialthickness gauge (Ozaki Seisakusho, JP), which can be used as an indicator for efficacy in a mouse DTH model.

[1024] Hapten-Applied Dermatitis Model. To the auricle (both sides of the right ear) of mice (male, Balb/c), 1% (w/v) TNCB solution (acetone:olive oil=4:1) (20 μL) can be applied to conduct the first sensitization. Seven days post-sensitization, 1% (w/v) TNCB (acetone:olive oil=4:1) (20 μL) can be applied to the auricle of mice to conduct the induction (Day 0); This procedure can be repeated on Days 2, 4, 6, 8, 10, 12, 14, and 16. A CCR4 antagonist (or antagonists) can be dissolved in a medium and applied to both sides of the right ear (20 μL) 2 h before TNCB application. To the control groups, only the medium can be applied. Immediately after administration of the compound (or compounds) and 24 h after TNCB application, the thickness of the auricles of the mice can be measured with a Dialthickness caliper, which can be used as an indicator of efficacy in a mouse dermatitis model to which hapten is continuously applied.

[1025] Infection. A representative procedure for evaluating the efficacy of CCR4 antagonists to enhance protective immunity against viruses, bacteria, and parasites is as described herein. Protective immunity to microbial pathogens is often mediated by Th1 regulatory T cells. Because CCR4 antagonists are believed to be inhibitors of Th2 regulatory cells, they may alter the cross-regulation that normally exists between Th1 and Th2 cells and enhance Th1 cells, thereby enhancing protection against infectious diseases.

[1026] Three groups of mice (15 mice per group) can be infected with the intracellular parasite Leishmania major (L. major) by injecting L. major promastigotes SC into their left hind paws. Four weeks after infection, mice can be challenged with freeze-chilled Leishmania antigen or PBS with a negative control, in the contralateral paw. One group of mice can also receive PBS and 0.5% Tween i.p. for initial sensitization, and on different dosing schedules thereafter, until Leishmania antigen challenge. A second group of mice can receive different doses of the CCR4 antagonist(s) given i.p., IV, SC, IM, PO, or by any other route of administration for initial sensitization, and on different dosing schedules thereafter, until Leishmania antigen challenge. A third group of mice, which serves as a positive control, may consist of mice treated with IL-12, anti-IL-4 antibodies i.p., or anti-IL-5 antibodies i.p. at initial sensitization, and at different dosing schedules thereafter, until challenge with Leishmania antigen.

[1027] Over the next 48 h, paw swelling, caused by a Delayed Type Hypersensitivity reaction to Leishmania antigen challenge, can be monitored with a metric caliper. The draining lymph node T cell response to Leishmania antigen challenge in vitro can also be measured, both in terms of proliferation, cytokine production, and other phenotypic criteria.

[1028] Rheumatoid arthritis. Rheumatoid arthritis (RA), which is generally characterized by chronic inflammation of the membrane lining (synovium) of the joints, affects approximately 1% of the US population, or 2.1 million people in the US. Increased understanding of the role of cytokines, including TNFα and IL-1, in the inflammatory process has allowed the development and introduction of a new class of disease-modifying antirheumatic drugs (DMARDs). Agents (some of which overlap with treatment modalities for RA) include ENBREL (etanorcept), REMICADE (infliximab), HUMIRA (adalimumab), and KINERET (anakinra). Although some of these agents relieve symptoms, inhibit the progression of structural damage, and improve physical function in particular patient populations, there is still a need for alternative agents with improved efficacy, complementary mechanisms of action, and fewer serious adverse effects.

[1029] A representative procedure for evaluating the efficacy of CCR4 antagonists for the treatment of rheumatoid arthritis is as described herein. An animal model of rheumatoid arthritis can be induced in rodents by injecting them with type II collagen in selected adjuvants. Three groups of rodents, each consisting of 15 genetically susceptible mice or rats, can be injected SC or intradermally with type II collagen emulsified in Complete Freund's Adjuvant on days 0 and 21. One group of rodents can additionally receive PBS and 0.5% Tween i.p. at initial sensitization, and at different dosing schedules thereafter. A second group of rodents can receive different doses of the CCR4 antagonist(s) given i.p., IV, SC, IM, PO or via any other mode of administration at initial sensitization, and at different dosing schedules thereafter. A third group, serving as a positive control, could consist of rodents treated with mouse IL-10 i.p., or anti-TNF antibodies i.p. at initial sensitization, and at different dosing schedules thereafter.

[1030] Animals can be monitored from 3 to 8 weeks for the development of swollen joints or feet, and graded on a standard disease severity scale. Disease severity can be confirmed by histological analysis of the joints.

[1031] Systemic Lupus Erythematosus. A representative procedure for evaluating the efficacy of CCR4 antagonists for the treatment of Systemic Lupus Erythematosus (SLE) is as described herein. Female NZB/W F1 mice spontaneously develop an SLE-like pathology beginning at 6 months of age that is characterized by proteinuria, serum autoantibodies, glomerulonephritis, and eventual death.

[1032] Three groups of NZB/W mice, each comprising 20 mice per group, may be evaluated. One group of mice may receive PBS and 0.5% Tween i.p. shortly after weaning, and thereafter on varying dosing schedules. A second group of mice may receive different doses of the CCR4 antagonist(s) given i.p., IV, SC, IM, PO or via any other mode of administration shortly after weaning, and thereafter on varying dosing schedules. A third group of mice, which serves as a positive control, may comprise mice treated with anti-IL-10 antibodies given shortly after weaning, and thereafter on varying dosing schedules. Disease development may be monitored in terms of eventual mortality, renal histology, serum autoantibody levels and proteinuria.

[1033] Cancer-Related Malignancy. A representative procedure for evaluating the efficacy of CCR4 antagonists for cancer treatment is as described herein. Mouse homozygotes for the spontaneous severe combined immune deficiency mutation Prkdcscid (SCID mice) are characterized by an absence of functional T cells and B cells, lymphopenia, hypogammaglobulinemia, and a normal hematopoietic microenvironment. Additional mouse genetic backgrounds can result in a lack of natural killer cells (in NOD-SCID); while the addition of IL2 receptor gamma chain mutations results in loss of much cytokine signaling resulting in highly immunodeficient (NSG) mice. Immunodeficient mice (SCID mice, NOD-SCID mice, NSG or others) can be engrafted with a human immune system after transplantation of PBMCs, CD34+ hematopoietic stem cells, or isolated immune effector populations. These humanized mice can be transplanted, cultured, and established human tumor cell lines (xenograft) or with primary human tumor cells to create a patient-derived xenograft (PDX). Additionally, normal mouse strains can be transplanted with a variety of well-characterized mouse tumor lines, including the thymoma EL4 cell line, that have been transfected with OVA to allow easy assessment of tumor-specific antigen responses following OVA vaccination. Three groups of mice from any of these tumor models can be tested for CCR4 antagonist efficacy. One group receives PBS and 0.5% Tween i.p. immediately following tumor transplantation, and thereafter on varying dosing schedules. A second group receives varying doses of the CCR4 antagonist(s) given i.p., IV, SC, IM, PO, or via any other route of administration following tumor transplantation, and thereafter on varying dosing schedules. A third group, which serves as a positive control, may comprise mice treated with anti-IL-4 antibodies, anti-ILNγ antibodies, IL-4, or TNF given i.p. shortly after tumor transplantation, and thereafter on varying dosing schedules. A second group receives varying doses of the CCR4 antagonist(s) given i.p., IV, SC, IM, PO, or via any other route of administration after tumor transplantation, and thereafter on varying dosing schedules. A third group, which serves as a positive control, may comprise mice treated with anti-IL-4 antibodies, anti-ILNγ antibodies, IL-4, or TNF given i.p. shortly after tumor transplantation, and thereafter on varying dosing schedules.

[1034] Efficacy can be monitored by tumor growth versus regression. In the case of the OVA-transfected EL4 thymoma model, OVA-specific cytolytic responses can be measured by stimulating draining lymph node cells with OVA in vitro, and measuring antigen-specific cytotoxicity at various time points, such as 72 h.

[1035] Allograft Transplant Models. Allograft mouse tumor systems, also known as syngeneic models, can be used to evaluate the compounds of the present invention. In contrast to conventional xenograft models, which often lack relevance due to the immunocompromised status of animals, the host immune system is normal in syngeneic models, which can more closely represent the native tumor microenvironment. Because they retain intact immune systems, syngeneic mouse models are particularly relevant for studies of immunologically-based targeted therapies that modulate the ability of the immune system to seek and destroy cancer cells. For example, the MC38 model of colorectal cancer can be used to explore the activity of treatment with a CCR4 inhibitor. Treatment with the CCR4 inhibitor and/or other agents can be initiated before, along with, or after MC38 cancer cells have been implanted or injected into the recipient mice. The mice are then divided or randomized into treatment groups, each containing multiple mice, and the impact of treatment can be measured. Endpoints for antitumor responses include the absence or presence of a tumor, its size, time to size (which includes any actual detection) or time to regression, long-term regression, or other accepted end points. Additional endpoints of activity include, for example, a characterization of immune cell populations in and around the tumor or systemically or markers of immune cell responses (e.g., cytokine levels).

[1036] Syngeneic models consist of tumor tissues derived from the same genetic background as a given mouse strain. Cancer cells or solid tumors can be transplanted into a host mouse. Because the cancerous tissues and the recipient share ancestry, the transplant is not rejected by the host's immune system. The tissues can then be monitored for changes such as growth or shrinkage, metastasis, and survival rate. Therapeutic interventions can be performed and the results evaluated to understand treatment potentials.

[1037] A discussion of syngeneic and other tumor models for efficacy determinations is presented in Teicher, B A, (October 2006) Mol Cancer Ther 5:2435. Multiple syngeneic tumor models with well-characterized responses to known immune checkpoint inhibitors (e.g., anti-PDL-1, anti-PD-1, and anti-CTLA-4) are commercially available (e.g., GenScript (Piscataway, NH, USA) and Charles River Labs (Wilmington, MA, USA)).

[1038] Psoriasis. Psoriasis, a constellation of common chronic immune-mediated skin diseases, affects more than 4.5 million people in the United States, of whom 1.5 million are considered to have a moderate to severe form of the disease. In addition, more than 10% of patients with psoriasis develop psoriatic arthritis, which damages the bone and connective tissue around the joints. An improved understanding of the underlying physiology of psoriasis has resulted in the introduction of agents that, for example, target the activity of T lymphocytes and cytokines responsible for the inflammatory nature of the disease. Such agents include TNFα inhibitors (also used in the treatment of rheumatoid arthritis (RA)), which include ENBREL (etanorcept), REMICADE (infliximab), and HUMIRA (adalimumab)), and T-cell inhibitors such as AMEVIVE (alefacept) and RAPTIVA (efalizumab). Although several of these agents are effective to some extent in certain patient populations, none have been shown to effectively treat all patients.

[1039] A representative procedure for evaluating the efficacy of CCR4 antagonists for the treatment of psoriasis is as described herein. A rodent model of psoriasis can be generated by intravenous transfer of a population of purified T cells (e.g., CD45Rbhi T cells) obtained from the spleens of BALB/c mice into immunodeficient recipient CB 17 scid/scid mice. The mice develop signs of redness, swelling, and skin lesions that resemble those of human psoriasis on their ears, feet, and tail by 8 weeks after transfer. Three groups of mice, each comprising 10-15 CB.17 scid/scid mice, can be injected with purified CD45Rbhi T cells. One group of mice can additionally receive PBS and 0.5% Tween i.p. at the initial cell transfer, and at different dosing schedules thereafter. A second group of mice may receive different doses of the CCR4 antagonist(s) given i.p., IV, SC, IM, PO, or via any other route of administration at the initial cell transfer, and on different dosing schedules thereafter. A third group of mice, which serves as a positive control, may consist of mice treated with antibodies to IL-12, IL-4, ILNY, or the cytokine IL-10 at the initial cell transfer, and on different dosing schedules thereafter. Animals may be monitored for the development of psoriatic-like lesions for 3 months after cell transfer.

[1040] Inflammatory Bowel Disease. Several murine models of iBD (e.g., Crohn's disease and ulcerative colitis) have been developed. Some of the models occur in genetically modified transgenic mice that have been depleted of certain cytokine genes (e.g., IL-10 or IL-2) by homologous recombination. A particular murine model of IBD is obtained by transferring highly purified populations of CD4+ T lymphocytes bearing the cd45rb hi surface marker phenotype into SCID mice.

[1041] Representative procedures for evaluating the efficacy of CCR4 antagonists for the treatment of inflammatory bowel disease comprise three groups of mice from any of the above models. One group of mice may receive PBS and 0.5% Tween i.p. shortly after weaning in the case of spontaneous transgenic mouse models, or at the time of cell transfer in SCID mice and varying dosages thereafter for the cell transfer model. A second group of mice may receive varying doses of the CCR4 antagonist(s) given i.p., IV, SC, IM, PO or via any other mode of administration shortly after weaning in the case of spontaneous transgenic mouse models, or at the time of cell transfer in SCID mice and varying dosages thereafter for the cell transfer model. A third group of mice, which serves as a positive control, may comprise mice treated with antibodies to ILNY or TNF, or with the cytokine IL-10 shortly after weaning in the case of spontaneous transgenic mouse models, or at the time of cell transfer in SCID mice and at varying dosages thereafter for the cell transfer model. Mice may be evaluated for 6-8 weeks for disease development, monitored initially for weight loss and/or prolapsed rectum, and subsequently for histological evaluation of their colons and intestinal tracts.

[1042] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are embraced within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims (26)

1. Compound having structural formula (II): or a pharmaceutically acceptable salt thereof, characterized in that: X2 is CR9 or N; X3 is CR10 or N; n1, n2, n3.2, n3.3, n4, n7, n9, and n10 are independently an integer from 0 to 4; m1, m2, m3.2, m3.3, m4, m7, m9, m10, v1, v2, v3.2, v3.3, v4, v7, and v10 are independently 1 or 2; z4 is an integer from 0 to 1; L7 is a bond, -O-, -S-, -NR7-2B-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, C1-C8 alkylene substituted or unsubstituted by R41, 2- to 8-membered heteroalkylene substituted or unsubstituted by R41, C3-C8 cycloalkylene substituted or unsubstituted by R41, 3- to 8-membered heterocycloalkylene substituted or unsubstituted by R41, C6-C10 arylene substituted or unsubstituted by R41, or 5- to 10-membered heteroarylene substituted or unsubstituted by R41; R41 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R42, 2- to 8-membered heteroalkyl substituted or unsubstituted by R42, C3-C8 cycloalkyl substituted or unsubstituted by R42, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R42, C6-C10 aryl substituted or unsubstituted by R42, or 5- to 10-membered heteroaryl substituted or unsubstituted by R42; R42 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R43, 2- to 8-membered heteroalkyl substituted or unsubstituted by R43, C3-C8 cycloalkyl substituted or unsubstituted by R43, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R43, C6-C10 aryl substituted or unsubstituted by R43, or 5- to 10-membered heteroaryl substituted or unsubstituted by R43; R43 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted 5- to 10-membered heteroaryl, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R1 is hydrogen, halogen, -CX1-13, -CHX1-12, -CH2X1-1, - CN, -N3, -SOniR1A, -SOviNR1BR1C, - NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)mi, —NR1BR1C, -C(O)R1D, - C(O)OR1D, -C(O)NR1BR1C, - OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, - NR1BC(O)OR1D, -NR1BOR1D, -OCX1-13, -OCHX1-12, C1-C8 alkyl substituted or unsubstituted by R11, 2- to 8-membered heteroalkyl substituted or unsubstituted by R11, C3-C8 cycloalkyl substituted or unsubstituted by R11, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R11, C6-C10 aryl substituted or unsubstituted by R11, or 5- to 10-membered heteroaryl substituted or unsubstituted by R11; R11 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R12, 2- to 8-membered heteroalkyl substituted or unsubstituted by R12, C3-C8 cycloalkyl substituted or unsubstituted by R12, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R12, C6-C10 aryl substituted or unsubstituted by R12, or 5- to 10-membered heteroaryl substituted or unsubstituted by R12; R12 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R13, 2- to 8-membered heteroalkyl substituted or unsubstituted by R13, C3-C8 cycloalkyl substituted or unsubstituted by R13, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R13, C6-C10 aryl substituted or unsubstituted by R13, or 5- to 10-membered heteroaryl substituted or unsubstituted by R13; R13 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, - NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to unsubstituted 8-membered, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R2 is hydrogen, halogen, -CX2-13, -CHX2-12, -CH2X2-1, - CN, -N3, — SOn2R2A, -SOv2NR2BR2C, - NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, —C(O)R2D, - C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, - NR2BC(O)OR2D, -NR2BOR2D, -OCX2-13, -OCHX2-12, C1-C8 alkyl substituted or unsubstituted by R14, 2- to 8-membered heteroalkyl substituted or unsubstituted by R14, C3-C8 cycloalkyl substituted or unsubstituted by R14, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R14, C6-C10 aryl substituted or unsubstituted by R14, or 5- to 10-membered heteroaryl substituted or unsubstituted by R14; R14 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R15, 2- to 8-membered heteroalkyl substituted or unsubstituted by R15, C3-C8 cycloalkyl substituted or unsubstituted by R15, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R15, C6-C10 aryl substituted or unsubstituted by R15, or 5- to 10-membered heteroaryl substituted or unsubstituted by R15; R15 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R16, 2- to 8-membered heteroalkyl substituted or unsubstituted by R16, C3-C8 cycloalkyl substituted or unsubstituted by R16, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R16, C6-C10 aryl substituted or unsubstituted by R16, or 5- to 10-membered heteroaryl substituted or unsubstituted by R16; R16 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted 5- to 10-membered heteroaryl, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R3-2 is independently hydrogen, halogen, -CX3.23, -CHX3-22, -CH2X3-2, -CN, -N3, — SOn3.2R3-2A, —SOv3.2NR3-2BR3-2C, -NHNR3 • 2BR3 -2C, -ONR3 • 2BR3 -2C, -NHC(O)NHNR3 • 2BR3 -2C, -NHC(O)NR 3-2BR3-2C, -N(O)m3.2, -NR3.2BR3.2C, -C(O)R3.2D, - C(O)OR3.2D, -C(O)NR3.2BR3.2C, -OR3.2A, -NR3.2BSO2R3.2A, - NR3.2BC(O)R3.2D, -NR3.2BC(O)OR3.2D, -NR3.2BOR3.2D, -OCX3.23, -OCHX3.22, C1-C8 alkyl substituted or unsubstituted by R17.2, 2- to 8-membered heteroalkyl substituted or unsubstituted by R17.2, C3-C8 cycloalkyl substituted or unsubstituted by R17.2, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R17.2, C6-C10 aryl substituted or unsubstituted by R17.2, or 5- to 10-membered heteroaryl substituted or unsubstituted by R17.2; R17.2 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R18.2, 2- to 8-membered heteroalkyl substituted or unsubstituted by R18.2, C3-C8 cycloalkyl substituted or unsubstituted by R18.2, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R18.2, C6-C10 aryl substituted or unsubstituted by R18.2, or 5- to 10-membered heteroaryl substituted or unsubstituted by R18.2; R18.2 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R19.2, 2- to 8-membered heteroalkyl substituted or unsubstituted by R19.2, C3-C8 cycloalkyl substituted or unsubstituted by R19.2, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R19.2, C6-C10 aryl substituted or unsubstituted by R19.2, or 5- to 10-membered heteroaryl substituted or unsubstituted by R19.2; R19.2 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H,-SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to unsubstituted 8-membered, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R3.3 is independently hydrogen, halogen, -CX3.33, -CHX3-32, -CH2X3-3, —CN, -N3, — SOn3.3R3-3A, —SOv3.3NR3-3BR3-3C, -NHNR3 • 3BR3 -3C, -ONR3 • 3BR3 -3C, -NHC(O)NHNR3 • 3BR3 -3C, —NHC(O)NR 3-3BR3-3C, -N(O)m3.3, -NR3.3BR3.3C, —C(O)R3.3D, - C(O)OR3-3D, -C(O)NR3-3BR3-3C, — OR3-3A, -NR3-3BSO2R3-3A, - NR3-3BC(O)R3-3D, -NR3-3BC(O)OR3-3D, -NR3-3BOR3-3D, — OCX3-33, — OCHX3-32, C1-C8 alkyl substituted or unsubstituted by R17-3, 2- to 8-membered heteroalkyl substituted or unsubstituted by R17-3, C3-C8 cycloalkyl substituted or unsubstituted by R17-3, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R17-3, C6-C10 aryl substituted or unsubstituted by R17-3, or 5- to 10-membered heteroaryl substituted or unsubstituted by R17-3; R17-3 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R18-3, 2- to 8-membered heteroalkyl substituted or unsubstituted by R18-3, C3-C8 cycloalkyl substituted or unsubstituted by R18-3, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R18-3, C6-C10 aryl substituted or unsubstituted by R18-3, or 5- to 10-membered heteroaryl substituted or unsubstituted by R18-3; R18-3 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R19-3, 2- to 8-membered heteroalkyl substituted or unsubstituted by R19-3, C3-C8 cycloalkyl substituted or unsubstituted by R19-3, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R19.3, C6-C10 aryl substituted or unsubstituted by R19.3, or 5- to 10-membered heteroaryl substituted or unsubstituted by R19.3; R19.3 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to unsubstituted 8-membered, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R4 is hydrogen, halogen, -CX4-13, -CHX4-12, -CH2X4-1, - CN, -N3, — SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, —C(O)R4D, - C(O)OR4D, -C(O)NR4BR4C, -OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, - NR4BC(O)OR4D, -NR4BOR4D, -OCX4-13, -OCHX4-12, Ci—Cs alkyl substituted or unsubstituted by R20, 2- to 8-membered heteroalkyl substituted or unsubstituted by R20, C3-C8 cycloalkyl substituted or unsubstituted by R20, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R20, C6-C10 aryl substituted or unsubstituted by R20, or 5- to 10-membered heteroaryl substituted or unsubstituted by R20; R20 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R21, 2- to 8-membered heteroalkyl substituted or unsubstituted by R21, C3-C8 cycloalkyl substituted or unsubstituted by R21, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R21, C6-C10 aryl substituted or unsubstituted by R21, or 5- to 10-membered heteroaryl substituted or unsubstituted by R21; R21 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R22, 2- to 8-membered heteroalkyl substituted or unsubstituted by R22, C3-C8 cycloalkyl substituted or unsubstituted by R22, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R22, C6-C10 aryl substituted or unsubstituted by R22, or 5- to 10-membered heteroaryl substituted or unsubstituted by R22; R22 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted 5- to 10-membered heteroaryl, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R7 is hydrogen, halogen, -CX7-13, -CHX7-12, -CH2X7-1, - CN, -N3, — SOn7R7A, -SOv7NR7BR7C, - NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, -NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, —C(O)R7D, - C(O)OR7D, -C(O)NR7BR7C, -OR7A, -NR7BSO2R7A, -NR7BC(O)R7D, - NR7BC(O)OR7D, -NR7BOR7D, -OCX7-13, -OCHX7-12, C1-C8 alkyl substituted or unsubstituted by R29, 2- to 8-membered heteroalkyl substituted or unsubstituted by R29, C3-C8 cycloalkyl substituted or unsubstituted by R29, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R29, C6-C10 aryl substituted or unsubstituted by R29 or 5- to 10-membered heteroaryl substituted or unsubstituted by R29; R29 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R30, 2- to 8-membered heteroalkyl substituted or unsubstituted by R30, C3-C8 cycloalkyl substituted or unsubstituted by R30, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R30, C6-C10 aryl substituted or unsubstituted by R30, or 5- to 10-membered heteroaryl substituted or unsubstituted by R30; R30 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R31, 2- to 8-membered heteroalkyl substituted or unsubstituted by R31, C3-C8 cycloalkyl substituted or unsubstituted by R31, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R31, C6-C10 aryl substituted or unsubstituted by R31, or 5- to 10-membered heteroaryl substituted or unsubstituted by R31; R31 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted 5- to 10-membered heteroaryl, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R9 is hydrogen, halogen, -CX9-13, -CHX9-12, -CH2X9-1, - CN, -N3, —SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, -NHC(O)NR9BR9C, -N(O)m9, -NR9BR9C, —C(O)R9D, - C(O)OR9D, -C(O)NR9BR9C, -OR9A, —NR9BSO2R9A, -NR9BC(O)R9D, - NR9BC(O)OR9D, -NR9BOR9D, -OCX9-13, -OCHX9-12, Ci—Cs alkyl substituted or unsubstituted by R35, 2- to 8-membered heteroalkyl substituted or unsubstituted by R35, C3-C8 cycloalkyl substituted or unsubstituted by R35, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R35, C6-C10 aryl substituted or unsubstituted by R35, or 5- to 10-membered heteroaryl substituted or unsubstituted by R35; R35 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R36, 2- to 8-membered heteroalkyl substituted or unsubstituted by R36, C3-C8 cycloalkyl substituted or unsubstituted by R36, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R36, C6-C10 aryl substituted or unsubstituted by R36, or 5- to 10-membered heteroaryl substituted or unsubstituted by R36; R36 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R37, 2- to 8-membered heteroalkyl substituted or unsubstituted by R37, C3-C8 cycloalkyl substituted or unsubstituted by R37, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R37, C6-C10 aryl substituted or unsubstituted by R37, or 5- to 10-membered heteroaryl substituted or unsubstituted by R37; R37 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted 5- to 10-membered heteroaryl, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R10 is hydrogen, halogen, -CX10-13, -CHX10-12, — CH2X10-1, -CN, -N3, -SOn1oR10A, -SOv1oNR10BR10C, - NHNR10BR10C, -ONR10BR10C, -NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, -N(O)m10, -NR10BR10C, -C(O)R10D, -C(O)OR10D, - C(O)NR10BR10C, -OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, - NR10BC(O)OR10D, -NR10BOR10D, -OCX10-13, -OCHX10-12, C1-C8 alkyl substituted or unsubstituted by R38, 2- to 8-membered heteroalkyl substituted or unsubstituted by R38, C3-C8 cycloalkyl substituted or unsubstituted by R38, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R38, C6-C10 aryl substituted or unsubstituted by R38, or 5- to 10-membered heteroaryl substituted or unsubstituted by R38; R38 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R39, 2- to 8-membered heteroalkyl substituted or unsubstituted by R39, C3-C8 cycloalkyl substituted or unsubstituted by R39, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R39, C6-C10 aryl substituted or unsubstituted by R39, or 5- to 10-membered heteroaryl substituted or unsubstituted by R39; R39 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCi3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, C1-C8 alkyl substituted or unsubstituted by R40, 2- to 8-membered heteroalkyl substituted or unsubstituted by R40, C3-C8 cycloalkyl substituted or unsubstituted by R40, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R40, C6-C10 aryl substituted or unsubstituted by R40, or 5- to 10-membered heteroaryl substituted or unsubstituted by R40; R40 is independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, - NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl unsubstituted 5- to 10-membered heteroaryl, unsubstituted C6-C10 aryl, or unsubstituted 5- to 10-membered heteroaryl; R1A, R1B, R1C, and R1D are independently hydrogen, halogen, -CF3, -CCI3, —CBr3, -CI3, -COOH, -CONH2, C1-C8 alkyl substituted or unsubstituted for R11, 2- to 8-membered heteroalkyl substituted or unsubstituted for R11, C3-C8 cycloalkyl substituted or unsubstituted for R11, 3- to 8-membered heterocycloalkyl substituted or unsubstituted for R11, C6-C10 aryl substituted or unsubstituted for R11, or 5- to 6-membered heteroaryl substituted or unsubstituted for R11; substituents R1B and R1C attached to the same nitrogen atom can optionally be joined to form a 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R11 or a 5- to 6-membered heteroaryl substituted or unsubstituted by R11; R2A, R2B, R2C, and R2D are independently hydrogen, halogen, -CF3, -CCls, -CBra, -CI3, -COOH, -CONH2, C1-C8 alkyl substituted or unsubstituted by R14, 2- to 8-membered heteroalkyl substituted or unsubstituted by R14, C3-C8 cycloalkyl substituted or unsubstituted by R14, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R14, C6-C10 aryl substituted or unsubstituted by R14, or 5- to 6-membered heteroaryl substituted or unsubstituted by R14; substituents R2B and R2C attached to the same nitrogen atom can optionally be joined to form a 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R14 or a 5- to 6-membered heteroaryl substituted or unsubstituted by R14; R3-2A, R3-2B, R3-2C, and R3-2D are independently hydrogen, halogen, -CF3, -CCla, -CBr3, -CI3, -COOH, -CONH2, C1-C8 alkyl substituted or unsubstituted by R17-2, 2- to 8-membered heteroalkyl substituted or unsubstituted by R17-2, C3-C8 cycloalkyl substituted or unsubstituted by R17-2, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R17-2, C6-C10 aryl substituted or unsubstituted by R17-2, or 5- to 6-membered heteroaryl substituted or unsubstituted by R17-2; R3.3A, R3.3B, R3.3C, and R3.3D, are independently hydrogen, halogen, -CF3, -CCI3, —CBr3, -CI3, —COOH, —CONH2, C1-C8 alkyl substituted or unsubstituted for R17.3, 2- to 8-membered heteroalkyl substituted or unsubstituted for R17.3, C3-C8 cycloalkyl substituted or unsubstituted for R17.3, 3- to 8-membered heterocycloalkyl substituted or unsubstituted for R17.3, C6-C10 aryl substituted or unsubstituted for R17.3, or 5- to 6-membered heteroaryl substituted or unsubstituted for R17.3; R4A, R4B, R4C, and R4D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, C1-C8 alkyl substituted or unsubstituted for R20, 2- to 8-membered heteroalkyl substituted or unsubstituted for R20, C3-C8 cycloalkyl substituted or unsubstituted for R20, 3- to 8-membered heterocycloalkyl substituted or unsubstituted for R20, C6-C10 aryl substituted or unsubstituted for R20, or 5- to 10-membered heteroaryl substituted or unsubstituted for R20; substituents R4B and R4C attached to the same nitrogen atom can optionally be joined to form a 3- to 8-membered heterocycloalkyl substituted or unsubstituted for R20 or 5- to 10-membered heteroaryl substituted or unsubstituted for R20; R7A, R7B, R7C, and R7D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, C1-C8 alkyl substituted or unsubstituted by R20, 2- to 8-membered heteroalkyl substituted or unsubstituted by R29, C3-C8 cycloalkyl substituted or unsubstituted by R29, 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R29, C6-C10 aryl substituted or unsubstituted by R29, or 5- to 10-membered heteroaryl substituted or unsubstituted by R29; substituents R7B and R7C attached to the same nitrogen atom can optionally be joined to form a 3- to 8-membered heterocycloalkyl substituted or unsubstituted by R29 or 5- to 10-membered heteroaryl substituted or unsubstituted by R29; R9A, R9B, R9C, and R9D are independently hydrogen, halogen, -CF3, -CCls, —CBra, -CI3, -COOH, -CONH2, C1-C8 alkyl substituted or unsubstituted for R35, 2- to 8-membered heteroalkyl substituted or unsubstituted for R35, C3-C8 cycloalkyl substituted or unsubstituted for R35, 3- to 8-membered heterocycloalkyl substituted or unsubstituted for R35, C6-C10 aryl substituted or unsubstituted for R35, or 5- to 10-membered heteroaryl substituted or unsubstituted for R35; substituents R9B and R9C attached to the same nitrogen atom can optionally be joined to form a 3- to 8-membered heterocycloalkyl substituted or unsubstituted for R35 or 5- to 10-membered heteroaryl substituted or unsubstituted for R35; R10A, R10B, R10C, and R10D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, C1-C8 alkyl substituted or unsubstituted for R38, 2- to 8-membered heteroalkyl substituted or unsubstituted for R38, C3-C8 cycloalkyl substituted or unsubstituted for R38, 3- to 8-membered heterocycloalkyl substituted or unsubstituted for R38, C6-C10 aryl substituted or unsubstituted for R38, or 5- to 10-membered heteroaryl substituted or unsubstituted for R38; substituents R10B and R10C attached to the same nitrogen atom can optionally be joined to form a 3- to 8-membered heterocycloalkyl substituted or unsubstituted for R38 or 5- to 10-membered heteroaryl substituted or unsubstituted for R38; and X1.1, X2.1, X3.2, X3.3, X4.1, X7.1, X9.1, and X10.1 are independently –Cl, –Br, –I, or –F, where at least one of X2 and X3 is N. 2. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized (IIb), (IIc) or (IId): 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein z4 is 1. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3-2 and R3-3 are independently halogen. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L7 is a C1-C4 alkylene bond or substituted or unsubstituted by R41. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one of R1 and R2 is hydrogen and the other is - CH3. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure: 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure: 9. Compound, according to claim 1, characterized by the fact that it has the Formula or a pharmaceutically acceptable salt thereof. 10. Compound, according to claim 1, characterized by the fact that it has the Formula or a pharmaceutically acceptable salt thereof. 11. Compound, according to claim 1, characterized by the fact that it has the formula: or a pharmaceutically acceptable salt thereof. 12. Compound, according to claim 1, characterized by the fact that it has the formula: or a pharmaceutically acceptable salt thereof. 13. Compound, according to claim 1, characterized by the fact that it has the Formula: or a pharmaceutically acceptable salt thereof. 14. Compound, according to claim 1, characterized by the fact that it has the Formula: or a pharmaceutically acceptable salt thereof. 15. Compound, according to claim 1, characterized by the fact that it has the formula: or a pharmaceutically acceptable salt thereof. 16. Compound, according to claim 1, characterized by the fact that it has the Formula: or a pharmaceutically acceptable salt thereof. 17. Compound, according to claim 1, characterized by the fact that it has the formula: or a pharmaceutically acceptable salt thereof. 18. Compound, according to claim 1, characterized by the fact that it has the Formula: or a pharmaceutically acceptable salt thereof. 19. Compound, according to claim 1, characterized by the fact that it has the formula: or a pharmaceutically acceptable salt thereof. 20. Compound, according to claim 1, characterized by the fact that it has the formula: or a pharmaceutically acceptable salt thereof. 21. Pharmaceutical composition characterized by comprising a compound of any one of claims 1 to 20 and a pharmaceutically acceptable excipient. 22. Use of the pharmaceutical composition of claim 21 characterized by the fact that it is for the production of a medicament for the treatment of a disease or disorder mediated by CCR4, in which said disease or disorder is an immune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, or cancer. 23. Use of a compound according to any one of claims 1 to 20, characterized in that it is for the production of a medicament for the treatment of a disease or disorder mediated by CCR4, in which said disease or disorder is an immune disease or disorder, an inflammatory disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, or cancer. 24. Use according to claim 23, characterized in that the disease or disorder is cancer, further comprising co-administration of a chemotherapeutic agent or anticancer agent. 25. Use according to claim 24, characterized in that the chemotherapeutic agent or anticancer agent is a CCR4 inhibitor, a PD-L1/PD-1 pathway inhibitor, a CTLA-4 inhibitor, or a CD137 agonistic antibody (4-1BB). 26. Use according to claim 25, characterized in that the PD-L1/PD-1 pathway inhibitor is pembrolizumab.