Nurr1 receptor modulators

Abstract

In particular, Nurr1 receptor modulators and uses thereof are described herein. In one aspect, there is provided a method for treating a disease associated with dopaminergic neuron dysregulation and / or degeneration of the central nervous system of a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

Description

[0001] This application is a divisional application of Chinese patent application 202080028466.6, filed on February 19, 2020, with the invention name “NURR1 receptor modulator”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 807,642, filed on February 19, 2019, which is incorporated herein by reference in its entirety for all purposes.

[0004] Reference to a "Sequence Listing", table or computer program listing appendix submitted as an ASCII file

[0005] The sequence listing written in the file 048536-637001WO_Sequence_Listing_ST25.txt, created on January 14, 2020, with 19,310 bytes, machine format IBM-PC, using MSWindows operating system, is incorporated herein by reference.

[0006] STATEMENT REGARDING RIGHTS TO INVENTS RESULTING FROM FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0007] This invention was made with government support under Contract No. R01 NS108404 awarded by the National Institutes of Health. The government has certain rights in this invention. Background Art

[0008] There are currently more than one million Americans suffering from Parkinson's disease (PD), and approximately 60,000 new cases are diagnosed each year. In an estimated 90% of PD patients, the cause of the disease is unknown, with no clear genetic or environmental origin. The most significant neuropathological feature of PD is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and the resulting decrease in dopamine levels in the striatum, which manifests as impaired motor function (e.g., rigidity, tremor, bradykinesia). Although the molecular basis of idiopathic PD is still not fully understood, it has been proposed to involve oxidative stress, mitochondrial dysfunction, and dopamine homeostasis disorders. Currently, there is no available treatment to prevent or even slow the progression of PD. Existing therapies relieve PD symptoms by increasing dopaminergic signaling through one of three mechanisms: (1) increasing dopamine levels by increasing the amount of its biosynthetic precursor L-DOPA; (2) blocking the breakdown of dopamine by inhibiting dopamine's metabolic enzymes (monoamine oxidase (MAO), COMT); (3) mimicking dopamine activity by directly exciting dopamine receptors. However, these drugs only partially relieve symptoms and can produce significant side effects, especially as the disease progresses. New therapies are urgently needed to combat the symptoms and progression of PD. Solutions to these and other problems in the art are disclosed herein, among other things. Summary of the invention

[0009] In one aspect, a compound having the following formula is provided:

[0010]

[0011] Ring A is an aryl group or a heteroaryl group.

[0012] L 1 For L 101 -L 102 -L 103 .

[0013] L 101 is a bond, -S(O) 2 -、-N(R 101 )-, -O-, -S-, -C(O)-, -C(O)N(R 101 )-、-N(R 101 )C(O)-、-N(R 101 )C(O)NH-、-NHC(O)N(R 101 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, L 104 -L105 , L 104 -NH-L 105 or L 104 -CH 2 -L 105 .

[0014] L 102 is a bond, -S(O) 2 -、-N(R 102 )-, -O-, -S-, -C(O)-, -C(O)N(R 102 )-、-N(R 102 )C(O)-、-N(R 102 )C(O)NH-、-NHC(O)N(R 102 )-, -C(O)O-, -OC(O)-, 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.

[0015] L 103 is a bond, -S(O) 2 -、-N(R 103 )-, -O-, -S-, -C(O)-, -C(O)N(R 103 )-、-N(R 103 )C(O)-、-N(R 103 )C(O)NH-、-NHC(O)N(R 103 )-, -C(O)O-, -OC(O)-, 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.

[0016] L 104 is a bond, -O-, -NH-, -S-, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0017] L 105 is a bond, -O-, -NH-, -S-, -S(O) 2-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

[0018] R 101 , R 102 and R 103 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 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.

[0019] R 1 For hydrogen, halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-OCX 1 3 、-OCH 2 X 1 、-OCHX 1 2 、-CN、-SO n1 R 1D 、-SO v1 NR 1A R 1B 、-NHC(O)NR 1A R 1B 、-N(O) m1 、-NR 1A R 1B 、-C(O)R 1C 、-C(O)OR 1C 、-SC(O)R 1C 、-C(O)NR 1A R 1B 、-OR 1D 、-SR 1D , -SeR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C 、-NR 1A C(O)OR 1C 、-NR 1A OR 1C 、-N 3 、-SSR 1D 、-SiR 1A R 1B R 1C 、-SP(O)(OH) 2 , E, 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.

[0020] E is an electrophilic part.

[0021] R 2 are independently halogen, -CX 2 3 、-CHX 2 2 、-CH2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR 2A R 2B 、-C(O)R 2C 、-SC(O)R 2C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-SR 2D , -SeR 2D 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 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; two R attached to adjacent atoms 2 The substituents may be linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0022] R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C and R 2D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B The substituents may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 2A and R 2B The substituents may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0023] n1 and n2 are independently integers from 0 to 4.

[0024] m1, m2, v1 and v2 are independently 1 or 2.

[0025] X 1 and X2 are independently -F, -Cl, -Br or -I.

[0026] z2 is an integer from 0 to 5.

[0027] In one aspect, a pharmaceutical composition is provided, comprising a compound described herein and a pharmaceutically acceptable excipient.

[0028] In one aspect, a method for treating a disease of the central nervous system associated with dopaminergic neuron dysregulation and / or degeneration in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0029] In one aspect, a method of modulating the level of Nurr1 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0030] In one aspect, a method of increasing the level of Nurr1 activity in a cell is provided, the method comprising contacting the cell with a compound described herein.

[0031] In one aspect, a method of increasing dopamine levels in a cell is provided, the method comprising contacting the cell with a compound described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figures 1A-1C : Crystal structure of the Nurr1-screening hit complex reveals two distinct ligand-binding sites and receptor conformations. Figure 1A : Screening hits 19.49 and 10.25 structures. Figure 1B : Structure of 19.49 screening hit covalently bound to Cys566. Figure 1C : Structure of a 10.25 screening hit covalently bound to Cys566.

[0033] Figure 2A-2B :Compound 85( Figure 2A ) and 87( Figure 2B ) bind to the Nurr1 ligand binding domain with high nanomolar affinity. Binding was measured by microscale thermophoresis.

[0034] Figure 3A-3B :Compound 85( Figure 3A ) and 87( Figure 3B ) stimulates transcription of Nurr1 target genes in MN9D cells. Gene expression is normalized to Hprt.

[0035] Figures 4A-4D : Reaction scheme used to select compounds. DETAILED DESCRIPTION

[0036] I. Definitions

[0037] Abbreviations used herein have conventional meanings within the chemical and biological arts.Chemical structures and formulae described herein are constructed according to standard rules of chemical valency known in the chemical arts.

[0038] When substituents are described by a conventional chemical formula written from left to right, the substituents equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.

[0039] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may include monovalent, divalent, and polyvalent groups. An alkyl group may contain a specified number of carbons (e.g., C 1 -C 10 Meaning one carbon to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers. Alkoxy is an alkyl group attached to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. An alkenyl group may contain more than one double bond and / or one or more triple bonds in addition to one or more double bonds. An alkynyl group may contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds.

[0040] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl radical, such as, but not limited to, a -CH 2 CH 2 CH 2 CH 2- exemplified. 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 eight or fewer carbon atoms. Unless otherwise stated, the term "alkenylene" by itself or as part of another substituent means a divalent radical derived from an alkene.

[0041] Unless otherwise stated, 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. One or more heteroatoms (e.g., N, S, Si, or P) may be placed 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: -CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-S-CH 2 -CH 2 、-S(O)-CH 3 、-CH 2 -CH 2 -S(O) 2 -CH 3 、-CH=CH-O-CH 3 、-Si(CH 3 ) 3 、-CH 2 -CH=N-OCH 3 、-CH=CH-N(CH 3 )-CH 3 、-O-CH 3 、-O-CH 2 -CH 3 and -CN. Up to two or three heteroatoms may be consecutive, e.g., -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may 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). Unless otherwise stated, the term "heteroalkenyl" by itself or in combination with another term means a heteroalkyl group containing at least one double bond. The heteroalkenyl group may optionally include more than one double bond and / or one or more triple bonds in addition to one or more double bonds. Unless otherwise stated, the term "heteroalkynyl" by itself or in combination with another term means a heteroalkyl group containing at least one triple bond. A heteroalkynyl group may optionally contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds.

[0042] Similarly, unless otherwise stated, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, such as, but not limited to, via -CH 2 -CH 2 -S-CH 2 -CH 2 -and-CH 2 -S-CH 2 -CH 2 -NH-CH 2 - exemplified. For heteroalkylene, heteroatoms may also occupy either or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, the direction in which the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O) 2 R'- represents -C(O) 2 R'- and -R'C(O) 2 As described above, heteroalkyl as used herein includes those groups attached to the rest of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR' and / or -SO 2 R'. It should be understood that where "heteroalkyl" is recited after reciting a specific heteroalkyl group such as -NR'R", the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited to increase clarity. Therefore, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups such as -NR'R".

[0043] Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms mean the cyclic forms of "alkyl" and "heteroalkyl", respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, heteroatoms can occupy the position of the rest of the heterocycle connected to the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocycloalkylene" alone or as part of another substituent mean a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively.

[0044] Unless otherwise indicated, 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 meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1 -C 4 )alkyl" includes but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

[0045] Unless otherwise indicated, 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.

[0046] Unless otherwise indicated, 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. Fused ring aryl refers to multiple rings fused together, wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom (such as N, O or S), wherein the nitrogen atom and the sulfur atom are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Therefore, the term "heteroaryl" includes fused ring heteroaryls (i.e., multiple rings fused together, wherein at least one of the fused rings is a heteroaromatic ring). 5,6-fused ring heteroaryl 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. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl , pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-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 noted aryl and heteroaryl ring systems are selected from the group 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- attached to a ring heteroatom nitrogen.

[0047] Spirocycle is two or more rings in which adjacent rings are connected by a single atom. The single rings in the spirocycle can be the same or different. The single ring in the spirocycle can be substituted or unsubstituted, and can have substituents different from other single rings in the spirocycle set. The possible substituents of each ring in the spirocycle are possible substituents of the same ring (when not part of the spirocycle) (for example, substituents of cycloalkyl rings or heterocycloalkyl rings). The spirocycle can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heterocycloalkylene, and each ring in the spirocyclic group can be any ring of the previous list, including all rings with one type (for example, all rings are substituted heterocycloalkylene, wherein each ring can be the same or different substituted heterocycloalkylene). When referring to the spirocyclic system, heterocyclic spirocycle means a spirocycle in which at least one ring is a heterocycle and each ring can be a different ring. When referring to a spiro ring system, substituted spiro means that at least one ring is substituted and each substituent may optionally be different.

[0048] symbol Indicates the point at which a chemical moiety is attached to the rest of a molecule or chemical formula.

[0049] As used herein, the term "oxo" means an oxygen doubly attached to a carbon atom.

[0050] The term "alkylarylene" is an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In an embodiment, the alkylarylene group has the formula:

[0051]

[0052] The alkylarylene moiety can be substituted (e.g., with a substituent) on the alkylene moiety or the arylene linker (e.g., at carbon 2, 3, 4, or 6): halogen, oxo, -N- 3 , -CF 3 , -CCl 3 , -CBr 3 、-CI 3 , -CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 2 CH 3 、-SO 3 H.-OSO 3 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2、-NHC(O)NHNH 2 , substituted or unsubstituted C 1 -C 5 In some embodiments, the alkylarylene group is unsubstituted.

[0053] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0054] Substituents for the alkyl and heteroalkyl groups (including those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may 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', -CO 2 R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O) 2 R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", -NRSO 2 R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN, -NO 2 、-NR'SO 2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", 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., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or aralkyl. When a compound described herein contains more than one R group, for example, each of the R groups is independently selected as each R' group, R" group, R"' group and R"" group is independently selected when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" means a group that includes a carbon atom attached to a group other than a hydrogen group, such as a haloalkyl group (e.g., -CF 3 and -CH 2 CF 3 ) and acyl groups (e.g., -C(O)CH 3 、-C(O)CF 3 、-C(O)CH 2 OCH 3 wait).

[0055] Similar to the substituents described for alkyl, the substituents for aryl and heteroaryl are varied and are selected, for example, from the following: -OR', -NR'R", -SR', halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O) 2 R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", -NRSO 2 R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN, -NO 2 , -R', -N 3 、-CH(Ph) 2 , fluorinated (C 1 -C 4) alkoxy and fluorinated (C 1 -C 4 )alkyl, -NR'SO 2 R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", the number ranges 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 the compounds described herein contain more than one R group, each of the R groups is independently selected, for example, as each R' group, R" group, R"' group and R"" group is independently selected when more than one of these groups is present.

[0056] The substituents of the ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene or heteroarylene) can be depicted as substituents on the ring rather than on a specific atom of the ring (commonly referred to as floating substituents). In this case, the substituent can be connected to any of the ring atoms (following the chemical valence rules), and in the case of a fused ring or spiro ring, the substituent depicted as being associated with a member of the fused ring or spiro ring (floating substituent on a single ring) can be a substituent on any of the fused rings or spiro rings (floating substituents on multiple rings). When the substituent is connected to the ring rather than a specific atom (floating substituent) and the subscript of the substituent is an integer greater than one, multiple substituents can be located on the same atom, the same ring, different atoms, different fused rings, different spiro rings, and each substituent can be optionally different. In the case where the connection point of the ring to the rest of the molecule is not limited to a single atom (floating substituent), the connection point can be any atom of the ring, and in the case of a fused ring or spiro ring, it can be any atom of any of the fused rings or spiro rings (following the chemical valence rules). In the case where a ring, fused ring, or spiro ring contains one or more ring heteroatoms and the ring, fused ring, or spiro ring is shown as having yet another floating substituent (including but not limited to a point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown bonded to one or more hydrogens in a structure or formula having a floating substituent (e.g., a ring nitrogen with two bonds to a ring atom and a third bond to a hydrogen), the substituent will be understood to replace the hydrogen when the heteroatom is attached to the floating substituent, while following chemical valence rules.

[0057] Two or more substituents can be optionally connected to form aryl, heteroaryl, cycloalkyl or heterocycloalkyl. This so-called ring-forming substituent is usually (although not necessarily) attached to the cyclic base structure. In one embodiment, the ring-forming substituent is connected to the adjacent members of the basic structure. For example, two rings connected to the adjacent members of the cyclic basic structure form substituents to produce condensed ring structure. In another embodiment, the ring-forming substituent is connected to a single member of the basic structure. For example, two rings connected to a single member of the cyclic basic structure form substituents to produce spirocyclic structure. In another embodiment, the ring-forming substituent is connected to the non-adjacent members of the basic structure.

[0058] Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the general 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 of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituted aryl group of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)- 2 -、-S(O) 2 NR'- or a single bond, and r is an integer from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a double bond of the formula -(CRR') s -X'-(C"R"R"') d -, 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) 2 NR'-. 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.

[0059] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In an embodiment, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0060] As used herein, "substituent" means a group selected from the following moieties:

[0061] (A) Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 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., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C5 -C 6 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., C 6 -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

[0062] (B) alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 -C 10 Aryl, C 10 aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), which is substituted with at least one substituent selected from the group consisting of:

[0063] (i) Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 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., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 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., C 6 -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

[0064] (ii) alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), which is substituted with at least one substituent selected from the following:

[0065] (a) Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 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., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 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., C 6 -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

[0066] (b) alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 -C 10 Aryl, C 10 aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), which is substituted by at least one substituent selected from the group consisting of oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 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., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 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., C 6 -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).

[0067] As used herein, "size-limited substituent" or "size-limited substituent group" means a group selected from all substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 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 C 6 -C 10 The substituted or unsubstituted heteroaryl group is an substituted or unsubstituted 5- to 10-membered heteroaryl group.

[0068] As used herein, "lower substituent" or "lower substituent group" means a group selected from all substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 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 C 3 -C 7 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 C 6 -C 10 The aryl group is substituted or unsubstituted, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group.

[0069] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one substituent of limited size. In other embodiments, at least one or all of these groups are substituted with at least one low substituent.

[0070] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 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 C 6 -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 C 1 -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 C 3 -C 8 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 C 6 -C 10 The arylene group, and / or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5- to 10-membered heteroarylene group.

[0071] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 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 -C 7 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 C 6 -C 10 In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C 1 -C 8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 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.

[0072] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted heteroarylene, and / or substituted heteroalkylene, respectively).

[0073] In embodiments, a substituted moiety (e.g., 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) is substituted with at least one substituent, wherein if the substituted moiety is substituted with multiple substituents, each substituent may optionally be different. In embodiments, if the substituted moiety is substituted with multiple substituents, each substituent is different.

[0074] In embodiments, a substituted moiety (e.g., a 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) is substituted with at least one size-restricted substituent, wherein if the substituted moiety is substituted with multiple size-restricted substituents, each size-restricted substituent may optionally be different. In embodiments, if the substituted moiety is substituted with multiple size-restricted substituents, each size-restricted substituent is different.

[0075] In an embodiment, a substituted moiety (e.g., a substituted alkyl, a substituted heteroalkyl, a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl, a substituted heteroaryl, a substituted alkylene, a substituted heteroalkylene, a substituted cycloalkylene, a substituted heterocycloalkylene, a substituted arylene, and / or a substituted heteroarylene) is substituted with at least one lower substituent, wherein if the substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In an embodiment, if the substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0076] In embodiments, a substituted moiety (e.g., 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) is substituted with at least one substituent, size-restricted substituent, or lower substituent; wherein if the substituted moiety is substituted with multiple groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In embodiments, if the substituted moiety is substituted with multiple groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent is different.

[0077] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms, and individual isomers that can be defined as (R)- or (S)- or (D)- or (L)- of amino acids, based on absolute stereochemistry, are all included within the scope of the present disclosure. The compounds of the present disclosure do not include compounds that are too unstable to be synthesized and / or separated as known in the art. The present disclosure 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 olefin bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that these compounds contain both E and Z geometric isomers.

[0078] 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 in the structural arrangement or configuration of the atoms.

[0079] 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.

[0080] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0081] Unless otherwise stated, structures depicted herein are also intended to encompass 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 mixtures and diastereomeric mixtures of the present compounds are within the scope of the present disclosure.

[0082] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. 13 C- or 14 Compounds of the present structures in which a C-enriched carbon replaces a carbon other than carbon are within the scope of the present disclosure.

[0083] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. For example, the compounds may be treated with, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14C) and other radioactive isotopes. All isotopic variations of the compounds of the present disclosure, whether radioactive or non-radioactive, are encompassed within the scope of the present disclosure.

[0084] It should be noted that throughout the application, alternatives are written in Markush groups, such as in 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 individually, thereby comprising another embodiment, and that a Markush group should not be understood as a single unit.

[0085] As used herein, the terms "bioconjugate" and "bioconjugate linker" refer to the associations that occur between atoms or molecules of a bioconjugate reactive group or a bioconjugate reactive moiety. The associations can be direct or indirect. For example, a first bioconjugate reactive group (e.g., -NH 2The conjugation between the bioconjugate reactive group (e.g., -COOH, -N-hydroxysuccinimide or -maleimide) and the second bioconjugate reactive group (e.g., a sulfhydryl, a sulfur-containing amino acid, an amine, an amine side chain containing an amino acid, or a carboxylate) can be directly, for example, via a covalent bond or a linker (e.g., a first linker of a second linker), or indirectly, for example, via a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (π effect), hydrophobic interactions, etc.). In embodiments, the bioconjugate or bioconjugate linker is formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups), including but not limited to nucleophilic substitution (e.g., reaction of amines and alcohols with acyl halides, active esters), electrophilic substitution (e.g., enamine reaction), and addition of carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, e.g., March, ADVANCED ORGANIC CHEMISTRY, 3rd ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Progress in Chemistry Series, Vol. 1, 198, American Chemical Society, Washington, DC, 1982. In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (e.g., an N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (e.g., a -sulfo-N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., an amino group).

[0086] Useful bioconjugate reactive moieties for use in the bioconjugate chemistry herein include, for example:

[0087] (a) carboxyl and its various derivatives, including but not limited to N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters;

[0088] (b) hydroxyl groups, which can be converted into esters, ethers, aldehydes, etc.;

[0089] (c) haloalkyl, where the halide can then be displaced with a nucleophilic group such as an amine, carboxylate anion, thiol anion, carbanion or alkoxide ion, thereby resulting in a new group covalently attached at the site of the halogen atom;

[0090] (d) a dienophile which is able to participate in a Diels-Alder reaction, such as, for example, a maleimido or maleimide group;

[0091] (e) aldehyde or keto groups which allow for subsequent derivatization by formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes or by mechanisms such as Grignard addition or alkyllithium addition;

[0092] (f) sulfonyl halides for subsequent reaction with amines, e.g. to form sulfonamides;

[0093] (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or attached to metals such as gold, or reacted with maleimides;

[0094] (h) an amine or thiol group (e.g., as present in cysteine), which may be, for example, acylated, alkylated or oxidized;

[0095] (i) olefins, which can undergo, for example, cycloaddition, acylation, Michael addition, etc.;

[0096] (j) epoxides, which can react with, for example, amines and hydroxy compounds;

[0097] (k) Phosphoramidites and other standard functional groups useful in nucleic acid synthesis;

[0098] (l) Metal oxide silicon connection;

[0099] (m) metal bonding to a reactive phosphorus group (e.g., a phosphine) to form, for example, a phosphodiester bond;

[0100] (n) attaching azides to alkynes using copper-catalyzed cycloaddition click chemistry; and

[0101] (o) The biotin conjugate can react with avidin or strepavidin to form an avidin-biotin complex or a strepavidin-biotin complex.

[0102] The bioconjugate reactive groups can be selected so that they do not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, the reactive functional groups can be protected from participating in the cross-linking reaction by the presence of a protecting group. In an embodiment, the bioconjugate includes a molecular entity derived from the reaction of an unsaturated bond such as maleimide with a sulfhydryl group.

[0103] "Analog," "analogue," or "derivative" is used according to its ordinary general meaning within chemistry and biology, and refers to a compound that is structurally similar but compositionally different from another compound (i.e., the so-called "reference" compound), for example in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or in 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 equivalent to a reference compound in function and appearance, but not similar or equivalent in structure or origin.

[0104] 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 an alkyl or heteroaryl group is "substituted with an unsubstituted C 1 -C 20 alkyl or unsubstituted 2- to 20-membered heteroalkyl”, the group may contain one or more unsubstituted C 1 -C 20 alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups.

[0105] In addition, where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted". Where 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 the description of a chemical genus such as Formula (I), a Roman letter symbol may be used to distinguish each appearance of the specific R group. For example, where multiple R 13 In the case of a substituent, each R 13 Substituents can be divided into R 13A , R 13B , R 13C , R13D etc., where R 13A , R 13B , R 13C , R 13D Each of the above is in R 13 and optionally different.

[0106] The description of the compounds of the present disclosure is limited by the chemical connection principles known to those skilled in the art. Therefore, when a group can be substituted by one or more of a plurality of substituents, such substitutions are selected so as to comply with the chemical connection principles and to obtain compounds that are not inherently unstable and / or will be known to those of ordinary skill in the art as being unstable under environmental conditions such as aqueous, neutral and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl group is attached to the rest of the molecule via a ring heteroatom in accordance with the chemical connection principles known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0107] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present disclosure 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 (neat or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or similar salts. When the compounds of the present disclosure 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, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include acid addition salts 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 nontoxic 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, etc. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow these compounds to be converted into either base or acid addition salts.

[0108] Therefore, the compounds of the present disclosure may exist in the form of salts such as having a pharmaceutically acceptable acid. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates or their mixtures comprising a racemic mixture), succinates, benzoates, and salts with amino acids (such as glutamic acid) and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0109] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0110] In addition to salt forms, the present disclosure also provides compounds in the form of prodrugs. Prodrugs of compounds described herein are those compounds that are susceptible to undergoing chemical changes under physiological conditions to provide compounds of the present disclosure. Prodrugs of compounds described herein can be transformed in vivo after administration. In addition, prodrugs can be converted into compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment (such as, for example, when contacted with a suitable enzyme or chemical reagent).

[0111] Some compounds of the present disclosure can exist in non-solvated form and solvated form (including hydrated form). Generally speaking, the solvated form is equivalent to the non-solvated form and is included in the scope of the present disclosure. Some compounds of the present disclosure can exist in multiple crystals or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes contemplated by the present disclosure, and are intended to be within the scope of the present disclosure.

[0112] A polypeptide or cell is "recombinant" when it is artificial or engineered or derived from an artificial or engineered protein or nucleic acid 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, such as the genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. Proteins expressed in vitro or in vivo by a recombinant polynucleotide are examples of recombinant polypeptides. Likewise, polynucleotide sequences that do not occur in nature (e.g., variants of naturally occurring genes) are recombinant.

[0113] "Co-administration" means administration of a composition described herein at the same time, just before, or just after administration of one or more additional therapies. The compounds of the invention may be administered alone or may be co-administered to a patient. Co-administration is meant to include simultaneous or sequential administration of compounds (more than one compound) alone or in combination. Thus, the formulation may also be combined with other active substances, if desired (e.g., to reduce metabolic degradation).

[0114] As used herein, "cell" refers to a cell that performs metabolic functions or other functions sufficient to maintain 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 reproduce offspring, or, if gametes are present, the ability to combine with a second gamete to produce viable offspring. Cells can include prokaryotic cells and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian cells, insect (e.g., noctuid) cells, and human cells. When cells are naturally non-adherent or are treated to be non-adherent to a surface by, for example, trypsin digestion, they may be useful.

[0115] The term "treating" or "treatment" refers to any indicator of successful treatment or improvement of an injury, disease, pathology or condition, including any objective or subjective parameter, such as elimination; relief; alleviation of symptoms or making an injury, pathology or condition more tolerable to the patient; slowing the rate of degeneration or decline; or making the end point of degeneration less declining; improving the patient's physical or mental health. The treatment or improvement of symptoms can be based on objective or subjective parameters; including the results of physical examinations, neuropsychiatric examinations, and / or psychiatric assessments. For example, certain methods presented herein successfully treat cancer by reducing the incidence of cancer and / or causing relief of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the growth or spread rate of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term "treatment" and its conjugates include preventing damage, pathology, condition or disease. In embodiments, treatment is prevention. In embodiments, treatment does not include prevention. In embodiments, treatment (treating or treatment) is not a preventive treatment.

[0116] "Effective amount" is an amount sufficient to achieve the stated purpose of the compound relative to the absence of the compound (e.g., achieving the effect to which it is applied, treating a disease, reducing enzyme activity, increasing enzyme activity, reducing signal transduction pathways, reducing one or more symptoms of a disease or condition). When mentioned in this context, an example of an "effective amount" is an amount sufficient to facilitate treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of one or more symptoms, or eliminating one or more symptoms. The "preventive effective amount" of a drug is the amount of the drug that will have the expected preventive effect when administered to a subject, such as preventing or delaying the onset (or recurrence) of damage, disease, pathology, or condition or reducing the likelihood of onset (or recurrence) of damage, disease, pathology, or condition or its symptoms. A complete preventive effect does not necessarily occur by administering a single dose, and may occur after administering only a series of doses. Therefore, a preventive effective amount may be administered in one or more administration forms. As used herein, "activity reduction amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of an antagonist. As used herein, a "function-destroying amount" refers to the amount of an antagonist required to destroy the function of an enzyme or protein relative to the absence of the antagonist. As used herein, an "activity-increasing amount" refers to the amount of an agonist required to reduce the activity of an enzyme relative to the absence of the agonist. As used herein, a "function-increasing amount" refers to the amount of an agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amount will depend on the purpose of the treatment, and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, ed., Lippincott, Williams & Wilkins).

[0117] "Control" or "control experiment" is used according to its ordinary and common meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment, except that the experimental procedures, reagents or variables are omitted. In some cases, the control is used as a standard of comparison when evaluating the effects of the experiment. In some embodiments, the control is a measure of the activity of a protein (e.g., a signaling pathway) in the absence of a compound as described herein (including embodiments, examples, figures or tables).

[0118] "Contacting" is used according to its ordinary general 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 understood that the resulting reaction product can be produced directly from the reaction between the added reagents, or from one or more intermediates of the added reagents that can be produced in the reaction mixture.

[0119] The term "contacting" can include allowing two species to react, interact, or physically contact, wherein the two species can be a compound as described herein and a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments, contacting includes allowing a compound as described herein to interact with a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) involved in a signaling pathway.

[0120] As defined herein, the term "activation (activation / activate / activating, etc.)" with respect to a protein refers to the conversion of a protein from an initial inactive or deactivated state to a biologically active derivative. The term refers to the activation (activation) of a protein that is reduced in a disease or activates (activating), sensitizes or upregulates a signal transduction or enzymatic activity or amount.

[0121] The terms "agonist", "activator", "up-regulator", etc. refer to substances that can detectably increase the expression or activity of a given gene or protein. Compared to a control in the absence of the agonist, an agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99%. In some cases, expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or more compared to expression or activity in the absence of the agonist.

[0122] As defined herein, the terms "inhibition / inhibit / inhibiting" and the like with respect to a cellular component-inhibitor interaction mean that in the absence of the inhibitor, the activity or function of the cellular component is negatively affected (e.g., reduced) (e.g., a signal transduction pathway stimulated by the cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cell compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate or macromolecule)) relative to the activity or function of the cellular component. In embodiments, inhibition means negatively affecting (e.g., reducing) the concentration or level of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or a symptom of a disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or a signal transduction pathway (e.g., a reduction in a pathway involving a cellular component). Thus, inhibition comprises, at least in part, partial or complete blocking of stimulation, reduction, prevention or delay of activation, desensitization or downregulation of a signal transduction pathway or enzyme activity or the amount of a cellular component.

[0123] Interchangeably, the terms "inhibitor", "repressor", "antagonist" or "downregulator" refer to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% compared to a control in the absence of the antagonist. In some cases, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or less lower than expression or activity in the absence of the antagonist.

[0124] The term "modulator" refers to an agent that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of a target of a molecule relative to the absence of the composition (e.g., the target can be a cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)).

[0125] The term "expression" includes any step involved in the production of the polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blot, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0126] The term "modulate" is used according to its ordinary and common meaning and refers to the action of changing or altering one or more properties. "Modulation" refers to the process of changing or varying one or more characteristics. For example, when applied to the effect of a modulator on a target protein, modulating means changing by increasing or decreasing a characteristic or function of the target molecule or the amount of the target molecule.

[0127] "Patient" or "subject 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, bovines, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0128] "Disease" or "condition" refers to a state or health condition in which a patient or subject can be treated with the compounds or methods provided herein. In some embodiments, the disease is a disease associated with (caused by) a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cell compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is cancer.

[0129] As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the function of the nervous system of a subject is impaired. Examples of neurodegenerative diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann- -Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, Kuru, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum's disease, Sandhoff's disease, Schilder's disease disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0130] 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 without the disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, type 1 diabetes, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, 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, scleroderma, and atopic dermatitis).

[0131] As used herein, the term "cancer" refers to all types of cancers, tumors or malignancies found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer or pancreatic cancer. Additional examples include: Hodgkin's Disease, Non-Hodgkin's Lymphoma, Multiple Myeloma, Neuroblastoma, Glioblastoma Multiforme, Ovarian Cancer, Rhabdomyosarcoma, Essential Thrombocythemia, Essential Macroglobulinemia, Primary Brain Tumor, Cancer, Malignant Pancreatic Cancer, Malignant Carcinoid, Bladder Cancer, Premalignant Skin Lesions, Testicular Cancer, Lymphoma, Thyroid Cancer, Esophageal Cancer, Genitourinary Tract Cancer, Malignant Hypercalcemia, Endometrial Cancer, Adrenal Cortical Cancer, Endocrine or Exocrine Pancreatic Neoplasm, Medullary Thyroid Cancer, Medullary Thyroid Carcinoma, Melanoma, Colorectal Cancer, Papillary Thyroid Cancer, Hepatocellular Carcinoma, or Prostate Cancer.

[0132] The term "leukemia" refers to a progressive, malignant disease of the blood-forming organs and is generally characterized by the unregulated proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias are usually classified clinically based on: (1) the duration and nature of the disease, whether acute or chronic; (2) the type of cells involved; myeloid (myeloid), lymphoid (lymphoid), or monocytic; and (3) the increase or non-increase in the number of abnormal cells in the blood - leukemic or non-leukemic (subleukemic). Exemplary leukemias that can be treated with the compounds or methods provided herein include, e.g., acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, leukemia), hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegelileukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia leukemia), stem cell leukemia, subleukemic leukemia or undifferentiated cell leukemia.

[0133] As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphoid tissues. It begins in lymphocytes, which are blood cells found primarily in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for about 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the growth rate of the cancer and the cell types involved. There are aggressive (high-grade) and indolent (low-grade) types of NHL. Based on the cell types 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, nodular (monocytoid B cell) lymphoma, splenic lymphoma, diffuse large cell B 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, pleomorphic large cell lymphoma, mycosis fungoides, and precursor T lymphoblastic lymphoma.

[0134] The term "sarcoma" generally refers to a tumor composed of material similar to embryonic connective tissue and usually composed of tightly 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 part sarcoma, ameloblastic sarcoma, botryoid sarcoma, green carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant stromal tumor sarcoma, extraperiosteal sarcoma, reticular cell sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0135] The term "melanoma" is understood to refer to tumors of the melanocyte system originating from the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0136] The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and give rise to metastases. Exemplary cancers that can be treated with the compounds or methods provided herein include, e.g., medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid cell tumor, basaloid carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, armored carcinoma, carcinoma cutaneum, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, scirrhous carcinoma, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, explant carcinoma, carcinoma ex ulcere, fibrocarcinoma, gelatinous carcinoma, gelatinous carcinoma, carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal carcinoma, embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous cell carcinoma mucocellulare), mucoepidermoid carcinoma, carcinoma mucosum, myxoid carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthocyte carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma, carcinoma scrotumscroti), signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spheroid cell carcinoma, spindle cell carcinoma, medullary carcinoma (carcinomaspongiosum), squamous cell carcinoma, squamous cell carcinoma, rope-shaped carcinoma, carcinoma vascular dilataticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0137] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of active agents to subjects and facilitate absorption by subjects, and the substances can be included in the compositions of the present invention without causing significant adverse toxicological effects to patients. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, carboxymethyl cellulose, polyvinyl pyrrolidone and pigments, etc. Such preparations can be sterilized and, if necessary, can be mixed with auxiliary agents that do not react harmfully with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring substances and / or aromatic substances, etc. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0138] The term "preparation" is intended to include the formulation of an active compound with encapsulating material in the form of a carrier providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier in which it is associated. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0139] As used herein, the term "about" means a range of values ​​that includes the specified value, which one of ordinary skill in the art would consider to be reasonably similar to the specified value. In embodiments, about means within the standard deviation of measurements generally accepted in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0140] As used herein, the term "administer" means oral administration to a subject, administration in the form of a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or implantation of a slow release device (e.g., a mini-osmotic pump). Administered by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, 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. "Co-administered" means that the compositions described herein are administered while, just before, or just after, one or more other therapies (e.g., cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy) are administered. The compounds of the present invention may be administered alone or may be co-administered to a patient. Co-administered means administering compounds (more than one compound) simultaneously or sequentially, either alone or in combination. Thus, the formulations may also be combined with other active substances if desired (e.g. to reduce metabolic degradation). The compositions of the invention may be delivered transdermally by topical routes, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols.

[0141] The compounds described herein may be used in combination with each other, with other active agents known to be useful in treating diseases associated with cells expressing disease-associated cellular components, or with adjunct agents that alone may not be effective but may aid in the efficacy of the active agents.

[0142] In some embodiments, co-administration comprises administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration comprises administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition comprising two active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agent and / or adjuvant can be connected or conjugated to each other.

[0143] The compounds described herein can be co-administered with conventional neurodegenerative disease treatments, including but not limited to Parkinson's disease treatments such as levodopa, carbidopa, selegiline, amantadine, donepezil, galanthamine, rivastigmine, tacrine, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole), anticholinergics (e.g., trihexyphenidyl, benztropine, biperiden, procyclidine), and catechol-O-methyl-converting enzyme inhibitors (e.g., tolcapone, entacapone).

[0144] The compounds described herein can also be co-administered with conventional anti-inflammatory disease treatments, including but not limited to analgesics (e.g., acetaminophen, duloxetine), nonsteroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen, diclofenac), corticosteroids (e.g., prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone), and opioids (e.g., codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, oxycodone).

[0145] "Anticancer" is used in accordance with its common general meaning and refers to a composition (e.g., a compound, a drug, an antagonist, an inhibitor, a modulator) having anti-tumor properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anti-tumor agent is a chemotherapeutic agent. In some embodiments, the anti-tumor agent is an agent identified herein as having utility in a method for treating cancer. In some embodiments, the anti-tumor agent is an agent approved by the FDA or similar regulatory agencies in countries other than the United States for the treatment of cancer. In an embodiment, the anti-tumor agent is an agent with anti-tumor properties that has not (e.g., not yet) been approved by the FDA or similar regulatory agencies in countries other than the United States for the treatment of cancer. Examples of anticancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., chloroethylamine, cyclophosphamide, chlorambucil, melphalan), ethyleneimine, and methylmelamine (e.g., hexamethyltriazine), melamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine), antimetabolites (e.g., 5-thiopurine, folinic acid, capecitabine, fludarabine, gemcitabine (gemcitabine), pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate (etoposide phosphate), etc.),phosphate), teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamicin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical hormone inhibitors (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituximab), gossyphol, genasense, polyphenol E, chloroofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine glycosides, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY11-7082, PKC412, PD184352, 20-epi-1, 25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; hexamethylmelamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors inhibitor; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostate cancer; antiestrogen; antineoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivative derivative; balanol; batimastat; BCR / ABL antagonist; benzochlorins; benzoylstaurosporine; β-lactam derivative; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene AA); bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calciphosphotin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; chondrogenic inhibitors; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B B); cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogue; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivative; curacin A A); cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin BB); deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonist; estrogen antagonist; etanidazole; etoposide phosphate phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezlastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitorsinhibitor; gemcitabine; glutathione inhibitor; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors inhibitor; interferon agonist; interferon; interleukin; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interleukin-1α; leuprorelin + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide7); lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptide; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrix lytic factor inhibitor inhibitor; matrix metalloproteinase inhibitor; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+ mycobacterial cell wall sk; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor factor 1-based therapy; mustard anticancer agent); mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamide; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acidacid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulator; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A A); plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2J2); proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxal hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinoic acid amide (RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetic; semustine; senoside inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction modulator; single-chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate phenylacetate; solverol; somatomedin binding protein; sonermin; sparlfosic acid; spicamycin D; spiromustine; splenopentin; spongin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic mucopolysaccharideglycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodeoxythiophene; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonists; thymotrinan; thyroid stimulating hormone hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitor; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitor; tyrosine phosphorylation inhibitor; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonist; vapreotide; variolin B B); vector system, red blood cell gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatinstimalamer, doxorubicin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adolesin, aldesleukin, altretamine, ambomycin, ametantron acetate acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; binasafide dimesylate; bisezole; bleomycin sulfate; brequinar sodium sodium; bropiridamine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; isothiocyanate; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citratecitrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etaninidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin I1 (including recombinant interleukin II, or rlL.sub.2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masorofol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetateacetate; melphalan; menolil; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perphosphamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; promestane; porfimer sodium; methyl mitomycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride hydrochloride; pyrazofurin; riboprine; roglulimide; safingol; safingol hydrochloride; semustine; simtrazene; spalfosatesodium; sparsomycin; spirogermanium hydrochloridehydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; fluridine; teloxantrone hydrochloride; temoporphine; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate phosphate; trimetrexate; trimetrexate glucuronide; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloridehydrochloride), agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol.TM (paclitaxel), Taxotere.TM, compounds comprising a taxane backbone, Erbulozole (i.e., R-55104), Aplysia 10 (i.e., DLS-10 and NSC-376128), Mivobulinisethionate (i.e., CI-980), vincristine, NSC-639829, Dinospermuminolide (D iscodermolide) (i.e., NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhyrtin (e.g., Altorhyrtin A and Altorhyrtin C), Spongistatin (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and S Spongistatin 9), Cemadotin hydrochloride (e.g., hydrochloride) (i.e., LU-103793 and NSC-D-669356), Epothilones (e.g., epothilone A, epothilone B, epothilone C (i.e., deoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., deoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristati PE (i.e., NSC-654663), Soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS- 4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),Sciences), BSF-223651 (BASF, i.e., ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Nostoc 52 (i.e., LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and R PR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Research Institute), Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-569), Narcosine (also known as NSC-5366), Nascapine D-24851 (Asta Pharmaceuticals, Inc.), Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Icahn School of Medicine at Mount Sinai, MF-191), TMPN (Arizona State University), Vanadoceneacetylacetonate), T-138026 (Dularik), Monsatrol, lnanocine (i.e., NSC-698666), 3-IAABE (Cytoskeleton / Icahn School of Medicine at Mount Sinai), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Annette), Eleutherobin (e.g., Deacetylcholine Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A and Z-Isoeleutherobin), Caribaeolin, Halichondrin B, D-64131 (Astar Pharmaceuticals), D-68144 (Astar Pharmaceuticals), Chlorocyclic peptide (D azonamide) A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Annette), A-259754 (Abbott), Diozostatin, (-)-phenylastatin (Phenylahistin) (i.e., NSCL-96F037), D-68838 (Astar Pharmaceuticals), D-68836 (Astar Pharmaceuticals), Myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin sodium phosphate phosphate sodium), BPR-OY-007 (National Health Research Institutes) and SSR-250411 (Sanofi), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocortical steroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate),caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin (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.), radioimmunotherapy (e.g., with 111 In, 90 Y or 131 I-conjugated anti-CD20 monoclonal antibodies, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapies or therapeutic agents (e.g., gefitinib) TM ), erlotinib (Tarceva TM ), cetuximab (Erbitux TM ), lapatinib (Tykerb TM ), panitumumab (Vectibix 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 / desmethyl erlotinib erlotinib), AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc. Some of the anticancer agents are monovalent anticancer agents (e.g., monovalent forms of the agents listed above).

[0146] In the therapeutic use of treating diseases, the compound used in the pharmaceutical composition of the present invention can be administered at an initial dose of about 0.001 mg / kg to about 1000 mg / kg per day. The daily dose range can be about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg. However, the dosage can vary according to the needs of the patient, the severity of the condition being treated, and the compound or drug used. For example, the dosage can be determined empirically based on the type and stage of cancer diagnosed in a particular patient. In the context of the present invention, the dosage administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dosage will also depend on the presence, nature, and extent of any adverse side effects associated with the administration of the compound in a particular patient. It is within the skill of the practitioner to determine the appropriate dosage for a specific situation. Typically, treatment begins with a smaller dose that is smaller than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the best effect is achieved in multiple cases. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

[0147] The compounds described herein may be used in combination with each other, with other active agents known to be useful in treating cancer, or with adjunct agents that may not be effective alone but may aid in the efficacy of the active agents.

[0148] In the context of a substance or substance activity or function associated with a disease (e.g., a protein-related disease, a disease associated with a cellular component), the term "associated" or "associated with..." means that the disease (e.g., neurodegenerative disease, cancer) is (in whole or in part) caused by the substance or substance activity or function, or the symptoms of the disease are (in whole or in part) caused by the substance or substance activity or function, or the disease or the symptoms of the disease can be treated by regulating (e.g., inhibiting or activating) a substance (e.g., a cellular component). For example, a neurodegenerative disease associated with protein aggregates can be a neurodegenerative disease caused (in whole or in part) by abnormal protein aggregation or a neurodegenerative disease in which specific symptoms of the disease are caused (in whole or in part) by abnormal protein aggregation. As used herein, if a pathogen can be a target for treating a disease, it is described as being associated with the disease. For example, a neurodegenerative disease associated with abnormal protein aggregation or a neurodegenerative disease associated with protein aggregation can be treated with a protein aggregation modulator.

[0149] As used herein, the term "abnormal" means different from normal. When used to describe enzymatic activity, abnormal refers to an activity that is greater or less than the average of a normal control or normal non-disease control sample. Abnormal activity can refer to an amount of activity that causes a disease, wherein returning the abnormal activity to a normal or non-disease associated amount (e.g., by administering a compound or using a method as described herein) results in a reduction in the disease or one or more disease symptoms.

[0150] As used herein, the term "electrophilic" refers to a chemical group that can accept electron density. "Electrophilic substituent", "electrophilic chemical part" or "electrophilic part" refers to an electron-deficient chemical group, substituent or part (monovalent chemical group), which can react with electron-donating groups such as nucleophiles to form a bond by accepting electron pairs or electron density. In certain embodiments, the electrophilic substituent of the compound can react with cysteine ​​residues. In certain embodiments, the electrophilic substituent can form a covalent bond with cysteine ​​residues and can be referred to as a "covalent cysteine ​​modification part" or "covalent cysteine ​​modification substituent." The covalent bond formed between the electrophilic substituent and the sulfhydryl of cysteine ​​can be a reversible or irreversible bond. In certain embodiments, the electrophilic substituent of the compound can react with lysine residues. In certain embodiments, the electrophilic substituent of the compound can react with serine residues. In certain embodiments, the electrophilic substituent of the compound can react with methionine residues.

[0151] As used herein, "nucleophile" refers to a chemical group that is capable of donating electron density.

[0152] The term "isolated" when applied to nucleic acids or proteins means that the nucleic acid or protein is substantially free of other cellular components with which it is associated in the native state. It may, for example, be in a homogeneous state and may be in a dry state or in aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. The major protein present in the preparation is substantially purified.

[0153] The term "amino acid" refers to naturally occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are amino acids encoded by the genetic code as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., the α carbon is bound to hydrogen, a carboxyl group, an amino group, and an R group), such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. The analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but the basic chemical structure remains the same as naturally occurring amino acids. Amino acid mimetics refer to compounds that have a structure that is different from the general chemical structure of amino acids but function in a manner similar to naturally occurring amino acids. The terms "non-natural amino acids" and "non-natural amino acids" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature.

[0154] Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0155] The terms "polypeptide", "peptide" and "protein" are used interchangeably herein to refer to polymers of amino acid residues, wherein the polymer may, in embodiments, 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 the corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0156] The "position" of an amino acid or nucleotide base is represented by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5' end). Since deletions, insertions, truncations, fusions, etc. must be considered when determining the best alignment, the numbering of the amino acid residues in the test sequence determined by counting only from the N-terminus is not necessarily the same as the numbering of the corresponding position in the reference sequence. For example, in the case where a variant has a deletion relative to the aligned reference sequence, there will be no amino acid in the variant corresponding to the position at the deletion site in the reference sequence. In the case of an insertion in the aligned reference sequence, the insertion will not correspond to the numbered amino acid position in the reference sequence. In the case of truncations or fusions, there may be amino acid segments in the reference sequence or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0157] The terms "numbered relative to" or "numbered corresponding to" when used in the context of numbering a given amino acid or polynucleotide sequence means that when comparing the given amino acid or polynucleotide sequence to a reference sequence, the residues of the reference sequence are numbered as specified.

[0158] The term "protein complex" is used according to its simple ordinary meaning and refers to a protein associated with another substance (e.g., another protein, a protein subunit, or a compound). A protein complex generally has a well-defined quaternary structure. The association between the protein and the other substance may be a covalent bond. In an embodiment, the association between the protein and the other substance (e.g., a compound) is by non-covalent interactions. In an embodiment, a protein complex refers to a group of two or more polypeptide chains. The proteins in the protein complex are connected by non-covalent protein-protein interactions. A non-limiting example of a protein complex is a proteasome.

[0159] The term "protein aggregate" is used according to its simple common meaning and refers to the abnormal collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are generally associated with diseases (e.g., amyloidosis). Typically, when a protein is misfolded due to changes in the amino acid sequence or changes in the natural environment that destroy normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that can be formed: amorphous aggregates, oligomers, and amyloid fibrils. In an embodiment, protein aggregates are referred to as aggresomes.

[0160] The term "Nurr1" or "NR4A2" refers to a protein encoded by the NR4A2 gene in humans. Nurr1 is a nuclear receptor and plays a key role in maintaining the brain dopaminergic system. The term "Nurr1" may refer to the nucleotide sequence or protein sequence of human NR4A2 (e.g., Entrez4929, Uniprot P43354, RefSeq NM_006186.3 or RefSeq NP_006177.1). In an embodiment, Nurr1 has the following amino acid sequence:

[0161] (SEQ ID NO: 1).

[0162] The term "pituitary homeobox 3" or "Pitx3" refers to a gene encoding a member of the RIEG / PITX homeobox family, which belongs to a dual class of homeodomain proteins and acts as a transcription factor. Pitx3 is involved in the maintenance of dopaminergic neurons. The term "Pitx3" may refer to the nucleotide sequence or protein sequence of human Pitx3 (e.g., Entrez 5309, UniprotO75364, RefSeq NM_005029.3 or RefSeq NP_005020.1). In an embodiment, Pitx3 has the following amino acid sequence:

[0163] MEFGLLSEAEARSPALSLSDAGTPHPQLPEHGCKGQEHSDSEKASASLPGGSPEDGSLKKKQRRQRTHFTSQQLQELEATFQRNRYPDMSTREEIAVWTNLTEARVRVWFKNRRAKWRKRERSQQAELCKGSFAAPLGGLVPPYEEVYPGYSY GNWPPKALAPPLAAKTFPFAFNSVNVGPLASQPVFSPPSSIAASMVPSAAAAPGTVPGPGALQGLGGGPPGLAPAAVSSGAVSCPYASAAAAAAAAASSPYVYRDPCNSSLASLRLKAKQHASFSYPAVHGPPPAANLSPCQYAVERPV(SEQ ID NO:2).

[0164] The term "tyrosine hydroxylase" or "tyrosine 3-monooxygenase" refers to the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). In humans, tyrosine hydroxylase is encoded by the TH gene. The term "TH" may refer to the nucleotide sequence or protein sequence of human TH (e.g., Entrez 7054, Uniprot P07101, RefSeq NM_199292.2, or RefSeq NP_954986.2). In an embodiment, TH has the following amino acid sequence:

[0165] (SEQ ID NO:3).

[0166] The term "vesicular monoamine transporter 2" or "VMAT2" refers to an integral membrane protein that transports neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine from the cytosol to synaptic vesicles. The term "VMAT2" may refer to the nucleotide sequence or protein sequence of human VMAT2 (e.g., Entrez 6571, Uniprot Q05940, RefSeq NM_003054.4, or RefSeq NP_003045.2). In an embodiment, VMAT2 has the following amino acid sequence:

[0167] MALSELALVRWLQESRRSRKLILFIVFLALLLDNMLLTVVVPIIPSYLYSIKHEKNATEIQTARPVHTASISDSFQSIFSYYDNSTMVTGNATRDLTLHQTATQHMVTNASAVPSDCPSEDKDLLNENV QVGLLFASKATVQLITNPFIGLLTNRIGYPIPIFAGFCIMFVSTIMFAFSSSYAFLLIARSLQGIGSSCSSVAGMGMLASVYTDDEERGNVMGIALGGLAMGVLVGPPFGSVLYEFVGKTAPFLVLAALV LLDGAIQLFVLQPSRVQPESQKGTPLTTLLKDPYILIAAGSICFANMGIAMLEPALPIWMMETMCSRKWQLGVAFLPASISYLIGTNIFGILAHKMGRWLCALLGMIIVGVSILCIPFAKNIYGLIAPN FGVGFAIGMVDSSMMPIMGYLVDLRHVSVYGSVYAIADVAFCMGYAIGPSAGGAIAKAIGFPWLMTIIGIIDILFAPLCFFLRSPPAKEEKMAILMDHNCPIKTKMYTQNNIQSYPIGEDEESESD(SEQ ID NO:4).

[0168] II.Compounds

[0169] In one aspect, a compound having the following formula is provided:

[0170]

[0171] Ring A is an aryl group or a heteroaryl group.

[0172] L 1 For L 101 -L 102 -L 103 .

[0173] L 101 is a bond, -S(O) 2 -、-N(R 101 )-, -O-, -S-, -C(O)-, -C(O)N(R 101 )-、-N(R 101 )C(O)-、-N(R 101 )C(O)NH-、-NHC(O)N(R 101)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, L 104 -L 105 , L 104 -NH-L 105 or L 104 -CH 2 -L 105 .

[0174] L 102 is a bond, -S(O) 2 -、-N(R 102 )-, -O-, -S-, -C(O)-, -C(O)N(R 102 )-、-N(R 102 )C(O)-、-N(R 102 )C(O)NH-、-NHC(O)N(R 102 )-, -C(O)O-, -OC(O)-, 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.

[0175] L 103 is a bond, -S(O) 2 -、-N(R 103 )-, -O-, -S-, -C(O)-, -C(O)N(R 103 )-、-N(R 103 )C(O)-、-N(R 103 )C(O)NH-、-NHC(O)N(R 103 )-, -C(O)O-, -OC(O)-, 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.

[0176] L 104 For bonds, -O-, -NH-, -S-, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0177] L 105is a bond, -O-, -NH-, -S-, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

[0178] R 101 , R 102 and R 103 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 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.

[0179] R 1 For hydrogen, halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-OCX 1 3 、-OCH 2 X 1 、-OCHX 1 2 、-CN、-SO n1 R 1D 、-SO v1 NR 1A R 1B 、-NHC(O)NR 1A R 1B 、-N(O) m1 、-NR 1A R 1B 、-C(O)R 1C 、-SC(O)R 1C 、-C(O)OR 1C 、-C(O)NR 1A R 1B 、-OR 1D 、-SR 1D , -SeR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C 、-NR 1A C(O)OR 1C 、-NR 1A OR 1C 、-N 3 、-SSR 1D 、-SiR 1A R 1B R 1C 、-SP(O)(OH) 2 , E, 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] E is an electrophilic part.

[0181] R 2 are independently halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR 2A R 2B 、-C(O)R 2C 、-SC(O)R 1C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-SR 2D , -SeR 2D 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 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; two R attached to adjacent atoms 2 The substituents may be linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0182] R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R2C and R 2D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B The substituents may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 2A and R 2B The substituents may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0183] n1 and n2 are independently integers from 0 to 4.

[0184] m1, m2, v1 and v2 are independently 1 or 2.

[0185] X 1 and X 2 are independently -F, -Cl, -Br or -I.

[0186] z2 is an integer from 0 to 5.

[0187] In an embodiment, L 101 is a bond, -S(O) 2 -、-N(R 101 )-, -O-, -S-, -C(O)-, -C(O)N(R 101 )-、-N(R 101 )C(O)-、-N(R 101 )C(O)NH-、-NHC(O)N(R 101 )-, -C(O)O-, -OC(O)-, 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.

[0188] In an embodiment, L 101 is a bond, -S(O) 2 -、-N(R 101 )-, -O-, -S-, -C(O)-, -C(O)N(R 101 )-、-N(R 101 )C(O)-、-N(R 101 )C(O)NH-、-NHC(O)N(R 101 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6), substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenylene), substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered), L 104 -L 105 , L 104 -NH-L 105 or L 104 -CH 2 -L 105 .

[0189] In an embodiment, L 101 is a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, R 101 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 101 Substituted or unsubstituted heteroalkylene (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), R 101 Substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 101 Substituted or unsubstituted heterocycloalkylene (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 101 Substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenylene), R 101 a substituted or unsubstituted heteroarylene group (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered), L 104 -L 105 , L 104 -NH-L 105 or L 104 -CH 2 -L 105 .

[0190] In an embodiment, L 102 is a bond, -S(O)2 -、-N(R 102 )-, -O-, -S-, -C(O)-, -C(O)N(R 102 )-、-N(R 102 )C(O)-、-N(R 102 )C(O)NH-、-NHC(O)N(R 102 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenylene) or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0191] In an embodiment, L 102 is a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, R 102 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 102 Substituted or unsubstituted heteroalkylene (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), R 102 Substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 102Substituted or unsubstituted heterocycloalkylene (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 102 Substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenylene) or R 102 Substituted or unsubstituted heteroarylene (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0192] In an embodiment, L 103 is a bond, -S(O) 2 -、-N(R 103 )-, -O-, -S-, -C(O)-, -C(O)N(R 103 )-、-N(R 103 )C(O)-、-N(R 103 )C(O)NH-、-NHC(O)N(R 103 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenylene) or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0193] In an embodiment, L 103 is a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, R 103 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C4 ), R 103 Substituted or unsubstituted heteroalkylene (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), R 103 Substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 103 Substituted or unsubstituted heterocycloalkylene (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 103 Substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenylene) or R 103 Substituted or unsubstituted heteroarylene (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0194] In an embodiment, R 1A , R 1B , R 1C and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 1A and R 1B The substituents may be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0195] In an embodiment, R 1A , R 1B , R 1C and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2, -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 10 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 10 Substituted or unsubstituted heteroalkyl (eg, 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), R 10 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 10 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 10 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 10 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 1A and R 1B Substituents may be linked to form R 10Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered) or R 10 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0196] In an embodiment, R 2A , R 2B , R 2C and R 2D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C4 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 2A and R 2B The substituents may be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0197] In an embodiment, R 2A , R 2B , R 2C and R 2D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 20 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 20 Substituted or unsubstituted heteroalkyl (eg, 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), R 20 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 20 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 20 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 20 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 2A and R 2B Substituents may be linked to form R 20 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered) or R 20 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0198] In an embodiment, -L 1 -R 1 for And R 1 As described herein, included in the Examples.

[0199] In an embodiment, the compound has the formula

[0200] Ring A, R1 , R 2 , L 103 , L 104 , L 105 and z2 are as described herein.

[0201] W is N or CH.

[0202] In an embodiment, L 103 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0203] In an embodiment, L 104 is a bond, -S(O) 2 -, -C(O)-, -NHC(O)-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0204] In an embodiment, L 105 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

[0205] In embodiments, Ring A is aryl (eg, C 6 -C 10 or phenyl) or heteroaryl (e.g., 5-10, 5-9, or 5-6 members). In embodiments, Ring A is C 6 -C 10 In an embodiment, ring A is phenyl. In an embodiment, ring A is a 5- to 10-membered heteroaryl. In an embodiment, ring A is a 5- to 9-membered heteroaryl. In an embodiment, ring A is a 5- to 6-membered heteroaryl.

[0206] In an embodiment, ring A is phenyl or a 5- to 10-membered heteroaryl. In an embodiment, ring A is phenyl. In an embodiment, ring A is naphthyl. In an embodiment, ring A is quinolyl. In an embodiment, ring A is isoquinolyl. In an embodiment, ring A is

[0207] In an embodiment, ring A is phenyl or a 5- to 10-membered heteroaryl. In an embodiment, ring A is phenyl. In an embodiment, ring A is naphthyl. In an embodiment, ring A is quinolyl. In an embodiment, ring A is isoquinolyl. In an embodiment, ring A is benzoxazolyl. In an embodiment, ring A is in Indicates with –L 1 -R 1 In an embodiment, ring A is in Indicates with –L 1 -R1 connection point.

[0208] In an embodiment, ring A is phenyl or 5- to 10-membered heteroaryl. In an embodiment, ring A is phenyl. In an embodiment, ring A is naphthyl. In an embodiment, ring A is quinolyl. In an embodiment, ring A is 3-quinolyl. In an embodiment, ring A is isoquinolyl. In an embodiment, ring A is benzoxazolyl. In an embodiment, ring A is 6-benzoxazolyl.

[0209] In an embodiment, the compound has the formula

[0210] R 1 , L 103 , L 104 , L 105 and W are as described herein.

[0211] R 2X , R 2Y and R 2Z are independently hydrogen or can be independently R 2 Any value of is included in the embodiments.

[0212] In an embodiment, R 2X , R 2Y and R 2Z are independently hydrogen, halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR 2A R 2B 、-C(O)R 2C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-NR 2A SO 2 R 2D 、-NR2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 3 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 2X and R 2Y The substituents may be linked to form a substituted or unsubstituted cycloalkyl group (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 2Y and R 2Z The substituents may be linked to form a substituted or unsubstituted cycloalkyl group (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0213] In an embodiment, R 2X , R 2Y and R 2Z are independently hydrogen, halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR 2A R 2B 、-C(O)R 2C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 3 , R 20 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 20 - substituted or unsubstituted heteroalkyl (eg, 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 20 - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6or C 5 -C 6 ), R 20 - substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 20 - substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 20 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 2X and R 2Y Substituents may be linked to form R 20 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 20 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 20 - substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), or R 20 substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 2Y and R 2Z Substituents may be linked to form R 20 - substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 20 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 20 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), or R 20 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0214] In an embodiment, R 2X R is independently halogen or unsubstituted heteroalkyl; 2Y are independently hydrogen or halogen; and R 2Z are independently hydrogen, halogen, -CN, -NR 2A C(O)R 2C, unsubstituted heteroalkyl, or substituted or unsubstituted heterocycloalkyl.

[0215] In an embodiment, R 2X is independently halogen or unsubstituted heteroalkyl. 2Y are independently hydrogen or halogen. 2Z are independently hydrogen, halogen, -CN, -NR 2A C(O)R 2C , unsubstituted heteroalkyl or substituted or unsubstituted heterocycloalkyl. 2X are independently halogen. 2X is independently unsubstituted heteroalkyl. 2Y are independently hydrogen. 2Y are independently halogen. 2Z are independently hydrogen. 2Z are independently halogen. 2Z In an embodiment, R 2Z Independently -NR 2A C(O)R 2C In an embodiment, R 2Z In an embodiment, R2Z is ​​independently unsubstituted heteroalkyl.

[0216] In an embodiment, R 2X are independently halogen; R 2Y are independently halogen; and R 2Z are independently hydrogen.

[0217] In an embodiment, R 2X are independently halogen. 2Y are independently halogen. 2Z are independently hydrogen.

[0218] In an embodiment, R 2X R is independently halogen or unsubstituted 2- to 4-membered heteroalkyl; 2Y are independently hydrogen; R 2Z are independently halogen, -CN, -NR 2A C(O)R 2C , unsubstituted 2- to 4-membered heteroalkyl or substituted or unsubstituted 5- to 6-membered heterocycloalkyl; R 2A are independently hydrogen; and R 2C is independently unsubstituted C 1 -C 2 alkyl.

[0219] In an embodiment, R 2X is independently halogen or unsubstituted 2- to 4-membered heteroalkyl. 2Y are independently hydrogen. 2Z are independently halogen, -CN, -NR 2A C(O)R 2C , unsubstituted 2- to 4-membered heteroalkyl, or substituted or unsubstituted 5- to 6-membered heterocycloalkyl. 2A are independently hydrogen. 2C is independently unsubstituted C 1 -C 2 In the embodiment, R 2X are independently halogen. 2X is independently an unsubstituted 2- to 4-membered heteroalkyl. 2Z are independently halogen. 2Z In an embodiment, R 2Z Independently -NR 2A C(O)R 2C In an embodiment, R 2Z is independently an unsubstituted 2- to 4-membered heteroalkyl. 2Z and independently substituted or unsubstituted 5- to 6-membered heterocycloalkyl.

[0220] In an embodiment, R 2X are independently halogen or -OCH 3 ; R 2Y are independently hydrogen; R 2Z are independently halogen, -CN, -NHC(O)CH 3 、-OCH 3 or a substituted or unsubstituted 5- to 6-membered heterocycloalkyl group; R 2A are independently hydrogen; and R 2C is independently unsubstituted C 1 -C 2 alkyl.

[0221] In an embodiment, R 2X are independently halogen or -OCH 3 In an embodiment, R 2Y are independently hydrogen. In an embodiment, R 2Z are independently halogen, -CN, -NHC(O)CH 3 、-OCH 3 or a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. 2A are independently hydrogen.2C is independently unsubstituted C 1 -C 2 In the embodiment, R 2X are independently halogen. 2X Independently -OCH 3 In an embodiment, R 2Z are independently halogen. 2Z In an embodiment, R 2Z are independently -NHC(O)CH 3 In an embodiment, R 2Z Independently -OCH 3 In an embodiment, R 2Z and independently substituted or unsubstituted 5- to 6-membered heterocycloalkyl.

[0222] In an embodiment, R 2X are independently halogen or -OCH 3 ; R 2Y are independently hydrogen; R 2Z are independently halogen, -CN, -NHC(O)CH 3 、-OCH 3 or a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. 2Z is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. 2Z is independently substituted 5- to 6-membered heterocycloalkyl. 2Z Independently

[0223] In an embodiment, L 103 is a bond, a substituted or unsubstituted alkylene group (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ) or substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered). In an embodiment, L 103 In the embodiment, L 103 is substituted or unsubstituted C 1 -C 8 In the embodiment, L 103 is substituted or unsubstituted C 1 -C 6 In the embodiment, L 103 is substituted or unsubstituted C 1 -C 4In the embodiment, L 103 is a substituted or unsubstituted 2- to 8-membered heteroalkylene group. 103 is a substituted or unsubstituted 2- to 6-membered heteroalkylene group. 103 is a substituted or unsubstituted 2- to 4-membered heteroalkylene group.

[0224] In an embodiment, L 103 is an unsubstituted alkylene group. 103 For unsubstituted C 1 -C 4 In the embodiment, L 103 It is an unsubstituted ethylene group.

[0225] In an embodiment, L 103 For key, R 103 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ) or R 103 Substituted or unsubstituted heteroalkylene (eg, 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered).

[0226] In an embodiment, R 101 , R 102 and R 103 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0227] In an embodiment, R 101 , R 102 and R 103 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2, -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0228] In an embodiment, R 101 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 111 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), R 111substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R 111 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), R 111 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R 111 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 111 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0229] In an embodiment, R 101 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 111 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), R 111 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R 111 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), R 111 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R 111 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 111 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0230] R 111 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0231] In an embodiment, R 101 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0232] In an embodiment, R 102 are independently hydrogen, oxo, halogen, -CCl3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 112 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), R 112 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R 112 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C6 , C 4 -C 6 or C 5 -C 6 ), R 112 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R 112 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 112 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0233] In an embodiment, R 102 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2、-OCHI 2 , R 112 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), R 112 substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R 112 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), R 112 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R 112 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 112 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0234] R 112 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0235] In an embodiment, R 102 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2, -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0236] In an embodiment, R 103 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 113 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 113 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 113 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 113 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 113 Substituted or unsubstituted aryl (e.g., C6 -C 10 or phenyl) or R 113 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0237] In an embodiment, R 103 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 113 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C4 ), R 113 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 113 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 113 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 113 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 113 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0238] R 113 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0239] In an embodiment, R 103 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0240] In an embodiment, L 104 is a bond, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0241] In an embodiment, L 104 is a bond, -O-, -NH-, -S-, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4) or substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered). In an embodiment, L 104 In the embodiment, L 104 In the embodiment, L 104 In the embodiment, L 104 In the embodiment, L 104 -S(O) 2 -. In the embodiment, L 104 In the embodiment, L 104 is -NHC(O)-. In the embodiment, L 104 is -C(O)NH-. In the embodiment, L 104 In the embodiment, L 104 is -C(O)O-. In the embodiment, L 104 is substituted or unsubstituted C 1 -C 8 In the embodiment, L 104 is substituted or unsubstituted C 1 -C 6 In the embodiment, L 104 is substituted or unsubstituted C 1 -C 4 In the embodiment, L 104 is a substituted or unsubstituted 2- to 8-membered heteroalkylene group. 104 is a substituted or unsubstituted 2- to 6-membered heteroalkylene group. 104 is a substituted or unsubstituted 2- to 4-membered heteroalkylene group. 104 For unsubstituted C 1 -C 8 In the embodiment, L 104 is an unsubstituted 2- to 8-membered heteroalkylene group.

[0242] In an embodiment, L 104 is a bond, -S(O) 2 -, -C(O)-, -NHC(O)-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ) or substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered). In an embodiment, L 104 In the embodiment, L104 -S(O) 2 -. In the embodiment, L 104 In the embodiment, L 104 is -NHC(O)-. In the embodiment, L 104 In the embodiment, L 104 is substituted or unsubstituted C 1 -C 8 In the embodiment, L 104 is substituted or unsubstituted C 1 -C 6 In the embodiment, L 104 is substituted or unsubstituted C 1 -C 4 In the embodiment, L 104 is a substituted or unsubstituted 2- to 8-membered heteroalkylene group. 104 is a substituted or unsubstituted 2- to 6-membered heteroalkylene group. 104 is a substituted or unsubstituted 2- to 4-membered heteroalkylene group. 104 For unsubstituted C 1 -C 8 In the embodiment, L 104 is an unsubstituted 2- to 8-membered heteroalkylene group.

[0243] In an embodiment, L 104 is a bond, -O-, -NH-, -S-, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, R 104 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ) or R 104 Substituted or unsubstituted heteroalkylene (eg, 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered).

[0244] In an embodiment, L 104 is a bond, -S(O) 2 -, -C(O)-, -NHC(O)-, -OC(O)-, R 104 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C1 -C 4 ) or R 104 Substituted or unsubstituted heteroalkylene (eg, 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered).

[0245] R 104 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0246] In an embodiment, R 104 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 114 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 114 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 114 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 114 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 114 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 114 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0247] R 114 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0248] In an embodiment, L 105 is a bond, -O-, -NH-, -S-, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C6 or C 5 -C 6 ) or substituted or unsubstituted heterocycloalkylene (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered).

[0249] In an embodiment, L 105 is a bond, -O-, -NH-, -S-, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ) or substituted or unsubstituted heterocycloalkylene (e.g., 3-8, 3-6, or 5-6). In an embodiment, L 105 In the embodiment, L 105 In the embodiment, L 105 In the embodiment, L 105 In the embodiment, L 105 -S(O) 2 -. In the embodiment, L 105 In the embodiment, L 105 is -NHC(O)-. In the embodiment, L 105 is -C(O)NH-. In the embodiment, L 105 In the embodiment, L 105 is -C(O)O-. In the embodiment, L 105 is substituted or unsubstituted C 1 -C 8 In the embodiment, L 105 is substituted or unsubstituted C 1 -C 6 In the embodiment, L 105 is substituted or unsubstituted C 1 -C 4 In the embodiment, L 105is a substituted or unsubstituted 2- to 8-membered heteroalkylene group. 105 is a substituted or unsubstituted 2- to 6-membered heteroalkylene group. 105 is a substituted or unsubstituted 2- to 4-membered heteroalkylene group. 105 is substituted or unsubstituted C 3 -C 8 In the embodiment, L 105 is substituted or unsubstituted C 3 -C 6 In the embodiment, L 105 is substituted or unsubstituted C 5 -C 6 In the embodiment, L 105 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene group. 105 is a substituted or unsubstituted 3- to 6-membered heterocycloalkylene group. 105 is a substituted or unsubstituted 5- to 6-membered heterocycloalkylene group. 105 For unsubstituted C 1 -C 8 In the embodiment, L 105 is an unsubstituted 2- to 8-membered heteroalkylene group. 105 For unsubstituted C 3 -C 8 In the embodiment, L 105 It is an unsubstituted 3- to 8-membered heterocycloalkylene group.

[0250] In an embodiment, L 105 is a bond, a substituted or unsubstituted alkylene group (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ) or substituted or unsubstituted heterocycloalkylene (e.g., 3-8, 3-6, or 5-6). In an embodiment, L 105 In the embodiment, L 105 is substituted or unsubstituted C1 -C 8 In the embodiment, L 105 is substituted or unsubstituted C 1 -C 6 In the embodiment, L 105 is substituted or unsubstituted C 1 -C 4 In the embodiment, L 105 is a substituted or unsubstituted 2- to 8-membered heteroalkylene group. 105 is a substituted or unsubstituted 2- to 6-membered heteroalkylene group. 105 is a substituted or unsubstituted 2- to 4-membered heteroalkylene group. 105 is substituted or unsubstituted C 3 -C 8 In the embodiment, L 105 is substituted or unsubstituted C 3 -C 6 In the embodiment, L 105 is substituted or unsubstituted C 5 -C 6 In the embodiment, L 105 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene group. 105 is a substituted or unsubstituted 3- to 6-membered heterocycloalkylene group. 105 is a substituted or unsubstituted 5- to 6-membered heterocycloalkylene group. 105 For unsubstituted C 1 -C 8 In the embodiment, L 105 is an unsubstituted 2- to 8-membered heteroalkylene group. 105 For unsubstituted C 3 -C 8 In the embodiment, L 105 It is an unsubstituted 3- to 8-membered heterocycloalkylene group.

[0251] In an embodiment, L 105 is an unsubstituted alkylene group. 105 For unsubstituted C 1 -C 4 In the embodiment, L 105 for In an embodiment, L 105 for

[0252] In an embodiment, L105 is a bond, -O-, -NH-, -S-, -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, R 105 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 105 Substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 105 Substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ) or R 105 Substituted or unsubstituted heterocycloalkylene (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered).

[0253] In an embodiment, L 105 For key, R 105 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 105 Substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 105 Substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ) or R 105 Substituted or unsubstituted heterocycloalkylene (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered).

[0254] R 105 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0255] In an embodiment, R 105 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 115 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 115 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 115 Substituted or unsubstituted cycloalkyl (e.g., C3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 115 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 115 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 115 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0256] R 115 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHC(NH)H, -NHC(NH)NH 2 、-NHOH、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0257] In an embodiment, W is N. In an embodiment, W is CH.

[0258] In an embodiment, for

[0259] In an embodiment, for In an embodiment, for In an embodiment, for In an embodiment, for

[0260] In an embodiment, for

[0261]

[0262] In an embodiment, for In an embodiment, for In an embodiment, for In an embodiment, for In an embodiment, for In an embodiment, for In an embodiment, for In an embodiment, for

[0263] In an embodiment, R 1 For hydrogen, halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-OCX 1 3 、-OCH 2 X 1 、-OCHX 1 2 、-CN、-SO n1 R 1D 、-SO v1 NR 1A R 1B 、-NHC(O)NR 1A R 1B 、-N(O) m1 、-NR 1A R 1B 、-C(O)R 1C 、-C(O)OR 1C 、-C(O)NR 1A R 1B 、-OR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C 、-NR 1A C(O)OR 1C 、-NR 1A OR 1C 、-N 3 、-SSR 1D 、-SiR 1A R 1B R 1C , E, 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.

[0264] In an embodiment, R 1 For hydrogen, halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-OCX 13 、-OCH 2 X 1 、-OCHX 1 2 、-CN、-SO n1 R 1D 、-SO v1 NR 1A R 1B 、-NHC(O)NR 1A R 1B 、-N(O) m1 、-NR 1A R 1B 、-C(O)R 1C 、-C(O)OR 1C 、-C(O)NR 1A R 1B 、-OR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C 、-NR 1A C(O)OR 1C 、-NR 1A OR 1C 、-N 3 、-SiR 1A R 1B R 1C , E, 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.

[0265] In an embodiment, R 1 For hydrogen, halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-OCX 1 3 、-OCH 2 X 1 、-OCHX 1 2 、-CN、-SO n1 R 1D 、-SO v1 NR 1A R 1B 、-NHC(O)NR 1A R 1B 、-N(O)m1 、-NR 1A R 1B 、-C(O)R 1C 、-SC(O)R 1C 、-C(O)OR 1C 、-C(O)NR 1A R 1B 、-OR 1D 、-SR 1D , -SeR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C 、-NR 1A C(O)OR 1C 、-NR 1A OR 1C 、-N 3 、-SiR 1A R 1B R 1C 、-SP(O)(OH) 2 , E, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0266] In an embodiment, R 1 For hydrogen, halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-OCX 1 3 、-OCH 2 X1 、-OCHX 1 2 、-CN、-SO n1 R 1D 、-SO v1 NR 1A R 1B 、-NHC(O)NR 1A R 1B 、-N(O) m1 、-NR 1A R 1B 、-C(O)R 1C 、-SC(O)R 1C 、-C(O)OR 1C 、-C(O)NR 1A R 1B 、-OR 1D 、-SR 1D , -SeR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C 、-NR 1A C(O)OR 1C 、-NR 1A OR 1C 、-N 3 、-SiR 1A R 1B R 1C 、-SP(O)(OH) 2 , E, R 10 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 10 Substituted or unsubstituted heteroalkyl (eg, 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), R 10 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 10 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 10 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R10 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0267] In an embodiment, R 1 are independently -C(O)R 1C .

[0268] In an embodiment, R 1 independently -SC(O)R 1C .

[0269] In an embodiment, R 1C are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO 3 H2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0270] In an embodiment, R 1C are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI2 、-N 3 ,-PO 3 H 2 , R 10 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 10 Substituted or unsubstituted heteroalkyl (eg, 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered), R 10 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 10 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0271] In an embodiment, R 1C are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 1C is independently unsubstituted C 1 -C 4 In the embodiment, R 1C is independently unsubstituted methyl. 1C is independently unsubstituted ethyl. 1C is independently unsubstituted propyl. 1C is independently unsubstituted n-propyl. 1C is independently unsubstituted isopropyl. 1C is independently unsubstituted butyl. 1C is independently unsubstituted n-butyl. 1C is independently unsubstituted tert-butyl.

[0272] In an embodiment, R 1C is independently substituted or unsubstituted aryl. 1C Independently for R 10 In one embodiment, R 1C Independently for R 10 In the embodiment, R 1C is independently unsubstituted phenyl.

[0273] In an embodiment, R 1 are independently -C(O)R1C And R 1C As described herein, included in the embodiments. In the embodiments, R 1 is independently -C(O)OH. 1 are independently -C(O)NH 2 .

[0274] In an embodiment, R 1 For-SSR 1D .

[0275] In an embodiment, R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO 3 H 2, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ) or substituted or unsubstituted heteroalkyl (e.g., 2-10 membered, 2-6 membered, or 2-4 membered).

[0276] In an embodiment, R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO 3 H 2 , R 10 Substituted or unsubstituted alkyl (e.g., C1 -C 8 , C 1 -C 6 or C 1 -C 4 ) or R 10 Substituted or unsubstituted heteroalkyl (eg, 2- to 10-membered, 2- to 6-membered, or 2- to 4-membered).

[0277] In an embodiment, R 1D is independently substituted or unsubstituted alkyl. 1D Independently for R 10 In an embodiment, R 1D Independently for R 10 Substituted or unsubstituted C 1 -C 16 In the embodiment, R 1D is independently unsubstituted C 1 -C 16 alkyl.

[0278] In an embodiment, R 1 For-SR 1D 、-NR 1A R 1B 、-OR 1D , E, unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; R 1A are independently hydrogen or unsubstituted C 1 -C 4 Alkyl; R 1B are independently hydrogen or unsubstituted C 1 -C 4 alkyl; and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO 3 H 2 or substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ).

[0279] In an embodiment, R 1 For-SR 1D 、-NR 1A R 1B 、-OR 1D , E, unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. In the embodiment, R 1A are independently hydrogen or unsubstituted C 1 -C 4 In the embodiment, R 1B are independently hydrogen or unsubstituted C 1 -C 4 In the embodiment, R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO 3 H 2 or substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ).

[0280] In an embodiment, R 1 For-SR 1D 、-NR 1A R 1B 、-OR 1D , E, unsubstituted C 1 -C 4 Alkyl, R 10 Substituted or unsubstituted phenyl or R 10 Substituted or unsubstituted 5- to 6-membered heteroaryl; R 1A are independently hydrogen or unsubstituted C 1 -C 4 Alkyl; R1B are independently hydrogen or unsubstituted C 1 -C 4 alkyl; and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO 3 H 2 , R 10 Substituted or unsubstituted C 1 -C 4 alkyl.

[0281] In an embodiment, R 1 For-SR 1D 、-NR 1A R 1B 、-OR1D , E, unsubstituted C 1 -C 4 Alkyl, R 10 Substituted or unsubstituted phenyl or R 10 is a substituted or unsubstituted 5- to 6-membered heteroaryl. 1A are independently hydrogen or unsubstituted C 1 -C 4 In the embodiment, R 1B are independently hydrogen or unsubstituted C 1 -C 4 In the embodiment, R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO3 H 2 , R 10 Substituted or unsubstituted C 1 -C 4 alkyl.

[0282] R 10 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0283] In an embodiment, R 1 For-SR 1D or R 10 Substituted phenyl; R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO 3 H 2 , R 10 Substituted or unsubstituted C 1 -C 4 alkyl; and R 10 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted C 1 -C 4alkyl, unsubstituted 2-membered to 4-membered heteroalkyl, unsubstituted C 5 -C 6 cycloalkyl, unsubstituted 5- to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5- to 6-membered heteroaryl.

[0284] In an embodiment, R 1 For-SR 1D or R 10 In the embodiment, R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 、-N 3 ,-PO 3 H 2 , R 10 Substituted or unsubstituted C1 -C 4 In the embodiment, R 10 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted C 1 -C 4 alkyl, unsubstituted 2-membered to 4-membered heteroalkyl, unsubstituted C 5 -C 6 cycloalkyl, unsubstituted 5- to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5- to 6-membered heteroaryl.

[0285] In an embodiment, R 1 -SH, -SC(O)CH 3 or -SSCH3 In an embodiment, R 1 In the embodiment, R 1 -SC(O)CH 3 In an embodiment, R 1 For-SSCH 3 .

[0286] In an embodiment, R 1 are independently halogen, -NO 2 , -SH, -SeH, -SO 3 H、-SC(O)CH 3 ,-SSCH 3 、-SP(O)(OH) 2 , R 10 Substituted or unsubstituted heteroalkyl or R 10 substituted or unsubstituted heteroaryl; and R 10 As described herein, included in the embodiments. In the embodiments, R 1 is independently -F. In an embodiment, R 1 In the embodiment, R 1 is independently -Br. In an embodiment, R 1 In an embodiment, R 1 Independently -NO 2。 In an embodiment, R 1 In an embodiment, R 1 is independently -SeH. 1 Independently-SO 3 H. In an embodiment, R 1 are independently -SC(O)CH 3 In an embodiment, R 1 Independently -SSCH 3。 In an embodiment, R 1 are independently -SP(O)(OH) 2 In an embodiment, R 1 Independently for R 10 In an embodiment, R 1 Independently for R 10 is a substituted or unsubstituted 2- to 20-membered heteroalkyl group. 1 Independently for R 10 substituted 2- to 20-membered heteroalkyl. 1 is independently an unsubstituted 2- to 20-membered heteroalkyl group. 1 Independently -S-(C 1 -C 20In an embodiment, R 1 Independently -SCH 3。 In an embodiment, R 1 independently -S(O) 2 CH 3 In an embodiment, R 1 Independently wherein m is independently an integer from 0 to 4. In an embodiment, R 1 Independently In an embodiment, R 1 are independently -Si(CH 3 ) 3 In an embodiment, R 1 are independently -Si(CH 2 CH 3 ) 3 In an embodiment, R 1 are independently -Si(CH 2 CH 2 CH 3 ) 3 In an embodiment, R 1 are independently -Si(CH(CH 3 ) 2 ) 3 In an embodiment, R 1 are independently -Si(CH 2 CH 2 CH 2 CH 3 ) 3 In an embodiment, R 1 are independently -Si(C(CH 3 ) 3 ) 3 In an embodiment, R 1 Independently for R 10 In one embodiment, R 1 Independently for R 10 substituted or unsubstituted 5- to 10-membered heteroaryl. 1 is independently an unsubstituted 5- to 10-membered heteroaryl. 1 is independently unsubstituted phenylthio. 1 is independently unsubstituted furanyl. 1 is independently unsubstituted pyrrolyl. 1 is independently unsubstituted imidazolyl. 1 is independently unsubstituted tetrazolyl. 1 Independently In an embodiment, R 1 Independently In an embodiment, R 1 Independently

[0287] In an embodiment, R 1 For R 10 substituted phenyl, and R 10 are independently halogen. 1 for Where R 10.1 and R 10.2 may each independently be hydrogen or R as described herein 10 Any value of is included in the embodiments. In the embodiments, R 10.1 and R 10.2 Each is independently halogen. 1 for

[0288] In an embodiment, R 1 Independently for R 10 substituted or unsubstituted 2- to 8-membered heteroalkyl, and R 10 As described herein, included in the embodiments. In the embodiments, R 1 Independently for R 10 substituted 2- to 8-membered heteroalkyl, and R 10 In an embodiment, R 1 are independently -NHC(O)-(R 10 Substituted or unsubstituted C 1 -C 4 In an embodiment, R 1 are independently -NHC(O)-(R 10 Substituted C 1 -C 4 In an embodiment, R 1 is independently -NHC(O)-(unsubstituted C 1 -C 4 In an embodiment, R 1 Independently In an embodiment, R 1 Independently In an embodiment, R 1 Independently In an embodiment, R 1 Independently In an embodiment, R 1 independently -NHS(O) 2 -(Unsubstituted C 1-C 4 In an embodiment, R 1 Independently

[0289] In an embodiment, R 1 For E.

[0290] In an embodiment, E is

[0291] R 16 are independently hydrogen, halogen, -CX 16 3 、-CHX 16 2 、-CH 2 X 16 、-CN、-SO n16 R 16A 、-SO v16 NR 16A R 16B 、-NHNR 16A R 16B 、-ONR 16A R 16B 、-NHC(O)NHNR 16A R 16B 、-NHC(O)NR 16A R 16B 、-N(O) m16 、-NR 16A R 16B 、-C(O)R 16A 、-C(O)-OR 16A 、-C(O)NR 16A R 16B 、-OR 16A 、-NR 16A SO 2 R 16B 、-NR 16A C(O)R 16B 、-NR 16A C(O)OR 16B 、-NR 16A OR 16B 、-OCX 16 3 、-OCHX 16 2 、-OCH 2 X 16 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0292] R 17 are independently hydrogen, halogen, -CX 17 3 、-CHX 17 2 、-CH 2 X 17 、-CN、-SO n17 R 17A 、-SO v17 NR 17A R 17B 、-NHNR 17A R 17B 、-ONR 17A R 17B 、-NHC(O)NHNR 17A R 17B 、-NHC(O)NR 17A R 17B 、-N(O) m17 、-NR 17A R 17B 、-C(O)R 17A 、-C(O)-OR 17A 、-C(O)NR 17A R 17B 、-OR 17A 、-NR 17A SO 2 R 17B 、-NR 17A C(O)R 17B 、-NR 17A C(O)OR 17B、-NR 17A OR 17B 、-OCX 17 3 、-OCHX 17 2 、-OCH 2 X 17 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0293] R 18 are independently hydrogen, halogen, -CX 18 3 、-CHX 18 2 、-CH 2 X 18 、-CN、-SO n18 R 18A 、-SO v18 NR 18A R 18B 、-NHNR 18A R 18B 、-ONR 18A R 18B 、-NHC(O)NHNR 18A R 18B 、-NHC(O)NR 18A R 18B 、-N(O) m18 、-NR 18A R 18B 、-C(O)R18A 、-C(O)-OR 18A 、-C(O)NR 18A R 18B 、-OR 18A 、-NR 18A SO 2 R 18B 、-NR 18A C(O)R 18B 、-NR 18A C(O)OR 18B 、-NR 18A OR 18B 、-OCX 18 3 、-OCHX 18 2 、-OCH 2 X 18 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0294] R 19 are independently hydrogen, halogen, -CX 19 3 、-CHX 19 2 、-CH 2 X 19 、-CN、-SO n19 R 19A 、-SO v19 NR 19A R19B 、-NHNR 19A R 19B 、-ONR 19A R 19B 、-NHC(O)NHNR 19A R 19B 、-NHC(O)NR 19A R 19B 、-N(O) m19 、-NR 19A R 19B 、-C(O)R 19A 、-C(O)-OR 19A 、-C(O)NR 19A R 19B 、-OR 19A 、-NR 19A SO 2 R 19B 、-NR 19A C(O)R 19B 、-NR 19A C(O)OR 19B 、-NR 19A OR 19B 、-OCX 19 3 、-OCHX 19 2 、-OCH 2 X 19 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0295] R 16A , R 16B , R 17A , R 17B , R 18A , R 18B , R 19A and R 19B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 16A and R 16B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 17A and R 17B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 18A and R 18B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 19A and R 19B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0296] X, X 16 , X 17 , X 18 and X 19 are independently -F, -Cl, -Br or -I.

[0297] n16, n17, n18 and n19 are independently integers of 0 to 4.

[0298] m16, m17, m18, m19, v16, v17, v18 and v19 are independently 1 or 2.

[0299] In an embodiment, R 16 are independently hydrogen, halogen, -CX 16 3 、-CHX 16 2 、-CH 2 X 16 、-CN、-SO n16 R 16A 、-SO v16 NR 16A R 16B 、-NHNR 16A R 16B 、-ONR 16A R 16B 、-NHC(O)NHNR 16A R 16B 、-NHC(O)NR 16A R 16B 、-N(O) m16 、-NR 16A R 16B 、-C(O)R 16A 、-C(O)-OR 16A 、-C(O)NR 16A R 16B 、-OR 16A 、-NR 16A SO 2 R 16B 、-NR 16A C(O)R 16B 、-NR 16A C(O)OR 16B 、-NR 16A OR 16B 、-OCX 16 3 、-OCHX 16 2 、-OCH 2 X 16, substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0300] In an embodiment, the substituted R 16 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 16 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 16 When substituted, it is substituted with at least one substituent. 16 When substituted, it is substituted with at least one substituent of limited size. 16 When substituted, it is substituted with at least one lower substituent.

[0301] In an embodiment, R16 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0302] In an embodiment, R 17 are independently hydrogen, halogen, -CX 17 3 、-CHX 17 2 、-CH 2 X 17 、-CN、-SO n17 R 17A 、-SO v17 NR 17A R 17B 、-NHNR 17A R 17B 、-ONR 17A R 17B 、-NHC(O)NHNR 17A R 17B 、-NHC(O)NR 17A R 17B 、-N(O) m17 、-NR 17A R 17B 、-C(O)R 17A 、-C(O)-OR 17A 、-C(O)NR 17A R 17B 、-OR 17A 、-NR 17A SO 2 R 17B 、-NR 17A C(O)R 17B 、-NR 17A C(O)OR 17B 、-NR 17A OR 17B 、-OCX 17 3 、-OCHX 17 2 、-OCH 2 X 17 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0303] In an embodiment, the substituted R 17 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 17 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 17 When substituted, it is substituted with at least one substituent. 17 When substituted, it is substituted with at least one substituent of limited size. 17 When substituted, it is substituted with at least one lower substituent.

[0304] In an embodiment, R 17 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0305] In an embodiment, R 18 are independently hydrogen, halogen, -CX 18 3 、-CHX 18 2 、-CH 2 X 18 、-CN、-SO n18 R 18A 、-SO v18 NR 18A R 18B 、-NHNR 18A R 18B 、-ONR 18A R 18B 、-NHC(O)NHNR 18A R 18B 、-NHC(O)NR 18A R 18B 、-N(O) m18 、-NR 18A R 18B 、-C(O)R 18A 、-C(O)-OR 18A 、-C(O)NR 18A R 18B 、-OR 18A 、-NR 18A SO 2 R 18B 、-NR 18A C(O)R 18B 、-NR 18A C(O)OR 18B 、-NR 18A OR 18B 、-OCX 18 3 、-OCHX 18 2 、-OCH 2 X 18 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0306] In an embodiment, the substituted R 18 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 18 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 18 When substituted, it is substituted with at least one substituent. 18 When substituted, it is substituted with at least one substituent of limited size. 18 When substituted, it is substituted with at least one lower substituent.

[0307] In an embodiment, R 18 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0308] In an embodiment, R 19 are independently hydrogen, halogen, -CX 19 3 、-CHX 19 2 、-CH 2 X 19 、-CN、-SO n19 R 19A 、-SO v19 NR 19A R 19B 、-NHNR 19A R 19B 、-ONR 19A R 19B 、-NHC(O)NHNR 19A R 19B 、-NHC(O)NR 19A R 19B 、-N(O) m19 、-NR 19A R 19B 、-C(O)R 19A 、-C(O)-OR 19A 、-C(O)NR 19A R 19B 、-OR 19A 、-NR 19A SO 2 R 19B 、-NR 19A C(O)R 19B 、-NR 19A C(O)OR 19B 、-NR 19A OR 19B 、-OCX 19 3 、-OCHX 19 2 、-OCH 2 X 19 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0309] In an embodiment, the substituted R 19 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 19 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 19 When substituted, it is substituted with at least one substituent. 19 When substituted, it is substituted with at least one substituent of limited size. 19 When substituted, it is substituted with at least one lower substituent.

[0310] In an embodiment, R 19 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0311] In an embodiment, R 16A are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0312] In an embodiment, the substituted R 16A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 16Asubstituted with a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 16A When substituted, it is substituted with at least one substituent. 16A When substituted, it is substituted with at least one substituent of limited size. In an embodiment, when R 16A When substituted, it is substituted with at least one lower substituent.

[0313] In an embodiment, R 16B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0314] In an embodiment, the substituted R 16B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 16B substituted with a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 16B When substituted, it is substituted with at least one substituent. 16B When substituted, it is substituted with at least one substituent of limited size. In an embodiment, when R 16B When substituted, it is substituted with at least one lower substituent.

[0315] In an embodiment, R 16A and R 16B The substituents may be optionally linked to form a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl.

[0316] In an embodiment, by connecting R 16A and R 16B The substituted moiety (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) formed by the connection of substituents is substituted with at least one substituent, a substituent of limited size, or a lower substituent; wherein if R 16A and R 16B The substituted moiety formed by the connection of substituents is substituted by a plurality of groups selected from substituents, substituents of limited size, and lower substituents; each substituent, substituent of limited size, and / or lower substituent may be optionally different. In an embodiment, when R 16A and R 16B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent. 16A and R 16B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent of limited size. 16A and R 16B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one lower substituent.

[0317] In an embodiment, R 17Aare independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0318] In an embodiment, the substituted R 17A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 17A substituted with a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 17A When substituted, it is substituted with at least one substituent. 17AWhen substituted, it is substituted with at least one substituent of limited size. In an embodiment, when R 17A When substituted, it is substituted with at least one lower substituent.

[0319] In an embodiment, R 17B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0320] In an embodiment, the substituted R 17B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 17Bsubstituted with a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 17B When substituted, it is substituted with at least one substituent. 17B When substituted, it is substituted with at least one substituent of limited size. In an embodiment, when R 17B When substituted, it is substituted with at least one lower substituent.

[0321] In an embodiment, R 17A and R 17B The substituents may be optionally linked to form a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl.

[0322] In an embodiment, by connecting R 17A and R 17B The substituted moiety (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) formed by the connection of substituents is substituted with at least one substituent, a substituent of limited size, or a lower substituent; wherein if R 17A and R 17B The substituted moiety formed by the connection of substituents is substituted by a plurality of groups selected from substituents, substituents of limited size, and lower substituents; each substituent, substituent of limited size, and / or lower substituent may be optionally different. In an embodiment, when R 17A and R 17B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent. 17A and R 17B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent of limited size. 17A and R 17B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one lower substituent.

[0323] In an embodiment, R 18A are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2, substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0324] In an embodiment, the substituted R 18A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 18A substituted with a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 18A When substituted, it is substituted with at least one substituent. 18A When substituted, it is substituted with at least one substituent of limited size. In an embodiment, when R 18A When substituted, it is substituted with at least one lower substituent.

[0325] In an embodiment, R18B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0326] In an embodiment, the substituted R 18B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 18B substituted with a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 18B When substituted, it is substituted with at least one substituent.18B When substituted, it is substituted with at least one substituent of limited size. In an embodiment, when R 18B When substituted, it is substituted with at least one lower substituent.

[0327] In an embodiment, R 18A and R 18B The substituents may be optionally linked to form a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl.

[0328] In an embodiment, by connecting R 18A and R 18B The substituted moiety (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) formed by the connection of substituents is substituted with at least one substituent, a substituent of limited size, or a lower substituent; wherein if R 18A and R 18B The substituted moiety formed by the connection of substituents is substituted by a plurality of groups selected from substituents, substituents of limited size, and lower substituents; each substituent, substituent of limited size, and / or lower substituent may be optionally different. In an embodiment, when R 18A and R 18B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent. 18A and R 18B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent of limited size. 18A and R 18B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one lower substituent.

[0329] In an embodiment, R 19A are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2 , substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1-C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0330] In an embodiment, the substituted R 19A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 19A substituted with a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 19A When substituted, it is substituted with at least one substituent. 19A When substituted, it is substituted with at least one substituent of limited size. In an embodiment, when R 19A When substituted, it is substituted with at least one lower substituent.

[0331] In an embodiment, R 19B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -CN, -OH, -COOH, -CONH 2, substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8, 2-6, 4-6, 2-3, or 4-5 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted (e.g., substituted with at least one substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 membered).

[0332] In an embodiment, the substituted R 19B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 19B substituted with a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 19B When substituted, it is substituted with at least one substituent. 19B When substituted, it is substituted with at least one substituent of limited size. In an embodiment, when R 19B When substituted, it is substituted with at least one lower substituent.

[0333] In an embodiment, R 19A and R 19B The substituents may be optionally linked to form a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocycloalkyl or a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl.

[0334] In an embodiment, by connecting R 19A and R 19B The substituted moiety (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) formed by the connection of substituents is substituted with at least one substituent, a substituent of limited size, or a lower substituent; wherein if R 19A and R 19B The substituted moiety formed by the connection of substituents is substituted by a plurality of groups selected from substituents, substituents of limited size, and lower substituents; each substituent, substituent of limited size, and / or lower substituent may be optionally different. In an embodiment, when R 19A and R 19B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent. 19A and R 19B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent of limited size. 19A and R 19B When a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one lower substituent.

[0335] In an embodiment, R 16A , R 16B , R 17A , R 17B , R 18A , R 18B , R 19A and R 19B are independently hydrogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2、-CHI 2 、-CN、-OH、-COOH、-CONH 2 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 16A and R 16B The substituents may be optionally linked to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl; R 17A and R 17B The substituents may be optionally linked to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl; R 18A and R 18B The substituents may be optionally linked to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl; R 19A and R 19B The substituents may be optionally linked to form an unsubstituted heterocycloalkyl or an unsubstituted heteroaryl.

[0336] In an embodiment, E is

[0337] In an embodiment, E is In an embodiment, E is In an embodiment, E is In an embodiment, E is In an embodiment, E is In an embodiment, E is In an embodiment, E is

[0338] In an embodiment, the compound has the formula Ring A, R 1 , R 2 , L 103 , L 104 , L 105 and z2 are as described herein.

[0339] In an embodiment, L 103 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0340] In an embodiment, L 104 is a bond, -O-, -NH-, -S-, or a substituted or unsubstituted alkylene group.

[0341] In an embodiment, L 105 -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)- or -C(O)O-.

[0342] In an embodiment, L 105 -S(O) 2 -, -C(O)-, -NHC(O)-, or -OC(O)-.

[0343] n is an integer from 0 to 4.

[0344] In an embodiment, the compound has the formula R 1 , R 2X , R 2Y , L 103 , L 104 , L 105 , n and z2 are as described herein. In an embodiment, L 103 is a bond, a substituted or unsubstituted C 1 -C 6 Alkylene or substituted or unsubstituted 2- to 6-membered heteroalkylene; L 104 is a bond, -O-, -NH-, -S-, or a substituted or unsubstituted C 1 -C 4 Alkylene; L 105 -S(O) 2 -, -C(O)-, -NHC(O)- or -OC(O)-; n is an integer from 0 to 4; and R 2X and R 2Y are independently hydrogen, halogen, -CX 2 3 、-CHX 2 2、-CH 2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR 2A R 2B 、-C(O)R 2C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 3 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted or unsubstituted heteroaryl (eg, 5-10, 5-9, or 5-6 members); R 2X and R 2Y The substituents may be linked to form a substituted or unsubstituted cycloalkyl group (e.g., C 3 -C8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0345] In an embodiment, L 103 is a bond, a substituted or unsubstituted C 1 -C 6 Alkylene or substituted or unsubstituted 2- to 6-membered heteroalkylene; L 104 is a bond, -O-, -NH-, -S-, or a substituted or unsubstituted C 1 -C 4 Alkylene; L 105 -S(O) 2 -, -C(O)-, -NHC(O)- or -OC(O)-; n is an integer from 0 to 4; and R 2X and R 2Y are independently hydrogen, halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR 2A R 2B 、-C(O)R 2C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 3 , R 20 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 20 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 20 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 20 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 20 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 20 substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); R 2X and R 2Y Substituents may be linked to form R 20 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 20 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 20 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), or R 20 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0346] In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4. In an embodiment, when n is 0, L 104 and L 105 Not a key.

[0347] In an embodiment, R 2X and R 2Y are independently halogen. 2X and R 2Y is independently -Cl.

[0348] In an embodiment, L 103 is an unsubstituted alkylene group. 103 For unsubstituted C 1 -C 6 In the embodiment, L 103 For unsubstituted C 1 -C 4 In the embodiment, L 103 is the key.

[0349] In an embodiment, L 104 is a bond, -O-, -NH-, -S-, or a substituted or unsubstituted alkylene group (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ). In an embodiment, L 104 In the embodiment, L 104 In the embodiment, L 104 In the embodiment, L 104 In the embodiment, L 104 is substituted or unsubstituted C 1 -C 8 In the embodiment, L 104 is substituted or unsubstituted C 1 -C 6 In the embodiment, L 104 is substituted or unsubstituted C 1 -C 4 In the embodiment, L 104 For unsubstituted C 1 -C 8 Alkylene.

[0350] In an embodiment, L 104 is a bond, -O-, -NH-, -S-, or R 104 Substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ).104 As described herein, included in the Examples.

[0351] In an embodiment, L 105 -S(O) 2 -, -C(O)-, -NHC(O)- or -OC(O)-. In the embodiment, L 105 -S(O) 2 -. In the embodiment, L 105 In the embodiment, L 105 is -NHC(O)-. In the embodiment, L 105 It is -OC(O)-.

[0352] In an embodiment, -L 104 -CH 2 -L 105 -NH-L 103 -for

[0353] In an embodiment, -L 104 -CH 2 -L 105 -NH-L 103 -for In an embodiment, -L 104 -CH 2 -L 105 -NH-L 103 -for In an embodiment, -L 104 -CH 2 -L 105 -NH-L 103 -for In an embodiment, -L 104 -CH 2 -L 105 -NH-L 103 -for In an embodiment, -L 104 -CH 2 -L 105 -NH-L 103 -for

[0354] In an embodiment, -L 104 -CH 2 -L 105 -NH-L 103 -for In an embodiment, -L 104 -CH 2 -L 105 -NH-L103 -for

[0355] In an embodiment, R 1 Hydrogen, -SR 1D 、-NR 1A R 1B 、-OR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C , E, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2- to 10-membered heteroalkyl, substituted or unsubstituted C 5 -C 6 cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; E is an electrophilic moiety; R 1A , R 1B , R 1C and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C 5 -C 6 cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

[0356] In an embodiment, R 1 Hydrogen, -SR 1D 、-NR 1A R 1B 、-OR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C , E, R 10 Substituted or unsubstituted C 1 -C 6 Alkyl, R 10 Substituted or unsubstituted 2- to 10-membered heteroalkyl, R 10 Substituted or unsubstituted C 5 -C 6 Cycloalkyl, R 10 Substituted or unsubstituted 5- to 6-membered heterocycloalkyl, R 10 Substituted or unsubstituted phenyl or R 10 is a substituted or unsubstituted 5- to 6-membered heteroaryl. 1A , R 1B , R 1C and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2, -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 10 Substituted or unsubstituted C 1 -C 6 Alkyl, R 10 Substituted or unsubstituted 2- to 10-membered heteroalkyl, R 10 Substituted or unsubstituted C 5 -C 6 Cycloalkyl, R 10 Substituted or unsubstituted 5- to 6-membered heterocycloalkyl, R 10 Substituted or unsubstituted phenyl or R 10 A substituted or unsubstituted 5- to 6-membered heteroaryl group.

[0357] In an embodiment, R 10 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2, -CHF 2 、-CHI 2 、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R 11 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 11 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 11 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 11 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 11 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 11 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0358] R 11 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R 12 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 12 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 12 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C8 , C 3 -C 6 or C 5 -C 6 ), R 12 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 12 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 12 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0359] R 12 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R 13 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 13 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 13 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 13 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 13 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 13 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0360] R 13 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0361] In an embodiment, R 2 are independently halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR2A R 2B 、-C(O)R 2C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 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; two R attached to adjacent atoms 2 The substituents may be linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0362] In an embodiment, R 2 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 members); two R 2 The substituents may be linked to form a substituted or unsubstituted cycloalkyl group (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0363] In an embodiment, R 2 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 20 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 20 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 20 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 20 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 20 Substituted or unsubstituted aryl (e.g., C 6-C 10 or phenyl) or R 20 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); two R attached to adjacent atoms 2 Substituents may be linked to form R 20 Substituted or unsubstituted cycloalkyl, R 20 Substituted or unsubstituted heterocycloalkyl, R 20 Substituted or unsubstituted aryl or R 20 A substituted or unsubstituted heteroaryl group.

[0364] R 20 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 21Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 21 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 21 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 21 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 21 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 21 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0365] R 21 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 22 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), R 22 Substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), R 22 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), R 22 Substituted or unsubstituted heterocycloalkyl (eg, 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), R 22 Substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 22 Substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0366] R 22 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 ,-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted aryl (e.g., C 1 -C 8 , C 1 -C 6 or C 1 -C 4 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, or 2- to 4-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl) (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0367] In an embodiment, the compound is

[0368] In an embodiment, the compound is

[0369] In an embodiment, the compound is

[0370] In an embodiment, the compound is

[0371] In an embodiment, the compound is

[0372] In an embodiment, the compound is

[0373] In an embodiment, the compound is

[0374] In an embodiment, the compound is

[0375] In an embodiment, the compound is

[0376] In an embodiment, the compound is

[0377] In an embodiment, the compound is

[0378] In an embodiment, the compound is

[0379] In an embodiment, the compound is

[0380] In an embodiment, the compound is

[0381] In an embodiment, the compound is

[0382] In an embodiment, the compound is

[0383] In an embodiment, the compound is

[0384] In an embodiment, the compound is

[0385] In an embodiment, the compound is

[0386] In an embodiment, the compound is

[0387] In an embodiment, the compound is

[0388] In an embodiment, the compound is

[0389] In an embodiment, the compound is

[0390] In an embodiment, the compound is

[0391] In an embodiment, the compound is

[0392] In an embodiment, the compound is

[0393] In an embodiment, the compound is

[0394] In an embodiment, the compound is

[0395] In an embodiment, the compound is

[0396] In an embodiment, the compound is

[0397] In an embodiment, the compound is

[0398] In an embodiment, the compound is

[0399] In an embodiment, the compound is

[0400] In an embodiment, the compound is

[0401] In an embodiment, the compound is

[0402] In an embodiment, the compound is

[0403] In an embodiment, the compound is

[0404] In an embodiment, the compound is

[0405] In an embodiment, the compound is

[0406] In an embodiment, the compound is

[0407] In an embodiment, the compound is

[0408] In an embodiment, the compound is

[0409] In an embodiment, the compound is

[0410] In an embodiment, the compound is

[0411] In an embodiment, the compound is

[0412] In an embodiment, the compound is

[0413] In an embodiment, the compound is

[0414] In an embodiment, the compound is

[0415] In an embodiment, the compound is

[0416] In an embodiment, the compound is

[0417] In an embodiment, the compound is

[0418] In an embodiment, the compound is

[0419] In an embodiment, the compound is

[0420] In an embodiment, the compound is

[0421] In an embodiment, the compound is

[0422] In an embodiment, the compound is

[0423] In an embodiment, the compound is

[0424] In an embodiment, the compound is

[0425] In an embodiment, the compound is

[0426] In an embodiment, the compound is

[0427] In an embodiment, the compound is

[0428] In an embodiment, the compound is

[0429] In an embodiment, the compound is

[0430] In an embodiment, the compound is

[0431] In an embodiment, the compound is

[0432] In an embodiment, the compound is

[0433] In an embodiment, the compound is

[0434] In an embodiment, the compound is

[0435] In an embodiment, the compound is

[0436] In an embodiment, the compound is

[0437] In an embodiment, the compound is

[0438] In an embodiment, the compound is

[0439] In an embodiment, the compound is

[0440] In an embodiment, the compound is

[0441] In an embodiment, the compound is

[0442] In an embodiment, the compound is

[0443] In an embodiment, the compound is

[0444] In an embodiment, the compound is

[0445] In an embodiment, the compound is

[0446] In an embodiment, the compound is

[0447] In an embodiment, the compound is

[0448] In an embodiment, the compound is

[0449] In an embodiment, the compound is

[0450] In an embodiment, the compound is

[0451] In an embodiment, the compound is

[0452] In an embodiment, the compound is

[0453] In an embodiment, the compound is

[0454] In an embodiment, the compound is

[0455] In an embodiment, the compound is

[0456] In an embodiment, the compound is

[0457] In an embodiment, the compound is

[0458] In an embodiment, the compound is

[0459] In an embodiment, the compound is

[0460] In an embodiment, the compound is

[0461] In an embodiment, the compound is

[0462] In an embodiment, the compound is

[0463] In an embodiment, the compound is

[0464] In an embodiment, the compound is

[0465] In an embodiment, the compound is

[0466] In an embodiment, the compound is

[0467] In an embodiment, the compound is

[0468] In an embodiment, the compound is

[0469] In an embodiment, the compound is

[0470] In an embodiment, the compound is

[0471] In an embodiment, the compound is

[0472] In an embodiment, the compound is

[0473] In an embodiment, the compound is

[0474] In an embodiment, the compound is

[0475] In embodiments, Ring A is not In embodiments, Ring A is not In embodiments, Ring A is not X 2 is independently -F, -Cl, -Br or -I. In an embodiment, X 2 independently –Cl.

[0476] In an embodiment, R 1 No - SSR 1D . R 1D As described herein.

[0477] In embodiments, E is not -SS- (unsubstituted C 1 -C 7 In an embodiment, E is not -SS-(3- to 7-membered unsubstituted heteroalkyl). In an embodiment, E is not -SSCH 2 CH 2 N(CH 3 ) 2 .

[0478] In embodiments, the compound is not In embodiments, the compound is not In embodiments, the compound is not

[0479] In embodiments, the compound covalently binds to Nurr1 (eg, human Nurr1). In embodiments, the compound irreversibly covalently binds to Nurr1 (eg, human Nurr1). In embodiments, the compound reversibly covalently binds to Nurr1 (eg, human Nurr1).

[0480] In embodiments, the compound contacts the amino acid corresponding to Cys566 of human Nurr1. In embodiments, the compound contacts the amino acid corresponding to Cys475 of human Nurr1. In embodiments, the compound contacts the amino acid corresponding to Cys534 of human Nurr1.

[0481] In embodiments, the compound contacts the amino acid corresponding to Arg515 of human Nurr1. In embodiments, the compound contacts the amino acid corresponding to Arg563 of human Nurr1. In embodiments, the compound contacts the amino acid corresponding to Glu445 of human Nurr1.

[0482] In embodiments, the compound covalently binds to the amino acid corresponding to Cys566 of human Nurr1. In embodiments, the compound irreversibly covalently binds to the amino acid corresponding to Cys566 of human Nurr1. In embodiments, the compound reversibly covalently binds to the amino acid corresponding to Cys566 of human Nurr1.

[0483] In embodiments, the compound stabilizes Nurr1 homomonomers. In embodiments, the compound stabilizes Nurr1 homodimers. In embodiments, the compound stabilizes head-to-tail Nurr1 homodimers. In embodiments, the compound stabilizes Nurr1 heterodimers. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0484] In embodiments, the compound stabilizes Nurr1 monomers relative to a control (e.g., in the absence of the compound). In embodiments, the compound stabilizes Nurr1 homodimers relative to a control (e.g., in the absence of the compound). In embodiments, the compound stabilizes head-to-tail Nurr1 homodimers relative to a control (e.g., in the absence of the compound). In embodiments, the compound stabilizes Nurr1 heterodimers relative to a control (e.g., in the absence of the compound). In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0485] In embodiments, the compound contacts a Nurr1 homomonomer. In embodiments, the compound contacts a Nurr1 homodimer. In embodiments, the compound contacts a head-to-tail Nurr1 homodimer. In embodiments, the compound contacts a Nurr1 heterodimer. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0486] In embodiments, the compound connects Nurr1 homomonomers. In embodiments, the compound connects Nurr1 homodimers. In embodiments, the compound connects head-to-tail Nurr1 homodimers. In embodiments, the compound connects Nurr1 heterodimers. In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0487] In embodiments, the compound excludes the formation of Nurr1:RXR heterodimers. In embodiments, the compound inhibits the formation of Nurr1:RXR heterodimers. In embodiments, the compound that binds to Nurr1 inhibits the binding of the resulting compound:Nurr1 complex to RXR.

[0488] In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is about (e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or In an embodiment, the compound stabilizes the Nurr1 dimer conformation, wherein the distance between the N-termini is at least (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or In an embodiment, the compound stabilizes the Nurr1 dimer conformation, wherein the distance between the N-termini is less than (For example, less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61 or ).

[0489] In embodiments, the compound contacts a Nurr1 dimer conformation wherein the distance between the N-termini is about (e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or In an embodiment, the compound contacts a Nurr1 dimer conformation wherein the distance between the N-termini is at least (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or In an embodiment, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is less than (For example, less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61 or ).

[0490] In an embodiment, the compound binds to a Nurr1 dimer conformation wherein the distance between the N-termini is about (e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or In an embodiment, the compound binds to a Nurr1 dimer conformation, wherein the distance between the N-termini is at least (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or In an embodiment, the compound binds to a Nurr1 dimer conformation, wherein the distance between the N-termini is less than (For example, less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 65, 64, 63, 62, 61 or ).

[0491] In embodiments, the compound stabilizes a Nurr1 dimer conformation in which the distance between the N-termini is about (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or In an embodiment, the compound stabilizes the Nurr1 dimer conformation, wherein the distance between the N-termini is at least (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or In an embodiment, the compound stabilizes the Nurr1 dimer conformation, wherein the distance between the N-termini is less than (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or ).

[0492] In embodiments, the compound contacts a Nurr1 dimer conformation wherein the distance between the N-termini is about (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or In an embodiment, the compound contacts a Nurr1 dimer conformation wherein the distance between the N-termini is at least (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or In an embodiment, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is less than (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or ).

[0493] In an embodiment, the compound binds to a Nurr1 dimer conformation wherein the distance between the N-termini is about (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or In an embodiment, the compound binds to a Nurr1 dimer conformation, wherein the distance between the N-termini is at least (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or In an embodiment, the compound binds to a Nurr1 dimer conformation, wherein the distance between the N-termini is less than (e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or ).

[0494] In embodiments, the compound ligates Nurr1 and induces Nurr1 to ligate to NBRE, NuRE, or DR-5 response element. In embodiments, the compound ligates Nurr1 and induces Nurr1 to ligate to NBRE. In embodiments, the compound ligates Nurr1 and induces Nurr1 to ligate to NuRE. In embodiments, the compound ligates Nurr1 and induces Nurr1 to ligate to DR-5 response element.

[0495] In embodiments, the compound is a compound as described herein, included in the embodiments. In embodiments, the compound is a compound as described herein (eg, in the Examples section, figures, tables, claims, or appendices).

[0496] III. Pharmaceutical Compositions

[0497] In one aspect, a pharmaceutical composition is provided, comprising a compound described herein and a pharmaceutically acceptable excipient.

[0498] In embodiments, the pharmaceutical composition comprises an effective amount of a compound. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound.

[0499] In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent for treating a neurodegenerative disease. In an embodiment, the neurodegenerative disease is Parkinson's disease. In an embodiment, the second agent is a Parkinson's disease drug, for example, levodopa, carbidopa, selegiline, amantadine, donepezil, galantamine, rivastigmine, tacrine, bromocriptine, pergolide, pramipexole, ropinirole, trihexyphenidyl, benztropine, biperiden, prucyclidine, tolcapone or entacapone. In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a second agent.

[0500] In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent for treating an inflammatory disease, for example, acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac sodium, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, codeine, fentanyl, hydrocodone, hydromorphone, morphine, pethidine or oxycodone. In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a second agent.

[0501] In embodiments, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an anti-cancer agent.

[0502] In one aspect, a pharmaceutical composition is provided, comprising 5,6-dihydroxyindole (DHI) and a pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition comprises an effective amount of 5,6-dihydroxyindole (DHI). In an embodiment, the pharmaceutical composition comprises a therapeutically effective amount of 5,6-dihydroxyindole (DHI). In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent described herein.

[0503] IV. How to use

[0504] In one aspect, a method for treating a disease of the central nervous system associated with dopaminergic neuron dysregulation and / or degeneration in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0505] In one aspect, a method for treating a disease associated with dopaminergic neuron dysregulation and / or degeneration in the central nervous system of a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5,6-dihydroxyindole (DHI).

[0506] In embodiments, the disease associated with dopaminergic neuron dysregulation and / or degeneration is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction. In embodiments, the disease is Parkinson's disease. In embodiments, the disease is Alzheimer's disease. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is amyotrophic lateral sclerosis. In embodiments, the disease is schizophrenia. In embodiments, the disease is drug addiction.

[0507] In an embodiment, the disease associated with dopaminergic neuron dysregulation and / or degeneration is cancer.

[0508] In one aspect, a method for treating a disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0509] In one aspect, a method for treating a disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5,6-dihydroxyindole (DHI).

[0510] In embodiments, the disease is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction. In embodiments, the disease is Parkinson's disease. In embodiments, the disease is Alzheimer's disease. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is amyotrophic lateral sclerosis. In embodiments, the disease is schizophrenia. In embodiments, the disease is drug addiction.

[0511] In embodiments, the disease is cancer.

[0512] In embodiments, the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid carcinoma, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical carcinoma, or cervical cancer.

[0513] In one aspect, a method for reducing inflammation in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0514] In embodiments, the method is for reducing inflammation in the central nervous system of a subject in need thereof.

[0515] In one aspect, a method for reducing oxidative stress in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

[0516] In embodiments, the method is for reducing oxidative stress in the central nervous system of a subject in need thereof.

[0517] On the one hand, a method for regulating the Nurr1 activity level of a subject in need is provided, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need. In an embodiment, the Nurr1 activity level of the subject is increased by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times or 1000 times. In embodiments, the subject's Nurr1 activity level is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0518] On the one hand, a method for increasing the Nurr1 activity level of a cell is provided, the method comprising contacting the cell with a compound described herein. In an embodiment, the Nurr1 activity level of the cell increases by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times or 1000 times. In embodiments, the level of Nurr1 activity in a cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0519] In one aspect, a method of increasing the level of Pitx3 activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the Pitx3 activity level of the subject is increased by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times, or 1000 times. In embodiments, the subject's Pitx3 activity level is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0520] In one aspect, a method of increasing the level of Pitx3 activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of Pitx3 activity in a cell is increased by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times, or 1000 times. In embodiments, the Pitx3 activity level of the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0521] In one aspect, a method of increasing the level of TH activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of TH activity in the subject is increased by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times, or 1000 times. In embodiments, the subject's TH activity level is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0522] In one aspect, a method of increasing the level of TH activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of TH activity in the cell is increased by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times, or 1000 times. In embodiments, the TH activity level of the cells is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0523] On the one hand, a method for increasing the VMAT2 activity level of a subject in need is provided, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need. In an embodiment, the VMAT2 activity level of the subject is increased by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times or 1000 times. In embodiments, the subject's VMAT2 activity level is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0524] On the one hand, a method for increasing the VMAT2 activity level of a cell is provided, the method comprising contacting the cell with a compound described herein. In an embodiment, the VMAT2 activity level of a cell increases by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times or 1000 times. In embodiments, the VMAT2 activity level of the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0525] On the one hand, a method for increasing the dopa decarboxylase (DDC) activity level of a subject in need is provided, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need. In an embodiment, the DDC activity level of the subject increases by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times or 1000 times. In embodiments, the subject's DDC activity level is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0526] On the one hand, a method for increasing the dopa decarboxylase (DDC) activity level of a cell is provided, the method comprising contacting the cell with a compound described herein. In an embodiment, the DDC activity level of a cell increases by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times or 1000 times. In embodiments, the level of DDC activity of the cells is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0527] On the one hand, a method for increasing the dopamine transporter (DAT) activity level of a subject in need is provided, the method comprising administering a therapeutically effective amount of a compound described herein to the subject in need. In an embodiment, the DAT activity level of the subject increases by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times or 1000 times. In embodiments, the subject's DAT activity level is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0528] On the one hand, a method for increasing the dopamine transporter (DAT) activity level of a cell is provided, the method comprising contacting the cell with a compound described herein. In an embodiment, the DAT activity level of a cell increases by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times or 1000 times. In embodiments, the level of DAT activity in the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0529] In one aspect, a method of increasing the level of BDNF activity in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of BDNF activity in the subject is increased by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times, or 1000 times. In embodiments, the subject's BDNF activity level is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

[0530] In one aspect, a method of increasing the level of BDNF activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of BDNF activity in the cell is increased by about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 40 times, 45 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 600 times, 700 times, 800 times, 900 times, or 1000 times. In embodiments, the BDNF activity level of the cells is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, ...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the formula L 104 is a bond, -O-, -NH-, -S-, or a substituted or unsubstituted alkylene group; L 105 -S(O) 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, or -OC(O)-; L 103 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R 1 Halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-OCX 1 3 、-OCH 2 X 1 、-OCHX 1 2 、-CN、-SO n1 R 1D 、-SO v1 NR 1A R 1B 、-NHC(O)NR 1A R 1B 、-N(O) m1 、-NR 1A R 1B 、-C(O)R 1C 、-SC(O)R 1C 、-C(O)OR 1C 、-C(O)NR 1A R 1B 、-OR 1D 、-SR 1D , -SeR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C 、-NR 1A C(O)OR 1C 、-NR 1A OR 1C 、-N 3 、-SSR 1D 、-SiR 1A R 1B R 1C 、-SP(O)(OH) 2 , E, 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; E is the electrophilic part; R 2X Halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR 2A R 2B 、-C(O)R 2C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2Y For hydrogen, halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 2 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-CN、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-N(O) m2 、-NR 2A R 2B 、-C(O)R 2C 、-C(O)OR 2C 、-C(O)NR 2A R 2B 、-OR 2D 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C and R 2D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B The substituents may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 2A and R 2B The substituents may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n1 and n2 are independently integers from 0 to 4; m1, m2, v1 and v2 are independently 1 or 2; and X 1 and X 2 are independently -F, -Cl, -Br or -I.

2. The compound according to claim 1, wherein R 2X and R 2Y It is a halogen.

3. The compound according to claim 1, wherein R 2X and R 2Y It is -Cl.

4. The compound according to claim 1, wherein L 104 It is -O-.

5. The compound according to claim 1, wherein L 105 It is -C(O)-.

6. The compound according to claim 1, wherein L 103 is an unsubstituted alkylene group.

7. The compound according to claim 1, wherein L 103 For unsubstituted C 1 -C 6 Alkylene.

8. The compound according to claim 1, wherein L 103 For unsubstituted C 1 -C 4 Alkylene.

9. The compound according to claim 1, wherein L 103 is the key.

10. The compound according to claim 1, wherein -L 104 -CH 2 -L 105 -NH-L 103 -for 11. The compound according to claim 1, wherein R 1 Hydrogen, -SR 1D 、-NR 1A R 1B 、-OR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C , E, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C 5 -C 6 Cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; E is the electrophilic part; R 1A , R 1B , R 1C and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C 5 -C 6 cycloalkyl, substituted or unsubstituted 5- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

12. The compound according to claim 1, wherein R 1 Hydrogen, -SR 1D 、-NR 1A R 1B 、-OR 1D 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C , E, R 10 Substituted or unsubstituted C 1 -C 6 Alkyl, R 10 Substituted or unsubstituted 2- to 6-membered heteroalkyl, R 10 Substituted or unsubstituted C 5 -C 6 Cycloalkyl, R 10 Substituted or unsubstituted 5- to 6-membered heterocycloalkyl, R 10 Substituted or unsubstituted phenyl or R 10 a substituted or unsubstituted 5- to 6-membered heteroaryl group; E is the electrophilic part; R 1A , R 1B , R 1C and R 1D are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , R 10 Substituted or unsubstituted C 1 -C 6 Alkyl, R 10 Substituted or unsubstituted 2- to 6-membered heteroalkyl, R 10 Substituted or unsubstituted C 5 -C 6 Cycloalkyl, R 10 Substituted or unsubstituted 5- to 6-membered heterocycloalkyl, R 10 Substituted or unsubstituted phenyl or R 10 a substituted or unsubstituted 5- to 6-membered heteroaryl group; R 10 Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R 11 Substituted or unsubstituted C 1 -C 4 Alkyl, R 11 Substituted or unsubstituted 2- to 4-membered heteroalkyl, R 11 Substituted or unsubstituted C 5 -C 6 Cycloalkyl, R 11 Substituted or unsubstituted 5- to 6-membered heterocycloalkyl, R 11 Substituted or unsubstituted phenyl or R 11 a substituted or unsubstituted 5- to 6-membered heteroaryl group; R 11 Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R 12 Substituted or unsubstituted C 1 -C 4 Alkyl, R 12 Substituted or unsubstituted 2- to 4-membered heteroalkyl, R 12 Substituted or unsubstituted C 5 -C 6 Cycloalkyl, R 12 Substituted or unsubstituted 5- to 6-membered heterocycloalkyl, R 12 Substituted or unsubstituted phenyl or R 12 a substituted or unsubstituted 5- to 6-membered heteroaryl; and R 12 Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted C 1 -C 4 alkyl, unsubstituted 2- to 4-membered heteroalkyl, unsubstituted C 5 -C 6 cycloalkyl, unsubstituted 5- to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5- to 6-membered heteroaryl.

13. The compound according to claim 1, wherein R 1 -SH, -SC(O)CH 3 or -SSCH 3 .

14. The compound according to claim 1, wherein R 1 is E; and E is in R 16 , R 17 , R 18 and R 19 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I. -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCBr 3 、-OCF 3 、-OCI 3 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I. -OCHCl 2 , -OCHBr 2 、-OCHF 2 、-OCHI 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; and X 17 is –F, -Cl, -Br or –I.

15. The compound according to claim 1, wherein R 1 is E; and E is 16. The compound according to claim 1, wherein R 1 for 17. The compound according to claim 1, having the formula:

18. The compound of claim 1, wherein the compound is not 19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

20. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with dopaminergic neuron dysregulation and / or degeneration of the central nervous system of a subject in need thereof.

21. The use according to claim 20, wherein the disease associated with dopaminergic neuron dysregulation and / or degeneration is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia or drug addiction.

22. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer in a subject in need thereof.

23. The use according to claim 22, wherein the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid carcinoma, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical carcinoma or cervical cancer.

24. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for modulating the level of Nurr1 activity in a subject in need thereof.

25. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for increasing the activity level of Nurr1 in a cell.

26. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for increasing dopamine levels in cells.

27. A pharmaceutical composition comprising 5,6-dihydroxyindole (DHI) and a pharmaceutically acceptable excipient.

28. Use of 5,6-dihydroxyindole (DHI) in the preparation of a medicament for treating a disease of the central nervous system associated with dopaminergic neuron dysregulation and / or degeneration in a subject in need thereof.

29. The use according to claim 28, wherein the disease associated with dopaminergic neuron dysregulation and / or degeneration is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia or drug addiction.

30. Use of 5,6-dihydroxyindole (DHI) in the preparation of a medicament for treating cancer in a subject in need thereof.

31. The use according to claim 30, wherein the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid carcinoma, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical carcinoma or cervical cancer.

Images