Chemokine receptor modulators and uses thereof

Abstract

Disclosed herein, inter alia, are compounds useful for modulating the activity of certain chemokine receptors and methods of their use.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 622,771, filed on January 26, 2018, U.S. Provisional Application No. 62 / 772,027, filed on November 27, 2018, and U.S. Provisional Application No. 62 / 784,161, filed on December 21, 2018. Background Art

[0003] The successful operation of the host defense system is the result of several processes working together to eliminate foreign pathogens. A coordinated innate and adaptive immune response is required, and many secreted factors and cell-related factors have been identified as important mediators for coordinating and regulating these two host defense weapons. Chemokines are a family of cytokines that act as chemoattractants to guide the migration of leukocytes. They are secreted by a variety of cells and can be functionally divided into two categories: hemostatic chemokines and inflammatory chemokines. Hemostatic chemokines are constitutively produced in certain tissues and control cells of the immune system during the immune surveillance process, such as directing lymphocytes to lymph nodes so that they can screen for invading pathogens. Inflammatory chemokines are released by cells in response to pathological events (e.g., proinflammatory stimuli such as IL-1 or viruses). They primarily act as chemoattractants as part of the inflammatory response and serve to guide cells of the innate and adaptive immune systems to sites of inflammation. CC chemokine receptor type 4 (CCR4) plays a role in the progression of many inflammation-related and other diseases. Identifying compounds that modulate CCR4 function is an ongoing challenge. Solutions to these and other problems in the art are disclosed herein, among other things. SUMMARY OF THE INVENTION

[0005] In one aspect, provided herein are compounds having structural formula (I):

[0006] Or a pharmaceutically acceptable salt thereof. 1 It's CR 8 or N. X 2 It's CR 9 or N. X 3 It's CR 10 or N. Symbols n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independently integers from 0 to 4. Symbol z3 is an integer from 0 to 11. 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. Symbol z1 is an integer from 0 to 5. Symbol z2 is an integer from 0 to 4. Symbol z4 is an integer from 0 to 2. L 7is 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 、-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. 2 Is hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 、-CN、-N3、-SO n2 R 2A 、-SOv2 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、-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. 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 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, substituted or unsubstituted heteroaryl; when X 2 It's CR 9 When 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. 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. -CHX6.1 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 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 、-OCX8.1 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; when X 2 It's CR 9 When 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; or, when X2 It's CR 9 And X 3 It's CR 10 When R 9 and R 10 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. 10 Is hydrogen, 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; or, when X 2 It's CR 9 And X 3 It's CR 10 When R 9 and R 10may 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. 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 、R44A 、R 44B 、R 44C and R 44D R is 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; 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 may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl. 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 X is independently -Cl, -Br, -I or -F. 1 、X 2 and X 3 At least one of them is N.

[0007] In one aspect, a pharmaceutical composition is provided comprising a compound as described herein (including the 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 as described herein (including the embodiments), or a pharmaceutically acceptable salt thereof.

[0009] One aspect provides a method of treating or preventing a disease or condition mediated by CCR4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein (including the embodiments) or a pharmaceutically acceptable salt thereof.

[0010] Another aspect of the present invention provides a kit comprising a compound described herein (e.g., a CCR4 inhibitor) or a pharmaceutical composition thereof. The kit can be in the form of a physical structure that houses various components, as described below, and can be used, for example, to practice the methods described herein.

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Graph depicting eosinophil counts in bronchoalveolar lavage fluid.

[0013] Figure 2 Graph depicting lymphocyte counts in bronchoalveolar lavage fluid.

[0014] Figure 3 Graph depicting the concentration of the inflammatory mediator IL-5 in bronchoalveolar lavage fluid.

[0015] Figure 4 Graph depicting the concentration of the inflammatory mediator IL-13 in bronchoalveolar lavage fluid.

[0016] Figure 5 Graph depicting the concentration of the inflammatory mediator CCL-17 in bronchoalveolar lavage fluid.

[0017] Figure 6 is a graph showing the concentration of the inflammatory mediator CCL-22 in bronchoalveolar lavage fluid.

[0018] Detailed description

[0019] Provided herein are compounds and compositions, for example, for inhibiting CC chemokine receptor type 4, and pharmaceutical compositions comprising the same. Also provided herein are methods for, for example, treating or preventing a disease, disorder or condition, or a symptom thereof, for example, by modulating (e.g., inhibiting) a CCR4-mediated disease, disorder or condition, or a symptom thereof.

[0020] I. Definition

[0021] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.Chemical structures and formulae depicted herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0022] Substituent groups are designated by their conventional chemical formula, which, when written left to right, also encompasses chemically identical substituents that would result from writing the structure right to left, for example, -CH2O- is equivalent to -OCH2-.

[0023] Unless otherwise specified, the term "alkyl", by itself or as part of another substituent, means a straight chain (i.e., unbranched) or branched carbon chain (or carbon), or combinations thereof, which may be fully saturated, mono- or polyunsaturated and may include monovalent, divalent, or polyvalent radicals. Alkyl groups may include a specified number of carbon atoms (e.g., C1-C 10 Meaning one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon groups include, but are not limited to, the following groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, (for example) n-pentyl, n-hexyl, n-heptyl, n-octyl, and homologues and isomers. Unsaturated alkyl groups are alkyl groups with one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers. Alkoxy is an alkyl group connected to the rest 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. The alkenyl group can include more than one double bond and / or one or more triple bonds in addition to one or more double bonds. An alkynyl group may include more than one triple bond and / or one or more double bonds in addition to one or more triple bonds.

[0024] Unless otherwise specified, the term "alkylene", by itself or as part of another substituent, means a divalent radical derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a short-chain alkyl or alkylene group, typically having 8 or fewer carbon atoms. Unless otherwise specified, the term "alkenylene", by itself or as part of another substituent, means a divalent radical derived from an alkene group.

[0025] Unless otherwise specified, the term "heteroalkyl", by itself or in combination with another term, means a stable straight or branched chain, or combination thereof, comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and 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 located at any interior position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. A heteroalkyl group is an uncyclized chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety can include one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety can include two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0026] Similarly, unless otherwise specified, the term "heteroalkylene," by itself or as part of another substituent, means a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy either or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not indicate the orientation of the linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As noted above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -S02R'. When "heteroalkyl" is recited, followed by a recitation of a specific heteroalkyl group, such as -NR'R", etc., it is understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the recitation of the specific heteroalkyl group is for added clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding the specific heteroalkyl group, such as -NR'R", etc.

[0027] Unless otherwise specified, the terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, mean cyclic forms of "alkyl" and "heteroalkyl", respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom may occupy the position at which the heterocycle is attached to the rest 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-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "Cycloalkylene" and "heterocycloalkylene", by themselves or as part of another substituent, mean a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively. "Cycloalkyl" also means bicyclic and polycyclic hydrocarbon rings, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0028] Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0029] Unless otherwise specified, the term "acyl" 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.

[0030] Unless otherwise specified, the term "aryl" means a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused ring aryl) or covalently linked. A fused ring aryl refers to multiple rings fused together, wherein at least one fused ring is an aryl ring. 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 heteroaryls (i.e., multiple rings fused together, wherein at least one fused ring is an aromatic heterocycle). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And 6,5- fused ring heteroaryl refers to two rings fused together, wherein one ring has 6 yuan and the other ring has 5 yuan, and wherein at least one ring is a heteroaryl ring.Heteroaryl can be connected to the rest of the molecule by carbon or heteroatom.The limiting examples of aryl and heteroaryl include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl ((thienyl)), pyridyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl ((benzothiophenyl)), isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 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-mentioned aryl and heteroaryl ring systems are selected from the group consisting of acceptable substituents described below. "Arylene" and "heteroarylene," by themselves or as part of another substituent, mean a divalent radical derived from aryl and heteroaryl, respectively. A heteroaryl substituent may be -O- bonded to a ring heteroatom nitrogen.

[0031] Spirocycle is two or more rings, wherein adjacent rings are connected by a single atom.The single ring in spirocycle can be identical or different.The single ring in spirocycle can be substituted or unsubstituted and can have the substituent that is different from other single rings in one group of spirocycle.The possible substituent of single ring in spirocycle, when not being a part of spirocycle, is the possible substituent of identical ring (for example, the substituent of cycloalkyl or heterocycloalkyl ring).Spirocycle can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene or substituted or unsubstituted heterocycloalkylene and the single ring in spirocyclic group can be any one in the previous list, including all rings with a type (for example, all rings are substituted heterocycloalkylene, wherein each ring can be the heterocycloalkylene of identical or different substitutions).When mentioning spirocycle ring system, heterocycle spirocycle means that wherein at least one ring is heterocycle and wherein each ring can be the spirocycle of different rings. When referring to a spirocyclic ring system, substituted spirocyclic means that at least one ring is substituted and each substituent may optionally be different.

[0032] symbol Indicates the point of attachment of a chemical moiety to the rest of a molecule or chemical formula.

[0033] As used herein, the term "oxo" means an oxygen double-bonded to a carbon atom.

[0034] The term "alkylenaryl" is an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In an embodiment, the alkylenaryl group has the formula:

[0035]

[0036] The alkylenearyl moiety can be substituted (e.g., substituted with a substituent) on the alkylene moiety or arylene linker (e.g., at carbon 2, 3, 4, or 6) 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 C1-C5 alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl. In an embodiment, the alkylenearyl group is unsubstituted.

[0037] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the designated radical. Preferred substituents for each type of radical are provided below.

[0038] Substituents for alkyl and heteroalkyl groups (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", ... (O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=N R"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN , -NO2, -NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", and the number ranges from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. 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., 1 -3 halogen-substituted aryl), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy or aralkyl. When the compounds described herein include more than one R group, for example, each R group is independently selected, as are 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 skilled in the art will understand that the term "alkyl" is intended to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0039] Similar to the substituents described for alkyl, substituents for aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, -NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", ranging in number from zero to the total number of open valences on the aromatic ring system; and wherein R', R", R'' and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each R group is independently selected, as are each R', R", R'' and R"" group when more than one of these groups is present.

[0040] Substituents of a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be described as being on the ring, rather than on a specific atom of the ring (often referred to as a floating substituent). In this case, the substituent may be attached to any ring atom (following valence rules) and, in the case of a fused or spiro ring, may be described as being associated with one member of the fused or spiro ring (a floating substituent on a single ring), or as being on any fused or spiro ring (a floating substituent on multiple rings). When a substituent is attached to the ring, rather than on a specific atom (a floating substituent), and the subscript of the substituent is an integer greater than one, the multiple substituents may be on the same atom, the same ring, different atoms, different fused or spiro rings, and each substituent may be optionally different. When the point of attachment of the 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 and, in the case of a fused or spiro ring, any atom of any fused or spiro ring simultaneously following valence rules. When a ring, fused ring, or spiro ring contains one or more ring heteroatoms and the ring, fused ring, or spiro ring is shown to have one or more floating substituents (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be bonded to the heteroatom. When a structure or formula having a floating substituent shows a ring heteroatom bound to one or more hydrogen atoms (e.g., a ring nitrogen has two bonds to ring atoms and a third bond to a hydrogen atom), when the heteroatom is bonded to the floating substituent, the substituent is understood to replace a hydrogen atom, while adhering to chemical valence rules.

[0041] Two or more substituents may optionally be connected to form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group. Such so-called ring-forming substituents are not necessarily but usually found to be connected to a cyclic base structure. In one embodiment, the ring-forming substituents are connected to adjacent members of the base structure. For example, two ring-forming substituents connected to adjacent members of the cyclic base structure produce a fused ring structure. In another embodiment, the ring-forming substituents are connected to a single member of the base structure. For example, two ring-forming substituents connected to a single member of the cyclic base structure produce a spirocyclic structure. In yet another embodiment, the ring-forming substituents are connected to non-adjacent members of the base structure.

[0042] Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula -TC(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH2) r-(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 single bond of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -(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. s -X'-(C”R”R”') d -substituted by a substituent of -, wherein 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.

[0043] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0044] As used herein, "substituent" means a group selected from the following moieties:

[0045] (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- 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 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0046] (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the group consisting of:

[0047] (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- 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 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0048] (ii) an alkyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, which is substituted with at least one substituent selected from the group consisting of:

[0049] (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- 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 (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0050] (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted by at least one substituent selected from the group consisting of 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- 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-C8 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).

[0051] As used herein, "a substituent of limited size" or "a substituent group of limited size" means a group selected from all substituents described above for a "substituent group", wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20 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 3-8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0052] As used herein, "lower substituent" or "lower substituent group" means a group selected from all 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, 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.

[0053] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one substituent group of limited size. In other embodiments, at least one or all of these groups are substituted with at least one low substituent group.

[0054] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C 20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 The arylene group, and / or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5- to 10-membered heteroarylene group.

[0055] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C8 alkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 2-8 membered heteroalkylene group, each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C3-C7 cycloalkylene group, each substituted or unsubstituted heterocycloalkylene group is a substituted or unsubstituted 3-7 membered heterocycloalkylene group, each substituted or unsubstituted arylene group is a substituted or unsubstituted C6-C8 alkylene group. 10 Arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a chemical species described in the Examples section, Figures, or Tables below.

[0056] Certain compounds of the present invention have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined as (R)- or (S)-, or (D)- or (L)- for amino acids and individual isomers, based on absolute stereochemistry, are encompassed within the scope of the present invention. The compounds of the present invention do not include those known in the art to be too unstable to synthesize and / or separate. The present invention is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0057] 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 respect to the structural arrangement or configuration of the atoms.

[0058] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0059] It will be apparent to those skilled in the art that certain compounds of the present invention may exist in tautomeric forms and all such tautomeric forms of the compounds are within the scope of the present invention.

[0060] Unless otherwise specified, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0061] Unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to the replacement of hydrogen by deuterium or tritium or the replacement of carbon by an isotopically enriched 13 C or 14 Compounds having the present structure except for carbon substitution at C are within the scope of the present invention.

[0062] 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 be treated with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14C) Radiolabeling. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0063] It should be noted that throughout the application, alternatives are written as Markush groups, for example, each amino acid position containing more than one possible amino acid. It is specifically contemplated that each member of a Markush group should be considered separate, thereby comprising another embodiment, and that the Markush group should not be read as a single unit.

[0064] "Analog" is used according to its plain ordinary meaning in chemistry and biology and refers to a chemical compound that is similar in structure to another compound (i.e., a so-called "reference" compound), but differs in composition, such as the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or in the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or analogous to a reference compound in function and appearance, but not in structure or origin.

[0065] As used herein, the term "a" or "an" means one or more. In addition, as used herein, the phrase "substituted with" means that the specified group may be substituted with one or more of any or all of the named substituents. For example, when a group, such as alkyl or heteroalkyl, is "substituted with an unsubstituted C1-C 20 When "substituted by alkyl or unsubstituted 2 to 20 membered heteroalkyl", the group may contain one or more unsubstituted C1-C 20 alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups.

[0066] Additionally, when a moiety is substituted with an R substituent, the group may be referred to as "substituted with R." 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 specific R group is present in a description of a chemical species (e.g., Formula (I)), the Roman letter symbol may be used to distinguish each appearance of that specific R group. For example, if multiple R 13 When substituents are present, each R 13 Substituents are divided into R 13A 、R 13B 、R 13C 、R 13D etc., where R 13A 、R 13B 、R 13C 、R 13D Each of the above in R 13 and optionally different.

[0067] As used herein, "detectable moiety" refers to a portion that can be covalently or non-covalently attached to a compound or biomolecule, for example, that can be detected using techniques known in the art. In embodiments, the detectable moiety is a covalent attachment. The detectable moiety can provide imaging of the attached 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 platinum iron and manganese.

[0068] The description of the compounds of the present invention is subject to the principles of chemical bonding known to those skilled in the art. Thus, when a group may be substituted with one or more of a variety of substituents, such substituents are selected so as to adhere to the principles of chemical bonding and produce a compound that is not inherently unstable and / or known to be likely to be unstable under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions) as known to those skilled in the art. For example, a heterocycloalkyl or heteroaryl group is attached to the remainder of the molecule via a ring heteroatom in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0069] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and 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-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, 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 functional groups, which allow the compounds to be converted into either base or acid addition salts.

[0070] Therefore, the compound of the present invention can exist as a salt formed with a pharmaceutically acceptable acid. The present invention includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, mesylate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate or its mixture, including racemic mixture)), succinate, benzoate and salts formed with amino acids such as glutamic acid, and quaternary ammonium salts (methyl iodide, ethyl iodide etc.). These salts can be prepared by methods known to those skilled in the art.

[0071] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In an embodiment, the compound of the present invention contains both basic and acidic functional groups so that the compound can be converted into a base or acid addition salt. The neutral form of the compound may be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless otherwise expressly stated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present invention.

[0072] In addition to salt forms, the present invention also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein can be converted in vivo after administration. Additionally, 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 an appropriate enzyme or chemical reagent.

[0073] Some compounds of the present invention may exist in unsolvated forms and solvated forms (including hydrated forms). Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes encompassed by the present invention and are intended to be within the scope of the present invention.

[0074] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of a compound to an individual and absorption by the individual and that can be included in the compositions of the present invention without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, and pigments. Such formulations can be sterilized and, if desired, can be mixed with adjuvants that do not adversely react with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring and / or aromatic substances, and the like. Those skilled in the art will recognize that pharmaceutical excipients are useful in the present invention.

[0075] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thereby in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0076] A "CCR4 inhibitor" is a compound (eg, a compound described herein) that reduces CCR4 activity (eg, by binding to CCR4) compared to a control (eg, no compound or a compound known to be inactive).

[0077] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residues is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. In embodiments, the terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymeric form 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 having a modified polypeptide backbone. These terms include fusion proteins, including but not limited to fusion proteins having heterologous amino acid sequences; fusion proteins having heterologous and homologous leader sequences, with or without an N-terminal methionine residue; immunolabeled proteins, and the like.

[0078] A polypeptide or cell is "recombinant" when it is artificial or engineered, or is derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or non-wild type). For example, a polynucleotide inserted into a vector or any other heterologous location (e.g., the genome of a recombinant organism so as not to be associated with nucleotide sequences that typically flank the polynucleotide as found in nature) is a recombinant polynucleotide. Proteins expressed in vitro or in vivo by recombinant polynucleotides are examples of recombinant polypeptides. Similarly, polynucleotide sequences that do not occur in nature (e.g., variants of naturally occurring genes) are recombinants.

[0079] "Contacting" is used according to its plain ordinary meaning and refers to the process of bringing at least two different species (e.g., chemical compounds, including biomolecules or cells) into close enough proximity to react, interact, or physically touch. However, it should be recognized that the resulting reaction product can be generated directly from the reaction between the added reagents or from an intermediate product from one or more of the added reagents that may be generated in the reaction mixture.

[0080] The term "contacting" can include reacting, interacting, or physically bringing two species into contact, wherein the two species can be a compound described herein and a protein or enzyme. In some embodiments, contacting includes interacting a compound described herein with a protein or enzyme involved in a signaling pathway (e.g., a MAP kinase pathway).

[0081] As defined herein, the terms "activation," "activate," "activating," and the like with respect to target-inhibitor interactions refer to actively affecting (e.g., increasing) the activity or function of a target (e.g., protein) relative to the activity or function of the target (e.g., protein) in the absence of the inhibitor. The term relates to activation, activating, sensitizing, or upregulating the amount of signal transduction or enzyme activity or protein reduction in a disease.

[0082] The terms "agonist", "activator", "up-regulator" and the like refer to a substance that can detectably increase the expression or activity of a given gene or protein relative to a control (e.g., in 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 without an agonist. In some instances, the expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or more than the expression or activity without an agonist. In embodiments, an agonist is a molecule that interacts with a target and causes or promotes an increase in target activation. In embodiments, an activator is a molecule that increases, activates, promotes, enhances activation, sensitizes or upregulates, for example, a gene, protein, ligand, receptor or cell.

[0083] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like with respect to target-inhibitor interactions mean negatively affecting (e.g., reducing) the activity or function of the target (e.g., protein) without the inhibitor, relative to the activity or function of the target (e.g., protein) without the inhibitor. In embodiments, inhibition means negatively affecting (e.g., reducing) the concentration or level of the target (e.g., protein) relative to the concentration or level of the target (e.g., protein) without the inhibitor. In embodiments, inhibition refers to reducing a disease or disease symptom. In embodiments, In the scheme, inhibition refers to reducing the activity of a specific protein target. Thus, inhibition includes at least partially, partially or completely blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing or downregulating the signal transduction or enzymatic activity or amount of the target (e.g., protein). In embodiments, inhibition refers to a reduction in the activity of the target (e.g., protein) caused by a direct interaction (e.g., an inhibitor binds to a target (e.g., protein)). In embodiments, inhibition refers to a reduction in the activity of the target (e.g., protein) caused by an indirect interaction (e.g., an inhibitor binds to a protein that activates the target (e.g., protein), thereby preventing the target (e.g., protein) from being activated).

[0084] The terms "inhibitor," "repressor," or "antagonist," or "downregulator" are used interchangeably and refer to a substance that can detectably reduce the expression or activity of a given gene or protein relative to a control (e.g., in the absence of the inhibitor). Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control without the antagonist. In some instances, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or less than the expression or activity without the antagonist. Antagonists prevent, reduce, inhibit, or neutralize the activity of an agonist, and even in the absence of a defined agonist, antagonists can prevent, inhibit, or reduce the intrinsic activity of a target (e.g., a target receptor). In embodiments, an inhibitor is a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor can also be defined as a molecule that reduces, blocks, or inactivates an intrinsic activity. An "antagonist" is a molecule that has the opposite effect of an agonist.

[0085] The terms "CC chemokine receptor type 4" and "CCR4" refer to proteins (including homologs, isoforms, and functional fragments thereof) that are high-affinity receptors for CC-type chemokines (e.g., CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC). It is referred to by many different names in the scientific literature, including "CC-CKR-4," "CC CKR-4," "K5-5," "CD194," "CMKBR4," "ChemR13," "HGCN," and "14099." The term encompasses any recombinant or naturally occurring form of CCR4 and / or variants thereof that maintain CCR4 activity (e.g., within 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 a CCR4 variant thereof (e.g., a frameshift mutation) that maintains CCR4 activity (e.g., within 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 as set forth in Entrez 1233, UniProt P51679, or RefSeq (protein) NP_005499.1, or corresponding thereto. In embodiments, the CCR4 gene has a nucleic acid sequence as 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 this application. In embodiments, the sequence corresponds to GI:5031627. In embodiments, the sequence corresponds to NP_005499.1. In embodiments, the sequence corresponds to NM_005508.4. In embodiments, the sequence corresponds to GI:48762930. In embodiments, CCR4 is human CCR4, such as the CCR4 that causes human cancer. Although often found on dendritic cells, macrophages, NK cells, platelets and basophils, CCR4 is mainly related to T cells. It works in the progression of multiple inflammation-related disorders, and as described herein, it is also related to many other conditions. The genomic sequence of CCR4 is present on chromosome 3 (NC_000003.12), and the CCR4 gene is conserved in many species, including chimpanzees, rhesus monkeys, dogs, cattle, mice, rats, chickens and zebrafish. The CCR4 polypeptide comprises 360 amino acid residues (NP_005499.1), and like other chemokine receptors, CCR4 is a G protein-coupled receptor that can be found on the surface of leukocytes (see, for example, Horuk (1994) Trends Pharm. Sci. 15:159-165).

[0086] The term "expression" includes any step involved in the production of the polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, immunoblotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0087] The term "disease" or "condition" refers to the state or health of a patient or individual that can be treated by the compounds or methods provided herein. The disease can be cancer. The disease can be an autoimmune disease. The disease can be an inflammatory disease. The disease can be an infectious disease. In some other examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphomas, kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testicles, gliomas, esophageal and liver cancers (including hepatocellular carcinoma), lymphomas (including B-acute lymphocytic lymphoma), non-Hodgkin's lymphomas (e.g., Burkitt's, small cell and large cell lymphomas), Hodgkin's lymphomas, leukemias (including MDS, AML, ALL, ATL and CML) or multiple myeloma.

[0088] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (eg, increased levels of inflammation compared to a control, such as a healthy person not suffering from 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 diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. These conditions are often inseparable from other diseases, disorders, and conditions. A non-limiting list of inflammation-related diseases, disorders, and conditions that can, for example, be caused by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing), anemia, and fibromyalgia. Other diseases and conditions that can be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczema, systemic sclerosis, transplantation, and multiple sclerosis. Compounds described herein (e.g., CCR4 inhibitors) that may be particularly effective for some of the above-mentioned diseases, disorders, and conditions (because, for example, they are limited by current therapies) are described in more detail below. Examples of inflammatory diseases include head injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0089] The term "cancer" as used herein refers to all types of cancers, tumors or malignancies found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas and sarcomas. Cancers that can be treated with the compounds or methods provided herein include, for example, brain cancer, gliomas, glioblastomas, neuroblastomas, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer and head cancer. Cancers that can be treated with the compounds or methods provided herein include, for example, 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, pancreatic cancer. Other examples include thyroid cancer, bile duct cancer, pancreatic cancer, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, cancer, malignant insulinoma, malignant carcinoid tumor, urinary bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic tumor, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0090] The term "leukemia" broadly refers to progressive malignancies of the blood-forming organs, typically characterized by abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on: (1) the duration and characteristics of the disease—acute or chronic; (2) the cell types involved—myeloid (myeloid), lymphoid (lymphoid), or monocytic; and (3) the increase or absence of an increase in the number of abnormal cells in the blood—leukocytosis or leukopenia (metaleukemia). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, leukemia), lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyelocytic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0091] As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphoid tissues. It begins in lymphocytes, blood cells found primarily in the lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's lymphoma. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. It is a cancer related to the Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the cancer's growth rate and the type of cells involved. There are aggressive (highly aggressive) and indolent (lowly aggressive) types of NHL. Depending on the type of cells involved, there are B-cell and T-cell NHL. Exemplary B cell lymphomas that can 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, lymph node (monocyte-like 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 can 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.

[0092] The term "sarcoma" generally refers to a tumor composed of a substance resembling embryonic connective tissue, typically composed of densely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, grape sarcoma, chloroma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, sarcoma, fibrosarcoma, fibroblastic ... 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, leukocytic sarcoma, malignant mesenchymal sarcoma, extraperiosteal sarcoma, reticulum sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0093] The term "melanoma" is considered to refer to a tumor caused by the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided by the invention 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.

[0094] The term "cancer" refers to a malignant new growth composed of epithelial cells that tends to invade surrounding tissues and cause metastasis. Cancers that can be treated with the compounds or methods provided herein include, for example, thyroid cancer, bile duct cancer, pancreatic cancer, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive cancer, lung adenocarcinoma, lung squamous cell carcinoma, medullary thyroid cancer, familial medullary thyroid cancer, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, adrenal cortical carcinoma, alveolar epithelial carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal epithelial cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebriform carcinoma, carcinoma), cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, uterine corpus carcinoma, cribriform carcinoma, armored carcinoma, skin cancer, columnar cell carcinoma, columnar cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma carcinoma), adenoid epithelial carcinoma, exophytic carcinoma, precancerous ulcer, fibrocarcinoma, carcinoma gelatiniforni, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granular cell carcinoma, pilostromal carcinoma, hematopoietic carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, colloid carcinoma, adrenal carcinoma, immature embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lentiform carcinoma, lentiform carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, mucous cell carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma cell carcinoma), osteoid carcinomaossificans), osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthoid cell carcinoma, encephaloid carcinoma, renal cell carcinoma of the kidney, reservoir cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectasia, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0095] As used herein, the term "autoimmune disease" refers to a disease or condition in which an individual's immune system has an abnormal immune response to substances that do not normally elicit an immune response in a healthy individual. 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 dysfunction, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Barlow's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, disease), chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler'sSyndrome), 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 Wegener's granulomatosis), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunomodulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile Myositis type 2, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytodestructive vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), systemic lupus erythematosus (SLE), Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's), neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease, PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococci), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry's disease Romberg syndrome, Parsonnage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyendocrine syndrome types I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, necrotic reflux disease Pyoderma gangrenosum, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, hard man syndrome, subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritisarteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, blistering skin disease, vitiligo, or Wegener's granulomatosis (also known as granulomatosis with polyangiitis [GPA]).

[0096] The term "treat" refers to any marker of successful treatment or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as alleviation of symptoms; remission; reduction or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the degenerative endpoint less debilitating; improving the patient's physical or mental well-being. Treatment or improvement 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 "treat" and variations thereof may include preventing an injury, pathology, condition, or disease. In embodiments, treatment is prevention. In embodiments, treatment does not include prevention. In embodiments, treatment is non-prophylactic treatment.

[0097] As used herein, "treatment" (and as is well known in the art) also broadly includes any method that can achieve a beneficial or desired result (including a clinical result) in an individual's condition. Favorable or desired clinical results can include, but are not limited to, alleviating or improving one or more symptoms or symptoms, reducing the extent of the disease, stabilizing the disease state (i.e., not worsening), preventing the spread or spread of the disease, delaying or slowing the progression of the disease, improving or palliating the disease state, reducing recurrence of the disease, and remission, whether partial or complete and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, improvement, or prevention of a disease. Treatment can prevent the disease from occurring; inhibit the spread of the disease; alleviate the symptoms of the disease (e.g., eye pain, seeing halos around lights, red eyes, very high intraocular pressure), completely or partially remove the underlying cause of the disease, shorten the duration of the disease, or a combination of these events.

[0098] As used herein, "treatment" includes prophylactic treatment. Treatment methods include administering to an individual a therapeutically effective amount of a compound described herein. The administration step may include a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the patient's age, the concentration of the compound, the activity of the composition used for treatment, and combinations thereof. It should also be understood that the effective amount of the agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regimen. Changes in dosage can be obtained and become apparent through standard diagnostic assays known in the art. In some instances, long-term administration may be required. For example, the composition is administered to an individual in an amount and for a duration sufficient to treat the patient.

[0099] The term "prevent" refers to reducing the occurrence of symptoms of a disease in a patient. As described above, prevention can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would occur without treatment. In embodiments, prevention refers to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state.

[0100] "Patient" or "individual in need thereof" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient is a human.

[0101] An "effective amount" is an amount that is sufficient to achieve the specified purpose of the compound (e.g., to achieve the effect of its administration, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or alleviate one or more symptoms of a disease or condition) relative to the absence of the compound. An example of an "effective amount" is an amount that is sufficient to promote the treatment, prevention, or alleviation of one or more symptoms of a disease, also referred to as a "therapeutically effective amount." "Alleviation" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptoms, or eliminating the symptoms. A "prophylactically effective amount" of a drug is an amount that, when administered to an individual, has the expected prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms. A complete prophylactic effect does not necessarily occur by administering one dose, and may only occur after administering a series of doses. Therefore, a prophylactically effective amount may be administered over the course of one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce enzyme activity relative to the absence of the antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amount will depend on the therapeutic goal and will be determined by one skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). A therapeutically effective amount can be determined by measuring relevant physiological effects and can be adjusted based on the individual's dosing regimen and diagnostic assays for the condition. For example, measuring serum levels of a CCR4 inhibitor (or, for example, a metabolite thereof) at a specific time after administration can indicate whether a therapeutically effective amount has been administered.

[0102] For any compound described herein, a therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of one or more active compounds that enable the methods described herein to be achieved, as measured using methods described herein or known in the art.

[0103] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dosage for use in humans can be formulated to achieve a concentration that has been found to be effective in animals. As described above, the dosage in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward. It is well within the capabilities of those skilled in the art to adjust the dosage based on the above methods and other methods to achieve maximum efficacy in humans. It is well within the capabilities of those skilled in the art to adjust the dosage based on the above methods and other methods to achieve maximum therapeutic window efficacy or toxicity in humans.

[0104] The term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to improve a condition as described above. For example, a therapeutically effective amount may increase or decrease a given parameter by at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The therapeutic effect may also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount may have an effect of at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more compared to a control.

[0105] The dosage can vary depending on the patient's needs and the compound used. In the context of the present invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of the practitioner. Generally speaking, treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Subsequently, the dosage is increased in small increments until the optimal effect under the circumstances is achieved. The dosage and interval can be adjusted individually to provide a level of the administered compound that is effective for the specific clinical indication being treated. This provides a treatment regimen commensurate with the severity of the individual's disease state.

[0106] The term "administration" as used herein means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or implanting a sustained-release device, such as a micro-osmotic pump, to an individual. Administered by any route, including parenteral and transmucosal (e.g., oral, sublingual, palate, gum, nose, vagina, rectum or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of delivery include, but are not limited to, the use of liposome formulations, intravenous infusions, transdermal patches, etc. "Combined administration" means administering a composition described herein while, just before, or just after administering one or more additional therapies (e.g., anticancer agents, chemotherapy, or treatment of neurodegenerative diseases). In an embodiment, administration does not include administering any active agent other than the active agent described. The compound of the present invention can be administered alone or can be administered in combination to a patient. Combined administration is intended to include administering the compound alone or in combination (more than one compound or agent) simultaneously or sequentially. Thus, the formulations may also be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the present invention may be delivered transdermally via topical routes and may be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, coatings, powders, and aerosols. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like suitable for patient ingestion. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form formulations include solutions, suspensions, and emulsions, such as aqueous solutions or water / propylene glycol solutions. The compositions of the present invention may further comprise components that provide sustained release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and finely divided drug carrier matrices. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. 7th ed., 623-645, 1995); can be administered as a biodegradable and injectable gel formulation (see, for example, Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997).In another embodiment, the preparation of the composition of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed by the cell, that is, by using receptor ligands connected to the liposomes for delivery, which bind to the surface membrane protein receptors of the cell, thereby causing endocytosis. By using liposomes, especially when the liposome surface carries receptor ligands that are specifically targeted to the target cell or preferentially involved in a specific organ, the composition of the present invention can be delivered to the target cell in the body in a concentrated manner. (See, for example, 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 composition of the present invention can also be delivered as nanoparticles. In an embodiment, administration does not include administration of any active agent other than the active agent.

[0107] "Administered in combination" means administering the compositions described herein simultaneously with, just before, or just after administration of one or more additional therapies. The compounds of the present invention may be administered alone or in combination to a patient. Administration in combination is intended to include administration of the compounds alone or in combination (more than one compound) simultaneously or sequentially. The compositions of the present invention may be delivered transdermally via a topical route or may be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, coatings, powders, and aerosols.

[0108] For any compound described herein, a therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of one or more active compounds that enable the methods described herein to be achieved, as measured using methods described herein or known in the art.

[0109] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dosage for use in humans can be formulated to achieve a concentration found to be effective in animals. As described above, the dosage in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward. Adjusting the dosage to achieve maximum efficacy in humans based on the above methods and other methods is well within the capabilities of those of ordinary skill in the art.

[0110] The dosage can vary depending on the patient's needs and the compound used. In the context of the present invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with a smaller dosage than the optimal dosage of the compound. Subsequently, the dosage is increased in small increments until the optimal effect under the circumstances is achieved.

[0111] Dosage amount and interval can be adjusted individually to provide levels of the administered compound that are effective for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual disease state.

[0112] Using the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause significant toxicity but is effective for treating the clinical symptoms exhibited by a particular patient. Such a plan should involve careful selection of the active compound by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, the preferred route of administration, and the toxicity profile of the selected agent.

[0113] The compounds described herein can be combined with each other, with other active agents known to be useful in treating cancer (eg, colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory diseases or disorders.

[0114] In some embodiments, co-administration includes administering one active agent within 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 2 days, 4 days, 1 week, or 1 month of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition comprising two active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjuvants can be connected or coupled 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 condition.

[0115] "Cardiovascular agent" is used in accordance with its ordinary meaning to refer to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) used in any manner to treat a condition of the heart or circulatory system or vascular system relative to a control. In some embodiments, a cardiovascular agent is an agent identified herein as useful in a method of treating a cardiovascular disease or condition. In some embodiments, a cardiovascular agent is an agent approved by the FDA or similar regulatory agency in other countries outside the United States for the treatment of a cardiovascular disease or condition.

[0116] "Anti-inflammatory agent" is used in accordance with its ordinary meaning to refer to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that is used in any manner to reduce inflammation or swelling relative to a control (e.g., in the absence of the agent). In some embodiments, the anti-inflammatory agent is an agent identified herein as useful in a method of treating an inflammatory disease or condition. In some embodiments, the anti-inflammatory agent is an agent approved by the FDA or similar regulatory agency in other countries outside the United States for reducing swelling and inflammation.

[0117] The compounds described herein can be administered to treat immune or inflammatory diseases or conditions, cardiovascular or metabolic diseases or conditions, and / or cancer. In this regard, the compounds disclosed herein can be administered alone to treat such diseases or conditions, or can be administered in combination with another therapeutic agent to treat such diseases or conditions.

[0118] The compounds disclosed herein can be administered in combination with cytokines or agonists or antagonists of 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 I (IGF-1); interleukins (ILs), including IL1 to 17, and interleukin antagonists or inhibitors, such as analcinra; tumor necrosis factor alpha (TNF-α) inhibitors, such as anti-TNF monoclonal antibodies (e.g., infliximab; adalimumab and CDP-870) and TNF receptor antagonists, including immunoglobulin molecules (such as etanercept) and low molecular weight agents, such as pentoxyverine.

[0119] The compounds disclosed herein can be administered in combination with an anti-inflammatory agent, such as thalidomide or its derivatives, retinoids, anthracene or calcipotriol, nonsteroidal anti-inflammatory agents (hereinafter referred to as NSAIDs), including non-selective cyclooxygenase COX-1 / COX-2 inhibitors, whether administered topically or systemically (e.g., piroxicam, diclofenac, propionic acid compounds such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib, and etoricoxib); cyclooxygenase-inhibiting nitric oxide donors (CINODs); glucocorticoids (whether administered topically, orally, intramuscularly, intravenously, or intraarticularly); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies, such as hyaluronic acid derivatives; and nutritional supplements, such as glucosamine.

[0120] The compounds disclosed herein can be administered in combination with: calcium channel blockers, beta-adrenergic receptor blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin-2 receptor antagonists; lipid-lowering agents, such as cholesterol synthase inhibitors or benzoic acids; blood cell morphology regulators, such as pentoxyverine; thrombolytics or anticoagulants, such as antiplatelet aggregation drugs.

[0121] 111 In, 90 Y, or 131 I, etc.), tripterygium wilfordii, homoharrington, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, simvastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, targeted therapy or treatment of epidermal growth factor receptor (EGFR) (e.g., gefitinib (Iressa), TM ), erlotinib (Tarceva TM ), Cetuximab (Erbitux TM ), Lapatinib (Tadalafil TM ), panitumumab (victib TM ), Vandetanib (Caprelsa TM ), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc.

[0122] "Chemotherapeutic agent" or "chemotherapeutic agent" are used according to their ordinary meaning to refer to a chemical composition or compound that has anti-tumor properties or the ability to inhibit cell growth or proliferation.

[0123] In addition, the compounds described herein can be administered in combination with conventional immunotherapeutic agents, including but not limited to immunostimulants (e.g., BCG, levamisole, interleukin-2, α-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., conjugated 111 In, 90 Y or 131 I anti-CD20 monoclonal antibody, etc.).

[0124] The compounds disclosed herein can be administered in combination with an antiproliferative / antineoplastic agent or a combination thereof used in oncology, such as an alkylating agent (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulphan, or nitrosourea); an antimetabolite (e.g., an antifolate such as a fluoropyrimidine, such as 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, gemcitabine, or paclitaxel); an antitumor antibiotic (e.g., anthracycline such as doxorubicin, bleomycin, doxorubicin, or paclitaxel); or a topoisomerase inhibitor (e.g., an epipodophyllotoxins such as etoposide, teniposide, amsacrine, topotecan, or camptothecin); (ii) a cytostatic agent such as an anti-estrogen (e.g., tamoxifen, toremifene, raloxifene, droloxifene, or iodoxyfene), estrogen receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, or cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, or buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, or exemestane), or 5α-reductase inhibitors such as finasteride; (iii) agents that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors such as marimastat or urokinase fibrinolytics (iv) inhibitors of growth factor function, such as growth factor antibodies (e.g., the anti-ErbB2 antibody trastuzumab, or the anti-ErbB1 antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors or serine / threonine kinase inhibitors, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as 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) anti-angiogenic agents such as agents that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab, compounds disclosed in WO 97 / 22596, WO 97 / 30035, WO 97 / 32856, or WO 98 / 13354) or compounds that work by another mechanism (e.g., tricarboxyaminoquinoline, inhibitors of integrin α, v, β, 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 for antisense therapy, for example, agents directed against one of the above targets such as ISIS 2503, anti-ras antisense agents; (viii) agents for gene therapy, for example, methods for replacing abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzymatic prodrug therapy) methods, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods for increasing a patient's tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; or (ix) agents for immunotherapy, for example, methods for increasing the immunogenicity of a patient's tumor cells in vitro and in vivo, such as transfection with cytokines (such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor), methods for reducing T-cell anergy, methods using transfected immune cells (such as cytokine-transfected dendritic cells), methods using cytokine-transfected tumor cell lines, and methods using anti-idiotypic antibodies.

[0125] In embodiments, the compounds disclosed herein can be administered in combination with antibodies, such as monoclonal antibodies that target B-lymphocytes (e.g., CD20 (rituximab), MRA-aIL16R and T-lymphocytes, CTLA4-Ig, HuMax II-15) or antibodies that modulate Ig function, such as anti-IgE (e.g., omalizumab).

[0126] In embodiments, cancer treatment includes administering an effective amount 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, an agonist antibody to CD137 (4-1BB). In some embodiments, the method may include the use of two or more combinations.

[0127] In embodiments, the cancer treatment comprises an effective amount of at least two or more of the following: a CCR4 inhibitor (e.g., a compound described herein) in combination with any agent that can be an immunomodulator, such as, but not limited to, those listed in Table 1 or described herein (e.g., an anticancer agent). These immunomodulators can be ablating antibodies, neutralizing antibodies, blocking antibodies, agonistic antibodies, small molecule modulators (inhibitors or stimulators), or small molecule analogs.

[0128] Table 1

[0129]

[0130]

[0131]

[0132] In further embodiments, the compounds described herein may be administered in combination with conventional radiotherapeutic agents, including but not limited to radionuclides, such as 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 Bi, which is optionally conjugated to an antibody directed against a tumor antigen.

[0133] 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 cells from patients, genetically related or unrelated donors, and they can be genetically modified (e.g., CAR-T cells, NK cells, etc.), cell lines, genetically modified cell lines, and the above-mentioned living or dead forms. CCR4 inhibitors can also be combined with any type of vaccine (e.g., protein / peptide, virus, bacteria, cell) to stimulate an immune response against cancer.

[0134] In an embodiment, treatment is the 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 to CD137 (4-1BB), or in combination with another immunomodulator as listed in Table 1.

[0135] In an embodiment, 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 to CD137 (4-1BB), or in combination with another immunomodulator as listed in Table 1. In an embodiment, when the tumor size reaches about 40-70 mm 3 Start treatment when

[0136] The CCR4 inhibitors disclosed herein (e.g., compounds described herein) can be administered by any acceptable route, such as orally, intraadipose, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularly, intravitreally, intraliposomally, locally, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, buccally, transdermally, vaginally, in a cream, in a lipid composition, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via local infusion, via direct bathing of target cells, or any combination thereof.

[0137] The immunomodulatory agents disclosed herein can be administered by any acceptable route, such as orally, intraadipose, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularly, intravitreally, intraliposomally, locally, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, buccally, transdermally, vaginally, in a cream, in a lipid composition, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via local infusion, via direct bathing of target cells, or any combination thereof.

[0138] The CCR4 inhibitors disclosed herein (e.g., compounds described herein) can be administered once daily until the study endpoint is reached. The immunomodulators disclosed herein can be administered at least three times, but in some trials, four or more times, depending on the length of the study and / or the design of the study.

[0139] The methods disclosed herein can be used in combination with other cancer treatments. In some embodiments, different cancer treatments include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy. In some embodiments, the cancer is resistant to chemotherapy or radiation.

[0140] As used herein, "cell" refers to a cell that performs metabolic or other functions sufficient to retain or replicate its genomic DNA. Cells can be identified by methods known in the art, including, for example, the presence of an intact membrane, staining with a specific dye, the ability to produce offspring, or the ability to combine with a second gamete to produce viable offspring when a gamete is present. Cells can 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 from plants and animals, such as mammals, insects (e.g., moths), and human cells. Cells are useful when they are naturally non-adherent or have been treated (e.g., by trypsin treatment) to prevent them from adhering to a surface.

[0141] "Control" or "control experiment" is used according to its plain ordinary meaning and refers to an experiment in which the experimental subjects or reagents are treated as in a parallel experiment, except that an experimental step, reagent, or variable is omitted. In some cases, a control serves as a comparison standard for evaluating the effectiveness of an experiment. In some embodiments, a control is a measurement of protein activity in the absence of a compound described herein, including embodiments and examples.

[0142] The term "modulator" refers to a composition that increases or decreases the level of a target molecule, or the function of a target molecule, or the physical state of a molecular target. In some embodiments, a CCR4-related disease modulator is a compound that reduces the severity of one or more symptoms of a CCR4-related disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease). A CCR4 modulator is a compound that increases or decreases the activity or function or activity level or functional level of CCR4. Modulators can act alone, or they can use cofactors, such as proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules. Many small molecule compound libraries (e.g., combinatorial libraries) are commercially available and can be used 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) in which such compound libraries can be screened to identify one or more compounds with desired properties; a skilled medicinal chemist can then optimize such one or more compounds by, for example, synthesizing and evaluating analogs and derivatives thereof. Synthesis and / or molecular modeling studies can also be used to identify activators.

[0143] The term "modulate" is used in its simple ordinary sense and refers to the act of changing or altering one or more properties. "Modulation" refers to the process of changing or altering one or more properties. For example, as applied to the effect of a modulator on a target protein, modulation 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," etc. refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly increase or decrease the function or activity of CCR4 relative to the absence of the molecule.

[0144] In the context of a substance, 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 terms "associated with," "associated with," or "mediated by" mean that the disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease) is caused (completely or partially) by the substance, substance activity, or function, or that the symptoms of the disease are caused (completely or partially) by the substance, substance activity, or function. For example, a cancer associated with CCR4 activity or function may be a cancer caused (completely or partially) by aberrant CCR4 function (e.g., enzymatic activity, protein-protein interaction, signaling pathway), or a cancer in which specific symptoms of the disease are caused (completely or partially) by aberrant CCR4 activity or function. As used herein, "a substance associated with a disease, if it is the cause of the disease, may be a target for treating the disease. For example, where increased CCR4 activity or function (e.g., signaling pathway activity) leads to a disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease), a compound as described herein (e.g., a CCR4 modulator or CCR4 inhibitor) can be used to treat a cancer or CCR4-related disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease). For example, where increased CCR4 activity or function (e.g., signaling pathway activity) leads to a disease, an inflammatory disease or CCR4-related inflammatory disease can be treated with a CCR4 modulator or CCR4 inhibitor.

[0145] As used herein, the term "abnormal" means different from normal. When used to describe enzyme activity or protein function, abnormal means that the activity or function is higher or lower than the average of a normal control or a normal disease-free control sample. Abnormal activity can refer to the amount of activity that causes the disease, wherein returning the abnormal activity to a normal or disease-free relevant amount (e.g., by administering a compound described herein or using a method described herein) results in a reduction of the disease or one or more disease symptoms.

[0146] As used herein, the term "signaling pathway" refers to a series of interactions between a cell and optional extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit changes in one component to one or more other components, which in turn transmit changes to other components, which optionally extend to other signaling pathway components. For example, binding of CCR4 to a compound as described herein can reduce the level of a product of a reaction catalyzed by CCR4 or the level of a downstream derivative of the product, or binding can reduce the interaction between CCR4 or a reaction product and a downstream effector or signaling pathway component (e.g., a MAP kinase pathway), resulting in changes in cell growth, proliferation, or survival.

[0147] 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 described below) refer to compounds that are capable of directly or indirectly detectably reducing the expression or activity of the CCR4 receptor in in vitro assays, in vivo models, and / or other modalities indicative of therapeutic efficacy. The terms may also refer to compounds that exhibit at least some therapeutic benefit in human subjects (e.g., as determined by objective parameters such as serum concentrations or subjective parameters such as a subject's sense of well-being).

[0148] The phrase "an amount sufficient to effect a change" means that there is a detectable difference between the level of an indicator measured before (e.g., baseline level or in the presence of a control) and after administration of a particular treatment. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., an individual's sense of well-being).

[0149] The "activity" of a molecule can describe or refer to binding of the molecule to a ligand or receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation or maturation; antigenic activity; modulating the activity of other molecules, etc. The term "proliferative activity" includes activities that are necessary or particularly relevant to promoting, for example, normal cell division as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.

[0150] "Substantially pure" refers to a component that comprises more than about 50% of the total amount of the composition, typically more than about 60% of the total amount of the polypeptide. More typically, "substantially pure" refers to a composition in which at least 75%, at least 85%, at least 90%, or more of the total composition is the component of interest. In some cases, the component will comprise more than about 90% or more of the total amount of the composition (percentages are calculated on a weight per weight basis).

[0151] The terms "specific binding" and "selective binding" when referring to a 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 biological substances). Thus, under specified conditions, a specified ligand binds to a specific receptor and does not bind to other proteins present in the sample in significant amounts. The antibodies or binding compositions derived from the antigen binding sites of the antibodies in the methods encompassed bind to their antigen or variants thereof with an affinity that is at least 2-fold, at least 10-fold, at least 20-fold, or at least 100-fold greater than their affinity for any other target or binding composition derived therefrom. In embodiments, the antibodies have an affinity greater than about 10 9 Liter / mole.

[0152] The terms "nucleic acid," "nucleic acid molecule," "polynucleotide," and the like are used interchangeably herein to refer to a polymeric form of nucleotides (e.g., deoxyribonucleotides or ribonucleotides) of any length or their analogs. 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.

[0153] As used herein, the terms "variant" and "homolog" are used interchangeably and refer to amino acid or nucleic acid sequences that are similar to reference amino acid or nucleic acid sequences, respectively. The term includes 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 between species) and allelic variants (polypeptides and nucleic acids that differ in amino acid or nucleotide sequence between individuals in a species). Therefore, variants and homologs include naturally occurring amino acids and nucleic acid sequences encoded by them and their isoforms, as well as splice variants of proteins or genes. The term also includes nucleic acid sequences in which one or more bases are different from naturally occurring nucleic acid sequences, but are still translated into amino acid sequences corresponding to naturally occurring proteins due to the degeneracy of the genetic code. Non-naturally occurring variants and homologs include polypeptides and nucleic acids that contain changes in amino acid or nucleotide sequences, respectively, wherein the changes in the sequence are artificially introduced; for example, changes are produced in the laboratory by human intervention ("manual") . Therefore, non-naturally occurring variants and homologs can also refer to those that are different from naturally occurring sequences by one or more conservative substitutions and / or tags and / or conjugates.

[0154] II.Compounds

[0155] In one aspect, provided herein are compounds having structural formula (I):

[0156] Or a pharmaceutically acceptable salt thereof. 1 It's CR 8 or N. X 2 It's CR 9 or N. X 3 It's CR 10 or N. Symbols n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independently integers from 0 to 4. 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. Symbol z1 is an integer from 0 to 5. Symbol z2 is an integer from 0 to 5. Symbol z3 is an integer from 0 to 11. Symbol z4 is an integer from 0 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 1.13. -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. 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、-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. 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 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; when X 2 It's CR 9 When R 4 and R 9 may be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, an unsubstituted aryl, or a substituted or unsubstituted heteroaryl.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)OR7D 、-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 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. 9 Is hydrogen, halogen, -CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 、-CN、-N3、-SOn9 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; when X 2 It's CR 9 When R 4 and R 9 may be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, an unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or, when X 2 It's CR 9 And X 3 It's CR 10 When R 9 and R 10 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. 10 Is hydrogen, halogen, -CX 10.1 3. -CHX 10.1 2. -CH2X10.1 、-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, when X 2 It's CR 9 And X 3 It's CR 10 When R 9 and R 10 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. 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)OR44D 、-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 R is 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; 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 may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl. 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, wherein X 1 、X 2 and X 3 At least one of them is N.

[0157] In an embodiment, X 1 It's CR 8 In an embodiment, X 2 It's CR 9 In an embodiment, X 3 It's CR 10 In an embodiment, X 1 is N. In an embodiment, X 2 is N. In an embodiment, X 3 is N. In an embodiment, X 1 、X 2 and X 3 At least one of them is N.

[0158] In an embodiment, R 1 Halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 、-CN、-N3、-SO n1 R 1A 、-SO v1 NR 1B R1C 、-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. In one embodiment, R 1 It's hydrogen.

[0159] In an embodiment, 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)R1D 、-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 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0160] In an embodiment, R 1 It is R 11 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 1 It is R 11 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 1 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0161] In an embodiment, R 1 It is R 11 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 1 It is R11 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 1 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0162] In an embodiment, R 1 It is R 11 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 1 It is R 11 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 1 is an unsubstituted cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0163] In an embodiment, R 1 It is R 11 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 1 It is R 11 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 1 is unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0164] In an embodiment, R 1 It is R 11 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 1 It is R 11 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 1 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0165] In an embodiment, R 1 It is R 11 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 1It is R 11 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 1 is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0166] In an embodiment, R 1 R 11 -substituted or unsubstituted alkyl (e.g. C1-C8 alkyl, C1-C6 alkyl or C1-C4 alkyl). 1 R 11 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 1 is an unsubstituted alkyl group (e.g., a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group). 1 For hydrogen.

[0167] In an embodiment, R 1 R 11 -substituted or unsubstituted methyl. In an embodiment, R 1 R 11 -substituted or unsubstituted C2 alkyl. In an embodiment, R 1 R 11 -substituted or unsubstituted C3 alkyl. In an embodiment, R 1 R 11 -substituted or unsubstituted C4 alkyl. In an embodiment, R 1 R 11 -substituted or unsubstituted C5 alkyl. In an embodiment, R 1 R 11 -substituted or unsubstituted C6 alkyl. In an embodiment, R 1 R 11 -substituted or unsubstituted C7 alkyl. In an embodiment, R 1 R 11 -substituted or unsubstituted C8 alkyl. In an embodiment, R 1 R 11 -substituted methyl. In an embodiment, R 1 R 11 -substituted C2 alkyl. In an embodiment, R 1 R 11 -substituted C3 alkyl. In an embodiment, R 1 R 11 -substituted C4 alkyl. In an embodiment, R 1 R11 -substituted C5 alkyl. In an embodiment, R 1 R 11 -substituted C6 alkyl. In an embodiment, R 1 R 11 -substituted C7 alkyl. In an embodiment, R 1 R 11 -substituted C8 alkyl. In an embodiment, R 1 is an unsubstituted methyl group. In an embodiment, R 1 is an unsubstituted C2 alkyl. In an embodiment, R 1 is an unsubstituted C3 alkyl. In an embodiment, R 1 is an unsubstituted C4 alkyl. In an embodiment, R 1 is an unsubstituted C5 alkyl. 1 is an unsubstituted C6 alkyl. In an embodiment, R 1 is an unsubstituted C7 alkyl. In an embodiment, R 1 It is an unsubstituted C8 alkyl group.

[0168] In an embodiment, R 2 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 、-NR2B 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. In one embodiment, R 2 It's hydrogen.

[0169] In an embodiment, 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 14- substituted 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 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0170] In an embodiment, R 2 It is R 14 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 2 It is R 14 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 2 is an unsubstituted alkyl group (e.g., a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group). 2 is unsubstituted ethyl. In an embodiment, R 2 is an unsubstituted C3 alkyl. In an embodiment, R 2 It is an unsubstituted C4 alkyl group.

[0171] In an embodiment, R 2 It is R 14 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 2 It is R 14 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 2 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0172] In an embodiment, R 2 It is R 14 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 2 It is R 14 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 2is an unsubstituted cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0173] In an embodiment, R 2 It is R 14 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 2 It is R 14 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 2 is unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0174] In an embodiment, R 2 It is R 14 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 2 It is R 14 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 2 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0175] In an embodiment, R 2 It is R 14 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 2 It is R 14 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 2 is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0176] In an embodiment, R 2 R 14 -substituted or unsubstituted alkyl (e.g. C1-C8 alkyl, C1-C6 alkyl or C1-C4 alkyl). 2 R 14 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 2is an unsubstituted alkyl group (e.g., a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group). 2 For hydrogen.

[0177] In an embodiment, R 2 R 14 -substituted or unsubstituted methyl. In an embodiment, R 2 R 14 -substituted or unsubstituted C2 alkyl. In an embodiment, R 2 R 14 -substituted or unsubstituted C3 alkyl. In an embodiment, R 2 R 14 -substituted or unsubstituted C4 alkyl. In an embodiment, R 2 R 14 -substituted or unsubstituted C5 alkyl. In an embodiment, R 2 R 14 -substituted or unsubstituted C6 alkyl. In an embodiment, R 2 R 14 -substituted or unsubstituted C7 alkyl. In an embodiment, R 2 R 14 -substituted or unsubstituted C8 alkyl. In an embodiment, R 2 R 14 -substituted methyl. In an embodiment, R 2 R 14 -substituted C2 alkyl. In an embodiment, R 2 R 14 -substituted C3 alkyl. In an embodiment, R 2 R 14 -substituted C4 alkyl. In an embodiment, R 2 R 14 -substituted C5 alkyl. In an embodiment, R 2 R 14 -substituted C6 alkyl. In an embodiment, R 2 R 14 -substituted C7 alkyl. In an embodiment, c is R 14 -substituted C8 alkyl. In an embodiment, R 2 is an unsubstituted methyl group. In an embodiment, R 2 is an unsubstituted C2 alkyl. In an embodiment, R 2 is an unsubstituted C3 alkyl. In an embodiment, R 2 is an unsubstituted C4 alkyl. In an embodiment, R 2is an unsubstituted C5 alkyl. 2 is an unsubstituted C6 alkyl. In an embodiment, R 2 is an unsubstituted C7 alkyl. In an embodiment, R 2 It is an unsubstituted C8 alkyl group.

[0178] In an embodiment, R 1 and R 2 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. 1 R 11 - substituted or unsubstituted alkyl. 2 is a substituted or unsubstituted alkyl group. 1 is -CH3. In an embodiment, R 2 is -CH3. In an embodiment, R 1 is hydrogen. In an embodiment, R 2 For hydrogen.

[0179] In an embodiment, 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. 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.

[0180] In an embodiment, 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-C 10 Aryl, C 10 aryl or phenyl) or R 17 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0181] In an embodiment, R 3 Independently R 17 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 3 Independently R 17 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 3 is independently an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0182] In an embodiment, R 3 Independently R 17 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 3 Independently R 17 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 3 and R is independently unsubstituted heteroalkyl (eg, 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0183] In an embodiment, R 3 Independently R 17 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 3 Independently R 17 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 3 is independently unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0184] In an embodiment, R 3 Independently R 17-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 3 Independently R 17 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 3 and independently unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0185] In an embodiment, R 3 Independently R 17 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 3 Independently R 17 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 3 are independently unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0186] In an embodiment, R 3 Independently R 17 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 3 Independently R 17 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 3 and 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10-membered heteroaryl. Each of the following groups is independently unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0187] In an embodiment, 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. It should be understood that when z3 is 0, R 3 is hydrogen. In an embodiment, R 3 is independently -Cl. In an embodiment, R 3is 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 is independently -SO2Cl.

[0188] In an embodiment, R 3 The definition of R 3.1 、R 3.2 、R 3.3 、R 3.4 、R 3.5 taken (independently assigned to R 3.1 、R 3.2 、R 3.3 、R 3.4 、R 3.5 ). Substituent R 3.1 、R 3.2 、R 3.3 、R 3.4 and R 3.5 Each is R at a fixed position of the connected ring 3 In an embodiment, R 3.2 R 3 In an embodiment, R 3.3 R 3 substituent or hydrogen.

[0189] In an embodiment, R 3.2 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)NR3.2B 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. X 3.2 is halogen. In an embodiment, R 3.2 is hydrogen. In an embodiment, R 3.2 is halogen. In an embodiment, R 3.2 is chlorine. In an embodiment, R 3.2 and R 3.3 are independently halogen. In an embodiment, R 3.2 and R 3.3 are independently chlorine. In an embodiment, R 3.2 and R 3.3 are independently fluorine. In an embodiment, R 3.2 and R 3.3 is independently bromine.

[0190] In an embodiment, 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)OR3.2D 、-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), R 17.2 - 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 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0191] In an embodiment, R 3.2 It is R 17.2 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 3.2 It is R 17.2 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 3.2 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0192] In an embodiment, R 3.2 It is 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). 3.2 It is R 17.2-substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 3.2 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0193] In an embodiment, R 3.2 It is R 17.2 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 3.2 It is R 17.2 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 3.2 is an unsubstituted cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0194] In an embodiment, R 3.2 It is 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). 3.2 It is R 17.2 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 3.2 is unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0195] In an embodiment, R 3.2 It is R 17.2 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 3.2 It is R 17.2 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 3.2 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0196] In an embodiment, R 3.2 It is R 17.2 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 3.2 It is R17.2 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 3.2 is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0197] In an embodiment, 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. It should be understood that when z3 is 0, R 3.2 is hydrogen. In an embodiment, R 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 is independently -SO2Cl.

[0198] In an embodiment, R 3.3 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 、-OR3.3A 、-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. X 3.3 is halogen. In an embodiment, R 3.3 is hydrogen. In an embodiment, R 3.3 is halogen. In an embodiment, R 3.3 It's chlorine.

[0199] In an embodiment, 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 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0200] In an embodiment, R 3.3 It is R 17.3 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 3.3 It is R 17.3 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 3.3 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0201] In an embodiment, R 3.3 It is 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). 3.3 It is R 17.3 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 3.3 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0202] In an embodiment, R 3.3 It is R 17.3 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R3.3 It is R 17.3 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 3.3 is an unsubstituted cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0203] In an embodiment, R 3.3 It is 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). 3.3 It is R 17.3 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 3.3 is unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0204] In an embodiment, R 3.3 It is R 17.3 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 3.3 It is R 17.3 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 3.3 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0205] In an embodiment, R 3.3 It is R 17.3 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 3.3 It is R 17.3 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 3.3 is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0206] In an embodiment, 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. It should be understood that when z3 is 0, R 3.3 is hydrogen. In an embodiment, R 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 is independently -SO2Cl.

[0207] In an embodiment, R 4 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, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one embodiment, R 4 It's hydrogen.

[0208] In an embodiment, R 4 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 20 -substituted 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 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 4 is -CN. In an embodiment, R 4 is -C(O)NH2. In an embodiment, R 4 is -CF3. In an embodiment, R 4 It is -CH3.

[0209] In an embodiment, R 4 It is R 20 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 4 It is R 20 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 4 is an unsubstituted alkyl group (e.g., a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group). 4 is unsubstituted ethyl. In an embodiment, R 4 is an unsubstituted C3 alkyl. In an embodiment, R 4 It is an unsubstituted C4 alkyl group.

[0210] In an embodiment, R 4 It is R 20 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 4 It is R 20 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 4 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0211] In an embodiment, R 4 It is R 20 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 4 It is R 20-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 4 is an unsubstituted cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0212] In an embodiment, R 4 It is R 20 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 4 It is R 20 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 4 is unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0213] In an embodiment, R 4 It is R 20 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 4 It is R 20 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 4 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0214] In an embodiment, R 4 It is R 20 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 4 It is R 20 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 4 is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0215] In an embodiment, R 4 For hydrogen, -CN, halogen, -CF3, -COOH, -COOCH2CH3, -CH3. In an embodiment, R 4 is hydrogen. In an embodiment, R4 In an embodiment, R 4 is halogen. In an embodiment, R 4 In an embodiment, R 4 In the embodiment, R 4 is -Br. In an embodiment, R 4 In an embodiment, R 4 In the embodiment, R 4 In an embodiment, R 4 is -COOCH2CH3. In an embodiment, R 4 is -CH3. In an embodiment, R 4 is -COOCH2CH3. In an embodiment, R 4 for In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl group. 4 is a substituted C1-C4 alkyl. 4 It is an unsubstituted C1-C4 alkyl group.

[0216] In an embodiment, R 4 Halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 4D 、-C(O)OR 4D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl. In an embodiment, R 4 Halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 4D 、-C(O)OR 4D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl.

[0217] In an embodiment, R 4 R 20 -substituted or unsubstituted alkyl (e.g. C1-C8 alkyl, C1-C6 alkyl or C1-C4 alkyl). 4 R 20 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 4 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0218] In an embodiment, R 4 R20 -substituted or unsubstituted alkylmethyl. In an embodiment, R 4 R 20 -substituted or unsubstituted alkylC2alkyl. In an embodiment, R 4 R 20 -substituted or unsubstituted alkylC3 alkyl. In an embodiment, R 4 R 20 -substituted or unsubstituted alkylC4alkyl. In an embodiment, R 4 R 20 -substituted or unsubstituted alkylC5 alkyl. In an embodiment, R 4 R 20 -substituted or unsubstituted alkylC6 alkyl. In an embodiment, R 4 R 20 -substituted or unsubstituted alkylC7alkyl. In an embodiment, R 4 R 20 -substituted or unsubstituted alkylC8alkyl. In an embodiment, R 4 R 20 -substituted methyl. In an embodiment, R 4 R 20 -substituted C2 alkyl. In an embodiment, R 4 R 20 -substituted C3 alkyl. In an embodiment, R 4 R 20 -substituted C4 alkyl. In an embodiment, R 4 R 20 -substituted C5 alkyl. In an embodiment, R 4 R 20 -substituted C6 alkyl. In an embodiment, R 4 R 20 -substituted C7 alkyl. In an embodiment, R 4 R 20 -substituted C8 alkyl. In an embodiment, R 4 is an unsubstituted methyl group. In an embodiment, R 4 is an unsubstituted C2 alkyl. In an embodiment, R 4 is an unsubstituted C3 alkyl. In an embodiment, R 4 is an unsubstituted C4 alkyl. In an embodiment, R 4 is an unsubstituted C5 alkyl. 4 is an unsubstituted C6 alkyl. In an embodiment, R 4 is an unsubstituted C7 alkyl. In an embodiment, R 4It is an unsubstituted C8 alkyl group.

[0219] In an embodiment, R 4 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. In one embodiment, R 4 For 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. In an embodiment, R 4 For 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 to 4 membered heteroalkyl. In an embodiment, R 4 In an embodiment, R 4 is hydrogen. In an embodiment, R 4 is halogen. In an embodiment, R 4 For-CX 4.1 3. In an embodiment, R 4 -CHX 4.1 2. In an embodiment, R 4 -CH2X4.1 In an embodiment, R 4 In an embodiment, R 4 -NR 4B R 4C In an embodiment, R 4 -C(O)R 4D In an embodiment, R 4 -C(O)OR 4D In an embodiment, R 4 -C(O)NR 4B R 4C In an embodiment, R 4 For-OR 4A In an embodiment, R 4 -NR 4B C(O)R 4D In an embodiment, R 4 -NR 4B C(O)OR 4D In an embodiment, R 4 For-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 a substituted or unsubstituted alkyl group. 4 is a substituted or unsubstituted heteroalkyl. 4 In the embodiment, R 4 is -Br. In an embodiment, R 4 In an embodiment, R 4 In an embodiment, R 4 In an embodiment, R 4 is -C(O)OCH2CH3. In an embodiment, R 4 is -C(CH3)2OH. In an embodiment, R 4 is -C(O)NH2. In an embodiment, R 4 In the embodiment, R 4 is -CH3.

[0220] In an embodiment, R 5 are independently halogen, oxo, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 、-CN、-N3、-SOn5 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.

[0221] In an embodiment, R 5 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 、-NR5B 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, C 10 aryl or phenyl) or R 23 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0222] In an embodiment, R 5 Independently R 23 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 5 Independently R 23 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 5 is independently an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0223] In an embodiment, R 5 Independently R 23-substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 5 Independently R 23 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 5 and R is independently unsubstituted heteroalkyl (eg, 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0224] In an embodiment, R 5 Independently R 23 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 5 Independently R 23 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 5 is independently unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0225] In an embodiment, R 5 Independently R 23 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 5 Independently R 23 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 5 and independently unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0226] In an embodiment, R 5 Independently R 23 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 5 Independently R 23 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 5 are independently unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0227] In an embodiment, R 5 Independently R 23 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 5 Independently R 23 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 5 and 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10-membered heteroaryl. Each of the following groups is independently unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0228] In an embodiment, 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. In one embodiment, R6 It is -COOH.

[0229] In an embodiment, 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 26 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R26 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0230] In an embodiment, R 6 It is R 26 -substituted or unsubstituted alkyl. In an embodiment, R 6 is unsubstituted phenyl. In an embodiment, R 6 is -F. In an embodiment, R 6 is -OH. In an embodiment, R 6 is -CH2OH. In an embodiment, R 6 is -(CH2)2OH. In an embodiment, R 6 is -(CH2)3OH. In an embodiment, R 6 is -C(CH3)2OH. In an embodiment, R 6 is -CH2SO2NH2. In an embodiment, R 6 is -(CH2)2SO2NH2. In an embodiment, R 6 is -CH2C(O)NH2. In an embodiment, R 6 is -(CH2)2C(O)NH2. In an embodiment, R 6 is -(CH2)3C(O)NH2. In an embodiment, R 6 is -CH2NHSO2CF3. In an embodiment, R 6 is -(CH2)2NHSO2CF3. In an embodiment, R 6 is -(CH2)3NHSO2CF3. In an embodiment, R 6 is -CH2NHSO2CH3. In an embodiment, R 6 is -(CH2)2NHSO2CH3. In an embodiment, R 6 is -(CH2)3NHSO2CH3. In an embodiment, R 6 is -CH2SO2CH3. In an embodiment, R 6 is -(CH2)2SO2CH3. In an embodiment, R 6 is -CH2SO2NH2. In an embodiment, R 6 It is -(CH2)2SO2NH2.

[0231] In an embodiment, R 6 Independently R 26 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 6Independently R 26 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 6 is independently an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0232] In an embodiment, R 6 Independently R 26 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 6 Independently R 26 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 6 and R is independently unsubstituted heteroalkyl (eg, 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0233] In an embodiment, R 6 Independently R 26 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 6 Independently R 26 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 6 is independently unsubstituted cycloalkyl (eg, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0234] In an embodiment, R 6 Independently R 26 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 6 Independently R 26 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 6 and independently unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0235] In an embodiment, R 6 Independently R 26 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R6 Independently R 26 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 6 are independently unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0236] In an embodiment, R 6 Independently R 26 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 6 Independently R 26 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 6 and 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10-membered heteroaryl. Each of the following groups is independently unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0237] In an embodiment, R 7 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 7BOR 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.

[0238] In an embodiment, R 7 is halogen. In an embodiment, R 7 Yes-CX 7.1 3. In an embodiment, R 7 Yes-CHX 7.1 2. In an embodiment, R 7 Yes-CH2X 7.1 In an embodiment, R 7 is -CN. In an embodiment, R 7 In an embodiment, R 7 Yes-SO n7 R 7A In an embodiment, R 7 Yes-SO v7 NR 7B R 7C In an embodiment, R 7 Yes-NHNR 7B R 7C In an embodiment, R 7 Yes-ONR 7B R 7C In an embodiment, R 7 Yes-NHC(O)NHNR 7B R 7C In an embodiment, R 7 Yes-NHC(O)NR 7B R 7C In an embodiment, R 7 Yes-N(O) m7 In an embodiment, R 7 Yes-NR 7B R 7C In an embodiment, R 7 Yes-C(O)R 7D In an embodiment, R 7 Yes-C(O)OR 7D In an embodiment, R 7 Yes -C(O)NR 7B R 7C In an embodiment, R 7 Yes-OR7A In an embodiment, R 7 Yes-NR 7B SO2R 7A In an embodiment, R 7 Yes-NR 7B C(O)R 7D In an embodiment, R 7 Yes-NR 7B C(O)OR 7D In an embodiment, R 7 Yes-NR 7B OR 7D In an embodiment, R 7 Yes-OCX 7.1 3. In an embodiment, R 7 Yes-OCHX 7.1 2. In an embodiment, R 7 Yes-OCH2X 7.1 In an embodiment, R 7 is -CF3. In an embodiment, R 7 is -CHF2. In an embodiment, R 7 is -CH2F. In an embodiment, R 7 is -SO2CH3. In an embodiment, R 7 is -SO2NH2. In an embodiment, R 7 is -NHNH2. In an embodiment, R 7 is -ONH2. In an embodiment, R 7 is -NHC(O)NHNH2. In an embodiment, R 7 is -NHC(O)NH2. In an embodiment, R 7 is -N(O)2. In an embodiment, R 7 is -NH2. In an embodiment, R 7 is -C(O)OH. In an embodiment, R 7 is -C(O)OCH3. In an embodiment, R 7 is -C(O)NH2. In an embodiment, R 7 is -OCH3. In an embodiment, R 7 is -NHSO2CH3. In an embodiment, R 7 is -NHC(O)CH3. In an embodiment, R 7 is -NHC(O)OH. In an embodiment, R 7 is -NHOH. In an embodiment, R 7 is -OCF3. In an embodiment, R 7 is -OCHF2. In an embodiment, R7 is -OCH2F. In an embodiment, R 7 is hydrogen. In an embodiment, R 7 is -C(O)OH. In an embodiment, R 7 is -OH. In an embodiment, R 7 is -NH2. In an embodiment, R 7 It is -C(O)NH2.

[0239] In an embodiment, R 7 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 29 - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R29 -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 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0240] In an embodiment, R 7 is -(CH2)3COOH. In an embodiment, R 7 is -(CH2)2COOH. In an embodiment, R 7 is -(CH2)COOH. In an embodiment, R 7 is -(CH2)2CONH2. In an embodiment, R 7 is -(CH2)3CONH2. In an embodiment, R 7 is -(CH2)3OH. In an embodiment, R 7 is a substituted cyclobutyl. In an embodiment, R 7 is -(CH2)2SO2CH3. In an embodiment, R 7 is -CH2CH(CH3)OH. In an embodiment, R 7 is -(CH2)2OH. In an embodiment, R 7 is -(CH2)4OH. In an embodiment, R 7 is -(CH2)OH. In an embodiment, R 7 is -(CH2)2NHSO2CH3. In an embodiment, R 7 is -(CH2)2NHSO2CH2CH3. In an embodiment, R 7 is -(CH2)2NHSO2(CH2)2CH3. In an embodiment, R 7 is -(CH2)2NHSO2CH(CH3)2. In an embodiment, R 7 is -(CH2)2NHC(O)OCH3. In an embodiment, R 7 is -(CH2)3SO2CH3. In an embodiment, R 7 is -(CH2)2NHC(O)CH3. In an embodiment, R 7 is -(CH2)2NHC(O)H. In an embodiment, R 7 is -CH2C(O)OCH3. In an embodiment, R 7is -CH2C(O)OCH2CH3. In an embodiment, R 7 is -(CH2)3SO2NH2. In an embodiment, R 7 is -(CH2)2SO2NH2. In an embodiment, R 7 is -(CH2)1SO2NH2. In an embodiment, R 7 is -(CH2)2NHC(O)CH2CH3. In an embodiment, R 7 It is -(CH2)2NHC(O)CH(CH3)2.

[0241] In an embodiment, R 7 is hydrogen. In an embodiment, R 7 It is R 29 -substituted or unsubstituted alkyl. In an embodiment, R 7 is substituted or unsubstituted phenyl. In one embodiment, R 7 is -(CH2)2OH. In an embodiment, R 7 is -CH2C(CH3)2OH. In an embodiment, R 7 is -(CH2)3OH. In an embodiment, R 7 is -(CH2)2CH(CH3)2OH. In an embodiment, R 7 is -(CH2)2SO2NH2. In an embodiment, R 7 is -(CH2)3SO2NH2. In an embodiment, R 7 is -(CH2)2CONH2. In an embodiment, R 7 is -(CH2)3CONH2. In an embodiment, R 7 is -(CH2)3CON(H)Me. In an embodiment, R 7 is -(CH2)3CON(Me)2. In an embodiment, R 7 is -(CH2)2SO2Me. In an embodiment, R 7 is -(CH2)3SO2Me. In an embodiment, R 7 is -CH2CH(OH)Me. In an embodiment, R 7 is -CH2CO2H. In an embodiment, R 7 is -(CH2)2CO2H. In an embodiment, R 7 is -CH(CH3)CH2CO2H. In an embodiment, R 7 is -(CH2)3CO2H. In an embodiment, R 7 is -(CH2)2SO2NHCH3. In an embodiment, R7 is -(CH2)2SO2N(CH3)2. In an embodiment, R 7 is -(CH2)2SO2-(N-morpholinyl). In an embodiment, R 7 is -(CH2)2NHCOCH3. In an embodiment, R 7 is -(CH2)2NHC(O)OCH3. In an embodiment, R 7 is -(CH2)3NHCOCH3. In an embodiment, R 7 is -(CH2)2NHCOCH(CH3)2. In an embodiment, R 7 is -(CH2)2NHSO2CH3. In an embodiment, R 7 is -(CH2)2NHSO2CF3. In an embodiment, R 7 is -(CH2)2NHSO2NHCH(CH3)2. In an embodiment, R 7 is -CH2CH(CH3)CH2OH(R and S). In an embodiment, R 7 is -CH(CH3)(CH2)2OH. In an embodiment, R 7 is -CH2-(2-imidazolyl). In an embodiment, R 7 is -CH2-(4-imidazolyl). In an embodiment, R 7 is -CH2-(3-pyrazolyl). In an embodiment, R 7 is 4-tetrahydropyranyl. In an embodiment, R 7 is 3-oxetanyl. In an embodiment, R 7 is -(CH2)2NHCO2Me. In an embodiment, R 7 It is -(CH2)3NHCO2Me.

[0242] In an embodiment, R 7 is hydrogen. In an embodiment, R 7 In the embodiment, R 7 In an embodiment, R 7 is a substituted pyrrolidinyl group (eg, an oxo-substituted pyrrolidinyl group). 7 In the embodiment, R 7 In the embodiment, R 7 is -NH2. In an embodiment, R 7 is -CH3. In an embodiment, R 7 is -CH2CH3. In an embodiment, R 7 is -NHCOCH3. In an embodiment, R7 is -CONHCH3. In an embodiment, R 7 is -NHSO2CH3. In an embodiment, R 7 -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 the embodiment, R 7 It is -COCH(CH3)2.

[0243] In an embodiment, R 7 It is -CH2OH. In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for

[0244] In the embodiment, 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(CH 3)2OH, -(CH2)2SO2NH2, -(CH2)3SO2NH2, -(CH2)2CONH2, -(CH2)3CONH2-(CH2)3CON(H)Me, -(CH2)3CON(Me)2, -(C H2)2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, -CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, -(CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH(CH3)2 , -(CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, -(CH2)2NHSO2NHCH(CH3)2, -CH2CH(CH3)CH2OH(R and S), -CH(CH3)(CH2)2OH, -CH2-(2-imidazolyl), -CH2-(4-imidazolyl), -CH2-(3-pyrazolyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me, -CH2OH,

[0245] In an embodiment, R 7 is substituted or unsubstituted aziridinyl, oxiranyl, thiirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, 1,4-dioxanyl, tetrahydropyranyl, thianyl, or dithianyl. In an embodiment, R 7is 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). In an embodiment, R 7 is substituted or unsubstituted indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolopyrimidinyl, purinyl, indolizinyl, pyrrolopyrazinyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridopyrazinyl, pteridinyl, pyrazolopyridinyl, quinolyl, isoquinolyl, naphthyridinyl, or carbazolyl.

[0246] In an embodiment, R 7 is a substituted aziridine group. In an embodiment, R 7 is a substituted oxirane. 7 is a substituted thiirane group. In an embodiment, R 7 is a substituted azetidinyl group. In an embodiment, R 7 is a substituted oxetane. In an embodiment, R 7 is a substituted thietanyl. In an embodiment, R 7 is a substituted pyrrolidinyl group. In an embodiment, R 7 is substituted pyrrolyl. In an embodiment, R 7 is a substituted imidazolyl group. In an embodiment, R 7 is a substituted imidazolinyl. In an embodiment, R 7 is substituted pyrazolinyl. In an embodiment, R 7 is substituted tetrahydrofuranyl. In an embodiment, R 7 is a substituted thiolanyl. 7 is a substituted piperidinyl. In an embodiment, R 7 is a substituted piperazinyl. In an embodiment, R 7 is substituted pyranyl. In an embodiment, R 7 is a substituted morpholinyl. In an embodiment, R 7 is a substituted 1,4-dioxanyl. In an embodiment, R 7 is substituted tetrahydropyranyl. In an embodiment, R 7 is a substituted thianyl group. In one embodiment, R 7 is substituted or dithianyl.

[0247] In an embodiment, R 7 is a substituted phenyl group. In an embodiment, R 7 is substituted thiofuranyl. In an embodiment, R 7 is a substituted imidazolyl group. In an embodiment, R 7 is substituted pyrazolyl. In an embodiment, R 7 is a substituted triazolyl. In an embodiment, R 7 is a substituted tetrazolyl. In an embodiment, R 7 is a substituted furyl. In an embodiment, R 7 is substituted oxazolyl. In an embodiment, R 7 is substituted isoxazolyl. In an embodiment, R 7 is a substituted oxadiazolyl. In an embodiment, R 7 is a substituted oxatriazolyl group. In an embodiment, R 7 is a substituted thienyl. In an embodiment, R 7 is a substituted thiazolyl. In an embodiment, R 7 is substituted isothiazolyl. In an embodiment, R 7 is a substituted pyridinyl. In an embodiment, R 7 is a substituted pyrazinyl. In an embodiment, R 7 is a substituted pyrimidinyl. In an embodiment, R 7 is a substituted pyridazinyl. In an embodiment, R 7 is substituted or triazinyl (eg, 1,3,5-triazinyl, 1,2,3-triazinyl, or 1,2,4-triazinyl).

[0248] In an embodiment, R 7 is a substituted indolyl. In an embodiment, R 7 is a substituted benzimidazolyl group. In an embodiment, R 7 is substituted indazolyl. In an embodiment, R 7 is a substituted benzotriazolyl group. In an embodiment, R 7 is substituted pyrrolopyrimidinyl. In an embodiment, R 7 is a substituted purinyl. In one embodiment, R 7 is a substituted indolizinyl. In an embodiment, R 7 is substituted pyrrolopyrazinyl. In an embodiment, R 7 is substituted pyrrolopyrimidinyl. In an embodiment, R 7 is a substituted imidazopyridazinyl. In an embodiment, R 7 is a substituted imidazopyridinyl.7 is a substituted imidazopyrimidinyl. 7 is a substituted cinnolinyl. In an embodiment, R 7 is a substituted quinazolinyl. In an embodiment, R 7 is a substituted quinoxalinyl. In an embodiment, R 7 is a substituted phthalazinyl. In an embodiment, R 7 is a substituted pyridopyrazinyl. In an embodiment, R 7 is a substituted pteridinyl. In an embodiment, R 7 is substituted pyrazolopyridinyl. In an embodiment, R 7 is a substituted quinolinyl. In one embodiment, R 7 is substituted isoquinolinyl. In an embodiment, R 7 is substituted naphthyridinyl. In an embodiment, R 7 is a substituted carbazolyl group.

[0249] In an embodiment, R 7 is an unsubstituted aziridinyl. In an embodiment, R 7 is an unsubstituted oxirane group. 7 is unsubstituted thiirane. In an embodiment, R 7 is unsubstituted azetidinyl. In an embodiment, R 7 is unsubstituted oxetane. In an embodiment, R 7 is unsubstituted thietanyl. In an embodiment, R 7 is unsubstituted pyrrolidinyl. In an embodiment, R 7 is unsubstituted pyrrolyl. In an embodiment, R 7 is unsubstituted imidazolyl. In an embodiment, R 7 is unsubstituted imidazolinyl. In the embodiment, R 7 is unsubstituted pyrazolyl. In an embodiment, R 7 is unsubstituted tetrahydrofuranyl. In an embodiment, R 7 is unsubstituted thiolanyl. In an embodiment, R 7 is unsubstituted piperidinyl. In an embodiment, R 7 is unsubstituted piperazinyl. In an embodiment, R 7 is unsubstituted pyranyl. In an embodiment, R 7 is unsubstituted morpholinyl. In an embodiment, R 7 is unsubstituted 1,4-dioxanyl. In an embodiment, R 7is unsubstituted tetrahydropyranyl. In an embodiment, R 7 is unsubstituted thianyl. In an embodiment, R 7 is an unsubstituted dithianyl group.

[0250] In an embodiment, R 7 is unsubstituted phenyl. In an embodiment, R 7 is unsubstituted thiofuranyl. In an embodiment, R 7 is unsubstituted imidazolyl. In an embodiment, R 7 is unsubstituted pyrazolyl. In an embodiment, R 7 is an unsubstituted triazolyl. In an embodiment, R 7 is an unsubstituted tetrazolyl. In an embodiment, R 7 is unsubstituted furyl. In an embodiment, R 7 is unsubstituted oxazolyl. In an embodiment, R 7 is unsubstituted isoxazolyl. In an embodiment, R 7 is unsubstituted oxadiazolyl. In an embodiment, R 7 is unsubstituted oxatriazolyl. In an embodiment, R 7 is unsubstituted thienyl. In an embodiment, R 7 is unsubstituted thiazolyl. In an embodiment, R 7 is unsubstituted isothiazolyl. In an embodiment, R 7 is unsubstituted pyridyl. In an embodiment, R 7 is unsubstituted pyrazinyl. In an embodiment, R 7 is unsubstituted pyrimidinyl. In an embodiment, R 7 is unsubstituted pyridazinyl. In an embodiment, R 7 is an unsubstituted triazinyl group (eg, a 1,3,5-triazinyl group, a 1,2,3-triazinyl group, or a 1,2,4-triazinyl group).

[0251] In an embodiment, R 7 is unsubstituted indolyl. In an embodiment, R 7 is unsubstituted benzimidazolyl. In an embodiment, R 7 is unsubstituted indazolyl. In an embodiment, R 7 is unsubstituted benzotriazolyl. In an embodiment, R 7 is unsubstituted pyrrolopyrimidinyl. In an embodiment, R 7 is an unsubstituted purinyl. In an embodiment, R 7 is unsubstituted indolizinyl. In an embodiment, R 7is unsubstituted pyrrolopyrazinyl. In an embodiment, R 7 is unsubstituted pyrrolopyrimidinyl. In an embodiment, R 7 is unsubstituted imidazopyridazinyl. In an embodiment, R 7 is unsubstituted imidazopyridinyl. In an embodiment, R 7 is unsubstituted imidazopyrimidinyl. In an embodiment, R 7 is unsubstituted cinnolinyl. In an embodiment, R 7 is unsubstituted quinazolinyl. In an embodiment, R 7 is unsubstituted quinoxalinyl. In an embodiment, R 7 is an unsubstituted phthalazinyl group. In an embodiment, R 7 is unsubstituted pyridopyrazinyl. In an embodiment, R 7 is unsubstituted pteridinyl. In an embodiment, R 7 is unsubstituted pyrazolopyridinyl. In an embodiment, R 7 is unsubstituted quinolinyl. In an embodiment, R 7 is unsubstituted isoquinolinyl. In an embodiment, R 7 is unsubstituted naphthyridinyl. In an embodiment, R 7 is an unsubstituted carbazolyl group.

[0252] In an embodiment, R 7 For 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. In one embodiment, R 7For-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. In one embodiment, R 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, -SO2NH2, -SO2NHCH3, -F, -OH, -CH2OH , -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SO2NH2, -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2 NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH3, -CH2SO2CH3, -(CH2)2SO2CH3, -CH2SO2NH2 or -(CH2)2SO2NH2.

[0253] In an embodiment, R 7 is hydrogen. In an embodiment, R 7 is a substituted or unsubstituted alkyl group. 7 is substituted or unsubstituted phenyl. In an embodiment, R 7 is -C(O)OH. In an embodiment, R 7 is -C(O)OCH3. In an embodiment, R 7 is -C(O)OCH2CH3. In an embodiment, R 7is -CH2C(O)OH. In an embodiment, R 7 is -NHC(O)OH. In an embodiment, R 7 is -NHC(O)OCH3. In an embodiment, R 7 is -NHC(O)OCH2CH3. In an embodiment, R 7 is -CH2C(O)OH. In an embodiment, R 7 is -CH2C(O)OCH3. In an embodiment, R 7 is -CH2C(O)OCH2CH3. In an embodiment, R 7 In the embodiment, R 7 is -SO2CH2CH3. In an embodiment, R 7 is -SO2CH(CH3)2. In an embodiment, R 7 is -NHSO2CH3. In an embodiment, R 7 is -NHSO2CH2CH3. In an embodiment, R 7 is -NHSO2CH(CH3)2. In an embodiment, R 7 In the embodiment, R 7 is -SO2NHCH3. In an embodiment, R 7 In an embodiment, R 7 In the embodiment, R 7 is -CH2OH. In an embodiment, R 7 is -(CH2)2OH. In an embodiment, R 7 is -(CH2)3OH. In an embodiment, R 7 is -C(CH3)2OH. In an embodiment, R 7 is -CH2SO2NH2. In an embodiment, R 7 is -(CH2)2SO2NH2. In an embodiment, R 7 is -CH2C(O)NH2. In an embodiment, R 7 is -(CH2)2C(O)NH2. In an embodiment, R 7 is -(CH2)3C(O)NH2. In an embodiment, R 7 is -CH2NHSO2CF3. In an embodiment, R 7 is -(CH2)2NHSO2CF3. In an embodiment, R 7 is -(CH2)3NHSO2CF3. In an embodiment, R 7 is -CH2NHSO2CH3. In an embodiment, R7 is -(CH2)2NHSO2CH3. In an embodiment, R 7 is -(CH2)3NHSO2CH3. In an embodiment, R 7 is -CH2SO2CH3. In an embodiment, R 7 is -(CH2)2SO2CH3. In an embodiment, R 7 is -CH2SO2NH2. In an embodiment, R 7 It is -(CH2)2SO2NH2.

[0254] In an embodiment, R 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, -SO2NH2, -SO2NHCH3, -(CH2)2O H, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH, -(CH2)2SO2NH2, -(CH2)3SO2NH2, -(CH2)2 CONH2, -(CH2)3CONH2-(CH2)3CON(H)Me, -(CH2)3CON(Me)2, -(CH2)2SO2Me, -(CH2)3SO2Me, -C H2CH(OH)Me, -CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, -(CH2)2SO2NHCH3, -(C H2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH( CH3)2, -(CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, -(CH2)2NHSO2NHCH(CH3)2, -CH2CH(CH3)CH2OH(R and S), -CH(CH3)(CH2)2OH, -CH2-(2-imidazolyl), -CH2-(4-imidazolyl), -CH2-(3-pyrazolyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, or -(CH2)3NHCO2Me.

[0255] In an embodiment, R 7 is hydrogen. In an embodiment, R 7 is a substituted or unsubstituted alkyl group. 7 is substituted or unsubstituted phenyl. In an embodiment, R 7 is -C(O)OH. In an embodiment, R 7 is -C(O)OCH3. In an embodiment, R 7 is -C(O)OCH2CH3. In an embodiment, R 7 is -CH2C(O)OH. In an embodiment, R 7 is -NHC(O)OH. In an embodiment, R 7 is -NHC(O)OCH3. In an embodiment, R 7 is -NHC(O)OCH2CH3. In an embodiment, R 7 is -CH2C(O)OH. In an embodiment, R 7 is -CH2C(O)OCH3. In an embodiment, R 7 is -CH2C(O)OCH2CH3. In an embodiment, R 7 In the embodiment, R 7 is -SO2CH2CH3. In an embodiment, R 7 is -SO2CH(CH3)2. In an embodiment, R 7 is -NHSO2CH3. In an embodiment, R 7 is -NHSO2CH2CH3. In an embodiment, R 7 is -NHSO2CH(CH3)2. In an embodiment, R 7 In the embodiment, R 7 is -SO2NHCH3. In an embodiment, R 7 is -(CH2)2OH. In an embodiment, R 7 is -CH2C(CH3)2OH. In an embodiment, R 7 is -(CH2)3OH. In an embodiment, R 7 is -(CH2)2CH(CH3)2OH. In an embodiment, R 7 is -(CH2)2SO2NH2. In an embodiment, R 7 is -(CH2)3SO2NH2. In an embodiment, R 7 is -(CH2)2CONH2. In an embodiment, R 7is -(CH2)3CONH2-(CH2)3CON(H)Me. In an embodiment, R 7 is -(CH2)3CON(Me)2. In an embodiment, R 7 is -(CH2)2SO2Me. In an embodiment, R 7 is -(CH2)3SO2Me. In an embodiment, R 7 is -CH2CH(OH)Me. In an embodiment, R 7 is -CH2CO2H. In an embodiment, R 7 is -(CH2)2CO2H. In an embodiment, R 7 is -CH(CH3)CH2CO2H. In an embodiment, R 7 is -(CH2)3CO2H. In an embodiment, R 7 is -(CH2)2SO2NHCH3. In an embodiment, R 7 is -(CH2)2SO2N(CH3)2. In an embodiment, R 7 is -(CH2)2SO2-(N-morpholinyl). In an embodiment, R 7 is -(CH2)2NHCOCH3. In an embodiment, R 7 is -(CH2)3NHCOCH3. In an embodiment, R 7 is -(CH2)2NHCOCH(CH3)2. In an embodiment, R 7 is -(CH2)2NHSO2CH3. In an embodiment, R 7 is -(CH2)2NHSO2CF3. In an embodiment, R 7 is -(CH2)2NHSO2NHCH(CH3)2. In an embodiment, R 7 is -CH2CH(CH3)CH2OH(R and S). In an embodiment, R 7 is -CH(CH3)(CH2)2OH. In an embodiment, R 7 is -CH2-(2-imidazolyl). In an embodiment, R 7 is -CH2-(4-imidazolyl). In an embodiment, R 7 is -CH2-(3-pyrazolyl). In an embodiment, R 7 is 4-tetrahydropyranyl. In an embodiment, R 7 In the embodiment, R 7 is -(CH2)2NHCO2Me. In an embodiment, R 7 It is -(CH2)3NHCO2Me.

[0256] In an embodiment, R 7 R 29 -substituted or unsubstituted C1-C6 alkyl. In an embodiment, R 7 R 29 -substituted C1-C6 alkyl. In an embodiment, R 7 is an unsubstituted C1-C6 alkyl. 7 R 29 -substituted or unsubstituted C2-C6 alkyl. In an embodiment, R 7 R 29 -substituted C2-C6 alkyl. In an embodiment, R 7 is an unsubstituted C2-C6 alkyl. 7 R 29 -substituted or unsubstituted C1 alkyl. In an embodiment, R 7 R 29 -substituted C1 alkyl. In an embodiment, R 7 is an unsubstituted C1 alkyl. In an embodiment, R 7 R 29 -substituted or unsubstituted C2 alkyl. In an embodiment, R 7 R 29 -substituted C2 alkyl. In an embodiment, R 7 is an unsubstituted C2 alkyl. In an embodiment, R 7 R 29 -substituted or unsubstituted C3 alkyl. In an embodiment, R 7 R 29 -substituted C3 alkyl. In an embodiment, R 7 is an unsubstituted C3 alkyl. In an embodiment, R 7 R 29 -substituted or unsubstituted C4 alkyl. In an embodiment, R 7 R 29 -substituted C4 alkyl. In an embodiment, R 7 is an unsubstituted C4 alkyl. In an embodiment, R 7 R 29 -substituted or unsubstituted C5 alkyl. In an embodiment, R 7 R 29 -substituted C5 alkyl. In an embodiment, R 7 is an unsubstituted C5 alkyl. 7 R 29 -substituted or unsubstituted C6 alkyl. In an embodiment, R7 R 29 -substituted C6 alkyl. In an embodiment, R 7 It is an unsubstituted C6 alkyl group.

[0257] In an embodiment, R 7 R 29 -substituted or unsubstituted 2 to 8 membered heteroalkyl. In an embodiment, R 7 R 29 -substituted 2 to 8 membered heteroalkyl. In an embodiment, R 7 is an unsubstituted 2 to 8 membered heteroalkyl group. 7 R 29 -substituted or unsubstituted 2-membered heteroalkyl. In an embodiment, R 7 R 29 -substituted 2-membered heteroalkyl. In an embodiment, R 7 is an unsubstituted 2-membered heteroalkyl. 7 R 29 -substituted or unsubstituted 3-membered heteroalkyl. In an embodiment, R 7 R 29 -substituted 3-membered heteroalkyl. In an embodiment, R 7 is an unsubstituted 3-membered heteroalkyl. 7 R 29 -substituted or unsubstituted 4-membered heteroalkyl. In an embodiment, R 7 R 29 -substituted 4-membered heteroalkyl. In an embodiment, R 7 is an unsubstituted 4-membered heteroalkyl. 7 R 29 -substituted or unsubstituted 5-membered heteroalkyl. In an embodiment, R 7 R 29 -substituted 5-membered heteroalkyl. In an embodiment, R 7 is an unsubstituted 5-membered heteroalkyl. 7 R 29 -substituted or unsubstituted 6-membered heteroalkyl. In an embodiment, R 7 R 29 -substituted 6-membered heteroalkyl. In an embodiment, R 7 is an unsubstituted 6-membered heteroalkyl. 7 R 29 -substituted or unsubstituted 7-membered heteroalkyl. In an embodiment, R 7 R 29 -substituted 7-membered heteroalkyl. In an embodiment, R7 is an unsubstituted 7-membered heteroalkyl group.

[0258] In an embodiment, R 7 R 29 -substituted or unsubstituted C4-C6 cycloalkyl. In an embodiment, R 7 R 29 -substituted C4-C6 cycloalkyl. In an embodiment, R 7 R 29 -substituted C4-C6 cycloalkyl. In an embodiment, R 7 R 29 -substituted or unsubstituted C4 cycloalkyl. In an embodiment, R 7 R 29 -substituted C4 cycloalkyl. In an embodiment, R 7 R 29 -substituted C4 cycloalkyl. In an embodiment, R 7 R 29 -substituted or unsubstituted C5 cycloalkyl. In an embodiment, R 7 R 29 -substituted C5 cycloalkyl. In an embodiment, R 7 R 29 -substituted C5 cycloalkyl.

[0259] In an embodiment, R 7 R 29 -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In an embodiment, R 7 R 29 -substituted 5 to 6 membered heterocycloalkyl. In an embodiment, R 7 is an unsubstituted 5- to 6-membered heterocycloalkyl. 7 R 29 -substituted or unsubstituted 5-membered heterocycloalkyl. In an embodiment, R 7 R 29 -substituted 5-membered heterocycloalkyl. In an embodiment, R 7 is an unsubstituted 5-membered heterocycloalkyl. 7 R 29 -substituted or unsubstituted 6-membered heterocycloalkyl. In an embodiment, R 7 R 29 -substituted 6-membered heterocycloalkyl. In an embodiment, R 7 is an unsubstituted 6-membered heterocycloalkyl.

[0260] In an embodiment, R 7 R 29-substituted or unsubstituted phenyl. In an embodiment, R 7 R 29 -substituted phenyl. In an embodiment, R 7 is an unsubstituted phenyl group.

[0261] In an embodiment, R 7 R 29 -substituted or unsubstituted 5- to 6-membered heteroaryl. In one embodiment, R 7 R 29 -substituted 5- to 6-membered heteroaryl. In an embodiment, R 7 is an unsubstituted 5- to 6-membered heteroaryl. 7 R 29 -substituted or unsubstituted 5-membered heteroaryl. In one embodiment, R 7 R 29 -substituted 5-membered heteroaryl. In one embodiment, R 7 is an unsubstituted 5-membered heteroaryl. 7 R 29 -substituted or unsubstituted 6-membered heteroaryl. In one embodiment, R 7 R 29 -substituted 6-membered heteroaryl. In an embodiment, R 7 is an unsubstituted 6-membered heteroaryl group.

[0262] In an embodiment, R 7 In the embodiment, R 7 In the embodiment, R 7 is -CHF2. In an embodiment, R 7 is -CH2F. In an embodiment, R 7 In the embodiment, R 7 In the embodiment, R 7 is -NHC(O)NH2. In an embodiment, R 7 is -NH2. In an embodiment, R 7 is -C(O)OH. In an embodiment, R 7 is -C(O)OCH3. In an embodiment, R 7 is -C(O)NH2. In an embodiment, R 7 is -OCH3. In an embodiment, R 7 is -NHSO2CH3. In an embodiment, R 7 is -NHC(O)CH3. In an embodiment, R 7 is -NHC(O)OH. In an embodiment, R7 In the embodiment, R 7 is -OCHF2. In an embodiment, R 7 is -OCH2F. In an embodiment, R 7 is hydrogen. In an embodiment, R 7 In the embodiment, R 7 is -C(O)OCH2CH3. In an embodiment, R 7 is -SO2CH2CH3. In an embodiment, R 7 is -SO2CH2CH2CH3. In an embodiment, R 7 is -SO2CH(CH3)2. In an embodiment, R 7 is -C(O)NHCH3. In an embodiment, R 7 is -C(O)N(CH3)2. In an embodiment, R 7 is -NHC(O)OCH3. In an embodiment, R 7 is -NHC(O)OCH2CH3. In an embodiment, R 7 is -NHC(O)OCH2CH2CH3. In an embodiment, R 7 is -NHC(O)OCH(CH3)2. In an embodiment, R 7 is -NHC(O)CH3. In an embodiment, R 7 is -NHC(O)CH2CH3. In an embodiment, R 7 is -NHC(O)CH2CH2CH3. In an embodiment, R 7 It is -NHC(O)CH(CH3)2.

[0263] In an embodiment, R 29 In the embodiment, R 29 In the embodiment, R 29 is -CHF2. In an embodiment, R 29 is -CH2F. In an embodiment, R 29 In the embodiment, R 29 In the embodiment, R 29 is -NHC(O)NH2. In an embodiment, R 29 is -NH2. In an embodiment, R 29 is -C(O)OH. In an embodiment, R 29 is -C(O)OCH3. In an embodiment, R 29 is -C(O)NH2. In an embodiment, R 29is -OCH3. In an embodiment, R 29 is -NHSO2CH3. In an embodiment, R 29 is -NHC(O)CH3. In an embodiment, R 29 is -NHC(O)OH. In an embodiment, R 29 In the embodiment, R 29 is -OCHF2. In an embodiment, R 29 is -OCH2F. In an embodiment, R 29 is hydrogen. In an embodiment, R 29 In the embodiment, R 29 is -C(O)OCH2CH3. In an embodiment, R 29 is -SO2CH2CH3. In an embodiment, R 29 is -SO2CH2CH2CH3. In an embodiment, R 29 is -SO2CH(CH3)2. In an embodiment, R 29 is -C(O)NHCH3. In an embodiment, R 29 is -C(O)N(CH3)2. In an embodiment, R 29 is -NHC(O)OCH3. In an embodiment, R 29 is -NHC(O)OCH2CH3. In an embodiment, R 29 is -NHC(O)OCH2CH2CH3. In an embodiment, R 29 is -NHC(O)OCH(CH3)2. In an embodiment, R 29 is -NHC(O)CH3. In an embodiment, R 29 is -NHC(O)CH2CH3. In an embodiment, R 29 is -NHC(O)CH2CH2CH3. In an embodiment, R 29 It is -NHC(O)CH(CH3)2.

[0264] In an embodiment, R 29 R 30 -substituted or unsubstituted C1-C6 alkyl. In an embodiment, R 29 R 30 -substituted C1-C6 alkyl. In an embodiment, R 29 is an unsubstituted C1-C6 alkyl. 29 R 30 -substituted or unsubstituted C2-C6 alkyl. In an embodiment, R 29 R 30-substituted C2-C6 alkyl. In an embodiment, R 29 is an unsubstituted C2-C6 alkyl. 29 R 30 -substituted or unsubstituted C1 alkyl. In an embodiment, R 29 R 30 -substituted C1 alkyl. In an embodiment, R 29 is an unsubstituted C1 alkyl. In an embodiment, R 29 R 30 -substituted or unsubstituted C2 alkyl. In an embodiment, R 29 R 30 -substituted C2 alkyl. In an embodiment, R 29 is an unsubstituted C2 alkyl. In an embodiment, R 29 R 30 -substituted or unsubstituted C3 alkyl. In an embodiment, R 29 R 30 -substituted C3 alkyl. In an embodiment, R 29 is an unsubstituted C3 alkyl. In an embodiment, R 29 R 30 -substituted or unsubstituted C4 alkyl. In an embodiment, R 29 R 30 -substituted C4 alkyl. In an embodiment, R 29 is an unsubstituted C4 alkyl. In an embodiment, R 29 R 30 -substituted or unsubstituted C5 alkyl. In an embodiment, R 29 R 30 -substituted C5 alkyl. In an embodiment, R 29 is an unsubstituted C5 alkyl. 29 R 30 -substituted or unsubstituted C6 alkyl. In an embodiment, R 29 R 30 -substituted C6 alkyl. In an embodiment, R 29 It is an unsubstituted C6 alkyl group.

[0265] In an embodiment, R 29 R 30 -substituted or unsubstituted 2 to 8 membered heteroalkyl. In an embodiment, R 29 R 30 -substituted 2 to 8 membered heteroalkyl. In an embodiment, R 29 is an unsubstituted 2 to 8 membered heteroalkyl group. 29 R30 -substituted or unsubstituted 2-membered heteroalkyl. In an embodiment, R 29 R 30 -substituted 2-membered heteroalkyl. In an embodiment, R 29 is an unsubstituted 2-membered heteroalkyl. 29 R 30 -substituted or unsubstituted 3-membered heteroalkyl. In an embodiment, R 29 R 30 -substituted 3-membered heteroalkyl. In an embodiment, R 29 is an unsubstituted 3-membered heteroalkyl. 29 R 30 -substituted or unsubstituted 4-membered heteroalkyl. In an embodiment, R 29 R 30 -substituted 4-membered heteroalkyl. In an embodiment, R 29 is an unsubstituted 4-membered heteroalkyl. 29 R 30 -substituted or unsubstituted 5-membered heteroalkyl. In an embodiment, R 29 R 30 -substituted 5-membered heteroalkyl. In an embodiment, R 29 is an unsubstituted 5-membered heteroalkyl. 29 R 30 -substituted or unsubstituted 6-membered heteroalkyl. In an embodiment, R 29 R 30 -substituted 6-membered heteroalkyl. In an embodiment, R 29 is an unsubstituted 6-membered heteroalkyl. 29 R 30 -substituted or unsubstituted 7-membered heteroalkyl. In an embodiment, R 29 R 30 -substituted 7-membered heteroalkyl. In an embodiment, R 29 is an unsubstituted 7-membered heteroalkyl group.

[0266] In an embodiment, R 29 R 30 -substituted or unsubstituted C4-C6 cycloalkyl. In an embodiment, R 29 R 30 -substituted C4-C6 cycloalkyl. In an embodiment, R 29 R 30 -substituted C4-C6 cycloalkyl. In an embodiment, R 29 R 30 -substituted or unsubstituted C4 cycloalkyl. In an embodiment, R29 R 30 -substituted C4 cycloalkyl. In an embodiment, R 29 R 30 -substituted C4 cycloalkyl. In an embodiment, R 29 R 30 -substituted or unsubstituted C5 cycloalkyl. In an embodiment, R 29 R 30 -substituted C5 cycloalkyl. In an embodiment, R 29 R 30 -substituted C5 cycloalkyl.

[0267] In an embodiment, R 29 R 30 -substituted or unsubstituted 5 to 6 membered heterocycloalkyl. In an embodiment, R 29 R 30 -substituted 5 to 6 membered heterocycloalkyl. In an embodiment, R 29 is an unsubstituted 5- to 6-membered heterocycloalkyl. 29 R 30 -substituted or unsubstituted 5-membered heterocycloalkyl. In an embodiment, R 29 R 30 -substituted 5-membered heterocycloalkyl. In an embodiment, R 29 is an unsubstituted 5-membered heterocycloalkyl. 29 R 30 -substituted or unsubstituted 6-membered heterocycloalkyl. In an embodiment, R 29 R 30 -substituted 6-membered heterocycloalkyl. In an embodiment, R 29 is an unsubstituted 6-membered heterocycloalkyl.

[0268] In an embodiment, R 29 R 30 -substituted or unsubstituted phenyl. In an embodiment, R 29 R 30 -substituted phenyl. In an embodiment, R 29 is an unsubstituted phenyl group.

[0269] In an embodiment, R 29 R 30 -substituted or unsubstituted 5- to 6-membered heteroaryl. In one embodiment, R 29 R 30 -substituted 5- to 6-membered heteroaryl. In an embodiment, R 29 is an unsubstituted 5- to 6-membered heteroaryl. 29 R30 -substituted or unsubstituted 5-membered heteroaryl. In one embodiment, R 29 R 30 -substituted 5-membered heteroaryl. In one embodiment, R 29 is an unsubstituted 5-membered heteroaryl. 29 R 30 -substituted or unsubstituted 6-membered heteroaryl. In one embodiment, R 29 R 30 -substituted 6-membered heteroaryl. In an embodiment, R 29 is an unsubstituted 6-membered heteroaryl group.

[0270] In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7for In an embodiment, R 7 for In an embodiment, R 7 for In an embodiment, R 7 for

[0271] In an embodiment, R 7 In the embodiment, R 7 is -CH3. In an embodiment, R 7 In an embodiment, R 7 is -NHC(O)NH2. In an embodiment, R 7 In the embodiment, R 7 is -NH2. In an embodiment, R 7 is -CONH2. In an embodiment, R 7 is -NHC(O)OH. In an embodiment, R 7 In the embodiment, R 7 is -NHSO2CH3. In an embodiment, R 7 is -SO2CH2CH3. In an embodiment, R 7 -SO2R 29 In an embodiment, R 7 is -SO2CH(CH3)2. In an embodiment, R 7 In the embodiment, R 7 is -NHCOCH3. In an embodiment, R 7 is -NHSO2CH(CH3)2. In an embodiment, R 7 is -NHCOCH(CH3)2. In an embodiment, R 7 is -NHCOOCH3. In an embodiment, R 7 is -SO2NHCH3. In an embodiment, R 7 is -CONHCH3. In an embodiment, R 7 is -CON(CH3)2. In an embodiment, R 7 In the embodiment, R 7 is unsubstituted morpholinyl. In an embodiment, R 7 is unsubstituted imidazolyl. In an embodiment, R 7 is unsubstituted thianyl. In an embodiment, R 7 is unsubstituted tetrahydropyranyl. In an embodiment, R 7 is unsubstituted pyrazolyl. In an embodiment, R7 is unsubstituted pyrrolidinyl. In an embodiment, R 7 R 29 -substituted morpholinyl. In an embodiment, R 7 R 29 -substituted imidazolyl. In an embodiment, R 7 R 29 -substituted thianyl. In an embodiment, R 7 R 29 -substituted tetrahydropyranyl. In an embodiment, R 7 R 29 -substituted pyrazolyl. In an embodiment, R 7 R 29 -substituted pyrrolidinyl. In an embodiment, R 7 is -CH3. In an embodiment, R 7 is an unsubstituted methyl group. In an embodiment, R 7 is an unsubstituted ethyl group. In an embodiment, R 7 is unsubstituted propyl. In an embodiment, R 7 is unsubstituted n-propyl. In an embodiment, R 7 is unsubstituted isopropyl. In an embodiment, R 7 is unsubstituted butyl. In an embodiment, R 7 is unsubstituted n-butyl. In an embodiment, R 7 is unsubstituted isobutyl. In one embodiment, R 7 is unsubstituted tert-butyl. In an embodiment, R 7 is unsubstituted pentyl. In an embodiment, R 7 is unsubstituted n-pentyl. In an embodiment, R 7 is an unsubstituted hexyl. In an embodiment, R 7 is unsubstituted heptyl. In an embodiment, R 7 R 29 -substituted methyl. In an embodiment, R 7 R 29 -substituted ethyl. In an embodiment, R 7 R 29 -substituted propyl. In an embodiment, R 7 R 29 -substituted n-propyl. In an embodiment, R 7 R 29 -substituted isopropyl. In an embodiment, R 7 R 29 -substituted butyl. In an embodiment, R 7 R29 -substituted n-butyl. In an embodiment, R 7 R 29 -substituted isobutyl In an embodiment, R 7 R 29 -substituted tert-butyl. In an embodiment, R 7 R 29 -substituted pentyl. In an embodiment, R 7 R 29 -substituted n-pentyl. In an embodiment, R 7 for R29 -substituted hexyl. In an embodiment, R 7 R 29 -substituted heptyl.

[0272] In an embodiment, R 7 is hydrogen, R 29 -substituted or unsubstituted alkyl, phenyl, -F, -OH, CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SO2NH2, -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH3, -CH2SO2CH3, -(CH2)2SO2CH3, -CH2SO2NH2, or -(CH2)2SO2NH2.

[0273] In an embodiment, R 7 It is R 29 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 7 It is R 29 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 7 is an unsubstituted alkyl group (e.g., a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group). 7 is unsubstituted C1-C4 alkyl. In an embodiment, R 7 is an unsubstituted C1-C3 alkyl. In an embodiment, R 7 is unsubstituted C1-C2 alkyl. In an embodiment, R 7 is an unsubstituted C4 alkyl. In an embodiment, R 7is an unsubstituted C3 alkyl. In an embodiment, R 7 It is R 29 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 7 It is R 29 -substituted C1-C4 alkyl. In an embodiment, R 7 It is R 29 -substituted C1-C3 alkyl. In an embodiment, R 7 It is R 29 -substituted C1-C2 alkyl. In an embodiment, R 7 It is R 29 -substituted C4 alkyl. In an embodiment, R 7 It is R 29 -substituted C3 alkyl.

[0274] In an embodiment, R 7 It is R 29 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 7 It is R 29 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 7 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0275] In an embodiment, R 7 It is R 29 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 7 It is R 29 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 7 is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). 7 is an unsubstituted C3-C6 cycloalkyl. In an embodiment, R 7 is an unsubstituted C3-C5 cycloalkyl. 7 is an unsubstituted C3-C4 cycloalkyl. In an embodiment, R 7 is unsubstituted C4 cycloalkyl. In an embodiment, R 7 It is R 29 -substituted C3-C6 cycloalkyl. In an embodiment, R7 It is R 29 -substituted C3-C5 cycloalkyl. In an embodiment, R 7 It is R 29 -substituted C3-C4 cycloalkyl. In an embodiment, R 7 It is R 29 Substituted C4 cycloalkyl.

[0276] In an embodiment, R 7 It is R 29 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 7 It is R 29 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 7 is unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 7 It is R 29 -substituted 5 to 6 membered heterocycloalkyl. In an embodiment, R 7 It is R 29 -substituted 5-membered heterocycloalkyl. 7 It is R 29 -substituted 6-membered heterocycloalkyl.

[0277] In an embodiment, R 7 It is R 29 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 7 It is R 29 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 7 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0278] In an embodiment, R 7 It is R 29 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 7 It is R 29 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 7is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0279] In an embodiment, R 8 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. In one embodiment, R 8 It's hydrogen.

[0280] In an embodiment, R 8 Halogen, -CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 、-CN、-N3、-SO n8 R 8A 、-SO v8 NR 8B R8C 、-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 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0281] In an embodiment, R 8 It is R 32 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 8 It is R 32-substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 8 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0282] In an embodiment, R 8 It is R 32 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 8 It is R 32 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 8 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0283] In an embodiment, R 8 It is R 32 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 8 It is R 32 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 8 is an unsubstituted cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0284] In an embodiment, R 8 It is R 32 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 8 It is R 32 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 8 is unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0285] In an embodiment, R 8 It is R 32 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 8 It is R 32 -substituted aryl (e.g., C6-C 10Aryl, C 10 aryl or phenyl). In an embodiment, R 8 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0286] In an embodiment, R 8 It is R 32 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 8 It is R 32 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 8 is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0287] In an embodiment, R 9 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. -OCH2X8.1 , 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. In one embodiment, R 9 It's hydrogen.

[0288] In an embodiment, R 9 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 、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 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0289] In an embodiment, R 9 It is R 35 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 9 It is R 35 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 9 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0290] In an embodiment, R 9 It is R 35 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 9 It is R 35 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 9 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0291] In an embodiment, R 9 It is R 35 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 9 It is R 35 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 9 is an unsubstituted cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0292] In an embodiment, R 9 It is R 35-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 9 It is R 35 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 9 is unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0293] In an embodiment, R 9 It is R 35 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 9 It is R 35 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 9 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0294] In an embodiment, R 9 It is R 35 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 9 It is R 35 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 9 is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0295] In an embodiment, R 9 For hydrogen, -CN, halogen, -CF3, -COOH, -COOCH2CH3, -CH3. In an embodiment, R 9 is hydrogen. In an embodiment, R 9 In an embodiment, R 9 is halogen. In an embodiment, R 9 In an embodiment, R 9 In the embodiment, R 9 is -Br. In an embodiment, R 9 In an embodiment, R 9In the embodiment, R 9 In an embodiment, R 9 is -COOCH2CH3. In an embodiment, R 9 is -CH3. In an embodiment, R 9 is -CHCH2CH2OH. In an embodiment, R 9 for In an embodiment, R 9 is a substituted or unsubstituted C1-C4 alkyl group. 9 is a substituted C1-C4 alkyl. 9 It is an unsubstituted C1-C4 alkyl group.

[0296] In an embodiment, R 9 Halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 9D 、-C(O)OR 9D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl. In an embodiment, R 9 Halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 9D 、-C(O)OR 9D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl.

[0297] In an embodiment, R 9 R 35 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 9 R 35 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 9 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0298] In an embodiment, R 9 R 35 -substituted or unsubstituted methyl. In an embodiment, R 9 R 35 -substituted or unsubstituted C2 alkyl. In an embodiment, R 9 R 35 -substituted or unsubstituted C3 alkyl. In an embodiment, R 9 R 35-substituted or unsubstituted C4 alkyl. In an embodiment, R 9 R 35 -substituted or unsubstituted C5 alkyl. In an embodiment, R 9 R 35 -substituted or unsubstituted C6 alkyl. In an embodiment, R 9 R 35 -substituted or unsubstituted C7 alkyl. In an embodiment, R 9 R 35 -substituted or unsubstituted C8 alkyl. In an embodiment, R 9 R 35 -substituted methyl. In an embodiment, R 9 R 35 -substituted C2 alkyl. In an embodiment, R 9 R 35 -substituted C3 alkyl. In an embodiment, R 9 R 35 -substituted C4 alkyl. In an embodiment, R 9 R 35 -substituted C5 alkyl. In an embodiment, R 9 R 35 -substituted C6 alkyl. In an embodiment, R 9 R 35 -substituted C7 alkyl. In an embodiment, R 9 R 35 -substituted C8 alkyl. In an embodiment, R 9 is an unsubstituted methyl group. In an embodiment, R 9 is an unsubstituted C2 alkyl. In an embodiment, R 9 is an unsubstituted C3 alkyl. In an embodiment, R 9 is an unsubstituted C4 alkyl. In an embodiment, R 9 is an unsubstituted C5 alkyl. 9 is an unsubstituted C6 alkyl. In an embodiment, R 9 is an unsubstituted C7 alkyl. In an embodiment, R 9 It is an unsubstituted C8 alkyl group.

[0299] In an embodiment, X 2 CR 9 ; and R 9 Hydrogen, -CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 , -CN, or substituted or unsubstituted C1-C4 alkyl. In the embodiment, X2 CR 9 ; and R 9 In an embodiment, X 2 CR 9 ; and R 9 For-CX 9.1 3. In the embodiment, X 2 CR 9 ; and R 9 -CHX 9.1 2. In the embodiment, X 2 CR 9 ; and R 9 -CH2X 9.1 In an embodiment, X 2 CR 9 ; and R 9 In the embodiment, X 2 CR 9 ; and R 9 is a substituted or unsubstituted C1-C4 alkyl group. 9 is hydrogen, -CF3, or unsubstituted methyl.

[0300] In an embodiment, R 4 and R 9 The alkyl radicals may be optionally linked to form substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6 ... 10 Aryl, C 10 aryl, or phenyl), or 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).

[0301] In an embodiment, R 4 and R 9 Can be optionally linked to form a substituted or unsubstituted C5-C7 cycloalkyl. In an embodiment, R 4 and R 9 Can be optionally linked to form a substituted C5-C7 cycloalkyl. In an embodiment, R 4 and R 9 Can be optionally linked to form an unsubstituted C5-C7 cycloalkyl.

[0302] In an embodiment, R 4 and R 9may be optionally linked to form a substituted or unsubstituted 5 to 7 membered heterocycloalkyl. 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.

[0303] In an embodiment, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted phenyl group. In an embodiment, R 4 and R 9 Can be optionally linked to form a substituted phenyl group. In an embodiment, R 4 and R 9 Optionally linked to form an unsubstituted phenyl group.

[0304] In an embodiment, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted 5 to 7 membered heteroaryl. In one embodiment, R 4 and R 9 may be optionally linked to form a substituted 5- to 7-membered heteroaryl. In an embodiment, R 4 and R 9 may be optionally linked to form an unsubstituted 5- to 7-membered heteroaryl. In one embodiment, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted 5- to 6-membered heteroaryl. In one embodiment, R 4 and R 9 may be optionally linked to form a substituted 5- to 6-membered heteroaryl. In an embodiment, R 4 and R 9 Optionally linked to form an unsubstituted 5- to 6-membered heteroaryl.

[0305] In an embodiment, R 4 and R 9 Can be optionally linked 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-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 4 and R 9 may be optionally linked to form an unsubstituted phenyl group. In an embodiment, R 4 and R 9 Can be optionally linked to form an unsubstituted C5 cycloalkyl. In an embodiment, R 4 and R 9 Can be optionally linked to form an unsubstituted C6 cycloalkyl. In an embodiment, R 4 and R 9 Optionally linked to form an unsubstituted thienyl group.

[0306] In an embodiment, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). 4 and R 9 may be optionally linked to form a substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 4 and R 9 Can be optionally linked to form R 20 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 4 and R 9 Can be optionally linked to form R 20 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 4 and R 9 They may be optionally linked to form an unsubstituted cycloalkyl group (eg, a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0307] In an embodiment, R 4 and R 9 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). 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). In an embodiment, R 4 and R 9Can be optionally linked to form R 20 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 4 and R 9 Can be optionally linked to form R 20 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, 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).

[0308] In an embodiment, R 4 and R 9 may be optionally linked to form a substituted or unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In an embodiment, R 4 and R 9 Can be optionally linked to form a substituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In an embodiment, R 4 and R 9 Can be optionally linked to form R 20 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In an embodiment, R 4 and R 9 Can be optionally linked to form R 20 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In an embodiment, R 4 and R 9 may be optionally linked to form an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0309] In an embodiment, 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 9may 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). In an embodiment, R 4 and R 9 Can be optionally linked to form R 20 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 4 and R 9 Can be optionally linked to form R 20 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 4 and R 9 It 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).

[0310] In an embodiment, X 2 CR 9 ; and R 4 and R 9 are connected to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In one embodiment, R 4 and R 9 are connected 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 connected to form an unsubstituted C5-C7 cycloalkyl, an unsubstituted 5- to 7-membered heterocycloalkyl, an unsubstituted phenyl, or an unsubstituted 5- to 6-membered heteroaryl. 4 and R 9 Connected to form an unsubstituted C5 cycloalkyl group, an unsubstituted thienyl group, or an unsubstituted phenyl group.

[0311] In one embodiment, Ring A is a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), a substituted or unsubstituted aryl (e.g., C6 ... 10 Aryl, C 10 aryl, or phenyl), or 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).

[0312] In an embodiment, Ring A is a substituted or unsubstituted C5-C7 cycloalkyl. In an embodiment, Ring A is a substituted C5-C7 cycloalkyl. In an embodiment, Ring A is an unsubstituted C5-C7 cycloalkyl.

[0313] In an embodiment, Ring A is a substituted or unsubstituted 5- to 7-membered heterocycloalkyl. In an embodiment, Ring A is a substituted 5- to 7-membered heterocycloalkyl. In an embodiment, Ring A is an unsubstituted 5- to 7-membered heterocycloalkyl.

[0314] In an embodiment, Ring A is a substituted or unsubstituted phenyl. In an embodiment, Ring A is a substituted phenyl. In an embodiment, Ring A is an unsubstituted phenyl.

[0315] In an embodiment, Ring A is a substituted or unsubstituted 5- to 7-membered heteroaryl. In an embodiment, Ring A is a substituted 5- to 7-membered heteroaryl. In an embodiment, Ring A is an unsubstituted 5- to 7-membered heteroaryl. In an embodiment, Ring A is a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, Ring A is a substituted 5- to 6-membered heteroaryl. In an embodiment, Ring A is an unsubstituted 5- to 6-membered heteroaryl.

[0316] In an embodiment, 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 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, Ring A is unsubstituted phenyl. In one embodiment, Ring A is unsubstituted C5 cycloalkyl. In one embodiment, Ring A is unsubstituted C6 cycloalkyl. In one embodiment, Ring A is unsubstituted thienyl.

[0317] In an embodiment, Ring A is a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, Ring A is a substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, Ring A is R 20-substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In one embodiment, Ring A is R 20 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, Ring A is unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0318] In an embodiment, Ring A is substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, Ring A is substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, Ring A is R 20 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, Ring A is R 20 -substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In an embodiment, Ring A is unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0319] In one embodiment, Ring A is a substituted or unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 In one embodiment, ring A is substituted aryl (e.g., C6-C 10 Aryl, C 10 In one embodiment, ring A is R 20 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 In one embodiment, ring A is R 20 -substituted aryl (e.g., C6-C 10 Aryl, C 10 In one embodiment, Ring A is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl).

[0320] 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). In an embodiment, Ring A 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). In an embodiment, Ring A is R20 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, Ring A is R 20 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, ring A is unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0321] In an embodiment, Ring A is substituted (eg, R 20 -substituted) or unsubstituted aziridinyl, oxiranyl, thiirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, 1,4-dioxanyl, tetrahydro-2H-pyranyl, thianyl, or dithianyl. In an embodiment, Ring A is substituted (e.g., R 20 -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). In an embodiment, Ring A is substituted (e.g., R 20 -substituted) or unsubstituted indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolopyrimidinyl, purinyl, indolizinyl, pyrrolopyrazinyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridopyrazinyl, pteridinyl, pyrazolopyridinyl, quinolyl, isoquinolyl, naphthyridinyl, or carbazolyl.

[0322] In an embodiment, R 9 and R 10 The alkyl radicals may be optionally linked to form substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6 ... 10 Aryl, C 10 aryl, or phenyl), or 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).

[0323] In an embodiment, R 9 and R10 Can be optionally linked to form a substituted or unsubstituted C5-C7 cycloalkyl. In an embodiment, R 9 and R 10 Can be optionally linked to form a substituted C5-C7 cycloalkyl. In an embodiment, R 9 and R 10 Can be optionally linked to form an unsubstituted C5-C7 cycloalkyl.

[0324] In an embodiment, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted 5 to 7 membered heterocycloalkyl. 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.

[0325] In an embodiment, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted phenyl group. In an embodiment, R 9 and R 10 Can be optionally linked to form a substituted phenyl group. In an embodiment, R 9 and R 10 Optionally linked to form an unsubstituted phenyl group.

[0326] In an embodiment, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted 5 to 7 membered heteroaryl. In one embodiment, R 9 and R 10 may be optionally linked to form a substituted 5- to 7-membered heteroaryl. In an embodiment, R 9 and R 10 may be optionally linked to form an unsubstituted 5- to 7-membered heteroaryl. In one embodiment, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted 5- to 6-membered heteroaryl. In one embodiment, R 9 and R 10 may be optionally linked to form a substituted 5- to 6-membered heteroaryl. In an embodiment, R 9 and R 10 Optionally linked to form an unsubstituted 5- to 6-membered heteroaryl.

[0327] In an embodiment, R 9 and R 10 Can be optionally linked to form R35 - 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 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 9 and R 10 may be optionally linked to form an unsubstituted phenyl group. In an embodiment, R 9 and R 10 Can be optionally linked to form an unsubstituted C5 cycloalkyl. In an embodiment, R 9 and R 10 Can be optionally linked to form an unsubstituted C6 cycloalkyl. In an embodiment, R 9 and R 10 Optionally linked to form an unsubstituted thienyl group.

[0328] In an embodiment, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). 9 and R 10 may be optionally linked to form a substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 9 and R 10 Can be optionally linked to form R 35 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 9 and R 10 Can be optionally linked to form R 35 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 9 and R 10 They may be optionally linked to form an unsubstituted cycloalkyl group (eg, a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0329] In an embodiment, R9 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). In an embodiment, R 9 and R 10 Can be optionally linked to form R 35 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 9 and R 10 Can be optionally linked to form R 35 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, 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).

[0330] In an embodiment, R 9 and R 10 may be optionally linked to form a substituted or unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In an embodiment, R 9 and R 10 Can be optionally linked to form a substituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In an embodiment, R 9 and R 10 Can be optionally linked to form R 35 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In an embodiment, R 9 and R 10 Can be optionally linked to form R 35 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In an embodiment, R 9 and R 10 may be optionally linked to form an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10aryl, or phenyl).

[0331] In an embodiment, 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). In an embodiment, R 9 and R 10 Can be optionally linked to form R 35 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 9 and R 10 Can be optionally linked to form R 35 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 9 and R 10 It 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).

[0332] In an embodiment, R 10 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. In one embodiment, R 10 It's hydrogen.

[0333] In an embodiment, R 10 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), R38 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 38 - substituted 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 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0334] In an embodiment, R 10 It is R 38 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 10 It is R 38 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 10 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0335] In an embodiment, R 10 It is R 38 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 10 It is R 38 -substituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl). 10 is unsubstituted heteroalkyl (eg, 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0336] In an embodiment, R 10 It is R 38 -substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 10 It is R 38 -substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In an embodiment, R 10is an unsubstituted cycloalkyl group (e.g., a C3-C8 cycloalkyl group, a C3-C6 cycloalkyl group, or a C5-C6 cycloalkyl group).

[0337] In an embodiment, R 10 It is R 38 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). 10 It is R 38 -substituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl). In an embodiment, R 10 is unsubstituted heterocycloalkyl (eg, 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl).

[0338] In an embodiment, R 10 It is R 38 -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 10 It is R 38 -substituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl). In an embodiment, R 10 is an unsubstituted aryl group (e.g., C6-C 10 Aryl, C 10 aryl or phenyl).

[0339] In an embodiment, R 10 It is R 38 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 10 It is R 38 -substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In one embodiment, R 10 is an unsubstituted heteroaryl group (eg, a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0340] In an embodiment, R 10 For hydrogen, -CN, halogen, -CF3, -COOH, -COOCH2CH3, -CH3. In an embodiment, R 10 is hydrogen. In an embodiment, R 10 In an embodiment, R 10 is halogen. In an embodiment, R 10In an embodiment, R 10 In the embodiment, R 10 is -Br. In an embodiment, R 10 In an embodiment, R 10 In the embodiment, R 10 In an embodiment, R 10 is -COOCH2CH3. In an embodiment, R 10 is -CH3. In an embodiment, R 10 is -CHCH2CH2OH. In an embodiment, R 10 for In an embodiment, R 10 is a substituted or unsubstituted C1-C4 alkyl group. 10 is a substituted C1-C4 alkyl. 10 It is an unsubstituted C1-C4 alkyl group.

[0341] In an embodiment, R 10 Halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 10D 、-C(O)OR 10D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl. In an embodiment, R 10 Halogen, -CF3, -CHF2, -CH2F, -CN, -N3, -SO2CH3, -C(O)R 10D 、-C(O)OR 10D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl.

[0342] In an embodiment, R 10 R 38 -substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 10 R 38 -substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In an embodiment, R 10 is an unsubstituted alkyl group (eg, a C1-C8 alkyl group, a C1-C6 alkyl group, or a C1-C4 alkyl group).

[0343] In an embodiment, R 10 R 38 -substituted or unsubstituted methyl. In an embodiment, R 10 R 38-substituted or unsubstituted C2 alkyl. In an embodiment, R 10 R 38 -substituted or unsubstituted C3 alkyl. In an embodiment, R 10 R 38 -substituted or unsubstituted C4 alkyl. In an embodiment, R 10 R 38 -substituted or unsubstituted C5 alkyl. In an embodiment, R 10 R 38 -substituted or unsubstituted C6 alkyl. In an embodiment, R 10 R 38 -substituted or unsubstituted C7 alkyl. In an embodiment, R 10 R 38 -substituted or unsubstituted C8 alkyl. In an embodiment, R 10 R 38 -substituted alkyl In an embodiment, R 10 R 38 -substituted C2 alkyl. In an embodiment, R 10 R 38 -substituted C3 alkyl. In an embodiment, R 10 R 38 -substituted C4 alkyl. In an embodiment, R 10 R 38 -substituted C5 alkyl. In an embodiment, R 10 R 38 -substituted C6 alkyl. In an embodiment, R 10 R 38 -substituted C7 alkyl. In an embodiment, R 10 R 38 -substituted C8 alkyl. In an embodiment, R 10 is an unsubstituted methyl group. In an embodiment, R 10 is an unsubstituted C2 alkyl. In an embodiment, R 10 is an unsubstituted C3 alkyl. In an embodiment, R 10 is an unsubstituted C4 alkyl. In an embodiment, R 10 is an unsubstituted C5 alkyl. 10 is an unsubstituted C6 alkyl. In an embodiment, R 10 is an unsubstituted C7 alkyl. In an embodiment, R 10 It is an unsubstituted C8 alkyl group.

[0344] In an embodiment, X 3 CR 10 ; and R10 Hydrogen, -CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 , -CN, or substituted or unsubstituted C1-C4 alkyl. In the embodiment, X 3 CR 10 ; and R 10 In an embodiment, X 3 CR 10 ; and R 10 For-CX 10.1 3. In the embodiment, X 3 CR 10 ; and R 10 -CHX 10.1 2. In the embodiment, X 3 CR 10 ; and R 10 -CH2X 10.1 In an embodiment, X 3 CR 10 ; and R 10 In the embodiment, X 3 CR 10 ; and R 10 is a substituted or unsubstituted C1-C4 alkyl group. 10 is hydrogen or -CN.

[0345] 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 a substituted or unsubstituted heteroarylene (e.g., a 5- to 10-membered heteroarylene, a 5- to 9-membered heteroarylene, or a 5- to 6-membered heteroarylene).

[0346] In an embodiment, L 7 is a bond, -O-, -S-, -NR7.2B -, -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 -substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene). In one embodiment, L 7 is a bond. In an embodiment, L 7 Yes 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 - a substituted or unsubstituted cycloalkylene group (e.g., a C3-C8 cycloalkylene group, a C3-C6 cycloalkylene group, or a C5-C6 cycloalkylene group).

[0347] In an embodiment, L 7 R 41 -substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). 7 R 41 -substituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In an embodiment, L 7 is an unsubstituted alkylene group (e.g., a C1-C8 alkylene group, a C1-C6 alkylene group, or a C1-C4 alkylene group). 7 For L 41-substituted or unsubstituted methylene. In an embodiment, L 7 For L 41 -substituted or unsubstituted C2 alkylene. In an embodiment, L 7 For L 41 -substituted or unsubstituted C3 alkylene. In an embodiment, L 7 For L 41 -substituted or unsubstituted C4 alkylene. In an embodiment, L 7 For L 41 -substituted or unsubstituted C5 alkylene. In an embodiment, L 7 For L 41 -substituted or unsubstituted C6 alkylene. In an embodiment, L 7 For L 41 -substituted or unsubstituted C7 alkylene. In an embodiment, L 7 For L 41 -substituted or unsubstituted C8 alkylene. In an embodiment, L 7 For L 41 -substituted methylene. In an embodiment, L 7 For L 41 -substituted C2 alkylene. In an embodiment, L 7 For L 41 -substituted C3 alkylene. In an embodiment, L 7 For L 41 -substituted C4 alkylene. In an embodiment, L 7 For L 41 -substituted C5 alkylene. In the embodiment, L 7 For L 41 -substituted C6 alkylene. In the embodiment, L 7 For L 41 -substituted C7 alkylene. In an embodiment, L 7 For L 41 -substituted C8 alkylene. In an embodiment, L 7 is an unsubstituted methylene group. In an embodiment, L 7 is an unsubstituted C2 alkylene. In an embodiment, L 7 is an unsubstituted C3 alkylene. In an embodiment, L 7 is an unsubstituted C4 alkylene. In an embodiment, L 7 is an unsubstituted C5 alkylene. 7 is an unsubstituted C6 alkylene. In an embodiment, L 7 is an unsubstituted C7 alkylene. In an embodiment, L 7It is an unsubstituted C8 alkylene group.

[0348] In an embodiment, L 7 R 41 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8-membered heteroalkylene, 2 to 6-membered heteroalkylene, or 2 to 4-membered heteroalkylene). In an embodiment, L 7 R 41 -substituted heteroalkylene (e.g., 2 to 8-membered heteroalkylene, 2 to 6-membered heteroalkylene, or 2 to 4-membered heteroalkylene). In an embodiment, L 7 is an unsubstituted heteroalkylene group (eg, a 2- to 8-membered heteroalkylene group, a 2- to 6-membered heteroalkylene group, or a 2- to 4-membered heteroalkylene group).

[0349] In an embodiment, L 7 R 41 -substituted or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In an embodiment, L 7 R 41 -substituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In an embodiment, L 7 is unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). 7 R 41 -substituted or unsubstituted C3-C8 cycloalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C4-C8 cycloalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C4-C6 cycloalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C4 cycloalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C5 cycloalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C6 cycloalkylene. In an embodiment, L 7 R 41 -substituted C3-C8 cycloalkylene. In an embodiment, L 7 R 41 -substituted C4-C8 cycloalkylene. In an embodiment, L 7 R 41-substituted C4-C6 cycloalkylene. In an embodiment, L 7 R 41 -substituted C4 cycloalkylene. In an embodiment, L 7 R 41 -substituted C5 cycloalkylene. In an embodiment, L 7 R 41 -substituted C6 cycloalkylene. In an embodiment, L 7 is an unsubstituted C3-C8 cycloalkylene. 7 is an unsubstituted C4-C8 cycloalkylene. 7 is an unsubstituted C4-C6 cycloalkylene. 7 is unsubstituted C4 cycloalkylene. In the embodiment, L 7 is an unsubstituted C5 cycloalkylene. 7 It is an unsubstituted C6 cycloalkylene group.

[0350] In an embodiment, L 7 It is R 41 -substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8-membered heterocycloalkylene, 3 to 6-membered heterocycloalkylene, or 5 to 6-membered heterocycloalkylene). 7 It is R 41 -substituted heterocycloalkylene (e.g., 3 to 8-membered heterocycloalkylene, 3 to 6-membered heterocycloalkylene, or 5 to 6-membered heterocycloalkylene). In an embodiment, L 7 is an unsubstituted heterocycloalkylene group (eg, a 3- to 8-membered heterocycloalkylene group, a 3- to 6-membered heterocycloalkylene group, or a 5- to 6-membered heterocycloalkylene group).

[0351] In an embodiment, L 7 It is R 41 -substituted or unsubstituted arylene (e.g., C6-C 10 Arylene, C 10 arylene or phenylene). In an embodiment, L 7 It is R 41 -substituted arylene (e.g., C6-C 10 Arylene, C 10 arylene or phenylene). In an embodiment, L 7 is an unsubstituted arylene group (e.g., C6-C 10 Arylene, C 10 arylene or phenylene).

[0352] In an embodiment, L 7 It is R 41-substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene). In one embodiment, L 7 It is R 41 -substituted heteroarylene (e.g., 5- to 10-membered heteroarylene, 5- to 9-membered heteroarylene, or 5- to 6-membered heteroarylene). In one embodiment, L 7 is an unsubstituted heteroarylene group (eg, a 5- to 10-membered heteroarylene group, a 5- to 9-membered heteroarylene group, or a 5- to 6-membered heteroarylene group).

[0353] In an embodiment, L 7 is a bond, a substituted or unsubstituted alkylene group, or a substituted or unsubstituted cycloalkylene group. 7 is a substituted or unsubstituted C4-C6 cycloalkylene group. 7 is an unsubstituted C4-C6 cycloalkylene. 7 is substituted or unsubstituted cyclobutylene. In the embodiment, L 7 is a substituted or unsubstituted alkylene group. 7 is a substituted or unsubstituted C1-C6 alkylene group. 7 is the key.

[0354] In an embodiment, L 7 R 41 -substituted or unsubstituted C1-C6 alkylene. In an embodiment, L 7 R 41 -substituted C1-C6 alkylene. In the embodiment, L 7 is an unsubstituted C1-C6 alkylene. 7 R 41 -substituted or unsubstituted C2-C6 alkylene. In an embodiment, L 7 R 41 -substituted C2-C6 alkylene. In an embodiment, L 7 is an unsubstituted C2-C6 alkylene group. 7 R 41 -substituted or unsubstituted C1 alkylene. In an embodiment, L 7 R 41 -substituted C1 alkylene. In an embodiment, L 7 is an unsubstituted C1 alkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C2 alkylene. In an embodiment, L 7 R41 -substituted C2 alkylene. In an embodiment, L 7 is an unsubstituted C2 alkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C3 alkylene. In an embodiment, L 7 R 41 -substituted C3 alkylene. In an embodiment, L 7 is an unsubstituted C3 alkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C4 alkylene. In an embodiment, L 7 R 41 -substituted C4 alkylene. In an embodiment, L 7 is an unsubstituted C4 alkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C5 alkylene. In an embodiment, L 7 R 41 -substituted C5 alkylene. In the embodiment, L 7 is an unsubstituted C5 alkylene. 7 R 41 -substituted or unsubstituted C6 alkylene. In an embodiment, L 7 R 41 -substituted C6 alkylene. In the embodiment, L 7 It is an unsubstituted C6 alkylene group.

[0355] In an embodiment, L 7 R 41 -substituted or unsubstituted 2 to 8 membered heteroalkylene. In an embodiment, L 7 R 41 -substituted 2 to 8 membered heteroalkylene. In an embodiment, L 7 is an unsubstituted 2 to 8 membered heteroalkylene. 7 R 41 -substituted or unsubstituted 2-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted 2-membered heteroalkylene. In an embodiment, L 7 is an unsubstituted 2-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted 3-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted 3-membered heteroalkylene. In an embodiment, L 7is an unsubstituted 3-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted 4-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted 4-membered heteroalkylene. In an embodiment, L 7 is an unsubstituted 4-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted 5-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted 5-membered heteroalkylene. In an embodiment, L 7 is an unsubstituted 5-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted 6-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted 6-membered heteroalkylene. In an embodiment, L 7 is an unsubstituted 6-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted 7-membered heteroalkylene. In an embodiment, L 7 R 41 -substituted 7-membered heteroalkylene. In an embodiment, L 7 is an unsubstituted 7-membered heteroalkylene group.

[0356] In an embodiment, L 7 R 41 -substituted or unsubstituted C4-C6 cycloalkylene. In an embodiment, L 7 R 41 -substituted C4-C6 cycloalkylene. In an embodiment, L 7 R 41 -substituted C4-C6 cycloalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C4 cycloalkylene. In an embodiment, L 7 R 41 -substituted C4 cycloalkylene. In an embodiment, L 7 R 41 -substituted C4 cycloalkylene. In an embodiment, L 7 R 41 -substituted or unsubstituted C5 cycloalkylene. In an embodiment, L 7 R 41 -substituted C5 cycloalkylene. In an embodiment, L 7 R41 -substituted C5 cycloalkylene.

[0357] In an embodiment, L 7 R 41 -substituted or unsubstituted 5 to 6 membered heterocycloalkylene. In an embodiment, L 7 R 41 -substituted 5 to 6 membered heterocycloalkylene. In an embodiment, L 7 is an unsubstituted 5- to 6-membered heterocycloalkylene. 7 R 41 -substituted or unsubstituted 5-membered heterocycloalkylene. In an embodiment, L 7 R 41 -substituted 5-membered heterocycloalkylene. In an embodiment, L 7 is an unsubstituted 5-membered heterocycloalkylene. 7 R 41 -substituted or unsubstituted 6-membered heterocycloalkylene. In an embodiment, L 7 R 41 -substituted 6-membered heterocycloalkylene. In an embodiment, L 7 is an unsubstituted 6-membered heterocycloalkylene.

[0358] In an embodiment, L 7 R 41 -substituted or unsubstituted phenylene. In an embodiment, L 7 R 41 -substituted phenylene. In an embodiment, L 7 is an unsubstituted phenylene group.

[0359] In an embodiment, L 7 R 41 -substituted or unsubstituted 5- to 6-membered heteroarylene. In an embodiment, L 7 R 41 -substituted 5- to 6-membered heteroarylene. In an embodiment, L 7 is an unsubstituted 5- to 6-membered heteroarylene. In an embodiment, L 7 R 41 -substituted or unsubstituted 5-membered heteroarylene. In an embodiment, L 7 R 41 -substituted 5-membered heteroarylene. In an embodiment, L 7 is an unsubstituted 5-membered heteroarylene. In an embodiment, L 7 R 41 -substituted or unsubstituted 6-membered heteroarylene. In an embodiment, L 7 R41 -substituted 6-membered heteroarylene. In an embodiment, L 7 is an unsubstituted 6-membered heteroarylene group.

[0360] In an embodiment, L 7 for In an embodiment, L 7 is -CH2CH2-. In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 is -CH2-. In an embodiment, L 7 is -CH2CH2CH2-. In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for In an embodiment, L 7 for

[0361] In an embodiment, L 7 is an unsubstituted methylene group. In an embodiment, L 7 is unsubstituted ethylene. In the embodiment, L 7 is unsubstituted propylene. In the embodiment, L 7 is unsubstituted n-propylene. In the embodiment, L7 is unsubstituted isopropylidene. In the embodiment, L 7 is unsubstituted butylene. In the embodiment, L 7 is unsubstituted n-butylene. In the embodiment, L 7 is unsubstituted isobutylene. In the embodiment, L 7 is unsubstituted tert-butylene. In the embodiment, L 7 is unsubstituted pentylene. In the embodiment, L 7 is unsubstituted n-pentylene. In the embodiment, L 7 is an unsubstituted hexamethylene group. 7 is unsubstituted heptylene. In the embodiment, L 7 is a substituted methylene. In an embodiment, L 7 is a substituted ethylene group. 7 is a substituted propylene group. In the embodiment, L 7 is a substituted n-propylene group. In the embodiment, L 7 is substituted isopropylidene. In the embodiment, L 7 is a substituted butylene group. In the embodiment, L 7 is a substituted n-butylene group. 7 is substituted isobutylene. In the embodiment, L 7 is a substituted tert-butylene group. 7 is a substituted pentylene. In the embodiment, L 7 is a substituted n-pentylene. In the embodiment, L 7 is a substituted hexamethylene. 7 is a substituted heptylene.

[0362] In an embodiment, -L 7 -R 7 is a carboxylic acid-substituted cyclobutyl group, a carboxylic acid-substituted cyclopentyl group, or a hydroxy-substituted ethyl group; all of which are further substituted by substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0363] In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7-R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for In an embodiment, -L 7 -R 7 for

[0364] In an embodiment, R 1A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 11A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 11A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 11A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 11A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 11A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 11A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0365] In an embodiment, R 2A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 14A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 14A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 14A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 14A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 14A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 14A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0366] In an embodiment, R 3A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 17A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 17A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 17A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 17A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 17A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0367] In an embodiment, R 3.2A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 17.2A- substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17.2A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 17.2A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 17.2A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 17.2A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 17.2A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0368] In an embodiment, R 3.3A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 17.3A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17.3A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 17.3A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 17.3A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 17.3A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 17.3A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0369] In an embodiment, R 4A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 20A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 20A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R20A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 20A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 20A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 20A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0370] In an embodiment, R 5A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 23A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 23A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 23A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 23A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 23A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 23A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0371] In an embodiment, R 6A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 26A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 26A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 26A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 26A-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 26A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 26A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0372] In an embodiment, R 7A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 29A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 29A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 29A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 29A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 29A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 29A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0373] In an embodiment, R 8A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 32A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 32A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 32A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 32A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 32A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C10 aryl or phenyl) or R 32A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0374] In an embodiment, R 9A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 35A - substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 35A -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 35A - substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl or C5-C6 cycloalkyl), R 35A -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 35A -substituted or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl) or R 35A - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0375] In an embodiment, R 10A It is hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 38A - substituted or unsubstituted a...

Claims

1. A compound having structural formula (IIa) or a pharmaceutically acceptable salt thereof: in: X 3 It's CR 10 ; z4 is 1; L 7 is an unsubstituted C1-C4 alkylene group or an unsubstituted C3-C8 cycloalkylene group; R 1 and R 2 are independently hydrogen or unsubstituted C1-C4 alkyl; R 3.2 and R 3.3 is a halogen; R 4 is hydrogen, -CN, or unsubstituted C1-C4 alkyl; R 7 is -C(O)OR 7D 、 or -OR 7A ; R 10 is hydrogen or -CN; R 44 is hydrogen; and R 7A and R 7D are independently hydrogen.

2. A compound having structural formula (IIb) or a pharmaceutically acceptable salt thereof: in: X 2 It's CR 9 ; z4 is 1; L 7 is an unsubstituted C1-C4 alkylene group, a C1-C4 alkylene group substituted by an oxo group, an unsubstituted C3-C8 cycloalkylene group, or a C3-C8 cycloalkylene group substituted by an unsubstituted C1-C4 alkyl group; R 1 and R 2 are independently hydrogen or unsubstituted C1-C4 alkyl; R 3.2 and R 3.3 are independently halogen; R 4 is hydrogen, halogen, -CN, unsubstituted C1-C4 alkyl, C1-C4 alkyl substituted with a substituent selected from oxo, halogen and unsubstituted 3-6 membered heterocycloalkyl, unsubstituted 2-4 membered heteroalkyl, 2-4 membered heteroalkyl substituted with unsubstituted C3-C6 cycloalkyl, or unsubstituted C3-C6 cycloalkyl, or R 4 and R 9 Can be optionally linked to form unsubstituted C5-C7 cycloalkyl, unsubstituted 5-7 membered heterocycloalkyl, unsubstituted C 6-10 aryl, or unsubstituted 5-10 membered heteroaryl; R 7 Yes-C(O)OR 7D 、-OR 7A , unsubstituted 2-4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by unsubstituted C1-C4 alkyl, or 3-6 membered heterocycloalkyl substituted by oxo; R 9 is hydrogen, unsubstituted C1-C4 alkyl, C1-C4 alkyl substituted with a substituent selected from oxo and halogen, unsubstituted 2-4 membered heteroalkyl, or unsubstituted C3-C6 cycloalkyl; R 44 is hydrogen; and R 7A and R 7D are independently hydrogen.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein: R 9 is hydrogen, unsubstituted C1-C2 alkyl, or C1-C2 alkyl substituted by a substituent selected from oxo and halogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 10 For hydrogen.

5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, halogen, -CN, unsubstituted C1-C2 alkyl, C1-C2 alkyl substituted by a substituent selected from oxo, halogen and unsubstituted 5-6 membered heterocycloalkyl, unsubstituted 2-3 membered heteroalkyl, or 2-3 membered heteroalkyl substituted by unsubstituted C3-C6 cycloalkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl, -Br, -F, -CN, -CF3 or -CH3.

7. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 9 The groups are connected to form an unsubstituted C5-C7 cycloalkyl group, an unsubstituted 5- to 7-membered heterocycloalkyl group, an unsubstituted phenyl group, or an unsubstituted 5- to 6-membered heteroaryl group.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 9 The groups are linked to form an unsubstituted C5 cycloalkyl group, an unsubstituted thienyl group, or an unsubstituted phenyl group.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 7 It is an unsubstituted C1-C3 alkylene group or an unsubstituted C4-C6 cycloalkylene group.

10. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein L 7 It is an unsubstituted C1-C3 alkylene group, a C1-C3 alkylene group substituted by an oxo group, an unsubstituted C4-C6 cycloalkylene group, or a C4-C6 cycloalkylene group substituted by an unsubstituted C1-C4 alkyl group.

11. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 7 For-OR 7A 、-C(O)OR 7D , unsubstituted 2-3 membered heteroalkyl, unsubstituted C4-C6 cycloalkyl, C4-C6 cycloalkyl substituted by unsubstituted C1-C4 alkyl, 4-6 membered heterocycloalkyl substituted by oxo, -C(O)OH, 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein -L 7 -R 7 It is a cyclobutyl group substituted by carboxylic acid, a cyclopentyl group substituted by carboxylic acid, or an ethyl group substituted by hydroxyl.

13. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein -L 7 -R 7 is a carboxylic acid-substituted cyclobutyl group, a carboxylic acid-substituted cyclopentyl group, or a hydroxy-substituted ethyl group, wherein the cyclobutyl group and the cyclopentyl group are optionally substituted with an unsubstituted C1-C4 alkyl group.

14. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein -L 7 -R 7 for 15. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein -L 7 -R 7 for 16. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

17. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

18. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

19. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

20. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

21. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

22. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

23. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

24. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

25. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

26. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

27. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

28. Compounds having the formula: or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

30. Use of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease or condition mediated by CCR4, wherein the disease or condition is selected from an immune or inflammatory disease or condition, a cardiovascular or metabolic disease or condition, or cancer.

31. The use of claim 30, wherein the disease or condition is an immune or inflammatory disease or condition, wherein the medicament is for administration to a subject in combination with an anti-inflammatory agent, wherein the anti-inflammatory agent is thalidomide or a derivative thereof, a retinoid, anthracenetriol, calcipotriol, a nonsteroidal anti-inflammatory agent, a cyclooxygenase inhibiting nitric oxide donor, a glucocorticoid, methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, an analgesic, diacerein, a hyaluronic acid derivative, or a nutritional supplement.

32. The use of claim 30, wherein the disease or condition is a cardiovascular or metabolic disease or condition, wherein the medicament is for administration to a subject in combination with a cardiovascular agent or a metabolic disorder agent, wherein the cardiovascular agent is a calcium channel blocker, a beta-adrenergic receptor blocker, an angiotensin converting enzyme inhibitor, an angiotensin-2 receptor antagonist, a lipid-lowering agent, a blood cell morphology regulator, a thrombolytic agent, or an anticoagulant.

33. The use of claim 30, wherein the disease or condition is cancer, wherein the cancer is colon cancer or pancreatic cancer.

34. The method of claim 33, wherein the medicament is administered to an individual in combination with a chemotherapeutic agent or an anticancer agent, wherein the chemotherapeutic agent or anticancer agent is an antiproliferative / antitumor agent, an antimetabolite, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, an inhibitor of 5α-reductase, an agent that inhibits cancer cell invasion, an inhibitor of growth factor function, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine / threonine kinase inhibitor, an inhibitor of the epidermal growth factor family, an inhibitor of the platelet-derived growth factor family, an inhibitor of the hepatocyte growth factor family; an anti-angiogenic agent, a vascular damaging agent, an agent for antisense therapy, an agent for gene therapy, an immunotherapeutic agent, or an antibody.

35. The use according to claim 34, wherein the antiproliferative / antitumor drug is an antitumor antibiotic.

36. The use according to claim 34, wherein the agent for antisense therapy is an anti-ras antisense agent.

37. The use according to claim 34, wherein the chemotherapeutic agent or anticancer agent is an inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, or an agonist antibody of CD137; or wherein the chemotherapeutic agent or anticancer agent is an immunomodulator, wherein the immunomodulator is selected from TIM-3, LAG-3, B7-H3, TIGIT, BTLA, CD28, CD40, CD80, GITR, ICOS, OX40, NKG2A, TGF-β, IL2, IL12, IL7, IL15, IL21, IL13, CSF1R, PI3Kδ, PI3Kγ, (DNA methyltransferase inhibitors, histone deacetylase, Brd4, histone methyltransferase, LSD 1. TNFa, IL1, IFNa, IFNb, IFNg, STING, TLR, IL10, CCR2, CCR5, CXCR4, LFA1, MICA / B, VISTA, adenosine, CD39, CD73, PD1, PD-L1, PD-L2, CTLA4, CD137, AXL, MERTK, TYRO, BTK, ITK, LCK, TET2, arginase, GCN2, B7-H4, HIF1α, LIGHT, FLT3, CD158, CD47, IDO, RORγ, TSR-022, MGB453, BMS-986016, IMP321, MGA271, MGD-009, RG-6058, AMG 557, SEA-CD40, daclizumab, CP-870,893, Chi Lob7 / 4, rukalimumab, galiximab, INCAGN1876, TRX518, MEDI-570, MEDI-6469, INCAGN1949, huMab OX40L, monalizumab, galunisertib, luspatercept, YH-14618, dalantercept, BG-00011, trabedersen, isth-0036, ace-083, NKTR-214, recombinant IL-2, aldesleukin, EGEN-001, NHS-IL12, recombinant IL-7, NIZ-985, ALT-803, recombinant IL-21, anti-CD20, IL-21, tralase okinumab, dupilumab, cabiralizumab, INCB50465, idealisib, TGR-1202, AMG319, IPI-549, azacytidine, decitabine, guadecitabine, vorinostat, panobinostat, belinostat, entinostat, modinostat, givinostat, cedabendine, quicinostat, esinostat, chr-3996, ar-42, INCN54329, INCB57643, bilarisib,Abelon, flavopiridol, PLX-51107, FT-1101, RG-6146, AZD-8186, CPI-0610, JQ1, INCB59872, IMG-7289, RG-6016, CC-90011, GSK-2879552, ORY-2001, 4SC-202, ORY-3001, recombinant TNFa, MEDI-1873, FPA-154, LKZ-145, recombinant IL1, recombinant interferon α-n1, recombinant interferon α-2b, recombinant interferon α-n3, recombinant IFNβ-1a, actimmune, cyclic dinucleotide, poly I:C, IMO-2055, TMX-101, miRNA Quinmod, CpG, MGN1703, glucopyranosyl lipid A, CBLB502, BCG, HILTONOL, AMPLIGEN, MOTOLIMOD, DUK-CPG-001, AS15, recombinant IL-10, CCX140, CCX872, BMS-813160, CENICRIVIROC, CNTX-6970, PF-4136309, plozalizumab, INCB-9471, PF-04634817, maraviroc, PRO-140, BMS-813160, NIFEVIROC, OHR-118, ulocuplumab, plerixafor, x4p-00 1. 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, Oleclumab, PBF-1662, anti-CD73 antibody, pembrolizumab, nivolumab, INCSHR1210, CT-011, AMP224, atezolizumab, Vetumab, tremelimumab, urelumab, utomilumab, BMS-663513, PF-05082566, BGB-324, BPI-9016M, S-49076, ibrutinib, Cb-1158, MDX-1140, AMP-110, PT2385, CDX-301, FLX925, quizartinib, gilteritinib, PKC412, midostaurin, crenolanib, lirlumab, IPH-2101, anti-CD47, TTI-621, NI-1701, SRF-231, Effi-DEM, RCT-1938, epacadostat,F287, BMS983205, GDC-0919, or indoximod, or any combination thereof.

38. The use according to claim 30, wherein the disease or disorder is an allergy-related disease or disorder.

39. The use according to claim 30, wherein the disease or disorder is inflammation.

40. The use according to claim 39, wherein the disease or condition is asthma, urticaria, rhinitis or dermatitis.

41. The use according to claim 40, wherein the asthma is allergic asthma.

42. The use according to claim 40, wherein the dermatitis is contact dermatitis.

43. The use according to claim 40, wherein the urticaria is autoimmune urticaria.

44. The use according to claim 40, wherein the rhinitis is allergic rhinitis.

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