Chemokine receptor modulators and uses thereof

Abstract

Disclosed herein are, inter alia, compounds of formula (I) and methods of their use for modulating certain chemokine receptor activity. TIFF2025512963000216.tif27170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 328,214, filed April 6, 2022, which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Successful operation of the host defense system is the result of several processes that work together to eliminate foreign pathogens. Coordination between the innate and adaptive immune responses is required, and many secreted and cell-associated factors have been identified as key 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. Chemokines are secreted by a wide variety of cells and can be functionally categorized into two groups: hemostatic chemokines and inflammatory chemokines. Hemostatic chemokines are constitutively produced in specific tissues and regulatory cells of the immune system during the process of immune surveillance, such as directing lymphocytes to lymph nodes to screen them against invading pathogens. Inflammatory chemokines are released from cells in response to pathological events (e.g., pro-inflammatory stimuli such as IL-1 or viruses). They primarily function as chemoattractants as part of the inflammatory response, directing cells of both the innate and adaptive immune systems to the site of inflammation. CC chemokine receptor type 4 (CCR4) plays a role in the progression of several inflammation-related and other disorders. Identifying compounds that modulate CCR4 function is an ongoing challenge. Disclosed herein, among other things, are solutions to these and other problems in the art. Summary of the Invention

[0003] In one aspect, provided herein is a compound of structural formula (I):

[0004] [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 8 or N and X 2 is CR 9 or N and X 3 is CR 10 or N and X 1 , X 2 and X 3 at least one of the above is N; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independently integers of 0 to 4; m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9, v10, and v44 are independently 1 or 2; z1 is an integer of 0 to 5, z2 is an integer of 0 to 4, z3 is an integer of 0 to 11, z4 is an integer of 0 to 2, and z5 is an integer of 1 to 2; L 7 is a bond, -O-, -S-, -NR 7.2B -, -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; R 1 is hydrogen, halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 , -CN, -N3, -SO n1 R 1A , -SO v1 NR 1B R 1C , -NHNR 1B R 1C , -ONR 1B R 1C , -NHC(O)NHNR 1B R 1C , -NHC(O)NR 1B R 1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D , -C(O)NR1B R 1C , -OR 1A , -NR 1B SO2R 1A , -NR 1B C(O)R 1D , -NR 1B C(O)OR 1D , -NR 1B OR 1D , -OCX 1.1 3. -OCHX 1.1 2, -OCH2X 1.1 , 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; and R 2 is hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 , -CN, -N3, -SO n2 R 2A , -SO v2 NR 2B R 2C , -NHNR 2B R 2C , -ONR 2B R 2C , -NHC(O)NHNR 2B R 2C , -NHC(O)NR 2B R 2C , -N(O) m2 , -NR 2B R 2C , -C(O)R 2D , -C(O)OR 2D , -C(O)NR 2B R 2C , -OR 2A , -NR 2B SO2R 2A , -NR 2B C(O)R 2D , -NR 2B C(O)OR 2D , -NR 2B OR 2D , -OCX 2.1 3. -OCHX 2.1 2, -OCH2X 2.1, 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; and R 3 are independently halogen, -CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 , -CN, -N3, -SO n3 R 3A , -SO v3 NR 3B R 3C , -NHNR 3B R 3C , -ONR 3B R 3C , -NHC(O)NHNR 3B R 3C , -NHC(O)NR 3B R 3C , -N(O) m3 , -NR 3B R 3C , -C(O)R 3D , -C(O)OR 3D , -C(O)NR 3B R 3C , -OR 3A , -NR 3B SO2R 3A , -NR 3B C(O)R 3D , -NR 3B C(O)OR 3D , -NR 3B OR 3D , -OCX 3.1 3. -OCHX 3.1 2, -OCH2X 3.1 , 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; and R 4 is hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 , -CN, -N3, -SO n4 R 4A , -SO v4 NR4B R 4C , -NHNR 4B R 4C , -ONR 4B R 4C , -NHC(O)NHNR 4B R 4C , -NHC(O)NR 4B R 4C , -N(O) m4 , -NR 4B R 4C , -C(O)R 4D , -C(O)OR 4D , -C(O)NR 4B R 4C , -OR 4A , -NR 4B SO2R 4A , -NR 4B C(O)R 4D , -NR 4B C(O)OR 4D , -NR 4B OR 4D , -OCX 4.1 3. -OCHX 4.1 2, -OCH2X 4.1 , 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; or X 2 is CR 9 If R 4 and R 9 may be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R 5 are independently halogen, oxo, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 , -CN, -N3, -SO n5 R 5A , -SO v5 NR 5B R 5C , -NHNR 5B R 5C , -ONR 5B R 5C, -NHC(O)NHNR 5B R 5C , -NHC(O)NR 5B R 5C , -N(O) m5 , -NR 5B R 5C , -C(O)R 5D , -C(O)OR 5D , -C(O)NR 5B R 5C , -OR 5A , -NR 5B SO2R 5A , -NR 5B C(O)R 5D , -NR 5B C(O)OR 5D , -NR 5B OR 5D , -OCX 5.1 3. -OCHX 5.1 2, -OCH2X 5.1 , 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; and R 6 are independently halogen, oxo, -CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 , -CN, -N3, -SO n6 R 6A , -SO v6 NR 6B R 6C , -NHNR 6B R 6C , -ONR 6B R 6C , -NHC(O)NHNR 6B R 6C , -NHC(O)NR 6B R 6C , -N(O) m6 , -NR 6B R 6C , -C(O)R 6D , -C(O)OR 6D , -C(O)NR 6B R 6C , -OR 6A , -NR 6B SO2R6A , -NR 6B C(O)R 6D , -NR 6B C(O)OR 6D , -NR 6B OR 6D , -OCX 6.1 3. -OCHX 6.1 2, -OCH2X 6.1 , 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; and R 7 is hydrogen, halogen, -CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 , -CN, -N3, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NHNR 7B R 7C , -ONR 7B R 7C , -NHC(O)NHNR 7B R 7C , -NHC(O)NR 7B R 7C , -N(O) m7 , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D , -C(O)NR 7B R 7C , -OR 7A , -NR 7B SO2R 7A , -NR 7B C(O)R 7D , -NR 7B C(O)OR 7D , -NR 7B OR 7D , -OCX 7.1 3. -OCHX 7.1 2, -OCH2X 7.1, 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; and R 8 is hydrogen, halogen, -CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 , -CN, -N3, -SO n8 R 8A , -SO v8 NR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(O)NHNR 8B R 8C , -NHC(O)NR 8B R 8C , -N(O) m8 , -NR 8B R 8C , -C(O)R 8D , -C(O)OR 8D , -C(O)NR 8B R 8C , -OR 8A , -NR 8B SO2R 8A , -NR 8B C(O)R 8D , -NR 8B C(O)OR 8D , -NR 8B OR 8D , -OCX 8.1 3. -OCHX 8.1 2, -OCH2X 8.1 , 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; and R 9 is hydrogen, halogen, -CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 , -CN, -N3, -SO n9 R 9A , -SO v9NR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(O)NHNR 9B R 9C , -NHC(O)NR 9B R 9C , -N(O) m9 , -NR 9B R 9C , -C(O)R 9D , -C(O)OR 9D , -C(O)NR 9B R 9C , -OR 9A , -NR 9B SO2R 9A , -NR 9B C(O)R 9D , -NR 9B C(O)OR 9D , -NR 9B OR 9D , -OCX 9.1 3. -OCHX 9.1 2, -OCH2X 9.1 , 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; or X 2 is CR 9 If R 4 and R 9 may be optionally linked to a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, or X 2 is CR 9 and X 3 is CR 10 If R 9 and R 10 may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10 is hydrogen, halogen, -CX 10.1 3. -CHX10.1 2. -CH2X 10.1 , -CN, -N3, -SO n10 R 10A , -SO v10 NR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(O) m10 , -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO2R 10A , -NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10.1 3. -OCHX 10.1 2, -OCH2X 10.1 , 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; or X 2 is CR 9 and X 3 is CR 10 If R 9 and R 10 may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 44 is hydrogen, -CX 44.1 3. -CHX 44.1 2. -CH2X 44.1 , -SO n44 R 44A , -SOv44 NR 44B R 44C , -C(O)R 44D , -C(O)OR 44D , -C(O)NR 44B R 44C , 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; and R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 7.2B , R 8A , R 8B , R 8C , R 8D , R 9A、 R 9B , R 9C , R 9D , R 10A , R 10B , R 10C , R 10D , R 44A , R 44B , R 44C , and R 44Dare 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; and R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B , R 5C , R 6B , R 6C , R 7B , R 7C , R 8B , R 8C , R 9B , R 9C , R 10B , R 10C , R 44B , and R 44C The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and X 1.1 , X 2.1 , X 3.1 , X 4.1 , X 5.1 , X 6.1 , X 7.1 , X 8.1 , X 9.1 , X 10.1 , and X 44.1 are independently -Cl, -Br, -I, or -F.

[0005] In one aspect, structural formula (II):

[0006] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X 2 , X 3 , z4, z5, L 7 , R7 and R 44 and R are as described elsewhere herein, including in the embodiments. 4 is hydrogen, halogen, -CX 4.1 3. -CN, -C(O)NR 4B R 4C , 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; and R 3.2 is hydrogen, halogen, -CX 3.2 3. -CHX 3.2 2. -CH2X 3.2 , -CN, -N3, -SO n3.2 R 3.2A , -SO v3.2 NR 3.2B R 3.2C , -NHNR 3.2B R 3.2C , -ONR 3.2B R 3.2C , -NHC(O)NHNR 3.2B R 3.2C , -NHC(O)NR 3.2B R 3.2C , -N(O) m3.2 , -NR 3.2B R 3.2C , -C(O)R 3.2D , -C(O)OR 3.2D , -C(O)NR 3.2B R 3.2C , -OR 3.2A , -NR 3.2B SO2R 3.2A , -NR 3.2B C(O)R 3.2D , -NR 3.2B C(O)OR 3.2D , -NR 3.2B OR 3.2D , -OCX 3.2 3. -OCHX 3.2 2, -OCH2X 3.2 , 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; and R3.3 is hydrogen, halogen, -CX 3.3 3. -CHX 3.3 2. -CH2X 3.3 , -CN, -N3, -SO n3.3 R 3.3A , -SO v3.3 NR 3.3B R 3.3C , -NHNR 3.3B R 3.3C , -ONR 3.3B R 3.3C , -NHC(O)NHNR 3.3B R 3.3C , -NHC(O)NR 3.3B R 3.3C , -N(O) m3.3 , -NR 3.3B R 3.3C , -C(O)R 3.3D , -C(O)OR 3.3D , -C(O)NR 3.3B R 3.3C , -OR 3.3A , -NR 3.3B SO2R 3.3A , -NR 3.3B C(O)R 3.3D , -NR 3.3B C(O)OR 3.3D , -NR 3.3B OR 3.3D , -OCX 3.3 3. -OCHX 3.3 2, -OCH2X 3.3 , 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; and R 3.2A、 R 3.2B , R 3.2C , R 3.2D , R 3.3A , R 3.3B , R 3.3C and R 3.3Dare 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; and R 3.2B , R 3.2C , R 3.3B and R 3.3C The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, wherein n3.2 and n3.3 are independently integers from 0 to 4, and m3.2, m3.3, v3.2 and v3.3 are independently 1 or 2; X 3.2 and X 3.3 are independently -Cl, -Br, -I, or -F.

[0007] In one aspect, a pharmaceutical composition is provided that includes a compound described herein, including embodiments, and a pharmaceutically acceptable excipient.

[0008] In one aspect, a method of inhibiting CC chemokine receptor type 4 (CCR4) is provided, comprising contacting CCR4 with a compound described herein, including embodiments, or a pharmaceutically acceptable salt thereof.

[0009] In one aspect, provided is a method for treating or preventing a disease or disorder mediated by CCR4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, including embodiments, described herein, or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, provided herein are kits comprising a compound (e.g., a CCR4 inhibitor) or pharmaceutical composition thereof described herein. The kits may be in the form of a physical structure housing various components, as described below, that may be utilized, for example, in practicing the methods described herein. DETAILED DESCRIPTION OF THE INVENTION

[0011] Provided herein are compounds and compositions, and pharmaceutical compositions comprising same, for example, for inhibiting CC chemokine receptor type 4. Also provided herein are methods for treating or preventing, e.g., a disease, disorder, or condition, or a symptom thereof, e.g., a disease, disorder, or condition, or a symptom thereof, mediated by modulation (e.g., inhibition) of CCR4.

[0012] I. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency well known in the chemical arts.

[0013] Substituent groups, when specified by their conventional chemical formula written from left to right, equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CHO- is equivalent to -OCH-.

[0014] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and which can include monovalent, divalent, and polyvalent radicals. An alkyl may contain the specified number of carbons (e.g., C1-C6). 10means 1 to 10 carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. The alkyl is an uncyclized 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, methyl, and the like, as well as homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those having one or more double 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 higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety can be fully saturated. An alkenyl can contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. An alkynyl can contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds.

[0015] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified by, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a short-chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term "alkynylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, an alkylene is fully saturated. In embodiments, an alkylene is monounsaturated. In embodiments, an alkylene is polyunsaturated. An alkenylene contains one or more double bonds. An alkynylene contains one or more triple bonds. The term "unsubstituted methylene" refers to the moiety -CH2-. The term "substituted methylene" refers to a moiety in which one or both hydrogen atoms are replaced with a substituent.

[0016] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl groups are non-cyclizing chains. 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)-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, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain two, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain three, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain four, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain five, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain up to eight, optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one double bond. A heteroalkenyl can optionally contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds.The term "heteroalkynyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkynyl containing at least one triple bond. A heteroalkynyl can optionally contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds. In embodiments, a heteroalkyl is fully saturated. In embodiments, a heteroalkyl is monounsaturated. In embodiments, a heteroalkyl is polyunsaturated.

[0017] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups, as used herein, include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -S02R'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, such as -NR'R'', it is understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R''. The term "heteroalkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term "heteroalkynylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, a heteroalkylene is fully saturated. In embodiments, a heteroalkylene is monounsaturated. In embodiments, a heteroalkylene is polyunsaturated. A heteroalkenylene contains one or more double bonds. A heteroalkynylene contains one or more triple bonds. The terms "cycloalkyl" and "heterocycloalkyl," by themselves 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 can 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. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and a heterocycloalkyl, respectively. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. In embodiments, a cycloalkyl is fully saturated. In embodiments, a cycloalkyl is monounsaturated. In embodiments, a cycloalkyl is polyunsaturated. In embodiments, a heterocycloalkyl is fully saturated. In embodiments, a heterocycloalkyl is monounsaturated. In embodiments, a heterocycloalkyl is polyunsaturated. In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to multiple rings fused together, where at least one of the fused rings is a cycloalkyl ring, and the rings are attached to the parent molecular moiety through any carbon atom contained within the cycloalkyl ring of the multiple rings.Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, a bridged monocyclic ring is one in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge of an additional 1 to 3 carbon atoms (i.e., (ch2)). wwhere w is 1, 2, or 3. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, the fused bicyclic cycloalkyl ring system comprises a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. A representative example of a polycyclic cycloalkyl ring system is adamantane. In embodiments, the cycloalkyl group is optionally substituted with one or two groups that are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, and is optionally substituted with one or two groups that are independently oxo or thia. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two additional ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.In embodiments, the polycyclic cycloalkyl ring system is (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) a monocyclic cycloalkyl ring (base ring) fused to either two additional ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl. In embodiments, the cycloalkyl is a cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, the cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. A bicyclic or polycyclic cycloalkenyl ring system refers to multiple rings fused together, at least one of the fused rings being a cycloalkenyl ring, and the multiple rings being attached to the parent molecular moiety through any carbon atom contained within the cycloalkenyl ring of the multiple rings. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups are unsaturated (i.e., contain at least one cyclic carbon-carbon double bond), but are not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is one in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge (i.e., of the form (CH)) between 1 to 3 additional carbon atoms. wwhere w is 1, 2, or 3. Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In embodiments, the fused bicyclic cycloalkenyl ring system comprises a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the polycyclic cycloalkenyl ring contains a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkenyl ring contains a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. In embodiments, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, or polycyclic heterocycloalkyl ring system. In embodiments, the heterocycloalkyl group is fully saturated.A bicyclic or polycyclic heterocycloalkyl ring system refers to multiple rings fused together, where at least one of the fused rings is a heterocycloalkyl ring, and the multiple rings are attached to the parent molecular moiety through any atom contained within the heterocycloalkyl ring of the multiple rings. In embodiments, the heterocycloalkyl is a heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring, where the ring is saturated or unsaturated but not aromatic, and contains at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring may contain at least one heteroatom independently selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring can contain zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, and oxazolinyl. Heterocyclyl bicyclic heterocycles include, but are not limited to, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is optionally substituted with one or two groups, independently oxo or thia.In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, optionally substituted with one or two groups that are independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two additional ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, the polycyclic cyclocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two additional ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0018] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant 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, and 3-bromopropyl.

[0019] The term "acyl," unless otherwise specified, means -C(O)R, where R is 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.

[0020] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring. In embodiments, fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring, and the multiple rings are bonded to the parent molecular moiety through any carbon atom contained within the aryl ring of the multiple rings. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, at least one of which is an aromatic heterocycle). In embodiments, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., at least one of the fused rings is a heteroaromatic ring, and the rings are bonded to the parent molecular moiety through any atom contained within the heteroaromatic ring of the rings). A 5,6-fused-ring heteroarylene refers to two rings fused together, one having 5 members and the other having 6 members, and at least one ring is a heteroaryl ring. Similarly, a 6,6-fused-ring heteroarylene refers to two rings fused together, one having 6 members and the other having 6 members, and at least one ring is a heteroaryl ring. Additionally, a 6,5-fused-ring heteroarylene refers to two rings fused together, one having 6 members and the other having 5 members, and at least one ring is a heteroaryl ring. Heteroaryl groups can be bonded to the remainder of the molecule through a carbon atom or a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, and the like. aryl, 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. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene," alone or as part of another substituent, mean divalent radicals derived from aryl and heteroaryl, respectively. Heteroaryl group substituents may be -O-bonded to a ring heteroatom nitrogen. A fused-ring heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused-ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl.Each fused-ring heterocycloalkyl-aryl, fused-ring heterocycloalkyl-heteroaryl, fused-ring heterocycloalkyl-cycloalkyl, or fused-ring heterocycloalkyl-heterocycloalkyl is independently unsubstituted or substituted with one or more of the substituents described herein.

[0021] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring can be the same or different. The individual rings within a spirocyclic ring can be substituted or unsubstituted and can have different substituents than the other individual rings within a set of spirocyclic rings. The possible substituents for each ring within a spirocyclic ring are the possible substituents for the same ring when not part of a spirocyclic ring (e.g., substituents for a cycloalkyl ring or heterocycloalkyl ring). The spirocyclic ring can be a 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 can be any of the rings in the list immediately above, including having all rings of one type (e.g., all rings are substituted heterocycloalkylene, and each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic, and each ring may be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substituent may optionally be different.

[0022] symbol

[0023] [ka] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0024] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0025] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0026] [ka] It has.

[0027] The alkylarylene moiety can be optionally substituted (e.g., by a substituent) at the alkylene portion or in the arylene linker (e.g., at 2, 3, 4, or 6 carbons) with halogen, oxo, -N, -CF, -CCl, -CBr, -CI, -CN, -CHO, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOCH-SOH, -OSOH, -SONH, -NHNH, -ONH, -NHC(O)NHNH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl. In some embodiments, the alkylarylene is unsubstituted.

[0028] 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 provided below.

[0029] Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can include -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR It can be one or more of a variety of groups selected from, but not limited to, —R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′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″. R, R', R'', R''', and R'''' each preferably independently 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 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group, or arylalkyl group. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected as each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined 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 meant to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0030] Similar to the substituents described for the alkyl radical, the substituents on the aryl and heteroaryl groups vary and include, for example, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′″, —NR″C(O)R′, —NR-C(NR′R″R′″)═NR′″, —NR-C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSO2R′, —NR′NR″R′″, —ONR′R″, —NR′C(O)NR″N R'"R"", -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'S02R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR" where 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 the compounds described herein include 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.

[0031] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be designated as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as attached to one member of the fused or spirocyclic ring (a floating substituent on a single ring) may also be a substituent on either the fused or spirocyclic ring (a floating substituent on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of the fused or spirocyclic ring, according to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown in a structure or formula with a floating substituent as being attached to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), and the heteroatom is attached to the floating substituent, it will be understood that the substituent replaces the hydrogen according to the rules of chemical valence.

[0032] Two or more substituents may optionally be linked to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but 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 form 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.

[0033] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(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 optionally form a ring of the formula -A-(CH2) r wherein 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 in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') dwherein 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.

[0034] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0035] As used herein, a "substituent" means a group selected from the following moieties: (A) oxo, halogen -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (i) 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, unsubstituted alkyl (e.g. , C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (a) 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, unsubstituted alkyl (e.g. , C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), or alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, 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-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0036] As used herein, a "size-limited substituent" or "size-limited substituent group" refers to a group selected from all of the substituents described above for "substituent group," and each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20 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; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0037] As used herein, a "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "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 2-8 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 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0038] In some embodiments, each substituent described in the compounds herein is substituted with at least one substituent. 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 with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0039] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20each 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; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 20 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; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0040] 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 2-8 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 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10In 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 2-8 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 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0041] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds, which may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present invention is intended to include compounds in racemic and optically pure 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 the compounds described herein contain olefinic bonds or other geometric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified.

[0042] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural arrangement or configuration of the atoms.

[0043] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0044] 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.

[0045] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., 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.

[0046] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0047] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0048] It should be noted that throughout this application, options, e.g., each amino acid position containing more than one possible amino acid, are described in terms of a Markush group. It is specifically contemplated that each member of a Markush group should be considered separately, thereby including alternative embodiments, and that a Markush group should not be read as a single unit.

[0049] "Analog" or "analogue" is used according to its plain and ordinary meaning within chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the replacement of one atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0050] As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, the phrase "substituted with a[n]" means that the specified group can be substituted with one or more of any or all of the specified substituents. For example, when a group such as an alkyl group or heteroaryl group is "unsubstituted C-C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is selected from the group consisting of one or more unsubstituted C-C 20 It may contain alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl.

[0051] Furthermore, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group occurs in a description of a chemical species (such as formula (I)), Roman alphabet symbols may be used to distinguish between each occurrence of that particular R group. For example, multiple R 13 When substituents are present, each R 13 The substituents are R 13A , R 13B , R 13C , R 13D can be distinguished from R 13A , R 13B , R 13C , R13D etc. are R 13 are defined within the scope of the definition of, and in some cases, differ.

[0052] As used herein, the term "detectable moiety" refers to a moiety that can be covalently or non-covalently bound to a compound or biomolecule that can be detected, for example, using techniques known in the art. In embodiments, the detectable moiety is covalently bound. The detectable moiety can provide imaging of the bound compound or biomolecule. The detectable moiety can indicate contact between two compounds. Exemplary detectable moieties are fluorophores, antibodies, reactive dyes, 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 iron platinum, and manganese.

[0053] The description of the compound of the present invention is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more of several substituents, such substitutions are selected to comply with the principles of chemical bonding and to bring about a compound that is not inherently unstable and / or is known to those skilled in the art to be likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0054] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound 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 salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as argininate, and salts of organic acids such as glucuronic acid or galacturonic acid (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 into either base or acid addition salts.

[0055] Therefore, the compounds of the present invention can exist as salts with pharmaceutically acceptable acids, etc. The present invention includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+) tartrate, (-) tartrate, or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0056] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the 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 functional groups, which allow the compounds to be converted into either base or acid addition salts. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. Although the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound of interest of the present invention.

[0057] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield the compounds of the present invention. Prodrugs of the compounds described herein may be converted in vivo after administration. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0058] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0059] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of a compound by a subject and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solution, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0060] The term "formulation" is intended to include a combination of an active compound and an encapsulating material as a carrier to provide a capsule, in which the active ingredient, with or without other carriers, is surrounded by the carrier and thus associated with it. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0061] "CCR4 inhibitor" refers to a compound (e.g., a compound described herein) that can reduce the activity of CCR4 (e.g., by binding to CCR4) compared to a control, such as the absence of the compound or a compound with known inactivity.

[0062] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acid residues, which may optionally be conjugated to moieties not composed of amino acids. The terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of corresponding naturally occurring amino acids, as well as to naturally occurring and non-naturally occurring amino acid polymers. In embodiments, the terms "polypeptide," "peptide," and "protein," used interchangeably herein, refer to polymeric forms of amino acids of any length, which may include genetically encoded and non-genetically encoded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides with modified polypeptide backbones. The terms include fusion proteins, including, but not limited to, fusion proteins with heterologous amino acid sequences; fusion proteins with heterologous and homologous leader sequences, with or without an N-terminal methionine residue; immunologically tagged proteins, and the like.

[0063] A polypeptide or cell is "recombinant" if it is artificial or engineered, or if it is derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-naturally occurring or non-wild-type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in the genome of a recombinant organism, so that it is not associated with nucleotide sequences that normally flank the polynucleotide as 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. Similarly, a polynucleotide sequence not found in nature, e.g., a variant of a naturally occurring gene, is recombinant.

[0064] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two different species (e.g., chemical compounds, including biomolecules or cells) to come into sufficient proximity to react, interact, or physically contact. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate from one or more of the added reagents that may be produced in the reaction mixture.

[0065] The term "contacting" can include allowing two species to react, interact, or come into physical contact, and the two species can be a compound described herein and a protein or enzyme. In some embodiments, contacting includes allowing a compound described herein to interact with a protein or enzyme involved in a signal transduction pathway (e.g., a MAP kinase pathway).

[0066] As defined herein, the terms "activation," "activate," "activating," and the like, with respect to target-inhibitor interactions, mean to positively affect (e.g., increase) the activity or function of a target (e.g., a protein) compared to the activity or function of the target (e.g., a protein) in the absence of the inhibitor. These terms refer to activating, or activating, sensitizing, or upregulating signal transduction or enzymatic activity or the amount of a protein that is decreased in a disease.

[0067] The terms "agonist," "activator," "up-regulator," and the like refer to a substance capable of detectably increasing the expression or activity of a given gene or protein compared to a control (e.g., the absence of an agonist). An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more higher than 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 increased activation of the target. In embodiments, an activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or up-regulates, for example, a gene, protein, ligand, receptor, or cell.

[0068] As defined herein, with respect to target-inhibitor interactions, the terms "inhibition," "inhibit," "inhibiting," and the like refer to negatively affecting (e.g., decreasing) the activity or function of a target (e.g., protein) compared to the activity or function of the target (e.g., protein) in the absence of the inhibitor. In embodiments, inhibition refers to negatively affecting (e.g., decreasing) the concentration or level of a target (e.g., protein) compared to the concentration or level of the target (e.g., protein) in the absence of the inhibitor. In embodiments, inhibition refers to a reduction in a disease or disease symptom. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or completely blocking stimulation, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzymatic activity or the amount of a target (e.g., protein). In embodiments, inhibition refers to a reduction in the activity of a target (e.g., protein) due to a direct interaction (e.g., an inhibitor binding to the target (e.g., protein)). In embodiments, inhibition refers to a decrease in the activity of a target (e.g., a protein) due to an indirect interaction (e.g., an inhibitor binds to a protein that activates the target (e.g., a protein), thereby preventing activation of the target (e.g., a protein).

[0069] The terms "inhibitor," "suppressor," "antagonist," or "down-regulator" refer interchangeably to a substance capable of detectably reducing the expression or activity of a given gene or protein compared to a control (e.g., the absence of the inhibitor). An antagonist can reduce 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 instances, 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; an antagonist can also prevent, inhibit, or reduce the constitutive activity of a target, e.g., a target receptor, even in the absence of a recognized agonist. In embodiments, an inhibitor is a molecule that decreases, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates constitutive activity. An "antagonist" is a molecule that opposes the action of an agonist.

[0070] The terms "CC chemokine receptor type 4" and "CCR4" refer to the protein (including homologs, isoforms, and functional fragments thereof) that is a high-affinity receptor for CC-type chemokines (e.g., CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC)). It is referred to by several different names in the scientific literature, including "CC-CKR-4," "CC CKR-4," "K5-5," "CD194," "CMKBR4," "ChemR13," "HGCN," and "14099." The terms include any recombinant or native form of CCR4 and / or variants thereof that maintain CCR4 activity (e.g., within the range of 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 or variants thereof (e.g., frameshift mutations) that maintain CCR4 activity (e.g., within the range of 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 an 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 a nucleic acid sequence set forth in RefSeq (mRNA) NM_005508. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application. In embodiments, the sequence corresponds to GI:5031627. In embodiments, the sequence corresponds to NP_005499.1. In embodiments, this sequence corresponds to NM_005508.4. In embodiments, this sequence corresponds to GI:48762930. In embodiments, the CCR4 is human CCR4, such as in human cancers that cause CCR4. Although frequently found on dendritic cells, macrophages, NK cells, platelets, and basophils, CCR4 is primarily associated with T cells. It plays a role in the progression of multiple inflammation-related disorders and has also been implicated in several other conditions, as described herein.The genomic sequence of CCR4 resides on chromosome 3 (NC_000003.12), and the CCR4 gene is conserved in several species, including chimpanzees, rhesus monkeys, dogs, cattle, mice, rats, chickens, and zebrafish. The CCR4 polypeptide contains 360 amino acid residues (NP_005499.1), and like other chemokine receptors, CCR4 is a G protein-coupled receptor that can be found on the surface of leukocytes (see, e.g., Horuk (1994) Trends Pharm. Sci. 15:159-165).

[0071] The term "expression" includes any step involved in polypeptide production, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0072] The term "disease" or "condition" refers to an existing state or state of health of a patient or subject that may be 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 further examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphatic cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, and liver cancer, including hepatocellular carcinoma, B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), lymphoma, including Hodgkin's lymphoma, leukemia (including MDS, AML, ALL, ATLL, and CML), or multiple myeloma.

[0073] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., increased levels of inflammation compared to a control, such as a healthy individual without the 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-onset diabetes, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, and the like. These conditions include ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. These conditions are frequently intertwined with other diseases, disorders, and conditions. For example, a non-limiting list of inflammation-related diseases, disorders, and conditions that may be caused by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., when inflammatory cytokines interfere with healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczema, systemic sclerosis, transplantation, and multiple sclerosis. Some of the aforementioned diseases, disorders, and conditions for which the compounds described herein (e.g., CCR4 inhibitors) may be particularly effective (e.g., due to limitations of current therapies) are described in more detail below.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-onset diabetes, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet'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.

[0074] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds or methods 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 the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, and pancreatic cancer. Additional examples include thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, squamous cell carcinoma of the head and neck, invasive carcinoma of the breast, 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 thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0075] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs, generally characterized by distorted proliferation and development of white blood cells and their precursor cells in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and character of the disease—acute or chronic, (2) the type of cell involved—myeloid (myeloid), lymphatic (lymphatic), or monocytic, and (3) the increased or non-increased number of abnormal cells in the blood—leukemia or non-leukemia (subleukemia). Exemplary leukemias that may be treated using the compounds or methods 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, leukocythemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, and leukemia of the genotype. leukemia), histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0076] As used herein, the term "lymphoma" refers to a group of cancers affecting hematopoietic and lymphatic tissues. It develops primarily in lymphocytes, which are blood cells found in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the rate at which the cancer grows and the type of cell involved. NHL includes aggressive (high-grade) and indolent (low-grade) types. Based on the type of cell involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytic B-cell) lymphoma, splenic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0077] The term "sarcoma" generally refers to tumors made up of a substance like embryonic connective tissue and generally composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated using the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastoma, botryoid fibrosarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, and 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, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0078] The term "melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds or methods 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, subungual melanoma, or superficial spreading melanoma.

[0079] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.Exemplary carcinomas that may be treated with the compounds or methods provided herein include, for example, thyroid carcinoma, bile duct carcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, invasive carcinoma of the breast, lung adenocarcinoma, lung squamous cell carcinoma, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, acinar cell carcinoma, adenocell carcinoma, adenoid cystic carcinoma, carcinoma adenomatous, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, carcinoma, cribriform carcinoma, armor carcinoma, skin cancer, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, compact carcinoma (carcinoma durum), embryonal carcinoma, encephalomyocellular carcinoma, epidermoid carcinoma, tonsillar carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, in situ carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, in situ carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma (carcinoma molle), mucinous carcinoma, mucus-secreting carcinoma muciparum, mucocytic carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, bony carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, porotic carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectatic-like carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), nodular carcinoma, verrucous carcinoma, or choriocarcinoma.

[0080] As used herein, the term "autoimmune disease" refers to a disease or condition in which a subject's immune system mounts an abnormal immune response to a substance that does not normally elicit an immune response in healthy individuals. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods 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 autonomic neuropathy, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, and autoimmune inflammatory bowel disease (AIED). Immune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Barrow's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas' disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multiple myelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital cardiac blockade Coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans' syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis), Graves' syndrome, disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus (SLE), Lyme disease, chronicMeniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic), neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis, PANDAS (Streptococcus-associated childhood autoimmune neuropsychiatric disorders), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Lee-Romberg syndrome, Parsonage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, type II, type III autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progestational dermatitis, primary biliary cirrhosis, primary sclerosing encephalopathy Cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-body syndrome, These include subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia, Takayasu's 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, bullous dermatoses, vitiligo, or Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)).

[0081] The term "treating" or "treatment" refers to any indication of success or improvement in therapy of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as alleviation, remission, a decrease in symptoms, or making the injury, disease state, or condition more tolerable for the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, improving the patient's physical or mental well-being, and any objective or subjective parameter, such as: remission, a decrease in symptoms, or making the injury, disease state, or condition more tolerable for the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, improving the patient's physical or mental well-being, etc. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treating" and its conjugations can include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, treating or treatment is not prophylactic treatment.

[0082] As used herein (and as is well understood in the art), "treating" or "treatment" broadly includes any approach to obtaining a beneficial or desired result in a subject's condition, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether partial or total, and whether detectable or undetectable, reduction in the extent of disease, stabilization of disease state (i.e., not worsening), prevention of disease infection or spread, delay or slowing of disease progression, improvement or relief of disease state, reduction in disease recurrence, and remission. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of disease. Treatment may prevent the onset of disease, inhibit the spread of disease, relieve symptoms of disease (e.g., eye pain, seeing halos around lights, eye redness, high intraocular pressure), completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination thereof.

[0083] As used herein, "treating" and "treatment" include prophylactic treatment. A method of treatment involves administering a therapeutically effective amount of a compound described herein to a subject. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the composition used for treatment, or a combination thereof. It will also be understood that the effective dosage of an agent used for treatment or prevention may increase or decrease during a particular treatment or prevention regimen. Dosage variations can be effected and made evident by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, a composition is administered to a subject in an amount and for a duration sufficient to treat the patient.

[0084] The term "preventing" refers to a reduction in the occurrence of disease symptoms in a patient. As noted above, prevention can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely develop without treatment. In embodiments, prevention refers to slowing or inhibiting the progression of a disease, disorder, or condition to an adverse or otherwise undesirable state.

[0085] A "patient" or "subject in need of treatment" refers to an organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0086] An "effective amount" is an amount sufficient for a compound to achieve a predetermined purpose (e.g., achieve the effect of being administered, treat a disease, decrease enzyme activity, increase enzyme activity, decrease a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of a symptom of a disease, which may also be referred to as a "therapeutically effective amount." "Alleviation" of a symptom(s) (and grammatical equivalents of this phrase) means a reduction in the severity or frequency of the symptom, or the elimination of the symptom. A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have an intended prophylactic effect, for example, an amount of a drug that prevents or delays the onset (or recurrence) of an injury, disease, pathology, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of the antagonist. As used herein, a "function-interfering amount" refers to the amount of antagonist required to interfere with the function of an enzyme or protein relative to the absence of the antagonist. The exact amount will depend on the purpose of the treatment and will be ascertainable by one of skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 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).A therapeutically effective amount can be ascertained by measuring relevant physiological effects and can be adjusted in conjunction with dosing regimens, diagnostic analyses of a subject's condition, etc. By way of example, measuring serum levels of a CCR4 inhibitor (or, e.g., a metabolite thereof) at particular times after administration can indicate whether a therapeutically effective amount has been administered.

[0087] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound that is capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0088] 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 found to be effective in animals. The human dosage can be adjusted by monitoring the efficacy of the compound and adjusting the dosage upward or downward, as described above. Adjusting the dosage to achieve maximum efficacy in humans based on the above and other methods is well within the ability of one of ordinary skill in the art. Adjusting the dosage to achieve maximal therapeutic window efficacy or toxicity in humans based on the above and other methods is well within the ability of one of ordinary skill in the art.

[0089] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to ameliorate a disorder, as described above. For example, for a given parameter, a therapeutically effective amount may exhibit an increase or decrease of at least 5%, 10%, 15%, 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 be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effective than a control.

[0090] Dosage may vary depending on the patient's requirements and the compound used. In the context of the present invention, the dosage administered to a patient should be sufficient to produce 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. Determining the appropriate dosage for a particular situation is within the ability of one skilled in the art. Generally, treatment is initiated with a lower dosage that is less than the optimal dose of the compound. Thereafter, the dosage is increased by small increments until the optimal effect under the circumstances is reached. Dosage amount and interval can be individually adjusted to provide a level of administered compound that is effective for the particular clinical indication being treated. This will provide a treatment regimen appropriate to the severity of the individual's condition.

[0091] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including 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 administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Co-administering" means that a composition described herein is administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., anti-cancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). In embodiments, administering does not include administration of any active agents other than the listed active agents. The compounds of the present invention can be administered alone or simultaneously to a patient. Simultaneous administration is intended to include simultaneous or sequential administration of compounds, individually or in combination (more than one compound or agent). Thus, the preparations can be combined with other active agents, if desired (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally or topically, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, nanoparticles, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, troches, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present invention may further comprise ingredients to provide sustained release and / or comfort, such as high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and finely divided drug carrier matrices.These components are discussed in more detail in U.S. Pat. Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for sustained release within the body. For example, microspheres can be delivered as subcutaneous slow-releasing drug-containing microspheres (Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gel formulations (e.g., Gao Pharm. Res. 12:857-863, 1995); or microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the present invention can be delivered by the use of liposomes that fuse with or are endocytosed by cell membranes, i.e., by using receptor ligands attached to the liposomes that bind to cell surface membrane protein receptors that trigger endocytosis. In particular, liposome surfaces may carry receptor ligands specific for target cells or otherwise The use of liposomes can focus delivery of the compositions of the present invention to target cells in vivo, where the liposomes are preferentially directed to specific organs. (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 delivered as nanoparticles. In embodiments, administering does not include administering any active agent other than the listed active agents.

[0092] By "co-administered" is meant that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies. The compounds of the present invention can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The compositions of the present invention can be delivered transdermally by topical routes or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0093] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound that is capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0094] As is well known in the art, the therapeutically effective amount for use in humans can also be determined from animal models.For example, human doses can be formulated to achieve a concentration that has been found to be effective in animals.Human dosages can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward, as described above.Based on the above and other methods, adjusting dosages to achieve maximum efficacy in humans is well within the capabilities of those skilled in the art.

[0095] Dosage may vary depending on the patient's requirements and the compound used. In the context of the present invention, the dose administered to a patient should be sufficient to produce 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. Determining the appropriate dosage for a particular situation is within the ability of one skilled in the art. Generally, treatment is initiated with smaller dosages that are less than the optimal dose of the compound. Thereafter, the dosage is increased by small increments until the optimal effect under the circumstances is reached.

[0096] Dosage amount and interval may be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, thereby providing a treatment regimen appropriate to the severity of the individual's condition.

[0097] The teachings provided herein can be used to design effective prophylactic or therapeutic treatment regimens that do not cause substantial toxicity and that are effective in treating the clinical symptoms exhibited by a particular patient. This design should include careful selection of an active compound by considering factors such as the compound's potency, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred method of administration, and the toxicity profile of the selected agent.

[0098] The compounds described herein can be used in combination with each other and with other active agents known to be useful in treating cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or disorders.

[0099] In some embodiments, simultaneous administration includes administering a first 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. Coadministration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, coadministration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjunct agents may be combined or conjugated to each other. In some embodiments, the compounds described herein can be combined with treatments for cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or disorder.

[0100] "Cardiovascular agent" is used according to its plain and ordinary meaning and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) used in any method of treating a condition of the heart or circulatory or vascular system relative to a control. In some embodiments, a cardiovascular agent is an agent identified herein that has utility in methods of treating a cardiovascular disease or disorder. In some embodiments, a cardiovascular agent is an agent approved by the FDA or similar regulatory agency in a country other than the United States to treat a cardiovascular disease or disorder.

[0101] "Anti-inflammatory agent" is used according to its plain and ordinary meaning and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) used in any manner to reduce inflammation or swelling compared to a control (e.g., the absence of the agent). In some embodiments, the anti-inflammatory agent is an agent identified herein that has utility in methods for treating an inflammatory disease or disorder. In some embodiments, the anti-inflammatory agent is an agent approved by the FDA or a similar regulatory agency in a country other than the United States to reduce swelling and inflammation.

[0102] The compounds described herein can be administered to treat immune or inflammatory diseases or disorders, cardiovascular or metabolic diseases or disorders, and / or cancer. In this regard, 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.

[0103] The compounds disclosed herein may be co-administered with agonists or antagonists of cytokines or cytokine function (including agents that act on cytokine signaling pathways, such as modulators of the SOCS system), including: alpha-, beta-, and gamma-interferons; insulin-like growth factor type 1 (IGF-1); interleukins (ILs), including IL1-17, and interleukin antagonists or inhibitors, such as analcinra; tumor necrosis factor alpha (TNF-alpha) inhibitors, e.g., anti-TNF monoclonal antibodies (e.g., infliximab; adalimumab, and CDP-870), and TNF receptor antagonists, including immunoglobulin molecules (such as etanercept) and small molecular weight agents, such as pentoxifylline.

[0104] The compounds disclosed herein are useful for treating various conditions including: anti-inflammatory agents, such as thalidomide or its derivatives, retinoids, dithranol or calcipotriol, nonsteroidal anti-inflammatory drugs (hereinafter NSAIDs) including topically or systemically applied non-selective cyclooxygenase COX-1 / COX-2 inhibitors (e.g., piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazones, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective C It may be co-administered with OX-2 inhibitors (e.g., meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib, and etoricoxib); cyclooxygenase-inhibiting nitric oxide donors (CINOD); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine d-penicillamine; auranofin or other parenteral or oral preparations; analgesics; diacerein; intra-articular therapies, such as hyaluronic acid derivatives; and nutritional supplements, such as glucosamine.

[0105] The compounds disclosed herein may be co-administered with anticoagulants such as calcium channel blockers, beta-adrenergic receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-2 receptor antagonists; lipid-lowering agents, e.g., statins or fibrates; modulators of blood cell morphology such as pentoxifylline; thrombolytic agents, or platelet aggregation inhibitors.

[0106] titutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens Anti-cancer drugs include but are not limited to: anti-cancer drugs (e.g., testosterone propionate, fluoxymesterone), anti-androgens (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, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to I, triptolide, homoharringtonine, 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 therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), ), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF 299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, and dasatinib.

[0107] "Chemotherapeutic agent" or "chemotherapeutic agent" is used according to its plain and ordinary meaning to refer to a chemical composition or compound that has anti-tumor properties or the ability to inhibit cell growth or proliferation.

[0108] Additionally, the compounds described herein can be used in combination with 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, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g.,111 In, 90 Y, or 131 The antibody may be co-administered with conventional immunotherapeutic agents, including, but not limited to, anti-CD20 monoclonal antibodies conjugated to IFN-γ or the like.

[0109] The compounds disclosed herein may be co-administered with antiproliferative / anti-tumor agents or combinations thereof, such as those used in medical oncology, including: alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, or nitrosoureas); antimetabolites (e.g., antifolates, such as fluoropyrimidines like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytochrome P450); antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, or mithramycin); antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, or vinorelbine, or taxoids such as taxol or taxotere); or topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide, teniposide, amsacrine, topotecan, or camptothecin); (ii) cytostatic agents, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, or iodoxifene), estrogen receptor down-modulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, or cyproterone acetate), LHRH antagonists, (iii) drugs that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors such as marimastat or inhibitors of urokinase plasminogen activator receptor function);(iv) inhibitors of growth factor function, for example, growth factor antibodies (e.g., the anti-erbb2 antibody trastuzumab, or the anti-erbb1 antibody cetuximab [C225]), farnesyltransferase inhibitors, tyrosine kinase inhibitors or serine / threonine kinase inhibitors, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, for example, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-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)quinazolin-4-amine (CI 1033), inhibitors of the platelet-derived growth factor family, or inhibitors of the hepatocyte growth factor family; (v) antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab, the compounds disclosed in WO 97 / 22596, WO 97 / 30035, WO 97 / 32856, or WO 98 / 13354), or compounds that act by another mechanism (e.g., linomide, integrin, inhibitors of phospho-alpha to beta 3 function or angiostatin; (vi) vascular damaging agents, such as combretastatin A4 or compounds disclosed in WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 or WO 02 / 08213; (vii) agents used in antisense therapy, such as those directed against one of the targets listed above, such as the anti-ras antisense ISIS 2503;(viii) Agents used in gene therapy approaches, such as approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes, and approaches to increase a patient's resistance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy; (ix) Agents used in immunotherapy approaches, such as ex vivo and in vivo approaches to increase the immunogenicity of a patient's tumor cells, for example, transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, approaches to reduce 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;

[0110] In embodiments, the compounds disclosed herein may be co-administered with antibodies, such as monoclonal antibodies that target B lymphocytes (e.g., CD20 (rituximab), MRA-aIL16R and T lymphocytes, CTLA4-Ig, HuMax I1-15) or antibodies that modulate Ig function, such as anti-IgE (e.g., omalizumab).

[0111] In embodiments, treating cancer involves administering effective amounts of at least two of the following: a CCR4 inhibitor (e.g., a compound described herein), an inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, or an agonistic antibody of CD137 (4-1BB). In some embodiments, the method may involve the use of a combination of two or more.

[0112] In embodiments, the treatment of cancer includes an effective amount of at least two or more of the following: a CCR4 inhibitor (e.g., a compound described herein) and any combination of an agent (e.g., an anti-cancer agent) that can be an immune modulator, such as, but not limited to, those listed in Table 1 or those described herein. These immune modulators can be depleting antibodies, neutralizing antibodies, blocking antibodies, agonist antibodies, small molecule modulators (inhibitors or stimulators), or small molecule analogs.

[0113] [Table 1-1]

[0114] [Table 1-2]

[0115] In further embodiments, the compounds described herein are radionuclides, for example, optionally conjugated to antibodies against tumor antigens. 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, 111 Ag, 111 In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, and 212 It can be co-administered with conventional radiotherapeutic agents, including but not limited to Bi.

[0116] In addition, CCR4 inhibitors (e.g., compounds described herein) can be combined with the therapeutic administration of immune cells, sometimes referred to as adoptive cell transfer. These cells can be derived from the patient, a genetically related donor, or an unrelated donor, and they can be genetically modified (e.g., CAR-T cells, NK cells, etc.), cell lines, genetically modified cell lines, and live or dead forms of the above. CCR4 inhibitors can also be combined with any type of vaccine (e.g., protein / peptide, viral, bacterial, or cellular vaccine) to stimulate an immune response against cancer.

[0117] In embodiments, the treatment is administration of an effective amount of a CCR4 inhibitor (e.g., a compound described herein) in combination with an inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, an agonistic antibody of CD137 (4-1BB), or in combination with another immune modulator listed in Table 1.

[0118] In embodiments, the treatment is therapeutic administration of an effective amount of a CCR4 inhibitor (e.g., a compound described herein) in combination with an inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, an agonistic antibody of CD137 (4-1BB), or in combination with another immune modulator listed in Table 1. In embodiments, the tumor is about 40-70 mm 3 Treatment begins when the size of

[0119] CCR4 inhibitors disclosed herein (e.g., compounds described herein) can be administered by any acceptable route, for example, orally, intraadiposely, intra-arterially, intra-articularly, intracerebrally, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumor tissue, intraumbilical, intravaginally, intravenously, intravesicularly, intravitreally, liposomally, topically, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, locally, bucally, transdermally, vaginally, in a cream, in a lipid composition, via a catheter, via a lavage solution, via continuous infusion, via injection, via inhalation, via injection, via topical delivery, via local perfusion, directly bathing target cells, or any combination thereof.

[0120] The immune modulators disclosed herein can be administered by any acceptable route, for example, orally, intraadipose, intra-arterial, intra-articular, intracerebral, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumor, intraumbilical, intravaginal, intravenous, intravesicular, intravitreal, liposomal, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, local, buccal, transdermal, vaginal, in a cream, in a lipid composition, via a catheter, via a lavage solution, via continuous infusion, via injection, via inhalation, via injection, via topical delivery, via local perfusion, directly bathing target cells, or any combination thereof.

[0121] The CCR4 inhibitors disclosed herein (e.g., compounds described herein) may be administered once daily until the study reaches its endpoint. The immune modulators disclosed herein may be administered at least three times, although in some studies, four or more times depending on the length and / or design of the study.

[0122] The methods disclosed herein can be used in combination with an additional cancer therapy. In some embodiments, the additional cancer therapy comprises surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy. In some embodiments, the cancer is a chemotherapy-resistant or radiation-resistant cancer.

[0123] As used herein, a "cell" refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with certain dyes, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells may include 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, such as mammalian cells, insect cells (e.g., Spodoptera), and human cells. Cells may be useful if they are naturally non-adherent or have been treated to prevent them from adhering to surfaces, for example, by trypsinization.

[0124] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subject or reagent is treated the same as in a parallel experiment except for the omission of the experimental procedure, reagent, or variable. In some cases, a control is used as a standard of comparison in evaluating experimental efficacy. In some embodiments, a control is a measurement of protein activity in the absence of a compound described herein (including embodiments and examples).

[0125] The term "modulator" refers to a composition that increases or decreases the level of a target molecule, the function of a target molecule, or the physical state of a molecular target. In some embodiments, a CCR4-associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with CCR4 (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 function of CCR4. Modulators can act alone or with a cofactor, e.g., a protein, metal ion, or small molecule. Examples of modulators include small molecule compounds and other bioorganic molecules. Numerous libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying modulators. One skilled in the art can develop one or more assays (e.g., biochemical or cell-based assays) that can screen such compound libraries to identify one or more compounds with desired properties, and a skilled medicinal chemist can then optimize such one or more compounds, e.g., by synthesizing and evaluating analogs and derivatives thereof. Synthesis and / or molecular modeling studies can also be used to identify activators.

[0126] The term "modulate" is used according to its plain and ordinary meaning and refers to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effect of a modulator on a target protein, modulating means changing by increasing or decreasing the 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 inhibitor) to increase or decrease, either directly or indirectly, the function or activity of CCR4 compared to the absence of the molecule.

[0127] In the context of a substance or substance activity or function associated with a disease (e.g., a protein-related disease, a cancer associated with CCR4 activity, a CCR4-related cancer, a CCR4-related disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease)), or a disease mediated by a substance, substance activity, or substance function, the term "associated with" or "related to" or "mediated by" 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 can be a cancer that results (in whole or in part) from aberrant CCR4 function (e.g., enzymatic activity, protein-protein interaction, signaling pathway), or a cancer in which a particular symptom of the disease is caused (in whole or in part) by aberrant CCR4 activity or function. As used herein, something described as being associated with a disease, if it is a causative agent, can be a target for treating the disease. For example, cancer or a CCR4-associated disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease) associated with CCR4 activity or function can be treated with a compound described herein (e.g., a CCR4 modulator or a CCR4 inhibitor) when increased CCR4 activity or function (e.g., activity of a signal transduction pathway) causes the disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease). For example, an inflammatory disease or a CCR4-associated inflammatory disease associated with CCR4 activity or function can be treated with a CCR4 modulator or a CCR4 inhibitor when increased CCR4 activity or function (e.g., activity of a signal transduction pathway) causes the disease.

[0128] As used herein, the term "aberrant" refers to something that is different from normal. When used to describe enzyme activity or protein function, abnormal refers to an activity or function that is higher or lower than the average of a normal control or normal, non-disease control sample. Abnormal activity can also refer to an amount of activity that results in disease, and restoring the abnormal activity to a normal or non-disease-associated amount (e.g., by administering a compound or using the methods described herein) results in a reduction of the disease or one or more symptoms.

[0129] As used herein, the term "signal transduction pathway" refers to a series of interactions between cellular and optional extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which may in turn transmit the change to additional components and optionally propagate to other signal transduction pathway components. For example, binding of CCR4 with a compound described herein may reduce the level of a product of a CCR4-catalyzed reaction or the level of a downstream derivative of that product, or binding may reduce the interaction between CCR4 or the reaction product and a downstream effector or component of a signal transduction pathway (e.g., a MAP kinase pathway), resulting in altered cell growth, proliferation, or survival.

[0130] As used herein, the terms "CCR4 inhibitor," "CCR4 antagonist," "CC chemokine receptor type 4 inhibitor," "CC chemokine receptor type 4 antagonist," and all other relevant art-accepted terms (many of which are provided below) refer to compounds that are capable of detectably reducing, either directly or indirectly, the expression or activity of the CCR4 receptor in in vitro assays, in vivo models, and / or other means of demonstrating therapeutic efficacy. These terms can also refer to compounds that demonstrate at least some therapeutic benefit in human subjects (e.g., as determined via objective parameters such as serum concentration or subjective parameters such as the subject's sense of well-being).

[0131] The phrase "in an amount sufficient to effect a change" means that there is a detectable difference between the level of an indicator measured before (e.g., in the presence of a baseline level or control) and after administration of a particular therapy. An indicator can be any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject's sense of well-being).

[0132] The "activity" of a molecule may describe or refer to: binding of the molecule to a ligand or receptor; catalytic activity; ability to stimulate gene expression or cell signaling, differentiation, or maturation; antigenic activity; modulation of the activity of other molecules, etc. The term "proliferative activity" includes, for example, activity that promotes, is necessary for, or is specifically associated with normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.

[0133] "Substantially pure" indicates that the component constitutes more than about 50% of the total content of the composition, typically more than about 60% of the total content. More typically, "substantially pure" refers to a composition in which the component in question constitutes at least 75%, at least 85%, at least 90% or more of the total composition. In some cases, the component constitutes more than about 90% or more than about 95% of the total content (percentage on a weight / weight basis) of the composition.

[0134] The terms "specifically bind" and "selectively bind," when referring to binder / target, ligand / receptor, antibody / antigen, or other binding pair, refer to a binding reaction that determines the presence of a target (e.g., a protein) in a heterogeneous population of components (e.g., proteins and other biologics). Thus, under specified conditions, a particular ligand binds to a specific receptor and does not bind in significant amounts to other proteins present in a sample. A contemplated method of binding compositions derived from an antibody or antigen-binding site of an antibody binds to its antigen or variants thereof with an affinity that is at least 2-fold greater, at least 10-fold greater, at least 20-fold greater, or at least 100-fold greater than the affinity for any other target or binding composition derived therefrom. In embodiments, the antibody binds to an antigen or variant ... variant thereof, as determined, for example, by Scatchard analysis (Munsen, et al. (1980) Analyt. Biochem. 107:220-239). 9 It will have an affinity greater than liter / mole.

[0135] The terms "nucleic acid," "nucleic acid molecule," "polynucleotide," and the like are used interchangeably herein to refer to polymeric forms of nucleotides of any length (e.g., either 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.

[0136] As used herein, the terms "variant" and "homolog" are used interchangeably to refer to an amino acid or nucleic acid sequence similar to a reference amino acid or nucleic acid sequence, respectively. The terms encompass 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 acids and nucleic acid sequences encoded thereby and their isoforms, as well as splice variants of proteins or genes. The terms also encompass nucleic acid sequences that vary by one or more bases from a naturally occurring nucleic acid sequence but that can still be translated into an amino acid sequence corresponding to a naturally occurring protein due to the degeneracy of the genetic code. Non-naturally occurring variants and homologs include polypeptides and nucleic acids containing amino acid or nucleotide sequence changes, respectively, where the sequence changes are artificially introduced. For example, the changes occur in a laboratory by human intervention ("hand of man"). Thus, non-naturally occurring variants and homologs can also refer to variants and homologs that differ from a naturally occurring sequence by one or more conservative substitutions and / or tags and / or conjugates.

[0137] II. Compounds In one aspect, provided herein is a compound of structural formula (I):

[0138] [ka] or a pharmaceutically acceptable salt thereof. 1 is CR 8 Or N. X 2 is CR 9 Or N. X 3 is CR 10or N. The symbols n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independently integers of 0 to 4. The symbols m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9, v10, and v44 are independently 1 or 2. The symbol z1 is an integer of 0 to 5. The symbol z2 is an integer of 0 to 5. The symbol z3 is an integer of 0 to 11. The symbol z4 is an integer of 0 to 2. The symbol z5 is 1 or 2. L 7 is a bond, -O-, -S-, -NR 7.2B -, -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. R 1 is hydrogen, halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 , -CN, -N3, -SO n1 R 1A , -SO v1 NR 1B R 1C , -NHNR 1B R 1C , -ONR 1B R 1C , -NHC(O)NHNR 1B R 1C , -NHC(O)NR 1B R 1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D , -C(O)NR 1B R 1C , -OR 1A , -NR 1B SO2R 1A , -NR 1B C(O)R 1D , -NR 1B C(O)OR 1D , -NR 1B OR 1D , -OCX1.1 3. -OCHX 1.1 2, -OCH2X 1.1 , 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. 2 is hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 , -CN, -N3, -SO n2 R 2A , -SO v2 NR 2B R 2C , -NHNR 2B R 2C , -ONR 2B R 2C , -NHC(O)NHNR 2B R 2C , -NHC(O)NR 2B R 2C , -N(O) m2 , -NR 2B R 2C , -C(O)R 2D , -C(O)OR 2D , -C(O)NR 2B R 2C , -OR 2A , -NR 2B SO2R 2A , -NR 2B C(O)R 2D , -NR 2B C(O)OR 2D , -NR 2B OR 2D , -OCX 2.1 3. -OCHX 2.1 2, -OCH2X 2.1 , 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. 3 are independently halogen, -CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 , -CN, -N3, -SOn3 R 3A , -SO v3 NR 3B R 3C , -NHNR 3B R 3C , -ONR 3B R 3C , -NHC(O)NHNR 3B R 3C , -NHC(O)NR 3B R 3C , -N(O) m3 , -NR 3B R 3C , -C(O)R 3D , -C(O)OR 3D , -C(O)NR 3B R 3C , -OR 3A , -NR 3B SO2R 3A , -NR 3B C(O)R 3D , -NR 3B C(O)OR 3D , -NR 3B OR 3D , -OCX 3.1 3. -OCHX 3.1 2, -OCH2X 3.1 , 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. 4 is hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 , -CN, -N3, -SO n4 R 4A , -SO v4 NR 4B R 4C , -NHNR 4B R 4C , -ONR 4B R 4C , -NHC(O)NHNR 4B R 4C , -NHC(O)NR 4B R 4C , -N(O) m4 , -NR 4B R4C , -C(O)R 4D , -C(O)OR 4D , -C(O)NR 4B R 4C , -OR 4A , -NR 4B SO2R 4A , -NR 4B C(O)R 4D , -NR 4B C(O)OR 4D , -NR 4B OR 4D , -OCX 4.1 3. -OCHX 4.1 2, -OCH2X 4.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and X 2 is CR 9 If R 4 and R 9 may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 5 are independently halogen, oxo, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 , -CN, -N3, -SO n5 R 5A , -SO v5 NR 5B R 5C , -NHNR 5B R 5C , -ONR 5B R 5C , -NHC(O)NHNR 5B R 5C , -NHC(O)NR 5B R 5C , -N(O) m5 , -NR 5B R 5C , -C(O)R 5D , -C(O)OR 5D , -C(O)NR 5B R 5C , -OR 5A, -NR 5B SO2R 5A , -NR 5B C(O)R 5D , -NR 5B C(O)OR 5D , -NR 5B OR 5D , -OCX 5.1 3. -OCHX 5.1 2, -OCH2X 5.1 , 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. 6 are independently halogen, oxo, -CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 , -CN, -N3, -SO n6 R 6A , -SO v6 NR 6B R 6C , -NHNR 6B R 6C , -ONR 6B R 6C , -NHC(O)NHNR 6B R 6C , -NHC(O)NR 6B R 6C , -N(O) m6 , -NR 6B R 6C , -C(O)R 6D , -C(O)OR 6D , -C(O)NR 6B R 6C , -OR 6A , -NR 6B SO2R 6A , -NR 6B C(O)R 6D , -NR 6B C(O)OR 6D , -NR 6B OR 6D , -OCX 6.1 3. -OCHX 6.1 2, -OCH2X 6.1, 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. 7 is hydrogen, halogen, -CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 , -CN, -N3, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NHNR 7B R 7C , -ONR 7B R 7C , -NHC(O)NHNR 7B R 7C , -NHC(O)NR 7B R 7C , -N(O) m7 , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D , -C(O)NR 7B R 7C , -OR 7A , -NR 7B SO2R 7A , -NR 7B C(O)R 7D , -NR 7B C(O)OR 7D , -NR 7B OR 7D , -OCX 7.1 3. -OCHX 7.1 2, -OCH2X 7.1 , 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. 8 is hydrogen, halogen, -CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 , -CN, -N3, -SO n8 R 8A , -SO v8 NR8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(O)NHNR 8B R 8C , -NHC(O)NR 8B R 8C , -N(O) m8 , -NR 8B R 8C , -C(O)R 8D , -C(O)OR 8D , -C(O)NR 8B R 8C , -OR 8A , -NR 8B SO2R 8A , -NR 8B C(O)R 8D , -NR 8B C(O)OR 8D , -NR 8B OR 8D , -OCX 8.1 3. -OCHX 8.1 2, -OCH2X 8.1 , 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. 9 is hydrogen, halogen, -CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 , -CN, -N3, -SO n9 R 9A , -SO v9 NR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(O)NHNR 9B R 9C , -NHC(O)NR 9B R 9C , -N(O) m9 , -NR 9B R 9C , -C(O)R 9D, -C(O)OR 9D , -C(O)NR 9B R 9C , -OR 9A , -NR 9B SO2R 9A , -NR 9B C(O)R 9D , -NR 9B C(O)OR 9D , -NR 9B OR 9D , -OCX 9.1 3. -OCHX 9.1 2, -OCH2X 9.1 , 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; and X 2 is CR 9 If R 4 and R 9 may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, unsubstituted aryl, or substituted or unsubstituted heteroaryl, or X 2 is CR 9 and X 3 is CR 10 If R 9 and R 10 may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 10 is hydrogen, halogen, -CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 , -CN, -SO n10 R 10A , -SO v10 NR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C, -N(O) m10 , -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO2R 10A , -NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10.1 3. -OCHX 10.1 2, -OCH2X 10.1 , 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; or X 2 is CR 9 and X 3 is CR 10 If R 9 and R 10 may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 44 is hydrogen, -CX 44.1 3. -CHX 44.1 2. -CH2X 44.1 , -SO n44 R 44A , -SO v44 NR 44B R 44C , -C(O)R 44D , -C(O)OR 44D , -C(O)NR 44B R 44C , 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. 1A , R 1B , R 1C, R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 7.2B , R 8A , R 8B , R 8C , R 8D , R 9A、 R 9B , R 9C , R 9D , R 10A , R 10B , R 10C , R 10D , R 44A , R 44B , R 44C and R 44D 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; and R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B , R 5C , R 6B , R 6C , R 7B , R 7C, R 8B , R 8C , R 9B , R 9C , R 10B , R 10C , R 44B , and R 44C The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. X 1.1 , X 2.1 , X 3.1 , X 4.1 , X 5.1 , X 6.1 , X 7.1 , X 8.1 , X 9.1 , X 10.1 , and X 44.1 are independently -Cl, -Br, -I or -F, and X 1 , X 2 and X 3 At least one of is N.

[0139] X 1 , X 2 and X 3 At least one of X is N. 1 is N. In an embodiment, X 2 is N. In an embodiment, X 3 is N. In an embodiment, X 1 and X 2 are N and X 3 is CR 10 In an embodiment, X 1 and X 3 are N and X 2 is CR 9 In an embodiment, X 1 , X 2 and X 3 Each of these is N.

[0140] In embodiments, R 1 is halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 , -CN, -N3, -SO n1 R 1A, -SO v1 NR 1B R 1C , -NHNR 1B R 1C , -ONR 1B R 1C , -NHC(O)NHNR 1B R 1C , -NHC(O)NR 1B R 1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D , -C(O)NR 1B R 1C , -OR 1A , -NR 1B SO2R 1A , -NR 1B C(O)R 1D , -NR 1B C(O)OR 1D , -NR 1B OR 1D , -OCX 1.1 3. -OCHX 1.1 2, -OCH2X 1.1 , 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. 1 is hydrogen.

[0141] In embodiments, R 1 is hydrogen, halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 , -CN, -N3, -SO n1 R 1A , -SO v1 NR 1B R 1C , -NHNR 1B R 1C , -ONR 1B R 1C , -NHC(O)NHNR 1B R 1C , -NHC(O)NR 1B R1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D , -C(O)NR 1B R 1C , -OR 1A , -NR 1B SO2R 1A , -NR 1B C(O)R 1D , -NR 1B C(O)OR 1D , -NR 1B OR 1D , -OCX 1.1 3. -OCHX 1.1 2, -OCH2X 1.1 , R 11 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 11 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 11 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 11 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 11 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 11 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0142] In embodiments, R 1 is R 11 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 1 is R 11In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 1 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0143] In embodiments, R 1 is R 11 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 1 is R 11 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 1 is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0144] In embodiments, R 1 is R 11 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 1 is R 11 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 1 is unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0145] In embodiments, R 1 is R 11 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 1 is R 11In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 1 is an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0146] In embodiments, R 1 is R 11 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 1 is R 11 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 1 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0147] In embodiments, R 1 is R 11 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 1 is R 11 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 1 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0148] In embodiments, R 1 is R 11 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 1 is R 11In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 1 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 1 is hydrogen.

[0149] In embodiments, R 1 is R 11 In embodiments, R 1 is R 11 In embodiments, R is a substituted or unsubstituted C alkyl. 1 is R 11 In embodiments, R is a substituted or unsubstituted C alkyl. 1 is R 11 In embodiments, R is a substituted or unsubstituted C4 alkyl. 1 is R 11 In an embodiment, R is a substituted or unsubstituted C alkyl. 1 is R 11 In an embodiment, R 1 is R 11 In embodiments, R is a substituted or unsubstituted C alkyl. 1 is R 11 In embodiments, R is a substituted or unsubstituted C alkyl. 1 is R 11 In embodiments, R 1 is R 11 In embodiments, R 1 is R 11 In embodiments, R 1 is R 11 In embodiments, R 1 is R 11 In embodiments, R 1 is R 11 In embodiments, R 1 is R 11 In embodiments, R 1 is R 11In embodiments, R 1 is unsubstituted methyl. In embodiments, R 1 is an unsubstituted C alkyl. In embodiments, R 1 is an unsubstituted C alkyl. In embodiments, R 1 is an unsubstituted C4 alkyl. In embodiments, R 1 is an unsubstituted C alkyl. In embodiments, R 1 is an unsubstituted C alkyl. In embodiments, R 1 is an unsubstituted C7 alkyl. In embodiments, R 1 is an unsubstituted C8 alkyl.

[0150] In embodiments, R 2 is halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 , -CN, -N3, -SO n2 R 2A , -SO v2 NR 2B R 2C , -NHNR 2B R 2C , -ONR 2B R 2C , -NHC(O)NHNR 2B R 2C , -NHC(O)NR 2B R 2C , -N(O) m2 , -NR 2B R 2C , -C(O)R 2D , -C(O)OR 2D , -C(O)NR 2B R 2C , -OR 2A , -NR 2B SO2R 2A , -NR 2B C(O)R 2D , -NR 2B C(O)OR 2D , -NR 2B OR 2D , -OCX 2.1 3. -OCHX 2.1 2, -OCH2X 2.1, 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. 2 is hydrogen.

[0151] In embodiments, R 2 is hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 , -CN, -N3, -SO n2 R 2A , -SO v2 NR 2B R 2C , -NHNR 2B R 2C , -ONR 2B R 2C , -NHC(O)NHNR 2B R 2C , -NHC(O)NR 2B R 2C , -N(O) m2 , -NR 2B R 2C , -C(O)R 2D , -C(O)OR 2D , -C(O)NR 2B R 2C , -OR 2A , -NR 2B SO2R 2A , -NR 2B C(O)R 2D , -NR 2B C(O)OR 2D , -NR 2B OR 2D , -OCX 2.1 3. -OCHX 2.1 2, -OCH2X 2.1 , R 14 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 14 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 14substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 14 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 14 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 14 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0152] In embodiments, R 2 is R 14 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 2 is R 14 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 2 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 2 is unsubstituted ethyl. In embodiments, R 2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C4 alkyl.

[0153] In embodiments, R 2 is R 14 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 2 is R 14 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 2is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0154] In embodiments, R 2 is R 14 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 2 is R 14 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 2 is unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0155] In embodiments, R 2 is R 14 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 2 is R 14 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 2 is an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0156] In embodiments, R 2 is R 14 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 2 is R 14 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 2is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0157] In embodiments, R 2 is R 14 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 2 is R 14 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 2 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0158] In embodiments, R 2 is R 14 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 2 is R 14 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 2 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 2 is hydrogen.

[0159] In embodiments, R 2 is R 14 In embodiments, R 2 is R 14 In embodiments, R is a substituted or unsubstituted C alkyl. 2 is R 14 In embodiments, R is a substituted or unsubstituted C alkyl. 2 is R 14 In embodiments, R is a substituted or unsubstituted C4 alkyl. 2 is R 14In an embodiment, R is a substituted or unsubstituted C alkyl. 2 is R 14 In an embodiment, R 2 is R 14 In embodiments, R is a substituted or unsubstituted C alkyl. 2 is R 14 In embodiments, R is a substituted or unsubstituted C alkyl. 2 is R 14 In embodiments, R 2 is R 14 In embodiments, R 2 is R 14 In embodiments, R 2 is R 14 In embodiments, R 2 is R 14 In embodiments, R 2 is R 14 In embodiments, R 2 is R 14 In embodiments, R 2 is R 14 In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C4 alkyl. In embodiments, R 2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C alkyl. In embodiments, R 2 is an unsubstituted C7 alkyl. In embodiments, R 2 is an unsubstituted C8 alkyl.

[0160] R 1 and R 2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. 1is a substituted or unsubstituted alkyl. 2 is substituted or unsubstituted alkyl. In embodiments, R 1 is —CH3. In an embodiment, R 2 is —CH3. In an embodiment, R 1 is hydrogen. In embodiments, R 2 is hydrogen.

[0161] In embodiments, R 3 are independently halogen, -CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 , -CN, -N3, -SO n3 R 3A , -SO v3 NR 3B R 3C , -NHNR 3B R 3C , -ONR 3B R 3C , -NHC(O)NHNR 3B R 3C , -NHC(O)NR 3B R 3C , -N(O) m3 , -NR 3B R 3C , -C(O)R 3D , -C(O)OR 3D , -C(O)NR 3B R 3C , -OR 3A , -NR 3B SO2R 3A , -NR 3B C(O)R 3D , -NR 3B C(O)OR 3D , -NR 3B OR 3D , -OCX 3.1 3. -OCHX 3.1 2, -OCH2X 3.1 , 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.

[0162] In embodiments, R 3 are independently halogen, -CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 , -CN, -N3, -SO n3 R 3A , -SO v3 NR 3B R 3C , -NHNR 3B R 3C , -ONR 3B R 3C , -NHC(O)NHNR 3B R 3C , -NHC(O)NR 3B R 3C , -N(O) m3 , -NR 3B R 3C , -C(O)R 3D , -C(O)OR 3D , -C(O)NR 3B R 3C , -OR 3A , -NR 3B SO2R 3A , -NR 3B C(O)R 3D , -NR 3B C(O)OR 3D , -NR 3B OR 3D , -OCX 3.1 3. -OCHX 3.1 2, -OCH2X 3.1 , R 17 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 17 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 17 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 17 Substituted or unsubstituted aryl (e.g., C6-C10 Aryl, C 10 aryl, or phenyl), or R 17 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0163] In embodiments, R 3 are independent, R 17 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 3 are independent, R 17 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 3 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0164] In embodiments, R 3 are independent, R 17 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 3 are independent, R 17 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 3 is independently unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0165] In embodiments, R 3 are independent, R 17 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 3 are independent, R 17 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl).3 is independently unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0166] In embodiments, R 3 are independent, R 17 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 3 are independent, R 17 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 3 is independently an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0167] In embodiments, R 3 are independent, R 17 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 3 are independent, R 17 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 3 are independently unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0168] In embodiments, R 3 are independent, R 17 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 3 are independent, R 17In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 3 is independently unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0169] In embodiments, R 3 are independently halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2R 3A , 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. When z3 is 0, R 3 It is understood that R is hydrogen. 3 is independently -Cl. In an embodiment, R 3 is independently -F. In an embodiment, R 3 is independently -Br. In an embodiment, R 3 is independently -I. In an embodiment, R 3 is independently —SO2CH3. In an embodiment, R 3 is independently -SO2CH2CH3. In an embodiment, R 3 are independently -SO2Cl.

[0170] In embodiments, R 3 The definition of R 3.1 , R 3.2 , R 3.3 , R 3.4 , R 3.5 (independently assigned thereto). 3.1 , R 3.2 , R 3.3 , R 3.4 and R 3.5 are R at fixed positions on the bonded rings, respectively. 3 In an embodiment, R 3.2 is R 3 or hydrogen. In an embodiment, R3.3 is R 3 or hydrogen.

[0171] In embodiments, R 3.2 is halogen, -CX 3.2 3. -CHX 3.2 2. -CH2X 3.2 , -CN, -N3, -SO n3.2 R 3.2A , -SO v3.2 NR 3.2B R 3.2C , -NHNR 3.2B R 3.2C , -ONR 3.2B R 3.2C , -NHC(O)NHNR 3.2B R 3.2C , -NHC(O)NR 3.2B R 3.2C , -N(O) m3.2 , -NR 3.2B R 3.2C , -C(O)R 3.2D , -C(O)OR 3.2D , -C(O)NR 3.2B R 3.2C , -OR 3.2A , -NR 3.2B SO2R 3.2A , -NR 3.2B C(O)R 3.2D , -NR 3.2B C(O)OR 3.2D , -NR 3.2B OR 3.2D , -OCX 3.2 3. -OCHX 3.2 2, -OCH2X 3.2 , 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. 3.2 is halogen. In embodiments, R 3.2 is hydrogen. In embodiments, R 3.2 is halogen. In embodiments, R 3.2 is chlorine. In embodiments, R 3.2 and R 3.3are independently halogen. In embodiments, R 3.2 and R 3.3 is independently chlorine. In an embodiment, R 3.2 and R 3.3 are independently fluorine. In embodiments, R 3.2 and R 3.3 are independently bromine.

[0172] In embodiments, R 3.2 is hydrogen, halogen, -CX 3.2 3. -CHX 3.2 2. -CH2X 3.2 , -CN, -N3, -SO n3.2 R 3.2A , -SO v3.2 NR 3.2B R 3.2C , -NHNR 3.2B R 3.2C , -ONR 3.2B R 3.2C , -NHC(O)NHNR 3.2B R 3.2C , -NHC(O)NR 3.2B R 3.2C , -N(O) m3.2 , -NR 3.2B R 3.2C , -C(O)R 3.2D , -C(O)OR 3.2D , -C(O)NR 3.2B R 3.2C , -OR 3.2A , -NR 3.2B SO2R 3.2A , -NR 3.2B C(O)R 3.2D , -NR 3.2B C(O)OR 3.2D , -NR 3.2B OR 3.2D , -OCX 3.2 3. -OCHX 3.2 2, -OCH2X 3.2 , R 17.2 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17.2 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R17.2 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 17.2 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 17.2 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 17.2 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0173] In embodiments, R 3.2 is R 17.2 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 3.2 is R 17.2 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 3.2 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0174] In embodiments, R 3.2 is R 17.2 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 3.2 is R 17.2 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 3.2 is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0175] In embodiments, R 3.2 is R 17.2and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 3.2 is R 17.2 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 3.2 is unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0176] In embodiments, R 3.2 is R 17.2 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 3.2 is R 17.2 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 3.2 is an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0177] In embodiments, R 3.2 is R 17.2 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 3.2 is R 17.2 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 3.2 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0178] In embodiments, R 3.2 is R 17.2In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 3.2 is R 17.2 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 3.2 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0179] In embodiments, R 3.2 are independently halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2R 3.2A , 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. When z3 is 0, R 3.2 It is understood that R is hydrogen. 3.2 is independently -Cl. In an embodiment, R 3.2 is independently -F. In an embodiment, R 3.2 is independently -Br. In an embodiment, R 3.2 is independently -I. In an embodiment, R 3.2 is independently —SO2CH3. In an embodiment, R 3.2 is independently -SO2CH2CH3. In an embodiment, R 3.2 are independently -SO2Cl.

[0180] In embodiments, R 3.3 is halogen, -CX 3.3 3. -CHX 3.3 2. -CH2X 3.3 , -CN, -N3, -SO n3.3 R 3.3A , -SO v3.3 NR 3.3B R 3.3C , -NHNR 3.3B R 3.3C , -ONR 3.3BR 3.3C , -NHC(O)NHNR 3.3B R 3.3C , -NHC(O)NR 3.3B R 3.3C , -N(O) m3.3 , -NR 3.3B R 3.3C , -C(O)R 3.3D , -C(O)OR 3.3D , -C(O)NR 3.3B R 3.3C , -OR 3.3A , -NR 3.3B SO2R 3.3A , -NR 3.3B C(O)R 3.3D , -NR 3.3B C(O)OR 3.3D , -NR 3.3B OR 3.3D , -OCX 3.3 3. -OCHX 3.3 2, -OCH2X 3.3 , 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. 3.3 is halogen. In embodiments, R 3.3 is hydrogen. In embodiments, R 3.3 is halogen. In embodiments, R 3.3 is chlorine.

[0181] In embodiments, R 3.3 is hydrogen, halogen, -CX 3.3 3. -CHX 3.3 2. -CH2X 3.3 , -CN, -N3, -SO n3.3 R 3.3A , -SO v3.3 NR 3.3B R 3.3C , -NHNR 3.3B R 3.3C , -ONR 3.3B R 3.3C , -NHC(O)NHNR 3.3B R 3.3C , -NHC(O)NR 3.3B R 3.3C, -N(O) m3.3 , -NR 3.3B R 3.3C , -C(O)R 3.3D , -C(O)OR 3.3D , -C(O)NR 3.3B R 3.3C , -OR 3.3A , -NR 3.3B SO2R 3.3A , -NR 3.3B C(O)R 3.3D , -NR 3.3B C(O)OR 3.3D , -NR 3.3B OR 3.3D , -OCX 3.3 3. -OCHX 3.3 2, -OCH2X 3.3 , R 17.3 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17.3 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 17.3 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 17.3 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 17.3 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 17.3 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0182] In embodiments, R 3.3 is R 17.3 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 3.3 is R 17.3In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 3.3 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0183] In embodiments, R 3.3 is R 17.3 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 3.3 is R 17.3 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 3.3 is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0184] In embodiments, R 3.3 is R 17.3 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 3.3 is R 17.3 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 3.3 is unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0185] In embodiments, R 3.3 is R 17.3 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 3.3 is R 17.3In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 3.3 is an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0186] In embodiments, R 3.3 is R 17.3 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 3.3 is R 17.3 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 3.3 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0187] In embodiments, R 3.3 is R 17.3 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 3.3 is R 17.3 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 3.3 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0188] In embodiments, R 3.3 are independently halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2R 3.3A, 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. When z3 is 0, R 3.3 It is understood that R is hydrogen. 3.3 is independently -Cl. In an embodiment, R 3.3 is independently -F. In an embodiment, R 3.3 is independently -Br. In an embodiment, R 3.3 is independently -I. In an embodiment, R 3.3 is independently —SO2CH3. In an embodiment, R 3.3 is independently -SO2CH2CH3. In an embodiment, R 3.3 are independently -SO2Cl.

[0189] R 4 is halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 , -CN, -N3, -SO n4 R 4A , -SO v4 NR 4B R 4C , -NHNR 4B R 4C , -ONR 4B R 4C , -NHC(O)NHNR 4B R 4C , -NHC(O)NR 4B R 4C , -N(O) m4 , -NR 4B R 4C , -C(O)R 4D , -C(O)OR 4D , -C(O)NR 4B R 4C , -OR 4A , -NR 4B SO2R 4A , -NR 4B C(O)R 4D , -NR 4B C(O)OR 4D , -NR 4BOR 4D , -OCX 4.1 3. -OCHX 4.1 2, -OCH2X 4.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. 4 is hydrogen.

[0190] In embodiments, R 4 is halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 , -CN, -N3, -SO n4 R 4A , -SO v4 NR 4B R 4C , -NHNR 4B R 4C , -ONR 4B R 4C , -NHC(O)NHNR 4B R 4C , -NHC(O)NR 4B R 4C , -N(O) m4 , -NR 4B R 4C , -C(O)R 4D , -C(O)OR 4D , -C(O)NR 4B R 4C , -OR 4A , -NR 4B SO2R 4A , -NR 4B C(O)R 4D , -NR 4B C(O)OR 4D , -NR 4B OR 4D , -OCX 4.1 3. -OCHX 4.1 2, -OCH2X 4.1 , R 20 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 20substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 20 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4 is -CN. In embodiments, R 4 is —C(O)NH. In embodiments, R 4 is —CF. In embodiments, R 4 is -CH3.

[0191] In embodiments, R 4 is R 20 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 4 is R 20 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 4 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 4 is unsubstituted ethyl. In embodiments, R 4 is an unsubstituted C alkyl. In embodiments, R 4 is an unsubstituted C4 alkyl.

[0192] In embodiments, R 4 is R 20In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 4 is R 20 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 4 is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0193] In embodiments, R 4 is R 20 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 4 is R 20 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 4 is unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0194] In embodiments, R 4 is R 20 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 4 is R 20 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 4 is an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0195] In embodiments, R 4 is R 20 Substituted or unsubstituted aryl (e.g., C6-C10 Aryl, C 10 aryl, or phenyl). In embodiments, R 4 is R 20 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 4 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0196] In embodiments, R 4 is R 20 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4 is R 20 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0197] In embodiments, R 4 are hydrogen, -CN, halogens, -CF3, -COOH, -COOCH2CH3,

[0198] [ka] In an embodiment, R 4 is hydrogen. In embodiments, R 4 is -CN. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In embodiments, R 4 is -Br. In embodiments, R 4 is -I. In an embodiment, R 4 is —CF. In embodiments, R4 is COOH. In embodiments, R 4 is -COOCH2CH3. In an embodiment, R 4 is —CH3. In an embodiment, R 4 is -CHCHCHOH. In embodiments, R 4 teeth,

[0199] [ka] In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is a substituted C1-C4 alkyl. In embodiments, R 4 is unsubstituted C1-C4 alkyl.

[0200] In embodiments, R 4 are halogens, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 4D , -C(O)OR 4D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl. In embodiments, R 4 are halogens, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 4D , -C(O)OR 4D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl.

[0201] In embodiments, R 4 is R 20 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 4 is R 20 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 4 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0202] In embodiments, R4 is R 20 In embodiments, R 4 is R 20 In embodiments, R is a substituted or unsubstituted C alkyl. 4 is R 20 In embodiments, R is a substituted or unsubstituted C alkyl. 4 is R 20 In embodiments, R is a substituted or unsubstituted C4 alkyl. 4 is R 20 In an embodiment, R is a substituted or unsubstituted C alkyl. 4 is R 20 In an embodiment, R 4 is R 20 In embodiments, R is a substituted or unsubstituted C alkyl. 4 is R 20 In embodiments, R is a substituted or unsubstituted C alkyl. 4 is R 20 In embodiments, R 4 is R 20 In embodiments, R 4 is R 20 In embodiments, R 4 is R 20 In embodiments, R 4 is R 20 In embodiments, R 4 is R 20 In embodiments, R 4 is R 20 In embodiments, R 4 is R 20 In embodiments, R 4 is unsubstituted methyl. In embodiments, R 4 is an unsubstituted C alkyl. In embodiments, R 4 is an unsubstituted C alkyl. In embodiments, R 4 is an unsubstituted C4 alkyl. In embodiments, R 4 is an unsubstituted C alkyl. In embodiments, R4 is an unsubstituted C alkyl. In embodiments, R 4 is an unsubstituted C7 alkyl. In embodiments, R 4 is an unsubstituted C8 alkyl.

[0203] In embodiments, R 4 is hydrogen, -CX 4.1 3. -CN, -C(O)NR 4B R 4C , 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. 4 is hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 , -CN, -NR 4B R 4C , -C(O)R 4D , -C(O)OR 4D , -C(O)NR 4B R 4C , -OR 4A , -NR 4B C(O)R 4D , -NR 4B C(O)OR 4D , -OCX 4.1 3. -OCHX 4.1 2, -OCH2X 4.1 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. 4 is hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 , -CN, -C(O)OR 4D , -C(O)NR 4B R 4C , substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 4 is -Cl, -Br, -F, -CN, -COOH, -C(O)OCH2CH3, -C(CH3)2OH, -C(O)NH 2、In an embodiment, R 4 is hydrogen. In embodiments, R 4 is halogen. In embodiments, R 4 -CX 4.1 3. In an embodiment, R 4 -CHX 4.1 2. In an embodiment, R 4 is -CH2X 4.1 In an embodiment, R 4 is -CN. In embodiments, R 4 is -NR 4B R 4C In an embodiment, R 4 is -C(O)R 4D In an embodiment, R 4 is -C(O)OR 4D In an embodiment, R 4 is -C(O)NR 4B R 4C In an embodiment, R 4 -OR 4A In an embodiment, R 4 is -NR 4B C(O)R 4D In an embodiment, R 4 is -NR 4B C(O)OR 4D In an embodiment, R 4 -OCX 4.1 3. In an embodiment, R 4 -OCHX 4.1 2. In an embodiment, R 4 -OCH2X 4.1 In an embodiment, R 4 is substituted or unsubstituted alkyl. In embodiments, R 4 is substituted or unsubstituted heteroalkyl. In embodiments, R 4 is —Cl. In embodiments, R 4 is -Br. In embodiments, R 4 is -F. In an embodiment, R 4 is -CN. In embodiments, R 4 is —COOH. In embodiments, R 4is —C(O)OCH2CH3. In embodiments, R 4 is —C(CH)OH. In embodiments, R 4 is —C(O)NH. In embodiments, R 4 is —CF. In embodiments, R 4 is -CH3.

[0204] In embodiments, R 5 are independently halogen, oxo, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 , -CN, -N3, -SO n5 R 5A , -SO v5 NR 5B R 5C , -NHNR 5B R 5C , -ONR 5B R 5C , -NHC(O)NHNR 5B R 5C , -NHC(O)NR 5B R 5C , -N(O) m5 , -NR 5B R 5C , -C(O)R 5D , -C(O)OR 5D , -C(O)NR 5B R 5C , -OR 5A , -NR 5B SO2R 5A , -NR 5B C(O)R 5D , -NR 5B C(O)OR 5D , -NR 5B OR 5D , -OCX 5.1 3. -OCHX 5.1 2, -OCH2X 5.1 , 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.

[0205] In embodiments, R5 are independently halogen, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 , -CN, -N3, -SO n5 R 5A , -SO v5 NR 5B R 5C , -NHNR 5B R 5C , -ONR 5B R 5C , -NHC(O)NHNR 5B R 5C , -NHC(O)NR 5B R 5C , -N(O) m5 , -NR 5B R 5C , -C(O)R 5D , -C(O)OR 5D , -C(O)NR 5B R 5C , -OR 5A , -NR 5B SO2R 5A , -NR 5B C(O)R 5D , -NR 5B C(O)OR 5D , -NR 5B OR 5D , -OCX 5.1 3. -OCHX 5.1 2, -OCH2X 5.1 , R 23 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 23 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 23 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 23 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 23 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C10 aryl, or phenyl), or R 23 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0206] In embodiments, R 5 are independent, R 23 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 5 are independent, R 23 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 5 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0207] In embodiments, R 5 are independent, R 23 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 5 are independent, R 23 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 5 is independently unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0208] In embodiments, R 5 are independent, R 23 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 5 are independent, R 23 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 5is independently unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0209] In embodiments, R 5 are independent, R 23 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 5 are independent, R 23 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 5 is independently an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0210] In embodiments, R 5 are independent, R 23 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 5 are independent, R 23 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 5 are independently unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0211] In embodiments, R 5 are independent, R 23 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 5 are independent, R 23In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 5 is independently unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0212] In embodiments, R 6 are independently halogen, oxo, -CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 , -CN, -N3, -SO n6 R 6A , -SO v6 NR 6B R 6C , -NHNR 6B R 6C , -ONR 6B R 6C , -NHC(O)NHNR 6B R 6C , -NHC(O)NR 6B R 6C , -N(O) m6 , -NR 6B R 6C , -C(O)R 6D , -C(O)OR 6D , -C(O)NR 6B R 6C , -OR 6A , -NR 6B SO2R 6A , -NR 6B C(O)R 6D , -NR 6B C(O)OR 6D , -NR 6B OR 6D , -OCX 6.1 3. -OCHX 6.1 2, -OCH2X 6.1 , 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. 6 is COOH.

[0213] In embodiments, R 6 are independently halogen, -CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 , -CN, -N3, -SO n6 R 6A , -SO v6 NR 6B R 6C , -NHNR 6B R 6C , -ONR 6B R 6C , -NHC(O)NHNR 6B R 6C , -NHC(O)NR 6B R 6C , -N(O) m6 , -NR 6B R 6C , -C(O)R 6D , -C(O)OR 6D , -C(O)NR 6B R 6C , -OR 6A , -NR 6B SO2R 6A , -NR 6B C(O)R 6D , -NR 6B C(O)OR 6D , -NR 6B OR 6D , -OCX 6.1 3. -OCHX 6.1 2, -OCH2X 6.1 , R 26 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 26 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 26 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 26 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 26Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 26 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0214] In embodiments, R 6 is R 26 In embodiments, R is a substituted or unsubstituted alkyl. 6 is unsubstituted phenyl. In embodiments, R 6 is -F. In an embodiment, R 6 is —OH. In embodiments, R 6 is —CHOH. In embodiments, R 6 is —(CH)OH. In embodiments, R 6 is —(CH)OH. In embodiments, R 6 is —C(CH)OH. In embodiments, R 6 is —CHSONH. In embodiments, R 6 is —(CH)SONH. In embodiments, R 6 is —CHC(O)NH. In embodiments, R 6 is —(CH)C(O)NH. In embodiments, R 6 is —(CH)C(O)NH. In embodiments, R 6 is —CH 2 NHSO 2 CF 3 . In an embodiment, R 6 is —(CH)NHSOCF. In embodiments, R 6 is —(CH)NHSOCF. In embodiments, R 6 is —CH 2 NHSO 2 CH 3 . In an embodiment, R 6 is —(CH)NHSOCH. In embodiments, R 6 is —(CH)NHSOCH. In embodiments, R 6 is —CHSOCH. In embodiments, R 6 is —(CH)SOCH. In an embodiment, R6 is —CHSONH. In embodiments, R 6 is -(CH2)2SO2NH2.

[0215] In embodiments, R 6 are independent, R 26 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 6 are independent, R 26 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 6 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0216] In embodiments, R 6 are independent, R 26 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 6 are independent, R 26 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 6 is independently unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0217] In embodiments, R 6 are independent, R 26 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 6 are independent, R 26 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 6is independently unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0218] In embodiments, R 6 are independent, R 26 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 6 are independent, R 26 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 6 is independently an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0219] In embodiments, R 6 are independent, R 26 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 6 are independent, R 26 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 6 are independently unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0220] In embodiments, R 6 are independent, R 26 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 6 are independent, R 26In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 6 is independently unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0221] In embodiments, R 7 is halogen, -CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 , -CN, -N3, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NHNR 7B R 7C , -ONR 7B R 7C , -NHC(O)NHNR 7B R 7C , -NHC(O)NR 7B R 7C , -N(O) m7 , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D , -C(O)NR 7B R 7C , -OR 7A , -NR 7B SO2R 7A , -NR 7B C(O)R 7D , -NR 7B C(O)OR 7D , -NR 7B OR 7D , -OCX 7.1 3. -OCHX 7.1 2, -OCH2X 7.1 , 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. 7 is halogen. In embodiments, R 7 -CX7.1 3. In an embodiment, R 7 -CHX 7.1 2. In an embodiment, R 7 is -CH2X 7.1 In an embodiment, R 7 is -CN. In embodiments, R 7 is -N3. In an embodiment, R 7 -SO n7 R 7A In an embodiment, R 7 -SO v7 NR 7B R 7C In an embodiment, R 7 is -NHNR 7B R 7C In an embodiment, R 7 -ONR 7B R 7C In an embodiment, R 7 is -NHC(O)NHNR 7B R 7C In an embodiment, R 7 is -NHC(O)NR 7B R 7C In an embodiment, R 7 is -N(O) m7 In an embodiment, R 7 is -NR 7B R 7C In an embodiment, R 7 is -C(O)R 7D In an embodiment, R 7 is -C(O)OR 7D In an embodiment, R 7 is -C(O)NR 7B R 7C In an embodiment, R 7 -OR 7A In an embodiment, R 7 is -NR 7B SO2R 7A In an embodiment, R 7 is -NR 7B C(O)R 7D In an embodiment, R 7 is -NR 7BC(O)OR 7D In an embodiment, R 7 is -NR 7B OR 7D In an embodiment, R 7 -OCX 7.1 3. In an embodiment, R 7 -OCHX 7.1 2. In an embodiment, R 7 -OCH2X 7.1 In an embodiment, R 7 is —CF. In embodiments, R 7 is -CHF2. In an embodiment, R 7 is —CHF. In embodiments, R 7 is —SO2CH3. In an embodiment, R 7 is —SO 2 NH 2 . In an embodiment, R 7 is -NHNH. In embodiments, R 7 is -ONH2. In embodiments, R 7 is —NHC(O)NHNH. In embodiments, R 7 is —NHC(O)NH. In embodiments, R 7 is —N(O)2. In embodiments, R 7 is —NH. In embodiments, R 7 is —C(O)OH. In embodiments, R 7 is —C(O)OCH. In embodiments, R 7 is —C(O)NH. In embodiments, R 7 is —OCH. In embodiments, R 7 is —NHSO2CH3. In an embodiment, R 7 is —NHC(O)CH. In embodiments, R 7 is —NHC(O)OH. In embodiments, R 7 is —NHOH. In embodiments, R 7 is -OCF3. In an embodiment, R 7 is -OCHF. In an embodiment, R 7 is -OCHF. In embodiments, R 7 is hydrogen. In embodiments, R7 is —C(O)OH. In embodiments, R 7 is —OH. In embodiments, R 7 is —NH. In embodiments, R 7 is -C(O)NH2.

[0222] In embodiments, R 7 is halogen, -CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 , -CN, -N3, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NHNR 7B R 7C , -ONR 7B R 7C , -NHC(O)NHNR 7B R 7C , -NHC(O)NR 7B R 7C , -N(O) m7 , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D , -C(O)NR 7B R 7C , -OR 7A , -NR 7B SO2R 7A , -NR 7B C(O)R 7D , -NR 7B C(O)OR 7D , -NR 7B OR 7D , -OCX 7.1 3. -OCHX 7.1 2, -OCH2X 7.1 , R 29 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 29 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 29substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 29 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 29 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 29 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0223] In embodiments, R 7 is —(CH)COOH. In embodiments, R 7 is —(CH)COOH. In embodiments, R 7 is —(CH)COOH. In embodiments, R 7 is —(CH)CONH. In an embodiment, R 7 is —(CH)CONH. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is a substituted cyclobutyl. In embodiments, R 7 is —(CH)SOCH. In an embodiment, R 7 is —CHCH(CH)OH. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is —(CH)NHSOCH. In embodiments, R 7 is —(CH)NHSOCHCH. In an embodiment, R 7 is —(CH)NHSO(CH)CH. In an embodiment, R 7 is —(CH)NHSOCH(CH). In an embodiment, R 7is —(CH)NHC(O)OCH. In embodiments, R 7 is —(CH)SOCH. In an embodiment, R 7 is —(CH)NHC(O)CH. In embodiments, R 7 is —(CH)NHC(O)H. In embodiments, R 7 is —CHC(O)OCH. In embodiments, R 7 is —CHC(O)OCHCH. In embodiments, R 7 is —(CH)SONH. In embodiments, R 7 is —(CH)SONH. In embodiments, R 7 is —(CH)SONH. In embodiments, R 7 is —(CH)NHC(O)CHCH. In embodiments, R 7 is -(CH2)2NHC(O)CH(CH3)2.

[0224] In embodiments, R 7 is hydrogen. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted alkyl. 7 is substituted or unsubstituted phenyl. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is —CHC(CH)OH. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is —(CH)CH(CH)OH. In embodiments, R 7 is —(CH)SONH. In embodiments, R 7 is —(CH)SONH. In embodiments, R 7 is —(CH)CONH. In an embodiment, R 7 is —(CH)CONH. In embodiments, R 7 is —(CH)CON(H)Me. In an embodiment, R 7is —(CH)CON(Me). In an embodiment, R 7 is —(CH)SOMe. In an embodiment, R 7 is —(CH)SOMe. In an embodiment, R 7 is —CHCH(OH)Me. In embodiments, R 7 is —CHCOH. In an embodiment, R 7 is —(CH)COH. In embodiments, R 7 is —CH(CH)CHCOH. In embodiments, R 7 is —(CH)COH. In embodiments, R 7 is —(CH)SONHCH. In embodiments, R 7 is —(CH)SON(CH). In an embodiment, R 7 is —(CH)SO—(N-morpholinyl). In embodiments, R 7 is —(CH)NHCOCH. In embodiments, R 7 is —(CH)NHC(O)OCH. In embodiments, R 7 is —(CH)NHCOCH. In embodiments, R 7 is —(CH)NHCOCH(CH). In an embodiment, R 7 is —(CH)NHSOCH. In embodiments, R 7 is —(CH)NHSOCF. In embodiments, R 7 is —(CH)NHSONHCH(CH). In an embodiment, R 7 is —CHCH(CH)CHOH(R and S). In embodiments, R 7 is —CH(CH)(CH)OH. In embodiments, R 7 is —CH—(2-imidazolyl). In embodiments, R 7 is —CH—(4-imidazolyl). In embodiments, R 7 is —CH—(3-pyrazolyl). In embodiments, R 7 is 4-tetrahydropyranyl. In embodiments, R7 is 3-oxetanyl. In embodiments, R 7 is —(CH)NHCOMe. In an embodiment, R 7 is -(CH2)3NHCO2Me.

[0225] In embodiments, R 7 is hydrogen. In embodiments, R 7 is —OH. In embodiments, R 7 is —COOH. In embodiments, R 7 is a substituted pyrrolidinyl (e.g., oxo-substituted pyrrolidinyl). 7 is oxo. In embodiments, R 7 is —SO 2 NH 2 . In an embodiment, R 7 is —NH. In embodiments, R 7 is —CH3. In an embodiment, R 7 is -CH2CH3. In embodiments, R 7 is —NHCOCH. In embodiments, R 7 is -CONHCH3. In an embodiment, R 7 is —NHSO2CH3. In an embodiment, R 7 is -NR 7B SO2R 7A In an embodiment, R 7 is —NHSO2CH3. In an embodiment, R 7 is —NHSO2CH2CH3. In an embodiment, R 7 is —NHSO2(C1-C6 alkyl). In an embodiment, R 7 is -COCH(CH3)2.

[0226] In embodiments, R 7 is -CHOH.

[0227] [ka] In embodiments, R 7 teeth,

[0228] [ka] In an embodiment, R 7 teeth,

[0229] [ka] In an embodiment, R 7 teeth,

[0230] [ka] In an embodiment, R 7 teeth,

[0231] [ka] In an embodiment, R 7 teeth,

[0232] [ka] is.

[0233] In embodiments, R 7is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -CH2C(O)OH, -NHC(O)OH, -NHC(O)OCH3, -NHC(O)OCH2CH3, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)OCH2CH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -NHSO2CH3 , -NHSO2CH2CH3, -NHSO2CH(CH3)2, -SO2NH2, -SO2NHCH3, -(CH2)2OH, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2 OH, -(CH2)2SO2NH2, -(CH2)3SO2NH2, -(CH2)2CONH2, -(CH2)3CONH2-(CH2)3CON(H)Me, -(CH2)3CON(Me)2, -(CH2)2SO 2Me, -(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)2N HSO2CH3, -(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, -CH2OH,

[0234] [ka] is.

[0235] In embodiments, R 7is substituted or unsubstituted aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, 1,4-dioxanyl, tetrahydropyranyl, thianyl, or dithianyl. 7 is a substituted or unsubstituted phenyl, thiofuranyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl (e.g., 1,3,5-triazinyl, 1,2,3-triazinyl, or 1,2,4-triazinyl). 7 is substituted or unsubstituted indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolopyrimidinyl, purinyl, indolizinyl, pyrrolopyriazinyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridopyrazinyl, pteridinyl, pyrazolopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, or carbazolyl.

[0236] In embodiments, R 7 is a substituted aziridinyl. In embodiments, R 7 is a substituted oxiranyl. In embodiments, R 7 is a substituted thiiranyl. In embodiments, R 7 is a substituted azetidinyl. In embodiments, R 7 is a substituted oxetanyl. In embodiments, R 7 is a substituted thietanyl. In embodiments, R 7 is a substituted pyrrolidinyl. In embodiments, R 7 is a substituted pyrrolyl. In embodiments, R 7 is a substituted imidazolyl. In embodiments, R 7is a substituted imidazolinyl. In embodiments, R 7 is a substituted pyrazolinyl. In embodiments, R 7 is a substituted tetrahydrofuranyl. In embodiments, R 7 is a substituted thiolanyl. In embodiments, R 7 is a substituted piperidinyl. In embodiments, R 7 is a substituted piperazinyl. In embodiments, R 7 is a substituted pyranyl. In embodiments, R 7 is a substituted morpholinyl. In embodiments, R 7 is a substituted 1,4-dioxanyl. In embodiments, R 7 is a substituted tetrahydropyranyl. In embodiments, R 7 is a substituted thianyl. In embodiments, R 7 is substituted or dithianyl.

[0237] In embodiments, R 7 is substituted phenyl. In embodiments, R 7 is a substituted thiofuranyl. In embodiments, R 7 is a substituted imidazolyl. In embodiments, R 7 is a substituted pyrazolyl. In embodiments, R 7 is a substituted thiazolyl. In embodiments, R 7 is a substituted tetrazolyl. In embodiments, R 7 is a substituted furanyl. In embodiments, R 7 is a substituted oxazolyl. In embodiments, R 7 is a substituted isoxazolyl. In embodiments, R 7 is a substituted oxadiazolyl. In embodiments, R 7 is a substituted oxatriazolyl. In embodiments, R 7 is substituted thienyl. In embodiments, R 7 is a substituted thiazolyl. In embodiments, R 7 is a substituted isothiazolyl. In embodiments, R 7 is a substituted pyridinyl. In embodiments, R 7is a substituted pyrazinyl. In embodiments, R 7 is a substituted pyrimidinyl. In embodiments, R 7 is a substituted pyridazinyl. In embodiments, R 7 is substituted or triazinyl (e.g., 1,3,5-triazinyl, 1,2,3-triazinyl, or 1,2,4-triazinyl).

[0238] In embodiments, R 7 is a substituted indolyl. In embodiments, R 7 is a substituted benzimidazolyl. In embodiments, R 7 is a substituted indazolyl. In embodiments, R 7 is a substituted benzotriazolyl. In embodiments, R 7 is a substituted pyrrolopyrimidinyl. In embodiments, R 7 is a substituted purinyl. In embodiments, R 7 is a substituted indolizinyl. In embodiments, R 7 is a substituted pyrrolopyrriazinyl. In embodiments, R 7 is a substituted pyrrolopyrimidinyl. In embodiments, R 7 is a substituted imidazopyridazinyl. In embodiments, R 7 is a substituted imidazopyridinyl. In embodiments, R 7 is a substituted imidazopyrimidinyl. In embodiments, R 7 is a substituted cinnolinyl. In embodiments, R 7 is a substituted quinazolinyl. In embodiments, R 7 is a substituted quinoxalinyl. In embodiments, R 7 is a substituted phthalazinyl. In embodiments, R 7 is a substituted pyridopyrazinyl. In embodiments, R 7 is a substituted pteridinyl. In embodiments, R 7 is a substituted pyrazolopyridinyl. In embodiments, R 7 is a substituted quinolinyl. In embodiments, R 7 is a substituted isoquinolinyl. In embodiments, R 7is a substituted naphthyridinyl. In embodiments, R 7 is a substituted carbazolyl.

[0239] In embodiments, R 7 is unsubstituted aziridinyl. In embodiments, R 7 is unsubstituted oxiranyl. In embodiments, R 7 is unsubstituted thiiranyl. In embodiments, R 7 is unsubstituted azetidinyl. In embodiments, R 7 is unsubstituted oxetanyl. In embodiments, R 7 is unsubstituted thietanyl. In embodiments, R 7 is unsubstituted pyrrolidinyl. In embodiments, R 7 is unsubstituted pyrrolyl. In embodiments, R 7 is unsubstituted imidazolyl. In embodiments, R 7 is unsubstituted imidazolinyl. In embodiments, R 7 is unsubstituted pyrazolinyl. In embodiments, R 7 is unsubstituted tetrahydrofuranyl. In embodiments, R 7 is unsubstituted thiolanyl. In embodiments, R 7 is unsubstituted piperidinyl. In embodiments, R 7 is unsubstituted piperazinyl. In embodiments, R 7 is unsubstituted pyranyl. In embodiments, R 7 is unsubstituted morpholinyl. In embodiments, R 7 is unsubstituted 1,4-dioxanyl. In embodiments, R 7 is unsubstituted tetrahydropyranyl. In embodiments, R 7 is unsubstituted thianyl. In embodiments, R 7 is unsubstituted dithianyl.

[0240] In embodiments, R 7 is unsubstituted phenyl. In embodiments, R 7 is unsubstituted thiofuranyl. In embodiments, R 7 is unsubstituted imidazolyl. In embodiments, R7 is unsubstituted pyrazolyl. In embodiments, R 7 is unsubstituted triazolyl. In embodiments, R 7 is unsubstituted tetrazolyl. In embodiments, R 7 is unsubstituted furanyl. In embodiments, R 7 is unsubstituted oxazolyl. In embodiments, R 7 is unsubstituted isoxazolyl. In embodiments, R 7 is unsubstituted oxadiazolyl. In embodiments, R 7 is unsubstituted oxatriazolyl. In embodiments, R 7 is unsubstituted thienyl. In embodiments, R 7 is unsubstituted thiazolyl. In embodiments, R 7 is unsubstituted isothiazolyl. In embodiments, R 7 is unsubstituted pyridinyl. In embodiments, R 7 is unsubstituted pyrazinyl. In embodiments, R 7 is unsubstituted pyrimidinyl. In embodiments, R 7 is unsubstituted pyridazinyl. In embodiments, R 7 is an unsubstituted triazinyl (e.g., 1,3,5-triazinyl, 1,2,3-triazinyl, or 1,2,4-triazinyl).

[0241] In embodiments, R 7 is an unsubstituted indolyl. In embodiments, R 7 is unsubstituted benzimidazolyl. In embodiments, R 7 is unsubstituted indazolyl. In embodiments, R 7 is unsubstituted benzotriazolyl. In embodiments, R 7 is unsubstituted pyrrolopyrimidinyl. In embodiments, R 7 is unsubstituted purinyl. In embodiments, R 7 is unsubstituted indolizinyl. In embodiments, R 7 is unsubstituted pyrrolopyrriazinyl. In embodiments, R 7 is unsubstituted pyrrolopyrimidinyl. In embodiments, R7 is unsubstituted imidazopyridazinyl. In embodiments, R 7 is unsubstituted imidazopyridinyl. In embodiments, R 7 is unsubstituted imidazopyrimidinyl. In embodiments, R 7 is unsubstituted cinnolinyl. In embodiments, R 7 is unsubstituted quinazolinyl. In embodiments, R 7 is unsubstituted quinoxalinyl. In embodiments, R 7 is unsubstituted phthalazinyl. In embodiments, R 7 is unsubstituted pyridopyrazinyl. In embodiments, R 7 is unsubstituted pteridinyl. In embodiments, R 7 is unsubstituted pyrazolopyridinyl. In embodiments, R 7 is unsubstituted quinolinyl. In embodiments, R 7 is unsubstituted isoquinolinyl. In embodiments, R 7 is unsubstituted naphthyridinyl. In embodiments, R 7 is unsubstituted carbazolyl.

[0242] In embodiments, R 7 is hydrogen, halogen, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NHC(O)NR 7B R 7C , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D , -C(O)NR 7B R 7C , -OR 7A , -NR 7B SO2R 7A , -NR 7B C(O)R 7D , -NR 7B C(O)OR 7D, 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. 7 -OR 7A , -C(O)R 7D , -C(O)OR 7D , -C(O)NR 7B R 7C , -SO n7 R 7A , -SO v7 NR 7B R 7C , 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. 7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -CH2C(O)OH, -NHC(O)OH, -NHC(O)OCH3, -NHC(O)OCH2CH3, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)OCH2CH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -NHSO2CH3, -NHSO2CH2CH3, -NHSO2CH(CH3)2, -SON2NH2, -SON2NHCH3, -F, -OH, -CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SON2NH 2、 -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH 3、 -CH2SO2CH3, -(CH2)2SO2CH3, -CH2SO2NH2 or -(CH2)2SO2NH2.

[0243] In embodiments, R 7 is hydrogen. In embodiments, R7 is substituted or unsubstituted alkyl. In embodiments, R 7 is substituted or unsubstituted phenyl. In embodiments, R 7 is —C(O)OH. In embodiments, R 7 is —C(O)OCH. In embodiments, R 7 is —C(O)OCH2CH3. In embodiments, R 7 is —CHC(O)OH. In embodiments, R 7 is —NHC(O)OH. In embodiments, R 7 is —NHC(O)OCH. In embodiments, R 7 is —NHC(O)OCH2CH3. In embodiments, R 7 is —CHC(O)OH. In embodiments, R 7 is —CHC(O)OCH. In embodiments, R 7 is —CHC(O)OCHCH. In embodiments, R 7 is —SO2CH3. In an embodiment, R 7 is —SO2CH2CH3. In an embodiment, R 7 is —SO2CH(CH3)2. In embodiments, R 7 is —NHSO2CH3. In an embodiment, R 7 is —NHSO2CH2CH3. In an embodiment, R 7 is —NHSO2CH(CH3)2. In embodiments, R 7 is —SO 2 NH 2 . In an embodiment, R 7 is —SO 2 NHCH 3 . In an embodiment, R 7 is -F. In an embodiment, R 7 is —OH. In embodiments, R 7 is —CHOH. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is —C(CH)OH. In embodiments, R 7 is —CHSONH. In embodiments, R 7is —(CH)SONH. In embodiments, R 7 is —CHC(O)NH. In embodiments, R 7 is —(CH)C(O)NH. In embodiments, R 7 is —(CH)C(O)NH. In embodiments, R 7 is —CH 2 NHSO 2 CF 3 . In an embodiment, R 7 is —(CH)NHSOCF. In embodiments, R 7 is —(CH)NHSOCF. In embodiments, R 7 is —CH 2 NHSO 2 CH 3 . In an embodiment, R 7 is —(CH)NHSOCH. In embodiments, R 7 is —(CH)NHSOCH. In embodiments, R 7 is —CHSOCH. In embodiments, R 7 is —(CH)SOCH. In an embodiment, R 7 is —CHSONH. In embodiments, R 7 is -(CH2)2SO2NH2.

[0244] In embodiments, R 7is hydrogen, substituted or unsubstituted alkyl, phenyl, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -CH2C(O)OH, -NHC(O)OH, -NHC(O)OCH3, -NHC(O)OCH2CH3, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)OCH2CH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -NHSO2CH3, -NHSO2 CH2CH3, -NHSO2CH(CH3)2, -SO2NH2, -SO2NHCH3, -(CH2)2OH, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH, -(C H2)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, -(CH 2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH(CH3)2, -(CH2)2NH SO2CH3, -(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, or -(CH2)3NHCO2Me.

[0245] In embodiments, R 7 is hydrogen. In embodiments, R 7 is substituted or unsubstituted alkyl. In embodiments, R 7 is substituted or unsubstituted phenyl. In embodiments, R 7 is —C(O)OH. In embodiments, R 7 is —C(O)OCH. In embodiments, R 7is —C(O)OCH2CH3. In embodiments, R 7 is —CHC(O)OH. In embodiments, R 7 is —NHC(O)OH. In embodiments, R 7 is —NHC(O)OCH. In embodiments, R 7 is —NHC(O)OCH2CH3. In embodiments, R 7 is —CHC(O)OH. In embodiments, R 7 is —CHC(O)OCH. In embodiments, R 7 is —CHC(O)OCHCH. In embodiments, R 7 is —SO2CH3. In an embodiment, R 7 is —SO2CH2CH3. In an embodiment, R 7 is —SO2CH(CH3)2. In embodiments, R 7 is —NHSO2CH3. In an embodiment, R 7 is —NHSO2CH2CH3. In an embodiment, R 7 is —NHSO2CH(CH3)2. In embodiments, R 7 is —SO 2 NH 2 . In an embodiment, R 7 is —SO 2 NHCH 3 . In an embodiment, R 7 is —(CH)OH. In embodiments, R 7 is —CHC(CH)OH. In embodiments, R 7 is —(CH)OH. In embodiments, R 7 is —(CH)CH(CH)OH. In embodiments, R 7 is —(CH)SONH. In embodiments, R 7 is —(CH)SONH. In embodiments, R 7 is —(CH)CONH. In an embodiment, R 7 is —(CH)CONH—(CH)CON(H)Me. In an embodiment, R 7 is —(CH)CON(Me). In an embodiment, R 7is —(CH)SOMe. In an embodiment, R 7 is —(CH)SOMe. In an embodiment, R 7 is —CHCH(OH)Me. In embodiments, R 7 is —CHCOH. In an embodiment, R 7 is —(CH)COH. In embodiments, R 7 is —CH(CH)CHCOH. In embodiments, R 7 is —(CH)COH. In embodiments, R 7 is —(CH)SONHCH. In embodiments, R 7 is —(CH)SON(CH). In an embodiment, R 7 is —(CH)SO—(N-morpholinyl). In embodiments, R 7 is —(CH)NHCOCH. In embodiments, R 7 is —(CH)NHCOCH. In embodiments, R 7 is —(CH)NHCOCH(CH). In an embodiment, R 7 is —(CH)NHSOCH. In embodiments, R 7 is —(CH)NHSOCF. In embodiments, R 7 is —(CH)NHSONHCH(CH). In an embodiment, R 7 is —CHCH(CH)CHOH(R and S). In embodiments, R 7 is —CH(CH)(CH)OH. In embodiments, R 7 is —CH—(2-imidazolyl). In embodiments, R 7 is —CH—(4-imidazolyl). In embodiments, R 7 is —CH—(3-pyrazolyl). In embodiments, R 7 is 4-tetrahydropyranyl. In embodiments, R 7 is 3-oxetanyl. In embodiments, R 7 is —(CH)NHCOMe. In an embodiment, R 7is -(CH2)3NHCO2Me.

[0246] In embodiments, R 7 is R 29 In an embodiment, R 7 is R 29 In an embodiment, R 7 is an unsubstituted C1-C6 alkyl. In embodiments, R 7 is R 29 In an embodiment, R 7 is R 29 In an embodiment, R 7 is an unsubstituted C2-C6 alkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted C alkyl. 7 is R 29 In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted C alkyl. 7 is R 29 In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted C alkyl. 7 is R 29 In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted C4 alkyl. 7 are independent, R 29 In embodiments, R 7 is an unsubstituted C4 alkyl. In embodiments, R 7 is R 29 In an embodiment, R is a substituted or unsubstituted C alkyl. 7 are independent, R29 In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R 7 is R 29 In an embodiment, R 7 are independent, R 29 In embodiments, R 7 is an unsubstituted C6 alkyl.

[0247] In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 2-8 membered heteroalkyl. 7 is R 29 In embodiments, R 7 is an unsubstituted 2-8 membered heteroalkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 2-membered heteroalkyl. 7 is R 29 In embodiments, R is a substituted 2-membered heteroalkyl. 7 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 3-membered heteroalkyl. 7 is R 29 In embodiments, R is a substituted 3-membered heteroalkyl. 7 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 4-membered heteroalkyl. 7 is R 29 In embodiments, R is a substituted 4-membered heteroalkyl. 7 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 5-membered heteroalkyl. 7 is R 29 In embodiments, R is a substituted 5-membered heteroalkyl. 7 is an unsubstituted 5-membered heteroalkyl. In embodiments, R7 is R 29 In embodiments, R is a substituted or unsubstituted 6-membered heteroalkyl. 7 is R 29 In embodiments, R is a substituted 6-membered heteroalkyl. 7 is an unsubstituted 6-membered heteroalkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 7-membered heteroalkyl. 7 is R 29 In embodiments, R is a substituted 7-membered heteroalkyl. 7 is an unsubstituted 7-membered heteroalkyl.

[0248] In embodiments, R 7 is R 29 In an embodiment, R is a substituted or unsubstituted C4-C6 cycloalkyl. 7 is R 29 In an embodiment, R 7 is R 29 In an embodiment, R 7 is R 29 In embodiments, R is a substituted or unsubstituted C4 cycloalkyl. 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In one embodiment, R is a substituted or unsubstituted C cycloalkyl. 7 is R 29 In embodiments, R 7 is R 29 It is a substituted C5 cycloalkyl.

[0249] In embodiments, R 7 is R 29 In one embodiment, R is a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. 7 is R 29 In one embodiment, R is a substituted 5- to 6-membered heterocycloalkyl. 7is an unsubstituted 5-6 membered heterocycloalkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 5-membered heterocycloalkyl. 7 is R 29 In embodiments, R is a substituted 5-membered heterocycloalkyl. 7 is an unsubstituted 5-membered heterocycloalkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 6-membered heterocycloalkyl. 7 is R 29 In embodiments, R is a substituted 6-membered heterocycloalkyl. 7 is an unsubstituted 6-membered heterocycloalkyl.

[0250] In embodiments, R 7 are independent, R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is unsubstituted phenyl.

[0251] In embodiments, R 7 is R 29 In an embodiment, R is a substituted or unsubstituted 5- to 6-membered heteroaryl. 7 is R 29 In embodiments, R 7 is an unsubstituted 5-6 membered heteroaryl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 5-membered heteroaryl. 7 is R 29 In embodiments, R 7 is an unsubstituted 5-membered heteroaryl. In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted 6-membered heteroaryl. 7 is R 29 In embodiments, R 7is an unsubstituted 6-membered heteroaryl.

[0252] In embodiments, R 7 is oxo. In embodiments, R 7 is —CF. In embodiments, R 7 is -CHF2. In an embodiment, R 7 is —CHF. In embodiments, R 7 is —SO2CH3. In an embodiment, R 7 is —SO 2 NH 2 . In an embodiment, R 7 is —NHC(O)NH. In embodiments, R 7 is —NH. In embodiments, R 7 is —C(O)OH. In embodiments, R 7 is —C(O)OCH. In embodiments, R 7 is —C(O)NH. In embodiments, R 7 is —OCH. In embodiments, R 7 is —NHSO2CH3. In an embodiment, R 7 is —NHC(O)CH. In embodiments, R 7 is —NHC(O)OH. In embodiments, R 7 is -OCF3. In an embodiment, R 7 is -OCHF. In an embodiment, R 7 is -OCHF. In embodiments, R 7 is hydrogen. In embodiments, R 7 is —OH. In embodiments, R 7 is independently —C(O)OCH2CH3. In embodiments, R 7 is —SO2CH2CH3. In an embodiment, R 7 is —SO2CH2CH2CH3. In an embodiment, R 7 is —SO2CH(CH3)2. In embodiments, R 7 is —C(O)NHCH. In embodiments, R 7 is —C(O)N(CH) In embodiments, R 7is —NHC(O)OCH. In embodiments, R 7 is —NHC(O)OCH2CH3. In embodiments, R 7 is —NHC(O)OCH CH CH. In embodiments, R 7 is —NHC(O)OCH(CH) In an embodiment, R 7 is —NHC(O)CH. In embodiments, R 7 is —NHC(O)CH2CH3. In embodiments, R 7 is —NHC(O)CH CH CH. In embodiments, R 7 is -NHC(O)CH(CH3)2.

[0253] In embodiments, R 29 is oxo. In embodiments, R 29 is —CF. In embodiments, R 29 is -CHF2. In an embodiment, R 29 is —CHF. In embodiments, R 29 is —SO2CH3. In an embodiment, R 29 is —SO 2 NH 2 . In an embodiment, R 29 is —NHC(O)NH. In embodiments, R 29 is —NH. In embodiments, R 29 is —C(O)OH. In embodiments, R 29 is —C(O)OCH. In embodiments, R 29 is —C(O)NH. In embodiments, R 29 is —OCH. In embodiments, R 29 is —NHSO2CH3. In an embodiment, R 29 is —NHC(O)CH. In embodiments, R 29 is —NHC(O)OH. In embodiments, R 29 is -OCF3. In an embodiment, R 29 is -OCHF. In an embodiment, R 29 is -OCHF. In embodiments, R 29 is hydrogen. In embodiments, R 29is —OH. In embodiments, R 29 is —C(O)OCH2CH3. In embodiments, R 29 is —SO2CH2CH3. In an embodiment, R 29 is —SO2CH2CH2CH3. In an embodiment, R 29 is —SO2CH(CH3)2. In embodiments, R 29 is —C(O)NHCH. In embodiments, R 29 is —C(O)N(CH) In embodiments, R 29 is —NHC(O)OCH. In embodiments, R 29 is —NHC(O)OCH2CH3. In embodiments, R 29 is —NHC(O)OCH CH CH. In embodiments, R 29 is —NHC(O)OCH(CH) In an embodiment, R 29 is —NHC(O)CH. In embodiments, R 29 is —NHC(O)CH2CH3. In embodiments, R 29 is —NHC(O)CH CH CH. In embodiments, R 29 is -NHC(O)CH(CH3)2.

[0254] In embodiments, R 29 is R 30 In an embodiment, R 29 is R 30 In an embodiment, R 29 is an unsubstituted C1-C6 alkyl. In embodiments, R 29 is R 30 In an embodiment, R 29 is R 30 In an embodiment, R 29 is an unsubstituted C2-C6 alkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted C alkyl. 29 is R 30In embodiments, R 29 is an unsubstituted C alkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted C alkyl. 29 is R 30 In embodiments, R 29 is an unsubstituted C alkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted C alkyl. 29 is R 30 In embodiments, R 29 is an unsubstituted C alkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted C4 alkyl. 29 is R 30 In embodiments, R 29 is an unsubstituted C4 alkyl. In embodiments, R 29 is R 30 In an embodiment, R is a substituted or unsubstituted C alkyl. 29 is R 30 In embodiments, R 29 is an unsubstituted C alkyl. In embodiments, R 29 is R 30 In an embodiment, R 29 is R 30 In embodiments, R 29 is an unsubstituted C6 alkyl.

[0255] In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 2-8 membered heteroalkyl. 29 is R 30 In embodiments, R 29 is an unsubstituted 2-8 membered heteroalkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 2-membered heteroalkyl.29 is R 30 In embodiments, R is a substituted 2-membered heteroalkyl. 29 is an unsubstituted 2-membered heteroalkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 3-membered heteroalkyl. 29 is R 30 In embodiments, R is a substituted 3-membered heteroalkyl. 29 is an unsubstituted 3-membered heteroalkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 4-membered heteroalkyl. 29 is R 30 In embodiments, R is a substituted 4-membered heteroalkyl. 29 is an unsubstituted 4-membered heteroalkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 5-membered heteroalkyl. 29 is R 30 In embodiments, R is a substituted 5-membered heteroalkyl. 29 is an unsubstituted 5-membered heteroalkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 6-membered heteroalkyl. 29 is R 30 In embodiments, R is a substituted 6-membered heteroalkyl. 29 is an unsubstituted 6-membered heteroalkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 7-membered heteroalkyl. 29 is R 30 In embodiments, R is a substituted 7-membered heteroalkyl. 29 is an unsubstituted 7-membered heteroalkyl.

[0256] In embodiments, R 29 is R 30 In an embodiment, R is a substituted or unsubstituted C4-C6 cycloalkyl. 29 is R 30 In an embodiment, R 29 is R30 In an embodiment, R 29 is R 30 In embodiments, R is a substituted or unsubstituted C4 cycloalkyl. 29 is R 30 In embodiments, R 29 is R 30 In embodiments, R 29 is R 30 In one embodiment, R is a substituted or unsubstituted C cycloalkyl. 29 is R 30 In embodiments, R 29 is R 30 It is a substituted C5 cycloalkyl.

[0257] In embodiments, R 29 is R 30 In one embodiment, R is a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. 29 is R 30 In one embodiment, R is a substituted 5- to 6-membered heterocycloalkyl. 29 is an unsubstituted 5-6 membered heterocycloalkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 5-membered heterocycloalkyl. 29 is R 30 In embodiments, R is a substituted 5-membered heterocycloalkyl. 29 is an unsubstituted 5-membered heterocycloalkyl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 6-membered heterocycloalkyl. 29 is R 30 In embodiments, R is a substituted 6-membered heterocycloalkyl. 29 is an unsubstituted 6-membered heterocycloalkyl.

[0258] In embodiments, R 29 is R 30 In embodiments, R 29 is R 30In embodiments, R 29 is unsubstituted phenyl.

[0259] In embodiments, R 29 is R 30 In an embodiment, R is a substituted or unsubstituted 5- to 6-membered heteroaryl. 29 is R 30 In embodiments, R 29 is an unsubstituted 5-6 membered heteroaryl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 5-membered heteroaryl. 29 is R 30 In embodiments, R 29 is an unsubstituted 5-membered heteroaryl. In embodiments, R 29 is R 30 In embodiments, R is a substituted or unsubstituted 6-membered heteroaryl. 29 is R 30 In embodiments, R 29 is an unsubstituted 6-membered heteroaryl.

[0260] In embodiments, R 7 teeth,

[0261] [ka] In an embodiment, R 7 teeth,

[0262] [ka] In an embodiment, R 7 teeth,

[0263] [ka] In an embodiment, R 7 teeth,

[0264] [ka] In an embodiment, R 7 teeth,

[0265] [ka] In an embodiment, R 7 teeth,

[0266] [ka] In an embodiment, R 7 teeth,

[0267] [ka] In an embodiment, R 7 teeth,

[0268] [ka] In an embodiment, R 7 teeth,

[0269] [ka] In an embodiment, R 7 teeth,

[0270] [ka] In an embodiment, R 7 teeth,

[0271] [ka] In an embodiment, R 7 teeth,

[0272] [ka] In an embodiment, R 7 teeth,

[0273] [ka] In an embodiment, R 7 teeth,

[0274] [ka] In an embodiment, R 7 teeth,

[0275] [ka] In an embodiment, R 7 teeth,

[0276] [ka] In an embodiment, R 7 teeth,

[0277] [ka] In an embodiment, R 7 teeth,

[0278] [ka] In an embodiment, R 7 teeth,

[0279] [ka] In an embodiment, R 7 teeth,

[0280] [ka] In an embodiment, R 7 teeth,

[0281] [ka] In an embodiment, R 7 teeth,

[0282] [ka] In an embodiment, R 7 teeth,

[0283] [ka] In an embodiment, R 7 teeth,

[0284] [ka] In an embodiment, R 7 teeth,

[0285] [ka] In an embodiment, R 7 teeth,

[0286] [ka] In an embodiment, R 7 teeth,

[0287] [ka] In an embodiment, R 7 teeth,

[0288] [ka] In an embodiment, R 7 teeth,

[0289] [ka] In an embodiment, R 7 teeth,

[0290] [ka] In an embodiment, R 7 teeth,

[0291] [ka] In an embodiment, R 7 teeth,

[0292] [ka] In an embodiment, R 7 teeth,

[0293] [ka] In an embodiment, R 7 teeth,

[0294] [ka] In an embodiment, R 7 teeth,

[0295] [ka] In an embodiment, R 7 teeth,

[0296] [ka] In an embodiment, R 7 teeth,

[0297] [ka] In an embodiment, R 7 teeth,

[0298] [ka] In an embodiment, R 7 teeth,

[0299] [ka] In an embodiment, R 7 teeth,

[0300] [ka] In an embodiment, R 7 teeth,

[0301] [ka] In an embodiment, R 7 teeth,

[0302] [ka] In an embodiment, R 7 teeth,

[0303] [ka] In an embodiment, R 7 teeth,

[0304] [ka] In an embodiment, R 7 teeth,

[0305] [ka] In an embodiment, R 7 teeth,

[0306] [ka] In an embodiment, R 7 teeth,

[0307] [ka] In an embodiment, R 7 teeth,

[0308] [ka] In an embodiment, R 7 teeth,

[0309] [ka] In an embodiment, R 7 teeth,

[0310] [ka] In an embodiment, R 7 teeth,

[0311] [ka] In an embodiment, R 7 teeth,

[0312] [ka] In an embodiment, R 7 teeth,

[0313] [ka] is.

[0314] In embodiments, R 7 is oxo. In embodiments, R 7 is —CH3. In an embodiment, R 7 is —COOH. In embodiments, R 7 is —NHC(O)NH. In embodiments, R 7 is —OH. In embodiments, R 7 is —NH. In embodiments, R 7 is -CONH. In an embodiment, R 7 is —NHC(O)OH. In embodiments, R 7 is —SO2CH3. In an embodiment, R 7 is —NHSO2CH3. In an embodiment, R 7 is —SO2CH2CH3. In an embodiment, R 7 is -SO2R 29 In an embodiment, R 7 is —SO2CH(CH3)2. In embodiments, R 7 is -COOEt. In an embodiment, R 7 is —NHCOCH. In embodiments, R 7 is —NHSO2CH(CH3)2. In embodiments, R 7 is —NHCOCH(CH) . In an embodiment, R 7 is -NHCOOCH3. In an embodiment, R 7 is —SO 2 NHCH 3 . In an embodiment, R 7 is -CONHCH3. In an embodiment, R 7 is -CON(CH3)2. In an embodiment, R 7 is —SO 2 NH 2 . In an embodiment, R 7 is unsubstituted morpholinyl. In embodiments, R 7 is unsubstituted imidazolyl. In embodiments, R 7 is unsubstituted thianyl. In embodiments, R 7 is unsubstituted tetrahydropyranyl. In embodiments, R 7is unsubstituted pyrazolyl. In embodiments, R 7 is unsubstituted pyrrolidinyl. In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R is a substituted tetrahydropyranyl. 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is —CH3. In an embodiment, R 7 is unsubstituted methyl. In embodiments, R 7 is unsubstituted ethyl. In embodiments, R 7 is unsubstituted propyl. In embodiments, R 7 is unsubstituted n-propyl. In embodiments, R 7 is unsubstituted isopropyl. In embodiments, R 7 is unsubstituted butyl. In embodiments, R 7 is unsubstituted n-butyl. In embodiments, R 7 is unsubstituted isobutyl. In embodiments, R 7 is unsubstituted tert-butyl. In embodiments, R 7 is unsubstituted pentyl. In embodiments, R 7 is unsubstituted n-pentyl. In embodiments, R 7 is unsubstituted hexyl. In embodiments, R 7 is unsubstituted heptyl. In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 In embodiments, R 7 is R 29 It is a substituted heptyl.

[0315] In embodiments, R 7 is a phosphine oxide moiety. In embodiments, R 7 is an alkylphosphine moiety such as -CH2PO(CH3)2 or -CH2CH2PO(CH3)2.

[0316] In embodiments, R 7 is hydrogen, R 29 Substituted or unsubstituted alkyl, phenyl, -F, -OH, CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SO2NH 2、 -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH 3、 -CH2SO2CH3, -(CH2)2SO2CH3, -CH2SO2NH2, or -(CH2)2SO2NH2.

[0317] In embodiments, R 7 is R 29 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 7 is R 29 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 7 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 7 is unsubstituted C1-C4 alkyl. In embodiments, R 7 is an unsubstituted C1-C3 alkyl. In embodiments, R 7 is an unsubstituted C1-C2 alkyl. In embodiments, R 7 is an unsubstituted C4 alkyl. In embodiments, R 7 is an unsubstituted C alkyl. In embodiments, R 7 is R 29 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 7 is R 29 In an embodiment, R 7 is R 29 In an embodiment, R 7 is R 29 In an embodiment, R 7 is R 29 In embodiments, R 7 is R 29 It is a substituted C3 alkyl.

[0318] In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 7 is R 29In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 7 is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0319] In embodiments, R 7 is R 29 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 7 is R 29 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 7 is unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 7 is unsubstituted C-C cycloalkyl. In embodiments, R 7 is unsubstituted C3-C5 cycloalkyl. In embodiments, R 7 is unsubstituted C-C cycloalkyl. In embodiments, R 7 is an unsubstituted C4 cycloalkyl. In embodiments, R 7 is R 29 In an embodiment, R 7 is R 29 In an embodiment, R 7 is R 29 In an embodiment, R 7 is R 29 It is a substituted C4 cycloalkyl.

[0320] In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).7 is R 29 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 7 is an unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 7 is R 29 In one embodiment, R is a substituted 5- to 6-membered heterocycloalkyl. 7 is R 29 In embodiments, R is a substituted 5-membered heterocycloalkyl. 7 is R 29 It is a substituted 6-membered heterocycloalkyl.

[0321] In embodiments, R 7 is R 29 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 7 is R 29 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 7 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0322] In embodiments, R 7 is R 29 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 7 is R 29 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 7 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0323] In embodiments, R 8 is halogen, -CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 , -CN, -N3, -SO n8 R 8A , -SO v8 NR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(O)NHNR 8B R 8C , -NHC(O)NR 8B R 8C , -N(O) m8 , -NR 8B R 8C , -C(O)R 8D , -C(O)OR 8D , -C(O)NR 8B R 8C , -OR 8A , -NR 8B SO2R 8A , -NR 8B C(O)R 8D , -NR 8B C(O)OR 8D , -NR 8B OR 8D , -OCX 8.1 3. -OCHX 8.1 2, -OCH2X 8.1 , 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. 8 is hydrogen.

[0324] In embodiments, R 8 is halogen, -CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 , -CN, -N3, -SO n8 R 8A , -SO v8 NR8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(O)NHNR 8B R 8C , -NHC(O)NR 8B R 8C , -N(O) m8 , -NR 8B R 8C , -C(O)R 8D , -C(O)OR 8D , -C(O)NR 8B R 8C , -OR 8A , -NR 8B SO2R 8A , -NR 8B C(O)R 8D , -NR 8B C(O)OR 8D , -NR 8B OR 8D , -OCX 8.1 3. -OCHX 8.1 2, -OCH2X 8.1 , R 32 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 32 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 32 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 32 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 32 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 32 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0325] In embodiments, R 8 is R 32 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 8 is R 32 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 8 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0326] In embodiments, R 8 is R 32 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 8 is R 32 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 8 is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0327] In embodiments, R 8 is R 32 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 8 is R 32 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 8 is unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0328] In embodiments, R 8 is R 32In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 8 is R 32 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 8 is an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0329] In embodiments, R 8 is R 32 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 8 is R 32 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 8 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0330] In embodiments, R 8 is R 32 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 8 is R 32 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 8 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0331] In embodiments, R 9 is halogen, -CX 9.13. -CHX 9.1 2. -CH2X 9.1 , -CN, -N3, -SO n9 R 9A , -SO v9 NR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(O)NHNR 9B R 9C , -NHC(O)NR 9B R 9C , -N(O) m9 , -NR 9B R 9C , -C(O)R 9D , -C(O)OR 9D , -C(O)NR 9B R 9C , -OR 9A , -NR 9B SO2R 9A , -NR 9B C(O)R 9D , -NR 9B C(O)OR 9D , -NR 9B OR 9D , -OCX 9.1 3. -OCHX 9.1 2, -OCH2X 9.1 , 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. 9 is hydrogen.

[0332] In embodiments, R 9 is halogen, -CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 , -CN, -N3, -SO n9 R 9A , -SO v9 NR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R9C , -NHC(O)NHNR 9B R 9C , -NHC(O)NR 9B R 9C , -N(O) m9 , -NR 9B R 9C , -C(O)R 9D , -C(O)OR 9D , -C(O)NR 9B R 9C , -OR 9A , -NR 9B SO2R 9A , -NR 9B C(O)R 9D , -NR 9B C(O)OR 9D , -NR 9B OR 9D , -OCX 9.1 3. -OCHX 9.1 2, -OCH2X 9.1 , R 35 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 35 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 35 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 35 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 35 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 35 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0333] In embodiments, R 9 is R 35and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 9 is R 35 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 9 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0334] In embodiments, R 9 is R 35 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 9 is R 35 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 9 is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0335] In embodiments, R 9 is R 35 and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 9 is R 35 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 9 is unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0336] In embodiments, R 9 is R 35 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).9 is R 35 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 9 is an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0337] In embodiments, R 9 is R 35 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 9 is R 35 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 9 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0338] In embodiments, R 9 is R 35 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 9 is R 35 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 9 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0339] In embodiments, R 9 are hydrogen, -CN, halogens, -CF3, -COOH, -COOCH2CH3,

[0340] [ka] In an embodiment, R 9 is hydrogen. In embodiments, R 9 is -CN. In embodiments, R 9 is halogen. In embodiments, R 9 is -F. In an embodiment, R 9 is —Cl. In embodiments, R 9 is -Br. In embodiments, R 9 is -I. In an embodiment, R 9 is —CF. In embodiments, R 9 is —COOH. In embodiments, R 9 is -COOCH2CH3. In an embodiment, R 9 is —CH3. In an embodiment, R 9 is -CHCHCHOH. In embodiments, R 9 teeth,

[0341] [ka] In an embodiment, R 9 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 9 is a substituted C1-C4 alkyl. In embodiments, R 9 is unsubstituted C1-C4 alkyl.

[0342] In embodiments, R 9 are halogens, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 9D , -C(O)OR 9D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl. In embodiments, R 9 are halogens, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 9D , -C(O)OR 9D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl.

[0343] In embodiments, R9 is R 35 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 9 is R 35 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 9 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0344] In embodiments, R 9 is R 35 In embodiments, R 9 is R 35 In embodiments, R is a substituted or unsubstituted C alkyl. 9 is R 35 In embodiments, R is a substituted or unsubstituted C alkyl. 9 is R 35 In embodiments, R is a substituted or unsubstituted C4 alkyl. 9 is R 35 In an embodiment, R is a substituted or unsubstituted C alkyl. 9 is R 35 In an embodiment, R 9 is R 35 In embodiments, R is a substituted or unsubstituted C alkyl. 9 is R 35 In embodiments, R is a substituted or unsubstituted C alkyl. 9 is R 35 In embodiments, R 9 is R 35 In embodiments, R 9 is R 35 In embodiments, R 9 is R 35 In embodiments, R 9 is R 35 In embodiments, R 9 is R 35 In embodiments, R9 is R 35 In embodiments, R 9 is R 35 In embodiments, R 9 is unsubstituted methyl. In embodiments, R 9 is an unsubstituted C alkyl. In embodiments, R 9 is an unsubstituted C alkyl. In embodiments, R 9 is an unsubstituted C4 alkyl. In embodiments, R 9 is an unsubstituted C alkyl. In embodiments, R 9 is an unsubstituted C alkyl. In embodiments, R 9 is an unsubstituted C7 alkyl. In embodiments, R 9 is an unsubstituted C8 alkyl.

[0345] In embodiments, X 2 is CR 9 and;R 9 is hydrogen, -CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 , —CN, or substituted or unsubstituted C1-C4 alkyl. 2 is CR 9 and R 9 is hydrogen. In an embodiment, X 2 is CR 9 and R 9 is CX 9.1 3. In an embodiment, X 2 is CR 9 and R 9 Ha-CHX 9.1 2. In an embodiment, X 2 is CR 9 and R 9 Ha-CH2X 9.1 In an embodiment, X 2 is CR 9 and R 9 is -CN. In embodiments, X 2 is CR 9 and R 9 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R9 is hydrogen, —CF 3 , or unsubstituted methyl.

[0346] In embodiments, R 4 and R 9 are optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), a substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0347] In embodiments, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted C5-C7 cycloalkyl. 4 and R 9 may be optionally linked to form a substituted C5-C7 cycloalkyl. 4 and R 9 may be optionally linked to form an unsubstituted C5-C7 cycloalkyl.

[0348] In embodiments, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted 5- to 7-membered heterocycloalkyl. In embodiments, R 4 and R 9 may be optionally linked to form a substituted 5- to 7-membered heterocycloalkyl. 4 and R 9 can be optionally linked to form an unsubstituted 5- to 7-membered heterocycloalkyl.

[0349] In embodiments, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted phenyl. In embodiments, R4 and R 9 may be optionally linked to form a substituted phenyl. In embodiments, R 4 and R 9 may be optionally linked to form an unsubstituted phenyl.

[0350] In embodiments, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted 5- to 7-membered heteroaryl. 4 and R 9 may be optionally linked to form a substituted 5- to 7-membered heteroaryl. 4 and R 9 may be optionally linked to form an unsubstituted 5- to 7-membered heteroaryl. 4 and R 9 may be optionally linked to form a substituted or unsubstituted 5-6 membered heteroaryl. 4 and R 9 may be optionally linked to form a substituted 5-6 membered heteroaryl. 4 and R 9 can be optionally linked to form an unsubstituted 5- to 6-membered heteroaryl.

[0351] In embodiments, R 4 and R 9 can be arbitrarily connected to form R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 20 It can form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4 and R9 may be optionally linked to form an unsubstituted phenyl. In embodiments, R 4 and R 9 may optionally be linked to form an unsubstituted C5 cycloalkyl. In embodiments, R 4 and R 9 may optionally be linked to form an unsubstituted C6 cycloalkyl. In embodiments, R 4 and R 9 can be optionally linked to form an unsubstituted thienyl.

[0352] In embodiments, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 4 and R 9 may be optionally linked to form a substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 4 and R 9 can be arbitrarily connected to form R 20 It can form a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 4 and R 9 can be arbitrarily connected to form R 20 It may form a substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). In embodiments, R 4 and R 9 can be optionally linked to form an unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0353] In embodiments, R 4 and R 9may be optionally linked to form a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 4 and R 9 may be optionally linked to form a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 4 and R 9 can be arbitrarily concatenated to form R 20 It can form a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). In embodiments, R 4 and R 9 can be arbitrarily concatenated to form R 20 Substituted heterocycloalkyls (e.g., 3- to 8-membered heterocycloalkyls, 3- to 6-membered heterocycloalkyls, or 5- to 6-membered heterocycloalkyls) may be formed. In embodiments, R 4 and R 9 can be optionally linked to form an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0354] In embodiments, R 4 and R 9 are optionally linked to a substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 4 and R 9 are optionally linked to a substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 4 and R 9 can be arbitrarily connected to form R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R4 and R 9 can be arbitrarily connected to form R 20 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 4 and R 9 are optionally linked to an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0355] In embodiments, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4 and R 9 may be optionally linked to form a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4 and R 9 can be arbitrarily connected to form R 20 It can form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4 and R 9 can be arbitrarily connected to form R 20 A substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl) may be formed. 4 and R 9 can be optionally linked to form an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0356] In embodiments, X 2 is CR 9 and R 4 and R 9may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 4 and R 9 are joined to form a substituted or unsubstituted C5-C7 cycloalkyl, a substituted or unsubstituted 5- to 7-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. 4 and R 9 are joined to form an unsubstituted C5-C7 cycloalkyl, an unsubstituted 5-7 membered heterocycloalkyl, an unsubstituted phenyl, or an unsubstituted 5-6 membered heteroaryl. 4 and R 9 are linked to form an unsubstituted C5 cycloalkyl, an unsubstituted thienyl, or an unsubstituted phenyl.

[0357] In embodiments, ring A is selected from the group consisting of substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0358] In embodiments, Ring A is substituted or unsubstituted (C5-C7)cycloalkyl. In embodiments, Ring A is substituted C5-C7 cycloalkyl. In embodiments, Ring A is unsubstituted C5-C7 cycloalkyl.

[0359] In embodiments, ring A is a substituted or unsubstituted 5-7 membered heterocycloalkyl. In embodiments, ring A is a substituted 5-7 membered heterocycloalkyl. In embodiments, ring A is an unsubstituted 5-7 membered heterocycloalkyl.

[0360] In embodiments, Ring A is substituted or unsubstituted phenyl. In embodiments, Ring A is substituted phenyl. In embodiments, Ring A is unsubstituted phenyl.

[0361] In embodiments, ring A is a substituted or unsubstituted 5- to 7-membered heteroaryl. In embodiments, ring A is a substituted 5- to 7-membered heteroaryl. In embodiments, ring A is an unsubstituted 5- to 7-membered heteroaryl. In embodiments, ring A is a substituted or unsubstituted 5- to 6-membered heteroaryl. In embodiments, ring A is a substituted 5- to 6-membered heteroaryl. In embodiments, ring A is an unsubstituted 5- to 6-membered heteroaryl.

[0362] In embodiments, ring A is R 20 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 20 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 20 In embodiments, Ring A is unsubstituted phenyl. In embodiments, Ring A is unsubstituted C5 cycloalkyl. In embodiments, Ring A is unsubstituted C6 cycloalkyl. In embodiments, Ring A is unsubstituted thienyl.

[0363] In embodiments, ring A is substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, ring A is substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, ring A is R20 In an embodiment, ring A is substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 20 In an embodiment, Ring A is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0364] In embodiments, ring A is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). In embodiments, ring A is a ... or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 20 In an embodiment, ring A is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 20 In an embodiment, ring A is an unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0365] In embodiments, ring A is a substituted or unsubstituted aryl (e.g., C-C 10 Aryl, C 10 In embodiments, ring A is a substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, ring A is R 20 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, ring A is R20 Substituted aryl (e.g., C6-C 10 Aryl, C 10 In embodiments, ring A is an unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl).

[0366] In embodiments, ring A is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In embodiments, ring A is a ... 20 In an embodiment, ring A is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 20 In an embodiment, ring A is an unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0367] In embodiments, ring A is substituted (e.g., R 20 In embodiments, Ring A is substituted (e.g., R 20In embodiments, Ring A is substituted (e.g., R 20 substituted) or unsubstituted indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolopyrimidinyl, purinyl, indolizinyl, pyrrolopyriazinyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridopyrazinyl, pteridinyl, pyrazolopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, or carbazolyl.

[0368] In embodiments, R 9 and R 10 are optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), a substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0369] In embodiments, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted C5-C7 cycloalkyl. 9 and R 10 may be optionally linked to form a substituted C5-C7 cycloalkyl. 9 and R 10may be optionally linked to form an unsubstituted C5-C7 cycloalkyl.

[0370] In embodiments, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted 5- to 7-membered heterocycloalkyl. In embodiments, R 9 and R 10 may be optionally linked to form a substituted 5- to 7-membered heterocycloalkyl. 9 and R 10 can be optionally linked to form an unsubstituted 5- to 7-membered heterocycloalkyl.

[0371] In embodiments, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted phenyl. In embodiments, R 9 and R 10 may be optionally linked to form a substituted phenyl. In embodiments, R 9 and R 10 may be optionally linked to form an unsubstituted phenyl.

[0372] In embodiments, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted 5- to 7-membered heteroaryl. 9 and R 10 may be optionally linked to form a substituted 5- to 7-membered heteroaryl. 9 and R 10 may be optionally linked to form an unsubstituted 5- to 7-membered heteroaryl. 9 and R 10 may be optionally linked to form a substituted or unsubstituted 5-6 membered heteroaryl. 9 and R 10 may be optionally linked to form a substituted 5-6 membered heteroaryl. 9 and R 10 can be optionally linked to form an unsubstituted 5- to 6-membered heteroaryl.

[0373] In embodiments, R9 and R 10 can be arbitrarily connected to form R 35 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 35 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 35 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 35 It can form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 9 and R 10 may be optionally linked to form an unsubstituted phenyl. In embodiments, R 9 and R 10 may optionally be linked to form an unsubstituted C5 cycloalkyl. In embodiments, R 9 and R 10 may optionally be linked to form an unsubstituted C6 cycloalkyl. In embodiments, R 9 and R 10 can be optionally linked to form an unsubstituted thienyl.

[0374] In embodiments, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 9 and R 10 may be optionally linked to form a substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 9 and R 10 can be arbitrarily connected to form R 35It can form a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R 9 and R 10 can be arbitrarily connected to form R 35 It may form a substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). In embodiments, R 9 and R 10 can be optionally linked to form an unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0375] In embodiments, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 9 and R 10 may be optionally linked to form a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 9 and R 10 can be arbitrarily connected to form R 35 It can form a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). In embodiments, R 9 and R 10 can be arbitrarily connected to form R 35 Substituted heterocycloalkyls (e.g., 3- to 8-membered heterocycloalkyls, 3- to 6-membered heterocycloalkyls, or 5- to 6-membered heterocycloalkyls) may be formed. In embodiments, R 9 and R 10 can be optionally linked to form an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0376] In embodiments, R 9 and R 10 are optionally linked to a substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 9 and R 10 are optionally linked to a substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 9 and R 10 can be arbitrarily connected to form R 35 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 9 and R 10 can be arbitrarily connected to form R 35 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 9 and R 10 are optionally linked to an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0377] In embodiments, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 9 and R 10 may be optionally linked to form a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 9 and R 10 can be arbitrarily connected to form R 35 It can form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 9and R 10 can be arbitrarily connected to form R 35 A substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl) may be formed. 9 and R 10 can be optionally linked to form an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0378] In embodiments, R 10 is halogen, -CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 , -CN, -N3, -SO n10 R 10A , -SO v10 NR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(O) m10 , -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO2R 10A , -NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10.1 3. -OCHX 10.1 2, -OCH2X 10.1, 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. 10 is hydrogen.

[0379] In embodiments, R 10 is halogen, -CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 , -CN, -N3, -SO n10 R 10A , -SO v10 NR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(O) m10 , -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO2R 10A , -NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10.1 3. -OCHX 10.1 2, -OCH2X 10.1 , R 38 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 38 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 38substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 38 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 38 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or R 38 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0380] In embodiments, R 10 is R 38 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 10 is R 38 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 10 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0381] In embodiments, R 10 is R 38 In embodiments, R is a substituted or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 10 is R 38 In embodiments, R is a substituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). 10 is an unsubstituted heteroalkyl (eg, a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl).

[0382] In embodiments, R 10 is R 38and substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 10 is R 38 substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). 10 is unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0383] In embodiments, R 10 is R 38 In embodiments, R is a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 10 is R 38 In embodiments, R is a substituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). 10 is an unsubstituted heterocycloalkyl (eg, a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0384] In embodiments, R 10 is R 38 Substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 10 is R 38 Substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 10 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0385] In embodiments, R 10 is R 38In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 10 is R 38 In embodiments, R is a substituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 10 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0386] In embodiments, R 10 are hydrogen, -CN, halogens, -CF3, -COOH, -COOCH2CH3,

[0387] [ka] In an embodiment, R 10 is hydrogen. In embodiments, R 10 is -CN. In embodiments, R 10 is halogen. In embodiments, R 10 is -F. In an embodiment, R 10 is —Cl. In embodiments, R 10 is -Br. In embodiments, R 10 is -I. In an embodiment, R 10 is —CF. In embodiments, R 10 is —COOH. In embodiments, R 10 is -COOCH2CH3. In an embodiment, R 10 is —CH3. In an embodiment, R 10 is -CHCHCHOH. In embodiments, R 10 teeth,

[0388] [ka] In an embodiment, R 10 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 10is a substituted C1-C4 alkyl. In embodiments, R 10 is unsubstituted C1-C4 alkyl.

[0389] In embodiments, R 10 are halogens, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 10D , -C(O)OR 10D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl. In embodiments, R 10 are halogens, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 10D , -C(O)OR 10D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl.

[0390] In embodiments, R 10 is R 38 and substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 10 is R 38 In embodiments, R is a substituted alkyl (e.g., a C1-C8 alkyl, a C1-C6 alkyl, or a C1-C4 alkyl). 10 is unsubstituted alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0391] In embodiments, R 10 is R 38 In embodiments, R 10 is R 38 In embodiments, R is a substituted or unsubstituted C alkyl. 10 is R 38 In embodiments, R is a substituted or unsubstituted C alkyl. 10 is R 38 In embodiments, R is a substituted or unsubstituted C4 alkyl. 10 is R 38 In an embodiment, R is a substituted or unsubstituted C alkyl. 10 is R 38In an embodiment, R 10 is R 38 In embodiments, R is a substituted or unsubstituted C alkyl. 10 is R 38 In embodiments, R is a substituted or unsubstituted C alkyl. 10 is R 38 In embodiments, R 10 is R 38 In embodiments, R 10 is R 38 In embodiments, R 10 is R 38 In embodiments, R 10 is R 38 In embodiments, R 10 is R 38 In embodiments, R 10 is R 38 In embodiments, R 10 is R 38 In embodiments, R 10 is unsubstituted methyl. In embodiments, R 10 is an unsubstituted C alkyl. In embodiments, R 10 is an unsubstituted C alkyl. In embodiments, R 10 is an unsubstituted C4 alkyl. In embodiments, R 10 is an unsubstituted C alkyl. In embodiments, R 10 is an unsubstituted C alkyl. In embodiments, R 10 is an unsubstituted C7 alkyl. In embodiments, R 10 is an unsubstituted C8 alkyl.

[0392] In embodiments, X 3 is CR 10 and;R 10 is hydrogen, -CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 , —CN, or substituted or unsubstituted C1-C4 alkyl.3 is CR 10 and R 10 is hydrogen. In an embodiment, X 3 is CR 10 and R 10 Ha-CX 10.1 3. In an embodiment, X 3 is CR 10 and R 10 Ha-CHX 10.1 2. In an embodiment, X 3 is CR 10 and R 10 Ha-CH2X 10.1 In an embodiment, X 3 is CR 10 and R 10 is -CN. In embodiments, X 3 is CR 10 and R 10 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 10 is hydrogen or —CN.

[0393] In an embodiment, L 7 is a bond, -O-, -S-, -NR 7.2B -, -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-C 10 Arylene, C 10 arylene, or phenylene), or substituted or unsubstituted heteroarylene (for example, 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene).

[0394] In an embodiment, L 7 is a bond, -O-, -S-, -NR 7.2B -, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, R 41 substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), R 41 substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene), R 41 substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene), R 41 substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene), R 41 Substituted or unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 arylene, or phenylene), or R 41 and substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene). 7 is a bond. In embodiments, L 7 is a bond, -O-, -S-, -NH-, -C(O)-, -C(O)O-, -S(O)-, -S(O)-2-, R 41 substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene), R 41 substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene), or R 41 It is a substituted or unsubstituted cycloalkylene (for example, C3 to C8 cycloalkylene, C3 to C6 cycloalkylene, or C5 to C6 cycloalkylene).

[0395] In an embodiment, L 7 is R 41and substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). 7 is R 41 substituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). 7 is unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). 7 L 41 In embodiments, L is a substituted or unsubstituted methylene. 7 L 41 In embodiments, L is a substituted or unsubstituted C alkylene. 7 L 41 In embodiments, L is a substituted or unsubstituted C alkylene. 7 L 41 In one embodiment, L is a substituted or unsubstituted C4 alkylene. 7 L 41 In one embodiment, L is a substituted or unsubstituted C alkylene. 7 L 41 In one embodiment, L is a substituted or unsubstituted C alkylene. 7 L 41 In embodiments, L is a substituted or unsubstituted C7 alkylene. 7 L 41 In one embodiment, L is a substituted or unsubstituted C alkylene. 7 L 41 In embodiments, L 7 L 41 In embodiments, L is a substituted C alkylene. 7 L 41 In embodiments, L is a substituted C alkylene. 7 L 41 In embodiments, L is a substituted C4 alkylene. 7 L 41 In embodiments, L is a substituted C alkylene. 7 L 41 In one embodiment, L is a substituted C alkylene. 7 L 41In embodiments, L is a substituted C7 alkylene. 7 L 41 In embodiments, L is a substituted C alkylene. 7 is unsubstituted methylene. In embodiments, L 7 is an unsubstituted C alkylene. In embodiments, L 7 is an unsubstituted C alkylene. In embodiments, L 7 is an unsubstituted C4 alkylene. In embodiments, L 7 is an unsubstituted C5 alkylene. In embodiments, L 7 is an unsubstituted C alkylene. In embodiments, L 7 is an unsubstituted C7 alkylene. 7 is an unsubstituted C8 alkylene.

[0396] In an embodiment, L 7 is R 41 and substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene). 7 is R 41 In embodiments, L is a substituted heteroalkylene (e.g., a 2- to 8-membered heteroalkylene, a 2- to 6-membered heteroalkylene, or a 2- to 4-membered heteroalkylene). 7 is unsubstituted heteroalkylene (eg, 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene).

[0397] In an embodiment, L 7 is R 41 and substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). 7 is R 41 substituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). 7is unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). 7 is R 41 In one embodiment, L is a substituted or unsubstituted C3-C8 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted or unsubstituted C4-C8 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted or unsubstituted C4-C6 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted or unsubstituted C4 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted or unsubstituted C5 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted or unsubstituted C6 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted C3-C8 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted C4-C8 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted C4-C6 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted C4 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted C5 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted C6 cycloalkylene. 7 is unsubstituted C3-C8 cycloalkylene. 7 is unsubstituted C4-C8 cycloalkylene. 7 is an unsubstituted C4-C6 cycloalkylene. 7 is an unsubstituted C4 cycloalkylene. In embodiments, L 7 is an unsubstituted C5 cycloalkylene. In embodiments, L 7 is an unsubstituted C6 cycloalkylene.

[0398] In an embodiment, L 7 is R 41 and substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene). 7 is R 41 In embodiments, L is a substituted heterocycloalkylene (e.g., a 3- to 8-membered heterocycloalkylene, a 3- to 6-membered heterocycloalkylene, or a 5- to 6-membered heterocycloalkylene). 7 is an unsubstituted heterocycloalkylene (eg, a 3- to 8-membered heterocycloalkylene, a 3- to 6-membered heterocycloalkylene, or a 5- to 6-membered heterocycloalkylene).

[0399] In an embodiment, L 7 is R 41 Substituted or unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 arylene, or phenylene). 7 is R 41 Substituted arylene (e.g., C6-C 10 Arylene, C 10 In one embodiment, L is an alkylene or aryl group. 7 is an unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 arylene, or phenylene).

[0400] In an embodiment, L 7 is R 41 and substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene). 7 is R 41 In embodiments, L is a substituted heteroarylene (e.g., a 5- to 10-membered heteroarylene, a 5- to 9-membered heteroarylene, or a 5- to 6-membered heteroarylene). 7is unsubstituted heteroarylene (for example, 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene).

[0401] In an embodiment, L 7 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted cycloalkylene. 7 is a substituted or unsubstituted C4-C6 cycloalkylene. 7 is an unsubstituted C4-C6 cycloalkylene. 7 is substituted or unsubstituted cyclobutylene. In embodiments, L 7 is a substituted or unsubstituted alkylene. 7 is a substituted or unsubstituted C1-C6 alkylene. 7 is a bond.

[0402] In an embodiment, L 7 is R 41 In an embodiment, L is a substituted or unsubstituted C1-C6 alkylene. 7 is R 41 In an embodiment, L is a substituted C1-C6 alkylene. 7 is unsubstituted C1-C6 alkylene. 7 is R 41 It is a substituted or unsubstituted C2-C6 alkylene. 7 is R 41 In an embodiment, L is a substituted C2-C6 alkylene. 7 is an unsubstituted C2-C6 alkylene. 7 is R 41 In embodiments, L is a substituted or unsubstituted C alkylene. 7 is R 41 In embodiments, L is a substituted C alkylene. 7 is an unsubstituted C alkylene. In embodiments, L 7 is R 41 In embodiments, L is a substituted or unsubstituted C alkylene. 7 is R 41In embodiments, L is a substituted C alkylene. 7 is an unsubstituted C alkylene. In embodiments, L 7 is R 41 In embodiments, L is a substituted or unsubstituted C alkylene. 7 is R 41 In embodiments, L is a substituted C alkylene. 7 is an unsubstituted C alkylene. In embodiments, L 7 is R 41 In one embodiment, L is a substituted or unsubstituted C4 alkylene. 7 is R 41 In embodiments, L is a substituted C4 alkylene. 7 is an unsubstituted C4 alkylene. In embodiments, L 7 is R 41 In one embodiment, L is a substituted or unsubstituted C alkylene. 7 is R 41 In embodiments, L is a substituted C alkylene. 7 is an unsubstituted C5 alkylene. In embodiments, L 7 is R 41 In one embodiment, L is a substituted or unsubstituted C alkylene. 7 is R 41 In one embodiment, L is a substituted C alkylene. 7 is an unsubstituted C6 alkylene.

[0403] In an embodiment, L 7 is R 41 In one embodiment, L is a substituted or unsubstituted 2- to 8-membered heteroalkylene. 7 is R 41 In one embodiment, L is a substituted 2-8 membered heteroalkylene. 7 is unsubstituted 2-8 membered heteroalkylene. 7 is R 41 In embodiments, L is a substituted or unsubstituted 2-membered heteroalkylene. 7 is R 41 In some embodiments, L is a substituted 2-membered heteroalkylene. 7 is an unsubstituted 2-membered heteroalkylene. In embodiments, L 7 is R 41In embodiments, L is a substituted or unsubstituted 3-membered heteroalkylene. 7 is R 41 In embodiments, L is a substituted 3-membered heteroalkylene. 7 is an unsubstituted 3-membered heteroalkylene. 7 is R 41 In embodiments, L is a substituted or unsubstituted 4-membered heteroalkylene. 7 is R 41 In embodiments, L is a substituted 4-membered heteroalkylene. 7 is an unsubstituted 4-membered heteroalkylene. In embodiments, L 7 is R 41 In one embodiment, L is a substituted or unsubstituted 5-membered heteroalkylene. 7 is R 41 In embodiments, L is a substituted 5-membered heteroalkylene. 7 is an unsubstituted 5-membered heteroalkylene. In embodiments, L 7 is R 41 In one embodiment, L is a substituted or unsubstituted 6-membered heteroalkylene. 7 is R 41 In embodiments, L is a substituted 6-membered heteroalkylene. 7 is an unsubstituted 6-membered heteroalkylene. In embodiments, L 7 is R 41 Substituted or unsubstituted 7 In one embodiment, L is a membered heteroalkylene. 7 is R 41 replacement 7 In one embodiment, L is a membered heteroalkylene. 7 is a non-permutation 7 It is a membered heteroalkylene.

[0404] In an embodiment, L 7 is R 41 In one embodiment, L is a substituted or unsubstituted C4-C6 cycloalkylene. 7 is R 41 In one embodiment, L is a substituted C4-C6 cycloalkylene. 7 is ...

Claims

1. Structural formula (I): 【Chemistry 1】 A compound having, or a pharmaceutically acceptable salt thereof, wherein, X １ CR ８ or N, X ２ CR ９ or N, X ３ CR １０ or N, X １ , X ２ and X ３ at least one of which is N, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independent integers between 0 and 4. m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9, v10, and v44 are independently 1 or 2. z1 is an integer between 0 and 5. z2 is an integer between 0 and 4. z3 is an integer between 0 and 11. z4 is an integer between 0 and 2. z5 is an integer between 1 and 2. L ７ The bonds are -O-, -S-, and -NR. ７．２Ｂ -, -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, R １ Hydrogen, halogen, -CX １．１ ３ EN-CHX １．１ ２ ien-CH ２ X １．１ -CN, -N ３ , -SO ｎ１ R １Ａ , -SO ｖ１ NR １Ｂ R １Ｃ ,-NHNR １Ｂ R １Ｃ , -ONR １Ｂ R １Ｃ , -NHC(O)NHNR １Ｂ R １Ｃ , -NHC(O)NR １Ｂ R １Ｃ , -N(O) ｍ１ , -NR １Ｂ R １Ｃ , -C(O)R １Ｄ , -C(O)OR １Ｄ , -C(O)NR １Ｂ R １Ｃ , -OR １Ａ , -NR １Ｂ SO ２ R １Ａ , -NR １Ｂ C(O)R １Ｄ , -NR １Ｂ C(O)OR １Ｄ , -NR １Ｂ OR １Ｄ , -OCX １．１ ３ , -OCHX １．１ ２ , -OCH ２ X １．１ , 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, R ２ is hydrogen, halogen, -CX ２．１ ３ , -CHX ２．１ ２ , -CH ２ X ２．１ , -CN, -N ３ , -SO ｎ２ R ２Ａ , -SO ｖ２ NR ２Ｂ R ２Ｃ , -NHNR ２Ｂ R ２Ｃ , -ONR ２Ｂ R ２Ｃ , -NHCO-NHNR ２Ｂ R ２Ｃ , -NHCONR ２Ｂ R ２Ｃ , -N(O) ｍ２ , -NR ２Ｂ R ２Ｃ , -COR ２Ｄ , -COOR ２Ｄ , -CONR ２Ｂ R ２Ｃ , -OR ２Ａ , -NR ２Ｂ SO ２ R ２Ａ , -NR ２Ｂ COR ２Ｄ , -NR ２Ｂ COOR ２Ｄ , -NR ２Ｂ OR ２Ｄ , -OCX ２．１ ３ , -OCHX ２．１ ２ , -OCH ２ X ２．１ is 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, R ３ These are independently halogen, -CX ３．１ ３ EN-CHX ３．１ ２ ien-CH ２ X ３．１ -CN, -N ３ , -SO ｎ３ R ３Ａ , -SO ｖ３ NR ３Ｂ R ３Ｃ ,-NHNR ３Ｂ R ３Ｃ , -ONR ３Ｂ R ３Ｃ , -NHC(O)NHNR ３Ｂ R ３Ｃ , -NHC(O)NR ３Ｂ R ３Ｃ , -N(O) ｍ３ , -NR ３Ｂ R ３Ｃ , -C(O)R ３Ｄ , -C(O)OR ３Ｄ , -C(O)NR ３Ｂ R ３Ｃ , -OR ３Ａ , -NR ３Ｂ SO ２ R ３Ａ , -NR ３Ｂ C(O)R ３Ｄ , -NR ３Ｂ C(O)OR ３Ｄ , -NR ３Ｂ OR ３Ｄ , -OCX ３．１ ３ , -OCHX ３．１ ２ , -OCH ２ X ３．１ , 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, R ４ Hydrogen, halogen, -CX ４．１ ３ EN-CHX ４．１ ２ ien-CH ２ X ４．１ -CN, -N ３ , -SO ｎ４ R ４Ａ , -SO ｖ４ NR ４Ｂ R ４Ｃ ,-NHNR ４Ｂ R ４Ｃ , -ONR ４Ｂ R ４Ｃ , -NHC(O)NHNR ４Ｂ R ４Ｃ , -NHC(O)NR ４Ｂ R ４Ｃ , -N(O) ｍ４ , -NR ４Ｂ R ４Ｃ , -C(O)R ４Ｄ , -C(O)OR ４Ｄ , -C(O)NR ４Ｂ R ４Ｃ , -OR ４Ａ , -NR ４Ｂ SO ２ R ４Ａ , -NR ４Ｂ C(O)R ４Ｄ , -NR ４Ｂ C(O)OR ４Ｄ , -NR ４Ｂ OR ４Ｄ , -OCX ４．１ ３ , -OCHX ４．１ ２ , -OCH ２ X ４．１ , 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, or X ２ CR ９ If R ４ and R ９ These can be arbitrarily linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ５ These are halogen, oxo, and -CX, independently. ５．１ ３ EN-CHX ５．１ ２ ien-CH ２ X ５．１ -CN, -N ３ , -SO ｎ５ R ５Ａ , -SO ｖ５ NR ５Ｂ R ５Ｃ ,-NHNR ５Ｂ R ５Ｃ , -ONR ５Ｂ R ５Ｃ , -NHC(O)NHNR ５Ｂ R ５Ｃ , -NHC(O)NR ５Ｂ R ５Ｃ , -N(O) ｍ５ , -NR ５Ｂ R ５Ｃ , -C(O)R ５Ｄ , -C(O)OR ５Ｄ , -C(O)NR ５Ｂ R ５Ｃ , -OR ５Ａ , -NR ５Ｂ SO ２ R ５Ａ , -NR ５Ｂ C(O)R ５Ｄ , -NR ５Ｂ C(O)OR ５Ｄ , -NR ５Ｂ OR ５Ｄ , -OCX ５．１ ３ , -OCHX ５．１ ２ , -OCH ２ X ５．１ , 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, R ６ These are halogen, oxo, and -CX, independently. ６．１ ３ EN-CHX ６．１ ２ ien-CH ２ X ６．１ -CN, -N ３ , -SO ｎ６ R ６Ａ , -SO ｖ６ NR ６Ｂ R ６Ｃ ,-NHNR ６Ｂ R ６Ｃ , -ONR ６Ｂ R ６Ｃ , -NHC(O)NHNR ６Ｂ R ６Ｃ , -NHC(O)NR ６Ｂ R ６Ｃ , -N(O) ｍ６ , -NR ６Ｂ R ６Ｃ , -C(O)R ６Ｄ , -C(O)OR ６Ｄ , -C(O)NR ６Ｂ R ６Ｃ , -OR ６Ａ , -NR ６Ｂ SO ２ R ６Ａ , -NR ６Ｂ C(O)R ６Ｄ , -NR ６Ｂ C(O)OR ６Ｄ , -NR ６Ｂ OR ６Ｄ , -OCX ６．１ ３ , -OCHX ６．１ ２ , -OCH ２ X ６．１ , 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, R ７ Hydrogen, halogen, -CX ７．１ ３ EN-CHX ７．１ ２ ien-CH ２ X ７．１ -CN, -N ３ , -SO ｎ７ R ７Ａ , -SO ｖ７ NR ７Ｂ R ７Ｃ ,-NHNR ７Ｂ R ７Ｃ , -ONR ７Ｂ R ７Ｃ , -NHC(O)NHNR ７Ｂ R ７Ｃ , -NHC(O)NR ７Ｂ R ７Ｃ , -N(O) ｍ７ , -NR ７Ｂ R ７Ｃ , -C(O)R ７Ｄ , -C(O)OR ７Ｄ , -C(O)NR ７Ｂ R ７Ｃ , -OR ７Ａ , -NR ７Ｂ SO ２ R ７Ａ , -NR ７Ｂ C(O)R ７Ｄ , -NR ７Ｂ C(O)OR ７Ｄ , -NR ７Ｂ OR ７Ｄ , -OCX ７．１ ３ , -OCHX ７．１ ２ , -OCH ２ X ７．１ , 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, R ８ Hydrogen, halogen, -CX ８．１ ３ EN-CHX ８．１ ２ ien-CH ２ X ８．１ -CN, -N ３ , -SO ｎ８ R ８Ａ , -SO ｖ８ NR ８Ｂ R ８Ｃ ,-NHNR ８Ｂ R ８Ｃ , -ONR ８Ｂ R ８Ｃ , -NHC(O)NHNR ８Ｂ R ８Ｃ , -NHC(O)NR ８Ｂ R ８Ｃ , -N(O) ｍ８ , -NR ８Ｂ R ８Ｃ , -C(O)R ８Ｄ , -C(O)OR ８Ｄ , -C(O)NR ８Ｂ R ８Ｃ , -OR ８Ａ , -NR ８Ｂ SO ２ R ８Ａ , -NR ８Ｂ C(O)R ８Ｄ , -NR ８Ｂ C(O)OR ８Ｄ , -NR ８Ｂ OR ８Ｄ , -OCX ８．１ ３ , -OCHX ８．１ ２ , -OCH ２ X ８．１ , 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, R ９ Hydrogen, halogen, -CX ９．１ ３ EN-CHX ９．１ ２ ien-CH ２ X ９．１ -CN, -N ３ , -SO ｎ９ R ９Ａ , -SO ｖ９ NR ９Ｂ R ９Ｃ ,-NHNR ９Ｂ R ９Ｃ , -ONR ９Ｂ R ９Ｃ , -NHC(O)NHNR ９Ｂ R ９Ｃ , -NHC(O)NR ９Ｂ R ９Ｃ , -N(O) ｍ９ , -NR ９Ｂ R ９Ｃ , -C(O)R ９Ｄ , -C(O)OR ９Ｄ , -C(O)NR ９Ｂ R ９Ｃ , -OR ９Ａ , -NR ９Ｂ SO ２ R ９Ａ , -NR ９Ｂ C(O)R ９Ｄ , -NR ９Ｂ C(O)OR ９Ｄ , -NR ９Ｂ OR ９Ｄ , -OCX ９．１ ３ , -OCHX ９．１ ２ , -OCH ２ X ９．１ , 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, or X ２ CR ９ If R ４ and R ９ They may be optionally linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or X ２ CR ９ X ３ CR １０ If R ９ and R １０ These can be arbitrarily linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R １０ Hydrogen, halogen, -CX １０．１ ３ EN-CHX １０．１ ２ ien-CH ２ X １０．１ -CN, -N ３ , -SO ｎ１０ R １０Ａ , -SO ｖ１０ NR １０Ｂ R １０Ｃ ,-NHNR １０Ｂ R １０Ｃ , -ONR １０Ｂ R １０Ｃ , -NHC(O)NHNR １０Ｂ R １０Ｃ , -NHC(O)NR １０Ｂ R １０Ｃ , -N(O) ｍ１０ , -NR １０Ｂ R １０Ｃ , -C(O)R １０Ｄ , -C(O)OR １０Ｄ , -C(O)NR １０Ｂ R １０Ｃ , -OR １０Ａ , -NR １０Ｂ SO ２ R １０Ａ , -NR １０Ｂ C(O)R １０Ｄ , -NR １０Ｂ C(O)OR １０Ｄ , -NR １０Ｂ OR １０Ｄ , -OCX １０．１ ３ , -OCHX １０．１ ２ , -OCH ２ X １０．１ , 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, or X ２ CR ９ X ３ CR １０ If R ９ and R １０ These can be arbitrarily linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R ４４ is hydrogen, -CX ４４．１ ３ EN-CHX ４４．１ ２ ien-CH ２ X ４４．１ , -SO ｎ４４ R ４４Ａ , -SO ｖ４４ NR ４４Ｂ R ４４Ｃ , -C(O)R ４４Ｄ , -C(O)OR ４４Ｄ , -C(O)NR ４４Ｂ R ４４Ｃ , 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, R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ , R ２Ａ , R ２Ｂ , R ２Ｃ , R ２Ｄ , R ３Ａ , R ３Ｂ , R ３Ｃ , R ３Ｄ , R ４Ａ , R ４Ｂ , R ４Ｃ , R ４Ｄ , R ５Ａ , R ５Ｂ , R ５Ｃ , R ５Ｄ , R ６Ａ , R ６Ｂ , R ６Ｃ , R ６Ｄ , R ７Ａ , R ７Ｂ , R ７Ｃ , R ７Ｄ , R ７．２Ｂ , R ８Ａ , R ８Ｂ , R ８Ｃ , R ８Ｄ , R ９Ａ、 R ９Ｂ , R ９Ｃ , R ９Ｄ , R １０Ａ , R １０Ｂ , R １０Ｃ , R １０Ｄ , R ４４Ａ , R ４４Ｂ , R ４４Ｃ , and R ４４Ｄ These are independently hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , 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, with R bonded to the same nitrogen atom １Ｂ , R １Ｃ , R ２Ｂ , R ２Ｃ , R ３Ｂ , R ３Ｃ , R ４Ｂ , R ４Ｃ , R ５Ｂ , R ５Ｃ , R ６Ｂ , R ６Ｃ , R ７Ｂ , R ７Ｃ , R ８Ｂ , R ８Ｃ , R ９Ｂ , R ９Ｃ , R １０Ｂ , R １０Ｃ , R ４４Ｂ , and R ４４Ｃ The substituents can be optionally linked to form substituted or unsubstituted heterocycloalkyl groups, or substituted or unsubstituted heteroaryl groups. X １．１ , X ２．１ , X ３．１ , X ４．１ , X ５．１ , X ６．１ , X ７．１ , X ８．１ , X ９．１ , X １０．１ , and X ４４．１ A compound, or a pharmaceutically acceptable salt thereof, in which is independently -Cl, -Br, -I, or -F.

2. z2 is 0 and / or z4 is 1 and / or The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein z1 is 2.

3. The aforementioned compound has structural formula (II): 【Chemistry 2】 It has, During the ceremony, R ４ However, hydrogen, halogen, -CX ４．１ ３ , -CN, -C(O)NR ４Ｂ R ４Ｃ , 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, R ３．２ However, hydrogen, halogen, -CX ３．２ ３ EN-CHX ３．２ ２ ien-CH ２ X ３．２ -CN, -N ３ , -SO ｎ３．２ R ３．２Ａ , -SO ｖ３．２ NR ３．２Ｂ R ３．２Ｃ ,-NHNR ３．２Ｂ R ３．２Ｃ , -ONR ３．２Ｂ R ３．２Ｃ , -NHC(O)NHNR ３．２Ｂ R ３．２Ｃ , -NHC(O)NR ３．２Ｂ R ３．２Ｃ , -N(O) ｍ３．２ , -NR ３．２Ｂ R ３．２Ｃ , -C(O)R ３．２Ｄ , -C(O)OR ３．２Ｄ , -C(O)NR ３．２Ｂ R ３．２Ｃ , -OR ３．２Ａ , -NR ３．２Ｂ SO ２ R ３．２Ａ , -NR ３．２Ｂ C(O)R ３．２Ｄ , -NR ３．２Ｂ C(O)OR ３．２Ｄ , -NR ３．２Ｂ OR ３．２Ｄ , -OCX ３．２ ３ , -OCHX ３．２ ２ , -OCH ２ X ３．２ , 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, R ３．３ However, hydrogen, halogen, -CX ３．３ ３ EN-CHX ３．３ ２ ien-CH ２ X ３．３ -CN, -N ３ , -SO ｎ３．３ R ３．３Ａ , -SO ｖ３．３ NR ３．３Ｂ R ３．３Ｃ ,-NHNR ３．３Ｂ R ３．３Ｃ , -ONR ３．３Ｂ R ３．３Ｃ , -NHC(O)NHNR ３．３Ｂ R ３．３Ｃ , -NHC(O)NR ３．３Ｂ R ３．３Ｃ , -N(O) ｍ３．３ , -NR ３．３Ｂ R ３．３Ｃ , -C(O)R ３．３Ｄ , -C(O)OR ３．３Ｄ , -C(O)NR ３．３Ｂ R ３．３Ｃ , -OR ３．３Ａ , -NR ３．３Ｂ SO ２ R ３．３Ａ , -NR ３．３Ｂ C(O)R ３．３Ｄ , -NR ３．３Ｂ C(O)OR ３．３Ｄ , -NR ３．３Ｂ OR ３．３Ｄ , -OCX ３．３ ３ , -OCHX ３．３ ２ , -OCH ２ X ３．３ , 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, R ３．２Ａ、 R ３．２Ｂ , R ３．２Ｃ , R ３．２Ｄ , R ３．３Ａ , R ３．３Ｂ , R ３．３Ｃ and R ３．３Ｄ These independently produce hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , 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, with R bonded to the same nitrogen atom ３．２Ｂ , R ３．２Ｃ , R ３．３Ｂ and R ３．３Ｃ The substituents can be arbitrarily linked to form substituted or unsubstituted heterocycloalkyl groups, or substituted or unsubstituted heteroaryl groups. n3.2 and n3.3 are independent integers between 0 and 4. m3.2, m3.3, v3.2, and v3.3 are independently 1 or 2. X ３．２ and X ３．３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the element is independently -Cl, -Br, -I, or -F.

4. The aforementioned compound has the structural formula (IIb): 【Transformation 3】 A compound according to claim 3, or a pharmaceutically acceptable salt thereof, having the above.

5. X ２ However, CR ９ And, R ９ However, hydrogen, -CX ９．１ ３ EN-CHX ９．１ ２ ien-CH ２ X ９．１ -CN, or substituted or unsubstituted C １ ~C ４ The compound according to claim 4, which is alkyl, or a pharmaceutically acceptable salt thereof.

6. The aforementioned compound has the structural formula (IIa): 【Chemistry 4】 A compound according to claim 3, or a pharmaceutically acceptable salt thereof, having the above.

7. X ３ However, CR １０ And, R １０ However, hydrogen, -CX １０．１ ３ EN-CHX １０．１ ２ ien-CH ２ X １０．１ -CN, or substituted or unsubstituted C １ ~C ４ The compound according to claim 6, which is alkyl, or a pharmaceutically acceptable salt thereof.

8. The aforementioned compound has structural formulas (IIIa), (IIIb), and (IIIc): 【Transformation 5】 Having one of the following, During the ceremony, X ２ However, CR ９ And, R ９ However, hydrogen, -CX ９．１ ３ EN-CHX ９．１ ２ ien-CH ２ X ９．１ -CN, or substituted or unsubstituted C １ ~C ４ The compound according to claim 3, which is alkyl, or a pharmaceutically acceptable salt thereof.

9. The aforementioned compound has the structural formula (IVa), (IVb), or (IVc): 【Transformation 6】 A compound according to claim 3, or a pharmaceutically acceptable salt thereof, having the above.

10. R ４ However, hydrogen, halogen, -CX ４．１ ３ EN-CHX ４．１ ２ ien-CH ２ X ４．１ -CN, -NR ４Ｂ R ４Ｃ , -C(O)R ４Ｄ , -C(O)OR ４Ｄ , -C(O)NR ４Ｂ R ４Ｃ , -OR ４Ａ , -NR ４Ｂ C(O)R ４Ｄ , -NR ４Ｂ C(O)OR ４Ｄ , -OCX ４．１ ３ , -OCHX ４．１ ２ , -OCH ２ X ４．１ The compound according to claim 1, which is a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl, or a pharmaceutically acceptable salt thereof.

11. R ４ However, -Cl, -Br, -F, -CN, -COOH, -C(O)OCH ２ CH ３ , -C(CH ３ ) ２ OH, -C(O)NH ２ , -CF ３ , or -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. X ２ However, CR ９ And, R ４ and R ９ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compounds are linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

13. R ４４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

14. R １ and R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each is independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group.

15. R １ And R2 independently become hydrogen or -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. R ３．２ and R ３．３ The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein is independently a halogen.

17. L ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a bonded, substituted, or unsubstituted alkylene, or a substituted or unsubstituted cycloalkylene.

18. R ７ However, hydrogen, halogens, -SO ｎ７ R ７Ａ , -SO ｖ７ NR ７Ｂ R ７Ｃ , -NHC(O)NR ７Ｂ R ７Ｃ , -NR ７Ｂ R ７Ｃ , -C(O)R ７Ｄ , -C(O)OR ７Ｄ , -C(O)NR ７Ｂ R ７Ｃ , -OR ７Ａ , -NR ７Ｂ SO ２ R ７Ａ , -NR ７Ｂ C(O)R ７Ｄ , -NR ７Ｂ C(O)OR ７Ｄ The compound according to claim 1, which is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, or a pharmaceutically acceptable salt thereof.

19. R ７ However, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, -C(O)OH, -C(O)OCH ３ , -C(O)OCH ２ CH ３ ien-CH ２ C(O)OH, -NHC(O)OH, -NHC(O)OCH ３ , -NHC(O)OCH ２ CH ３ ien-CH ２ C(O)OH, -CH ２ C(O)OCH ３ ien-CH ２ C(O)OCH ２ CH ３ , -SO ２ CH ３ , -SO ２ CH ２ CH ３ , -SO ２ CH (CH ３ ) ２ , - NHSO ２ CH ３ , - NHSO ２ CH ２ CH ３ , - NHSO ２ CH (CH ３ ) ２ , -SO ２ NH ２ , -SO ２ NHCH ３ ,-(CH ２ ) ２ OH, -CH ２ C (CH ３ ) ２ OH, - (CH ２ ) ３ OH, - (CH ２ ) ２ CH (CH ３ ) ２ OH, - (CH ２ ) ２ SO ２ NH ２ ,-(CH ２ ) ３ SO ２ NH ２ ,-(CH ２ ) ２ CONH ２ 、-(CH ２ ) ３ CONG ２ 、-(CH ２ ) ３ CON(H)Me、-(CH ２ ) ３ CON(Me) ２ 、-(CH ２ ) ２ SO ２ Me, - (CH ２ ) ３ SO ２ Me, -CH ２ CH(OH)Me、-CH ２ CO ２ H, -(CH) ２ ) ２ CO ２ H, -CH(CH) ３ )CH ２ CO ２ H, -(CH) ２ ) ３ CO ２ H, -(CH) ２ ) ２ SO ２ NHCH ３ 、-(CH ２ ) ２ SO ２ N(CH) ３ ) ２ 、-(CH ２ ) ２ SO ２ -(N-モルホリニル)、-(CH ２ ) ２ NHCOCH ３ 、-(CH ２ ) ３ NHCOCH ３ 、-(CH ２ ) ２ NHCOCH(CH) ３ ) ２ 、-(CH ２ ) ２ NHSO ２ CH ３ 、-(CH ２ ) ２ NHSO ２ CF ３ 、-(CH ２ ) ２ NHSO ２ NHCH(CH ３ ) ２ 、-CH ２ CH(CH ３ )CH ２ OH (R and S), -CH(CH ３ )(CH ２ ) ２ OH、-CH ２ -(2-imidazolyl), -CH ２ -(4-imidazolyl), -CH ２ -(3-pyrazolyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH ２ ) ２ NHCO ２ Me、-(CH ２ ) ３ NHCO ２ Me、-CH ２ OH、 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. -L ７ -R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a carboxylic acid-substituted cyclobutyl, a carboxylic acid-substituted cyclopentyl, or a hydroxysubstituted ethyl, and any of these may be further optionally substituted with a substituted or unsubstituted alkyl group.

21. The aforementioned compound has the following structure: 【Transformation 8】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

22. The aforementioned compound has the following structure: 【Chemistry 9】 【Chemistry 10】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

23. The following formula: 【Chemistry 11】 [In the formula, R 3.2 and R 3.3 are each independently an unsubstituted C1-C6 alkyl or halogen; R4 is a halogen; R9 is hydrogen or an unsubstituted C1-C6 alkyl group. A compound having [a certain property], or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition according to claim 24, for use in a method for treating or preventing a CCR4-mediated disease or disorder in a subject requiring treatment or prevention of a CCR4-mediated disease or disorder, wherein the method comprises administering the pharmaceutical composition to the subject.

26. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmacopoeia for the treatment or prevention of a CCR4-mediated disease or disorder, for a subject requiring treatment or prevention of a CCR4-mediated disease or disorder.

27. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmacopoeia for inhibiting C-C chemokine receptor type 4 (CCR4).

28. The use according to claim 26, wherein the disease or disorder is an immune or inflammatory disease or disorder.

29. The method further includes administering an anti-inflammatory agent concomitantly to the subject, The use according to claim 28, wherein the anti-inflammatory agent is thalidomide or a derivative thereof, retinoids, ditranol, calcipotriol, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase inhibitors, nitric oxide donors (CINODs), glucocorticosteroids, methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, analgesics, diaselein, hyaluronic acid derivatives, or nutritional supplements.

30. The use according to claim 26, wherein the disease or disorder is a cardiovascular or metabolic disease or disorder.

31. This further includes co-administering a cardiovascular agent or a metabolic disorder agent to the subject, The use according to claim 30, wherein the cardiovascular agent is a calcium channel blocker, a beta-adrenergic receptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a lipid-lowering agent, a blood cell morphology modulator, a thrombolytic agent, or an anticoagulant.

32. The use according to claim 26, wherein the disease or disorder is cancer, and optionally, the cancer is colon cancer or pancreatic cancer.

33. This further includes administering a chemotherapy agent or anticancer agent in combination to the subject, The aforementioned chemotherapeutic agent or anticancer agent, (i) Antiproliferative / antinomatous drugs, antimetabolites, antitumor antibiotics, antimitotic agents, topoisomerase inhibitors, cell quiescent agents, estrogen receptor downregulators, antiandrogens, LHRH antagonists or LHRH agonists, progestogens, aromatase inhibitors, 5α-reductase inhibitors, drugs that inhibit cancer cell invasion, growth factor function inhibitors, farnesyltransferase inhibitors, tyrosine kinase inhibitors, serine / threonine kinase inhibitors, inhibitors of the epidermal growth factor family, inhibitors of the platelet-derived growth factor family, inhibitors of the hepatocyte growth factor family; anti-angiogenic agents, vascular damage agents, drugs used in antisense therapy, anti-ras antisense, drugs used in gene therapy, immunotherapy agents, or antibodies. (ii) An inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, or a CD137 agonist antibody (4-1BB), (iii) TSR-022, MGB453, BMS-986016, IMP321, MGA271, MGD-009, RG-6058, AMG 557, SEA-CD40, dacetuzumab, CP-870, 893, Chi Lab 7 / 4, lucatumumab, galiximab, INCAGN1876, TRX518, MEDI-570, MEDI-6469, INCAGN1949, huMabOX40L, monalizumab, garnicertive, raspatercept, YH-14618, dalantercept, BG-00011, trabedersen, isth-0036, ace-083, NKTR-214, recombinant IL-2, aldesleukin, EGEN-001, NHS-IL-12, recombinant IL-7, NIZ-985, ALT-803, recombinant IL-21, anti-CD20. IL21, tralokinumab, dupilumab, cabilalizumab, INCB50465, idealisib, TGR-1202, AMG319, IPI-549, azacitidine, decitabine, guadecitabine, vorinostat, panobinostat, bellinostat, Entinostat, mocetinostat, givinostat, chidamide, quisinostat, abexinostat, chr-3996, ar-42, INCN54329, INCB5764 3. Birabrecib, apabetalone, alvocidib, PLX-51107, FT-1101, RG-6146, AZD-8186, CPI-0610, JQ1, INCB59872, IMG-7289, RG-6016, CC-90011, GSK-2879552, OR Y-2001, 4SC-202, ORY-3001, Recombinant TNFa, MEDI-1873, FPA-154, LKZ-145, Recombinant IL-1, Recombinant Interferon α-n1, Recombinant Interferon α-2b, Recombinant Interferon α-n3, Recombinant IFNβ-1a, Actimune, Cyclic Dinucleotide, PolyI:C, IMO-2055, TMX-101, Imiquimod, CpG, MGN1703, Glucopyranosyllipid A, CBLB502, BCG, HILTONOL, AMPLIGEN, MOTOLIMOD, DUK-CPG-001, AS15, Recombinant IL-10, CCX140, CCX872, BMS-813160, CENICRIVIROC, CNTX-6970, PF-4136309, Prozarizumab, INCB-9471, PF-04634817, Maraviroc, PRO-140, B MS-813160, NIFEVIROC, OHR-118, Ulocuplumab, Prelixafor, x4p-001, usl-311, ly-2510924, APH-0812, BL-8040, BURIXAFOR, BALIXAFORTIDE, PTX-9908, GMI-1359, F-50067, IPH-4301, CA-170, ISTRADEFYLLINE, TOZADENANT, PBF-509, PBF-999, CPI-444, OREG-103, Anti-CD39 antibody, Olec Oleclumab, PBF-1662, anti-CD73 antibody, pembrolizumab, nivolumab, INCSHHR1210, CT-011, AMP224, atezolizumab, avelumab, tremelimumab, urelumab, utomirumab, BMS-663513, PF-05082566, BGB-324, BPI-9016M, S-49076, BGB-324, BPI-9016M, S-49076, BGB-324, BPI-9016M, S-49076, ibrutinib, The use according to claim 32, wherein the agent is selected from Cb-1158, MDX-1140, AMP-110, PT2385, CDX-301, FLX925, quizartinib, gilteritinib, PKC412, midostaurin, clenolanib, lirirumab, IPH-2101, anti-CD47 antibody, TTI-621, NI-1701, SRF-231, Effi-DEM, RCT-1938, epacadostat, F287, BMS983205, GDC-0919, and indoximod.

34. The use according to claim 26, wherein the disease or disorder is allergy-related, inflammation, asthma, urticaria, rhinitis, or dermatitis.

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