PCNA inhibitor

Abstract

To provide ligands for a proliferating cell nuclear antigen (PCNA), and methods of using the same.SOLUTION: The invention provides a compound having the formula in the figure. In the formula, Ring A is phenyl or heteroaryl; Ring B is naphthyl, quinolinyl, or isoquinolinyl; R1 is halogen, alkyl, or the like; R2 and R3 are hydrogen, halogen, alkyl, or the like; and z1 is independently an integer from 0 to 4.SELECTED DRAWING: Figure 10A

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 220,014, filed on September 17, 2015; U.S. Provisional Patent Application No. 62 / 313,592, filed on March 25, 2016; and U.S. Provisional Patent Application No. 62 / 340,964, filed on May 24, 2016, the contents of which are hereby incorporated by reference in their entirety for all purposes.

[0002] Reference to a "Sequence Listing", Table, or Computer Program Listing Appendix Submitted as an ASCII File The sequence listing written in the file 48440 - 512001WO_ST25.TXT, created on September 13, 2016, 4,862 bytes, in IBM - PC, MS - Windows operating system machine format, is hereby incorporated by reference into this specification.

[0003] Statement Regarding Rights to Inventions Made Under Federally Sponsored Research and Development This invention was made with government support under R01 CA121289, R01CA120954, and P30CA033572 awarded by the National Institutes of Health, U.S.A., and under W81XWH - 11 - 1 - 0786 awarded by the U.S. Department of Defense. The government has certain rights in this invention.

Background Art

[0004] Neuroblastoma (NB) arises from neural crest progenitor cells of the sympathetic nervous system and accounts for approximately 15% of all pediatric cancer deaths and is one of the most common pediatric malignancies [1]. The most important single factor for determining treatment options and prognosis in NB patients is risk stratification. Survival rates are excellent in the low-risk and intermediate-risk groups [2]. Localized perinatal adrenal tumors often regress spontaneously. Current treatment for high-risk NB consists of induction therapy, high-dose chemotherapy and autologous stem cell transplantation (HDCT / autoSCT) as intensification therapy, and maintenance therapy with 13-cis-retinoic acid and immunotherapy to reduce relapse from minimal residual disease [3]. Despite an aggressive treatment regimen that often causes severe side effects and probably secondary malignancies [4], approximately 50% of patients with advanced disease show resistance to treatment or relapse. The outlook for survival in high-risk NB patients is poor [5, 6]. Therefore, there is a significant medical need for new therapies to improve cancer treatment outcomes. Disclosed herein are solutions to these and other problems in the art.

Summary of the Invention

[0005] Provided herein are, in particular, ligands for proliferating cell nuclear antigen (PCNA), and methods of using the same.

[0006] In one aspect, compounds having the following formula are provided,

Chemical formula

[0007] In another aspect, there is provided a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In another aspect, provided is a method for treating cancer in a subject in need thereof, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, provided is a method for inhibiting PCNA activity in a subject in need thereof, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0010]

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Modes for Carrying Out the Invention

[0011] Proliferating cell nuclear antigen (PCNA) plays an important role in the regulation of DNA synthesis and repair and is essential for the growth and survival of cancer cells. To date, a novel cancer-related PCNA isoform (dubbed caPCNA) that is ubiquitously expressed in a wide range of cancer cells and tumor tissues but not significantly expressed in non-malignant cells has been reported. The caPCNA-specific antigenic site was found to be between L126 and Y133 within the domain-connecting loop of PCNA. By computer modeling a binding pocket partially delineated by the L126-Y133 region of PCNA and targeting it for drug discovery chemistry, AOH1160, a potent PCNA inhibitor that selectively kills neuroblastoma (NB) cells without significant toxicity to a wide range of non-malignant cells, was identified. Mechanistically, AOH1160 interferes with DNA replication, blocks homologous recombination-mediated DNA repair, and causes cell cycle arrest. AOH1160 induces apoptosis in NB cells and sensitizes NB cells to cisplatin treatment. AOH1160 is orally administrable to animals and suppresses tumor growth without causing death or significant weight loss in mice. These results demonstrate the favorable pharmacological and therapeutic properties of AOH1160 and its potential as a novel therapeutic agent for treating NB.

[0012] PCNA is positioned at the center of important cellular processes including DNA replication, cell cycle control, and DNA damage repair that are essential for cancer cell proliferation and survival

[10] . Inhibition of PCNA is considered an effective way to suppress tumor growth, and several attempts have been made in recent years to block various aspects of PCNA function [13, 19, 39 - 42]. The structural differences and accessibility in the L126 - Y133 region between nmPCNA and caPCNA

[16] , as well as studies showing that cell-permeable peptides containing the L126 - Y133 octapeptide can block PCNA interaction with its interaction partners and selectively kill NB cells without causing significant toxicity to non-malignant cells

[18] , indicate that the L126 - Y133 region on PCNA is an attractive target.

[0013] Described herein is the successful identification of small molecule compounds that inhibit PCNA function and contain AOH1160. The compounds are chemically novel in the drug discovery space. AOH1160 has particularly remarkable and suitable therapeutic properties. AOH1160 is a small molecule PCNA inhibitor that can be administered orally and kills tumors in vivo without causing significant toxicity after systemic administration to animals. Therefore, successfully translating this compound into clinical practice can bring about a new class of anti-cancer drugs and significantly improve the treatment options for NB. In addition to the potential of AOH1160 as an effective monotherapy, its ability to sensitize NB cells to treatment with DNA-damaging agents (e.g., platinum-containing compounds) can significantly improve efficacy and reduce the dose-limiting side effects of conventional chemotherapy in clinical practice.

[0014] A. Definitions The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valence known in the chemical field.

[0015] When a substituent is specified by its conventional chemical formula written from left to right, this equally encompasses chemically identical substituents that would result from writing the structure from right to left. For example, -CH 2 O- is -OCH 2 - and is equal.

[0016] The term "alkyl", by itself or as part of another substituent, unless otherwise specified, means a straight-chain (i.e., unbranched) or branched acyclic carbon chain (or carbon) or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and can include divalent and polyvalent groups, which have the specified number of carbon atoms (i.e., C 1 -C 10(wherein it means 1 to 10 carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers such as, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are those having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers. Alkoxy is alkyl bonded to the remainder of the molecule via an oxygen linker (-O-). The alkyl portion may be an alkenyl portion. The alkyl portion may be an alkynyl portion. The alkyl portion may be fully saturated.

[0017] The term "alkylene", by itself or as part of another substituent, unless otherwise specified, is, but is not limited to, -CH 2 CH 2 CH 2 CH 2 - means a divalent radical derived from alkyl as exemplified by. Typically, an alkyl (or alkylene) group has 1 to 24 carbon atoms, and groups having 10 or fewer carbon atoms are preferred in the present invention. "Lower alkyl" or "lower alkylene" is a short-chain alkyl group or alkylene group and generally has 8 or fewer carbon atoms. The term "alkenylene", by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from alkene.

[0018] The term "heteroalkyl", by itself or in combination with another term, unless otherwise specified, refers to a stable straight-chain or branched acyclic chain or combinations thereof containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, P, S, or Si) may be located at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. 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 、-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. Two or up to three heteroatoms may be consecutive, e.g., -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3and the like. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain two different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain three different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain four different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain five different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may optionally contain up to eight different heteroatoms (e.g., O, N, S, Si, or P).

[0019] Similarly, the term "heteroalkylene" by itself or as part of another substituent, unless otherwise specified, is not limited, but -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 - means a divalent radical derived from heteroalkyl as exemplified by. For a heteroalkylene group, the heteroatom(s) can occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not indicated by the direction in which the formula of the linking group is written. For example, the formula -C(O) 2 R'- represents both -C(O) 2 R'- and -R'C(O) 2 -. As described above, as used herein, a heteroalkyl group is a group that is bonded to the remainder of the molecule through a heteroatom, e.g., -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO 2It includes R’. When “heteroalkyl” is recited and subsequently a specific heteroalkyl group, such as -NR’R’’, etc., is recited, it should be understood that the terms heteroalkyl and -NR’R’’ are neither redundant nor mutually exclusive. Rather, the specific heteroalkyl group is recited for the sake of clarity. Thus, the term “heteroalkyl” should not be construed herein as excluding specific heteroalkyl groups, such as -NR’R’’, etc.

[0020] The terms "cycloalkyl" and "heterocycloalkyl", alone or in combination with other terms, unless otherwise specified, each mean non-aromatic cyclic forms of "alkyl" and "heteroalkyl", respectively, where the carbons forming the ring or rings are not necessarily bonded to hydrogen since all carbon valences are involved in bonds with non-hydrogen atoms. Further, for heterocycloalkyl, the heteroatom can occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, 3-hydroxy-cyclobuta-3-enyl-1,2-dione, 1H-1,2,4-triazolyl-5(4H)-one, 4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "Cycloalkylene" and "heterocycloalkylene", alone or as part of another substituent, each mean a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively. The heterocycloalkyl moiety may contain one ring heteroatom (e.g., O, N, S, Si, or P). The heterocycloalkyl moiety may optionally contain two different ring heteroatoms (e.g., O, N, S, Si, or P). The heterocycloalkyl moiety may optionally contain three different ring heteroatoms (e.g., O, N, S, Si, or P). The heterocycloalkyl moiety may optionally contain four different ring heteroatoms (e.g., O, N, S, Si, or P). The heterocycloalkyl moiety may optionally contain five different ring heteroatoms (e.g., O, N, S, Si, or P). The heterocycloalkyl moiety may optionally contain up to eight different ring heteroatoms (e.g., O, N, S, Si, or P).

[0021] The term "halo" or "halogen", by itself or as part of another substituent, means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, unless otherwise specified. Further, terms such as "haloalkyl" are intended 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.

[0022] The term "acyl", unless otherwise specified, means -C(O)R where R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0023] The term "aryl" means a polyvalent unsaturated aromatic hydrocarbon substituent which, unless otherwise specified, may be a fused (i.e., fused-ring aryl) or covalently linked monocyclic or polycyclic (preferably 1 to 3 rings) group. Fused-ring aryl refers to polycyclic rings fused together where at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, e.g., N, O or S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., polycyclic rings fused together where at least one of the fused rings is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two fused rings where one ring has 5 members, the other ring has 6 members, and at least one of the rings is a heteroaryl ring. Similarly, 6,6-fused-ring heteroarylene refers to two fused rings where one ring has 6 members, the other ring has 6 members, and at least one of the rings is a heteroaryl ring. And 6,5-fused-ring heteroarylene refers to two fused rings where one ring has 6 members, the other ring has 5 members, and at least one of the rings is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule via a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.The substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene" each mean a divalent radical derived from aryl and heteroaryl, either alone or as part of another substituent. Non-limiting examples of aryl and heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolinyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl or quinolinyl. The above examples may be substituted or unsubstituted, and the divalent groups of each of the above heteroaryl examples are non-limiting examples of heteroarylene. The heteroaryl moiety may contain one ring heteroatom (e.g., O, N or S). The heteroaryl moiety may optionally contain two different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may optionally contain three different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may optionally contain four different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may optionally contain five different ring heteroatoms (e.g., O, N or S). The aryl moiety may have a single ring. The aryl moiety may optionally have two different rings. The aryl moiety may optionally have three different rings. The aryl moiety may optionally have four different rings. The heteroaryl moiety may have one ring.The heteroaryl moiety may optionally have two different rings. The heteroaryl moiety may optionally have three different rings. The heteroaryl moiety may optionally have four different rings. The heteroaryl moiety may optionally have five different rings.

[0024] Fused-ring heterocycloalkyl-aryl is aryl fused to heterocycloalkyl. Fused-ring heterocycloalkyl-heteroaryl is heteroaryl fused to heterocycloalkyl. Fused-ring heterocycloalkyl-cycloalkyl is heterocycloalkyl fused to cycloalkyl. Fused-ring heterocycloalkyl-heterocycloalkyl is heterocycloalkyl fused to another heterocycloalkyl. Fused-ring heterocycloalkyl-aryl, fused-ring heterocycloalkyl-heteroaryl, fused-ring heterocycloalkyl-cycloalkyl or fused-ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0025] As used herein, the term "oxo" means oxygen double-bonded to a carbon atom.

[0026] As used herein, the term "alkylsulfonyl" means a moiety having the formula -S(O 2 )-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., "C 1 -C 4 alkylsulfonyl").

[0027] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl" and "heteroaryl") includes both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of radical are provided below.

[0028] Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) are not limited, but are in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms of such a radical, and include -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 and can be one or more of various groups selected from. R, R', R'', R''', and R'''' are each preferably independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with one to three halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group or arylalkyl group. When the compound of the present invention contains more than one R group, for example, each of the R groups is independently selected, and the same is true for each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are bonded to the same nitrogen atom, they can bond with the nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above considerations regarding substituents, the term "alkyl" includes haloalkyl (e.g., -CF3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 etc.), including groups containing carbon atoms bonded to groups other than hydrogen groups, will be understood by those skilled in the art.

[0029] Similar to the substituents described for alkyl radicals, the substituents for aryl and heteroaryl groups are also diverse. For example, in numbers ranging from zero to the total number of open valences of the aromatic ring system, -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 , fluoro(C 1 -C 4 ) alkoxy and fluoro(C 1 -C 4)Selected from alkyl, and 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 compound of the present invention contains more than one R group, for example, each of the R groups is independently selected, and the same applies when more than one of each R', R'', R''', and R'''' group is present.

[0030] Two or more substituents can be optionally joined to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found to be attached to the cyclic basal structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the basal structure. For example, two ring-forming substituents attached to adjacent members of a cyclic basal structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the basal structure. For example, two ring-forming substituents attached to a single member of a cyclic basal structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the basal structure.

[0031] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring can optionally form a ring of the formula -T-C(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 an aryl or heteroaryl ring can optionally be replaced with a substituent 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)[ 2NR’ or a single bond, and r is an integer from 1 to 4. Optionally, one of the single bonds of the newly formed ring can be replaced by a double bond. Alternatively, optionally, two of the substituents on adjacent atoms of an aryl or heteroaryl ring can be replaced by a substituent of the formula -(CRR’) s -X’-(C’’R’’R’’’) d -, where s and d are independently integers from 0 to 3, and X’ is -O-, -NR’-, -S-, -S(O)-, -S(O) 2 - or -S(O) 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.

[0032] As used herein, the terms “heteroatom” or “ring heteroatom” are intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0033] As used herein, a substituent means a group selected from the following moieties: (A) oxo, halogen, -CF 3 , -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, -OCF 3 , -OCHF 2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from the following: (i) oxo, halogen, -CF 3 , -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, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from the following: (a) oxo, halogen, -CF 3 , -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, -OCF 3, -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from the following: oxo, halogen, -CF 3 , -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, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0034] As used herein, "size-limited substituent" or "size-limited substituent group" means a group selected from all the substituents described above with respect to "substituent", where 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, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6 -C 10 is aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0035] As used herein, "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above with respect to "substituent", and each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, and each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0036] 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 size-limiting substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0037] In other embodiments of the compounds of this specification, 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 of this specification, 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 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0038] 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 C 3 -C 7It is cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and 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 9-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene 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, and 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, and 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 following Examples section, figure, or table.

[0039] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds in undiluted or in a suitable inert solvent with a sufficient amount of the desired base. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds in undiluted or in a suitable inert solvent with a sufficient amount of the desired acid. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic or phosphorous acids and relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic acids and the like. Also included are salts of amino acids such as arginate and the like and salts of organic acids such as glucuronic or galactunoric acids (see, for example, Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present invention contain both basic and acidic functionalities such that the compounds can be converted into either a base addition salt or an acid addition salt. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in histidine in the pH range of 4.5 to 5.5 at 1 mM to 50 mM, sucrose at 0.1% to 2%, mannitol at 2% to 7%, which is combined with a buffer prior to use.

[0040] Accordingly, the compounds of the present invention can exist, for example, as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof including the racemic mixture), succinate, benzoate, and salts with amino acids such as glutamate. These salts can be prepared by methods known to those skilled in the art.

[0041] The neutral form of the compound is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents.

[0042] Agents (e.g., compounds, drugs, therapeutic agents) that can be in prodrug form are provided herein. A prodrug of a compound described herein is a compound that readily undergoes a chemical change under selected physiological conditions to provide the final agent (e.g., compound, drug, therapeutic agent). Further, the prodrug can be converted to the agent (e.g., compound, drug, therapeutic agent) by chemical or biochemical means in an ex vivo environment. The prodrugs described herein include compounds that readily undergo a chemical change under selected physiological conditions to provide the agent (e.g., compound, drug, therapeutic agent) to a biological system (e.g., in a subject, in cancer cells, in the extracellular space near cancer cells).

[0043] Certain compounds of the present invention can exist in unsolvated and solvated forms (including hydrated forms). In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent with respect to the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0044] As used herein, the term "salt" refers to an acid or base salt of a compound used in the methods of the present invention. Examples of acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid), and salts of quaternary ammonium (such as methyl iodide, ethyl iodide).

[0045] Certain compounds of the present invention possess an asymmetric carbon atom (an optical or chiral center) or a double bond and can be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers, and individual isomers are included within the scope of the present invention. The present invention does not include those compounds known in the art to be too unstable to be synthesized and / or isolated. The present invention is intended to include compounds in racemic form and optically pure form. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers.

[0046] As used herein, the term "isomer" refers to compounds having the same number and kinds of atoms and thus the same molecular weight, but differing with respect to the structural arrangement or configuration of the atoms.

[0047] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another.

[0048] Certain compounds of the present invention can exist in tautomeric forms, and it will be apparent to those skilled in the art that all such tautomeric forms of the compounds are within the scope of the present invention.

[0049] Unless otherwise indicated, the structures shown in this specification are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each chiral center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds are within the scope of the present invention.

[0050] Unless otherwise indicated, the structures shown in this specification are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium or 13 C- or 14 replacement of carbon by C-enriched carbon, compounds having the present structure are within the scope of the present invention.

[0051] The compounds of the present invention can also include unnatural ratios of atomic isotopes in one or more of the atoms that make up such compounds. For example, the compounds can be radiolabeled with radioactive isotopes such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Whether radioactive or not, all isotopic variations of the compounds of the present invention are encompassed within the scope of the present invention.

[0052] The symbol “” indicates the point of attachment of a chemical moiety to the remainder of the molecule or chemical formula.

[0053] As used herein, the terms “a” or “an” mean one or more. Further, as used herein, “substituted with a[n] (substituted with)” means that a particular group can be substituted with one or more of any or all of the designated substituents. For example, when a group such as an alkyl or heteroaryl group is “substituted with unsubstituted C 1 -C 20 alkyl or unsubstituted 2-20 membered heteroalkyl”, the group is one or more unsubstituted C 1 -C 20It can contain alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl. Further, when a moiety is substituted by one or more R substituents, such a group can be referred to as "R-substituted". When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different.

[0054] The description of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Thus, when a group can be substituted by one or more of several substituents, such substitution is selected to be in accordance with the principles of chemical bonding and to result in compounds that are not inherently unstable and / or that are not likely to be unstable under ambient conditions such as aqueous, neutral, and some known physiological conditions. For example, heterocycloalkyl or heteroaryl is bonded to the remainder of the molecule via a ring heteroatom in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding compounds that are inherently unstable.

[0055] The term "treating" or "treatment" refers to any objective or subjective parameter, such as alleviation of symptoms, remission, reduction, or making an injury, pathology or condition more tolerable to the patient, slowing the rate of degeneration or decline; making the end point of degeneration less debilitating, improving the physical or mental health of the patient, including any indication of success in the treatment or amelioration of an injury, disease, pathology or condition. Treatment or amelioration of symptoms can be based on objective or subjective parameters including the results of a physical examination, neuropsychological examination, and / or psychiatric evaluation. For example, certain methods herein treat diseases associated with PCNA activity. Certain methods described herein can treat diseases associated with PCNA activity (e.g., cancer or neuroblastoma) by inhibiting PCNA activity. For example, certain methods herein treat cancer. For example, certain methods herein treat cancer by reducing the symptoms of cancer. The symptoms of cancer are known to those of skill in the art or can be determined by those of skill in the art. The term "treating" and its conjugations include the prevention of an injury, pathology, condition or disease.

[0056] "Effective amount" means an amount sufficient to achieve a defined purpose (e.g., to achieve the purpose for which it is administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce the function of a protein, to reduce one or more symptoms of a disease or condition). Examples of "effective amount" are amounts sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, which can also be referred to as "therapeutically effective amount". "Reduction" of one or more symptoms (and grammatical equivalents of this expression) means a decrease in the severity or frequency of the symptom(s), or the disappearance of the symptom(s). The "prophylactically effective amount" of a drug or prodrug, when administered to a subject, has the intended prophylactic effect, e.g., to prevent or delay the onset (or recurrence) of an injury, disease, disorder, or condition, or to reduce the likelihood of the onset (or recurrence) of an injury, disease, disorder, or condition or their symptoms. The complete prophylactic effect may not necessarily occur with a single dose administration and may occur only after a series of doses are administered. Thus, a prophylactically effective amount can be administered in one or more administrations. The exact amount depends on the purpose of the treatment and can be determined by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0057] In the context of a substance or the activity or function of a substance associated with a disease (e.g., cancer), the terms "associated with" or "associated" mean that the disease is (wholly or partially) caused by the substance or the activity or function of the substance, or that the symptoms of the disease are (wholly or partially) caused by the substance or the activity or function of the substance. As used herein, being described as associated with a disease can, if it is a causative factor, be a target for the treatment of the disease. For example, a disease associated with PCNA activity can be treated with an agent (e.g., a compound described herein) effective to reduce the level of PCNA activity.

[0058] "Control" or "control experiment" or "standard control" is used in accordance with its plain ordinary meaning and refers to an experiment in which the subject or reagent of the experiment is treated in the same manner as a parallel experiment, except for the omission of the experimental procedure, reagent or variable factor. In some cases, the control is used as a standard of comparison when evaluating the effect of the experiment. In an embodiment, the control is the same experimental or treatment method in the absence of the compound (e.g., as described herein) used in the non-control experiment or treatment method being compared to the control.

[0059] "Contacting" is used in its plain ordinary meaning and refers to a process that allows at least two different species (such as chemical compounds including biomolecules or cells) to be proximal enough to react, interact, or physically touch. However, it should be understood that the resulting reaction product can be generated directly from the reaction between the added reagents or from intermediates from one or more of the added reagents that can be formed in the reaction mixture. The term "contacting" can include allowing two species to react, interact, or physically touch (where the two species may be the compounds and proteins or enzymes described herein). In some embodiments, contacting includes allowing the compounds described herein to interact with a protein (such as PCNA) or an enzyme. In an embodiment, contacting includes allowing the compounds described herein to interact with SEQ ID NO: 2. In an embodiment, contacting includes allowing the compounds described herein to interact with SEQ ID NO: 3. In an embodiment, it includes allowing the compounds described herein to interact with SEQ ID NO: 4.

[0060] As defined herein, "inhibit", "inhibiting", "inhibition", etc. in the context of protein-inhibitor (such as antagonist) interactions mean to negatively affect (such as decrease) the level of activity or function of a protein as compared to the level of activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to the reduction of a disease or symptoms of a disease. Thus, inhibition can include, at least in part, partially or completely blocking a stimulus, reducing, preventing or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction, enzyme activity, or protein amount.

[0061] As defined herein, the terms “activate,” “activating,” “activation,” etc. in the context of protein-activator (e.g., agonist) interactions mean to positively affect (e.g., increase) the activity or function of a protein as compared to the activity or function of the protein in the absence of an activator (e.g., a compound described herein). Thus, activation can include, at least in part, increasing, in part or completely, a stimulus, increasing or enabling activation, or activating, sensitizing, or upregulating a signaling or enzyme activity or protein amount that is decreased in a disease. Activation can include, at least in part, in part or completely, increasing a stimulus, increasing or enabling activation, or activating, sensitizing, or upregulating a signaling or enzyme activity or protein amount.

[0062] The term “modulator” refers to a composition that increases or decreases the level or function of a target molecule. In embodiments, the modulator is an anti-cancer agent. In embodiments, the modulator is a PCNA antagonist. In embodiments, the modulator is a PCNA inhibitor.

[0063] "Anticancer agent" or "anticancer drug" is used according to its plain and ordinary meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) having the property of combating malignancy or the ability to inhibit cell growth or proliferation. In some embodiments, the anticancer agent is a chemotherapeutic agent. In some embodiments, the anticancer agent is a drug approved by the FDA or a similar regulatory authority in a country other than the USA for treating cancer. Examples of anticancer agents include, but are not limited to, antiandrogens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), 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., mechlorethamine, cyclophosphamide, chlorambucil, melphalan), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin), triazenes (dacarbazine)), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), 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,Teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaliplatin, carboplatin), anthraquinone (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide), epipodophyllotoxin (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, BAY43-9006, wortmannin, or LY294002), mTOR inhibitors, antibodies (e.g., rituxan), 5-aza-2'-deoxycytidine, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), bortezomib, trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogens,Anti-estrogen; antisense oligonucleotide; apoptosis gene modulator; apoptosis regulator; arginine deaminase; BCR / ABL antagonist; beta-lactam derivative; bFGF inhibitor; bicalutamide; camptothecin derivative; casein kinase inhibitor (ICOS); clomifene analogue; cytarabine-daclituximab; dexamethasone; estrogen agonist; estrogen antagonist; etanidazole; etoposide phosphate; exemestane; fadrozole; finasteride; fludarabine; fluorodaunorubicin hydrochloride; gadolinium texaphyrin; gallium nitrate; gelatinase inhibitor; gemcitabine; glutathione inhibitor; hepsulfam; immunostimulatory peptide; insulin-like growth factor-1 receptor inhibitor; interferon agonist; interferon; interleukin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprolide; matrilysin inhibitor; matrix metalloproteinase inhibitor; MIF inhibitor; mifepristone; mismatched double-stranded RNA; monoclonal antibody; mycobacterial cell wall extract; nitric oxide modulator; oxaliplatin; panomifene; pentrozole; phosphatase inhibitor; plasminogen activator inhibitor; platinum complex; platinum compound; prednisone; proteasome inhibitor; protein A-based immunomodulator; protein kinase C inhibitor; protein tyrosine phosphatase inhibitor; purine nucleoside phosphorylase inhibitor; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; ribozyme; signal transduction inhibitor; signal transduction modulator; single-chain antigen-binding protein; stem cell inhibitor; stem cell division inhibitor; stromelysin inhibitor; synthetic glycosaminoglycan; tamoxifen methiodide; telomerase inhibitor; thyroid stimulating hormone; translation inhibitor; tyrosine kinase inhibitor; urokinase receptor antagonist; steroid (e.g., dexamethasone), finasteride, aromatase inhibitor, gonadotropin-releasing hormone agonist (GnRH), e.g., goserelin or leuprolide, adrenal cortical steroid (e.g., prednisone),Progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen drugs (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131Anti-CD20 monoclonal antibody conjugated to I, etc.), triptolide, homohalichondrin, duocarmycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitor, epidermal growth factor receptor (EGFR) targeted therapy or therapeutic agent (e.g., gefitinib (Iressa (trademark)), erlotinib (Tarceva (trademark)), cetuximab (Erbitux (trademark)), lapatinib (Tykerb (trademark)), panitumumab (Vectibix (trademark)), vandetanib (Caprelsa (trademark)), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, pyrrolobenzodiazepine (e.g., tomamycin), carboplatin, CC-1065 and CC-1065 analogs including amino-CBI, nitrogen mustard (e.g., chlorambucil and melphalan), dolastatin and dolastatin analogs (including auristatin: e.g., monomethyl auristatin E), anthracycline antibiotics (e.g., doxorubicin, daunorubicin, etc.), duocarmycin and duocarmycin analogs, enediyne (e.g., neocarzinostatin and calicheamicin), leptomycin derivatives, maytansinoid and maytansinoid analogs (e.g., mertansine), methotrexate, mitomycin C, taxoid, vinca alkaloid (e.g., vinblastine and vincristine), epothilone (e.g., epothilone B), camptothecin and its clinical analogs topotecan and irinotecan, etc.

[0064] The "chemotherapeutic agent" or "chemotherapeutic drug" is used according to its plain and ordinary meaning and refers to a chemical composition or compound having the property of inhibiting anti-cancer or the growth or proliferation of cells.

[0065] "Patient" or "subject in need thereof" or "subject" refers to a living organism suffering from, or susceptible to, a disease or condition that can be treated by administration of a compound or pharmaceutical composition, or by a method, provided herein. Non-limiting examples include humans, other mammals, bovine animals, rats, mice, dogs, monkeys, goats, sheep, female cows, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the subject is a human. In some embodiments, the subject is a human child (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than 1 year old).

[0066] "Disease" or "condition" refers to the life situation or health status of a patient or subject who can be treated with the compounds, pharmaceutical compositions or methods provided herein. In some embodiments, the disease is a disease having symptoms of cell overgrowth. In some embodiments, the disease is a disease having symptoms of abnormal levels of PCNA activity. In some embodiments, the disease is cancer. In some further examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, cancers of the kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus and liver (including hepatocellular carcinoma), lymphomas, such as B-acute lymphoblastic lymphoma, non-Hodgkin lymphoma (e.g., Burkitt, small cell and large cell lymphoma), Hodgkin lymphoma, leukemias (including AML, ALL and CML) or multiple myeloma. In an embodiment, the disease is a cancer of the brain. In an embodiment, the disease is neuroblastoma. In an embodiment, the disease is glioblastoma. In an embodiment, the disease is a central nervous system (CNS) cancer. In an embodiment, the disease is a sympathetic nervous system (SNS) cancer. In an embodiment, the disease is an adrenal cancer. In an embodiment, the disease is a cancer of nerve cells in the neck, chest, abdomen, or pelvis. In an embodiment, the disease is nasal neuroblastoma. In an embodiment, the disease is stage 1 neuroblastoma (e.g., a localized tumor confined to an area near the origin). In an embodiment, the disease is stage 2A neuroblastoma (e.g., a unilateral tumor by incomplete total resection, and / or identifiable ipsilateral and contralateral lymph nodes negative for the tumor). In an embodiment, the disease is stage 2B neuroblastoma (e.g., a unilateral tumor by complete or incomplete total resection; ipsilateral lymph nodes positive for the tumor; identifiable contralateral lymph nodes negative for the tumor). In an embodiment, the disease is stage 3 neuroblastoma (e.g., a tumor infiltrating across the midline with or without regional lymph node metastasis; or a unilateral tumor with contralateral lymph node metastasis; or a midline tumor with bilateral lymph node metastasis).In an embodiment, the disease is neuroblastoma at stage 4 (e.g., metastasis to distant lymph nodes, bone marrow, bone, liver, or other organs of the tumor, except when defined by stage 4S). In an embodiment, the disease is neuroblastoma at stage 4S (e.g., the primary tumor described in stage 1 or stage 2 with metastasis limited to the liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumor) in a child less than 1 year of age). In an embodiment, the disease is neuroblastoma at stage L1 according to the International Neuroblastoma Risk Group (INRG) staging system (e.g., a localized disease without imaging-diagnosed risk factors). In an embodiment, the disease is neuroblastoma at stage L2 according to the International Neuroblastoma Risk Group (INRG) staging system (e.g., a localized disease with imaging-diagnosed risk factors). In an embodiment, the disease is neuroblastoma at stage M according to the International Neuroblastoma Risk Group (INRG) staging system (e.g., a metastatic disease). In an embodiment, the disease is neuroblastoma at stage MS according to the International Neuroblastoma Risk Group (INRG) staging system (e.g., MS is a "special" metastatic disease equal to stage 4S as described above). In an embodiment, the disease is a pre-treatment group of very low-risk neuroblastoma risk stratification according to the International Neuroblastoma Risk Group (INRG) staging system. In an embodiment, the disease is a pre-treatment group of low-risk neuroblastoma risk stratification according to the International Neuroblastoma Risk Group (INRG) staging system. In an embodiment, the disease is a pre-treatment group of intermediate-risk neuroblastoma risk stratification according to the International Neuroblastoma Risk Group (INRG) staging system. In an embodiment, the disease is a pre-treatment group of high-risk neuroblastoma risk stratification according to the International Neuroblastoma Risk Group (INRG) staging system.

[0067] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumor found in mammals (e.g., humans), including leukemia, carcinoma and sarcoma. Exemplary cancers that can be treated with the compounds or methods provided herein include prostate, thyroid, endocrine, brain, breast, cervical, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma cancer, colorectal cancer, pancreatic cancer. Further examples include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, hypercalcemia of malignancy, endometrial cancer, adrenocortical cancer, neoplasm of endocrine or exocrine pancreas, medullary thyroid cancer, medullary carcinoma of thyroid, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0068] The term "leukemia" broadly refers to a progressive malignant disease of the hematopoietic organs and is generally characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and nature of the disease, i.e., acute or chronic, (2) the type of cells involved: myeloid (myelogenous), lymphoid (lymphocytic) or monocytic, and (3) the increase or non-increase in the number of abnormal cells in the blood, i.e., leukemic or non-leukemic (sub-leukemic). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphoid leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micro myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, sub-leukemic leukemia, or undifferentiated cell leukemia.

[0069] The term "sarcoma" generally refers to a tumor composed of substances such as embryonic connective tissue, generally consisting of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, cystosarcoma phyllodes, enamel epithelial sarcoma, sarcoma botryoides, chloroma, choriocarcinoma, fetal 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, Kupffer stellate cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, juxtacortical osteosarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystadenosarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0070] The term "melanoma" is interpreted to mean a tumor arising from the melanocyte system of 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 melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant acral lentiginous melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0071] The term "cancer" refers to a malignant neoplasm composed of epithelial cells that tend to invade surrounding tissues and metastasize. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular carcinoma, alveolar carcinoma, cystadenocarcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar adenocarcinoma, alveolar epithelial carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar epithelial carcinoma, bronchioloalveolar carcinoma, bronchiogenic carcinoma, encephaloid carcinoma, cholangiocarcinoma, chorionic carcinoma, colloid carcinoma, acne carcinoma, corpus carcinoma, cribriform carcinoma, scirrhous carcinoma, cutaneous carcinoma, cylindroma, cylindrocellular carcinoma, ductal carcinoma, scirrhous carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, ulcerating carcinoma, fibrosarcoma, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, adenocarcinoma, granular cell carcinoma, trichoblastoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenoid carcinoma, fetal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, muciparous carcinoma, mucinous cell carcinoma, carcinomamucocellulare), mucosal epidermoid carcinoma, mucinous carcinoma, mucous carcinoma, mucinous tumor-like carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, spinous cell carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, precursor cell carcinoma, sarcomatous carcinoma, Schneider carcinoma, Skills carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spindle elliptical cell carcinoma, spindle cell carcinoma, sponge-like carcinoma, squamous cell carcinoma, squamous epithelial cell carcinoma, string carcinoma, angiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma or carcinoma villosum.

[0072] As used herein, the term "signaling pathway" refers to a series of interactions between cellular components and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) where a change in one component can convey a change to one or more other components, which in turn can convey a change to additional components, which optionally propagates to other signaling pathway components.

[0073] As used herein, the term "abnormal" refers to being different from normal. When used to describe enzyme activity, abnormal refers to an activity that is higher or lower than the average of a normal control or normal non-diseased control sample. Abnormal activity can refer to the amount of activity that causes a disease, where reducing the abnormal activity to a normal amount or an amount associated with non-disease (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.

[0074] As used herein, "nucleic acid" or "oligonucleotide" or "polynucleotide" or grammatical equivalents thereof means at least two nucleotides covalently linked to each other. The term "nucleic acid" includes single-stranded, double-stranded, or multi-stranded DNA, RNA, and their analogs (derivatives). Oligonucleotides typically have a length of about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides, with a maximum length of about 100 nucleotides. Nucleic acids and polynucleotides are polymers of any length, including longer ones, such as 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. Nucleic acids containing one or more carbocyclic sugars are also included in the definition of nucleic acids.

[0075] A particular nucleic acid sequence also encompasses "splice variants". Similarly, a particular protein encoded by a nucleic acid encompasses any protein encoded by a splice variant of that nucleic acid. As the name suggests, "splice variants" are the products of alternative splicing of a gene. After transcription, the initial nucleic acid transcript can be spliced so that different (distinct) nucleic acid splice products encode different polypeptides. The mechanisms for the production of splice variants vary, but include alternative splicing of exons. Other polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any product of the splicing reaction, including recombinant forms of splice products, is included in this definition.

[0076] A nucleic acid is "operably linked" when it is in a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned to promote translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, are in reading phase. However, enhancers do not have to be contiguous. The linkage is accomplished by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adapters or linkers are used in accordance with conventional practice.

[0077] The terms "identity" or percent "identity" with respect to two or more nucleic acid or polypeptide sequences refers to sequences or subsequences that are the same or have the same amino acid residues or nucleotides at a specified percentage (i.e., about 60% identity, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity in a particular region when compared and aligned for maximum correspondence over a comparison window or designated region) when measured using the BLAST or BLAST 2.0 sequence comparison algorithms with the default parameters described below, or by manual alignment and visual inspection (see, e.g., the NCBI website, etc.). Such sequences are, as a result, referred to as "substantially identical." This definition can also refer to, or be applied to, the complement of a test sequence. This definition also includes sequences with deletions and / or additions, as well as those with substitutions. As described herein, preferred algorithms can account for gaps, etc. Preferably, identity exists over a region of at least about 10 amino acids or 20 nucleotides in length, or more preferably, over a region of 10 to 50 amino acids or 20 to 50 nucleotides in length. As used herein, the percentage of amino acid sequence identity (%) is defined as the percentage of amino acids in a candidate sequence that are identical to the amino acids in a reference sequence after alignment of the sequences and introduction of gaps, if necessary, to obtain the maximum percentage of sequence identity (%). Alignment for determining the percentage of sequence identity can be achieved by various methods within the capabilities of one of ordinary skill in the art, e.g., using publicly available computer programs such as BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software.Suitable parameters for measuring alignment, including any algorithm necessary to achieve a maximum alignment over the entire length of the arrays being compared, can be determined by known methods.

[0078] For array comparison, typically one array functions as a reference array against which a test array is compared. When using an array comparison algorithm, the test and reference arrays are input into a computer, the coordinates of the subsequences are specified, and, if necessary, the parameters of the array algorithm program are specified. Preferably, default program parameters may be available or alternative parameters may be specified. The array comparison algorithm then calculates the percent sequence identity of the test array to the reference array based on the parameters of the program.

[0079] As used herein, a "comparison window" refers to a reference to any one segment of contiguous position numbers selected from the group consisting of 10 to 600, usually about 50 to about 200, more usually about 100 to about 150, which allows an array to be compared to a reference array at the same contiguous position numbers after the two arrays are optimally aligned. Methods for aligning arrays for comparison are well known in the art. Optimal alignment of arrays for comparison can be performed, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the similarity search method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), by computer implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Current Protocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).

[0080] The phrase "hybridizes selectively (or specifically) to" means that a molecule binds, duplexes, or hybridizes with higher affinity to a particular nucleotide sequence under more stringent conditions than to other nucleotide sequences (e.g., total cellular DNA or RNA, or library DNA or RNA).

[0081] The term "stringent hybridization conditions" refers to conditions under which a probe will typically hybridize to its target subsequence in a complex mixture of nucleic acids, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences will hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen, Techniques in Biochemistry and Molecular Biology - Hybridization with Nucleic Probes, “Overview of principles of hybridization and the strategy of nucleic acid assays” (1993). Generally, stringent conditions are selected to be about 5 - 10 °C lower than the thermal melting point (T m ) for the specific sequence at a defined ionic strength and pH. The T m is the temperature (under defined ionic strength, pH, and nucleic acid concentration) at which 50% of the probe complementary to the target hybridizes to the target sequence at equilibrium (since the target sequence is present in excess, at T m , 50% of the probe is occupied at equilibrium). Stringent conditions can also be achieved by the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal is at least 2-fold, preferably 10-fold, that of background hybridization. Exemplary stringent hybridization conditions can be as follows: Incubate at 42 °C in 50% formamide, 5× SSC, and 1% SDS, or incubate at 65 °C in 5× SSC, 1% SDS, and wash at 65 °C in 0.2× SSC and 0.1% SDS.

[0082] Nucleic acids that do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides they encode are substantially identical. This occurs, for example, when copies of the nucleic acid are made using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions. Exemplary "moderately stringent hybridization conditions" include hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37°C, and washing in 1× SSC at 45°C. Positive hybridization is at least twice the background. One of ordinary skill in the art will readily understand that alternative hybridization and wash conditions can be utilized to provide similar stringency conditions. Further guidance for determining hybridization parameters is provided, for example, in numerous references and Current Protocols in Molecular Biology, ed. Ausubel, et al.

[0083] Twenty amino acids are commonly found in proteins. These amino acids can be grouped into nine classes or groups based on the chemical nature of their side chains. Substituting one amino acid residue with another within the same class or group is referred to herein as a "conservative" substitution. Conservative amino acid substitutions can often be made in a protein without significantly altering the conformation or function of the protein. Substituting one amino acid residue with another from a different class or group is referred to herein as a "non-conservative" substitution. In contrast, non-conservative amino acid substitutions tend to modify the conformation and function of a protein. Examples of Amino Acid Classification Small / Aliphatic Residues: Gly, Ala, Val, Leu, Ile Cyclic Amino Acid: Pro Hydroxyl-Containing Residues: Ser, Thr Acidic Residues: Asp, Glu Amide Residues: Asn, Gln Basic residues: Lys, Arg Imidazole residue: His Aromatic residues: Phe, Tyr, Trp Sulfur-containing residues: Met, Cys

[0084] In some embodiments, conservative amino acid substitutions include substituting any other of these aliphatic amino acids with glycine (G), alanine (A), isoleucine (I), valine (V), and leucine (L); substituting threonine (T) with serine (S), and vice versa; substituting glutamic acid (E) with aspartic acid (D), and vice versa; substituting asparagine (N) with glutamine (Q), and vice versa; substituting arginine (R) with lysine (K), and vice versa; substituting any other of these aromatic amino acids with phenylalanine (F), tyrosine (Y), and tryptophan (W); and substituting cysteine (C) with methionine (M), and vice versa. Depending on the environment and role of a particular amino acid in the three-dimensional structure of the protein, other substitutions can also be considered conservative. For example, glycine (G) and alanine (A) are often interchangeable, as are alanine (A) and valine (V). Methionine (M), which is relatively hydrophobic, can often be exchanged with leucine and isoleucine, and sometimes with valine. Lysine (K) and arginine (R) are often interchangeable at positions where the important feature of the amino acid residue is its charge and the different pKs of these two amino acid residues are not important. Still other changes can be considered "conservative" in certain environments (see, for example, BIOCHEMISTRY at pp. 13-15, 2nd ed. Lubert Stryer ed. (Stanford University); Henikoff et al., Proc. Nat’l Acad. Sci. USA (1992) 89: 10915-10919; Lei et al., J. Biol. Chem. (1995) 270(20): 11882-11886).

[0085] "Polypeptide", "peptide" and "protein" are used interchangeably herein and mean any peptide-bonded chain of amino acids, regardless of length or post-translational modification. As described below, the polypeptides described herein can be, for example, wild-type proteins, biologically active fragments of wild-type proteins or variants of wild-type proteins or fragments. Variants according to the present disclosure can include amino acid substitutions, deletions or insertions. Substitutions can be conservative or non-conservative.

[0086] Following expression, the protein can be isolated. When applied to any of the proteins described herein, the terms "purified" or "isolated" refer to a polypeptide that has been separated or purified from components that are naturally associated with the polypeptide (e.g., proteins or other naturally occurring biomolecules or organic molecules) (e.g., other proteins, lipids and nucleic acids in the cells in which the protein is expressed). Typically, a polypeptide is purified when it constitutes at least 60 (e.g., at least 65, 70, 75, 80, 85, 90, 92, 95, 97 or 99) weight % of the total protein in a sample.

[0087] An amino acid residue of a protein "corresponds" to a given residue if it occupies the same basic structural position within the protein as the given residue. For example, a selected residue of a selected protein corresponds to L126 - Y133 of human PCNA if the selected residue is in the same basic spatial or other structural relationship as L126 - Y133 in human PCNA. In some embodiments, when the selected protein is aligned for maximum homology to the human PCNA protein, the positions in the aligned selected protein that align with L126 - Y133 are said to correspond to L126 - Y133. For example, when the structure of the selected protein is aligned for maximum identity to the human PCNA protein and comparing the overall structures, three - dimensional structure alignment can also be used instead of primary sequence alignment. In this case, the amino acids that occupy the same essential position as L126 - Y133 in the structural model are said to correspond to the L126 - Y133 residues.

[0088] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that assist in the administration of the active agent to the subject and its absorption by the subject and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non - limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and coloring agents, etc. Such preparations can be sterilized and, if necessary, can be mixed with adjuvants that do not react detrimentally with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for affecting osmotic pressure, buffers, coloring agents, and / or aromatic substances, etc. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0089] The term "preparation" is intended to include a formulation of an active compound with an encapsulating agent as a carrier which results in a capsule in which the active ingredient is surrounded by, and thus associated with, the carrier, with or without other carriers. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0090] As used herein, the term "administering" means administering to a subject by oral administration, administration as a suppository, topical contact administration, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration or implantation of a sustained release device, e.g., a mini osmotic pump. Administration can be 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, arteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusions, transdermal patches, etc. "Co-administering" means that the compositions described herein are administered simultaneously with, immediately before or immediately after the administration of one or more additional therapeutic agents (e.g., anti-cancer agents). The compounds of the invention may be administered to a patient alone or co-administered. Co-administration is intended to include simultaneous or sequential administration of the compounds, individually or in combination (more than one compound or agent). Thus, the preparations can also be combined with other active substances, if desired (e.g., to reduce metabolic degradation, to enhance the degradation of prodrugs and the release of drugs, detectable agents). The compositions of the invention can be delivered transdermally, by topical routes, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, coatings, powders and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, solutions, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for oral ingestion by a patient. Preparations in solid form include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. Preparations in liquid form include solutions, suspensions and emulsions, e.g., aqueous or water / propylene glycol solutions. The compositions of the invention can further comprise components that provide sustained release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelling polysaccharides and micronized drug carrier substrates.These components are discussed in more detail in U.S. Pat. Nos. 4,911,920, 5,403,841, 5,212,162 and 4,861,760. The entire contents of these patents are hereby incorporated by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gels (e.g., see Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (e.g., see Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulation of the composition of the present invention can be delivered by using liposomes that fuse with cell membranes or are endocytosed, i.e., by using receptor ligands bound to liposomes that bind to cell surface membrane protein receptors that cause endocytosis. By using liposomes, particularly when the liposome surface bears receptor ligands specific for target cells or is otherwise preferentially directed to a particular organ, the delivery of the composition of the present invention can be concentrated on target cells in vivo (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.

[0091] The pharmaceutical composition provided by the present invention includes a composition containing a therapeutically effective amount, that is, an amount effective to achieve its intended purpose, of an active ingredient (for example, the compounds described in this specification including embodiments or examples). The actual amount effective for a particular use depends in particular on the condition being treated. When administered in a method for treating a disease, such a composition contains an amount of the active ingredient effective to achieve a desired result, such as reducing, eliminating, or slowing the progression of disease symptoms (for example, cancer or symptoms of abnormal PCNA activity). Determination of the therapeutically effective amount of the compounds of the present invention is well within the ability of those skilled in the art, especially in light of the detailed disclosure herein.

[0092] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending on a variety of factors, such as whether the mammal has another disease and its route of administration; the size, age, sex, health status, weight, body mass index and diet of the recipient; the nature and degree of the symptoms of the disease being treated (for example, cancer symptoms), the type of combination therapy, and complications or other health-related problems from the disease being treated. Other treatment regimens or agents can be used in combination with the methods and compounds of the invention by the applicants. Adjustment and manipulation of established dosages (for example, frequency and duration) are well within the scope of those skilled in the art.

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

[0094] As is well known in the art, a therapeutically effective amount for use in humans can also be determined from animal models. For example, the dosage for humans can be formulated to achieve a concentration known to be effective in animals. The dosage in humans can be adjusted, as described above, by monitoring the effectiveness of the compound and adjusting the dosage up or down. Based on the above methods and other methods, adjusting the dosage to achieve maximum efficacy in humans is well within the ability of one of ordinary skill in the art.

[0095] The dosage can vary depending on the requirements of the patient and the compound used. In the present invention, the dosage administered to a patient should be sufficient to provide a beneficial therapeutic response over time in the patient. The size of the dosage is also determined by the presence, nature and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of a physician. Generally, treatment is initiated at a lower dosage, less than the optimal dosage of the compound. Thereafter, the dosage is increased little by little until the optimal effect is reached under the circumstances.

[0096] The amount and interval of dosing can be adjusted individually to provide an administered compound level effective for the particular clinical signs being treated. This provides a treatment regimen appropriate to the severity of the individual's condition.

[0097] Using the teachings provided herein, a prophylactic or therapeutically effective treatment regimen can be planned that causes substantially no toxicity and, moreover, is effective in treating the clinical symptoms exhibited in a particular patient. This plan should include a careful selection of the active compound by considering factors such as the potency of the compound, relative bioavailability, patient weight, presence and severity of adverse side effects, preferred mode of administration and toxicity profile of the agent selected.

[0098] The compounds described herein can be used in combination with other active agents known to be useful for treating cancer, or with adjuvant agents that may not be effective alone but can contribute to the efficacy of the active agent.

[0099] In some embodiments, co - administration includes 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 includes administering the two active agents simultaneously, substantially 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 preparing a co - formulation, i.e., a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agent and / or adjuvant agent can be conjugated or coupled to each other. In some embodiments, the compounds described herein can be combined with cancer treatments such as radiation therapy or surgery.

[0100] As used herein, the term "about" means a range of values that would be naturally considered by one of ordinary skill in the art to be similar to the specified value. In embodiments, about means within one standard deviation using generally acceptable measurements in the art. In embodiments, about means a range extending up to + / - 10% of the specified value. In embodiments, about means the specified value.

[0101] The term "proliferating cell nuclear antigen" or "PCNA" refers to a protein of approximately 29 kDa that self-associates to a protein complex consisting of three subunits of individual PCNA proteins. These associated PCNA molecules together form a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells. The term "PCNA" can refer to the nucleotide or protein sequence of human PCNA (e.g., Entrez 5111, Uniprot P12004, RefSeq NM_002592 (SEQ ID NO: 1), or RefSeq NP_002583 (SEQ ID NO: 2)). The term "PCNA" includes both the nucleotide sequence or protein in wild-type form, as well as any variants thereof. In some embodiments, "PCNA" is wild-type PCNA. In some embodiments, "PCNA" is in one or more variant forms. The term "PCNA" XYZ refers to the nucleotide or protein sequence of variant PCNA, where the amino acid at position Y of PCNA, which normally has amino acid X in the wild-type, instead has amino acid Z in the variant. In embodiments, PCNA is human PCNA. In embodiments, PCNA has a nucleotide sequence corresponding to reference number GI:33239449 (SEQ ID NO: 1). In embodiments, PCNA has a nucleotide sequence corresponding to RefSeq NM_002592.2 (SEQ ID NO: 1). In embodiments, PCNA has a protein sequence corresponding to reference number GI:4505641 (SEQ ID NO: 2). In embodiments, PCNA has a nucleotide sequence corresponding to RefSeq NP_002583.1 (SEQ ID NO: 2). In embodiments, PCNA has the following amino acid sequence: MFEARLVQGSILKKVLEALKDLINEACWDISSSGVNLQSMDSSHVSLVQLTLRSEGFDTYRCDRNLAMGVNLTSMSKILKCAGNEDIITLRAEDNADTLALVFEAPNQEKVSDYEMKLMDLDVEQLGIPEQEYSCVVKMPSGEFARICRDLSHIGDAVVISCAKDGVKFSASGELGNGNIKLSQTSNVDKEEEAVTIEMNEPVQLTFALRYLNFFTKATPLSSTVTLSMSADVPLVVEYKIADMGHLKYYLAPKIEDEEGS (SEQ ID NO: 2).

[0102] In an embodiment, PCNA is a mutant PCNA. In an embodiment, the mutant PCNA is associated with a disease not associated with wild-type PCNA. In an embodiment, PCNA contains at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to the above sequence. PCNA may be post-translationally modified. The modification may include phosphorylation, methylation, methyl ester of acidic amino acids, ribosylation, acetylation, glycosylation with various sugars, lipidation with various different lipids, poly(ADP) ribosylation, or other post-translational modifications known in the art. Differences in the degree and type of modification affect the levels (e.g., protein levels) of the ca- and nm-PCNA isoforms. In an embodiment, the post-translational modification or multiple post-translational modifications modify the binding of the compounds described herein (e.g., AOH1160, PCNA7) to PCNA, i.e., to PCNA without the post-translational modification(s).

[0103] As used herein, the term "cancer-associated proliferating cell nuclear antigen" or "caPCNA" refers to an isoform of PCNA having an acidic isoelectric point (e.g., a peptide containing a protonated amine and / or carboxyl group, an acidic isoelectric point compared to non-cancer-associated PCNA, PCNA in non-cancerous cells, non-malignant PCNA, a PCNA isoform spreading in non-cancerous cells, or a PCNA isoform with a low acidity in non-cancerous cells). In embodiments, the caPCNA protein refers to methylated amino acids (e.g., glutamic acid, aspartic acid). In embodiments, the caPCNA protein is post-translationally modified with methyl esters of acidic amino acids. In embodiments, the methylation of acidic amino acid residues on PCNA is approximately T of 20 minutes at pH 8.5 1 / 2 as shown. In embodiments, caPCNA is post-translationally modified as described in F. Shen, et al. J Cell Biochem. 2011 Mar;112(3):756-760, which is hereby incorporated by reference in its entirety for all purposes.

[0104] As used herein, the term "non-malignant proliferating cell nuclear antigen" or "nmPCNA" refers to an isoform of PCNA having a basic isoelectric point (e.g., a peptide containing a deprotonated amine and / or carboxyl group, a basic isoelectric point compared to caPCNA, caPCNA in cancerous cells). In embodiments, nmPCNA is a PCNA isoform spreading in non-cancerous cells.

[0105] B. Compounds Provided herein are, in particular, compositions of compounds having the following formula or pharmaceutically acceptable salts thereof:

Chemical formula

[0106] Ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. Ring B is a substituted or unsubstituted naphthyl, a substituted or unsubstituted quinolinyl, or a substituted or unsubstituted isoquinolinyl.

[0107] R 1 is independently halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-CN、-SO 2 Cl、-SO n1 R 10 、-SO v1 NR 7 R 8 、-NHNR 7 R 8 、-ONR 7 R 8 、-NHC=(O)NHNR 7 R 8 、-NHC=(O)NR 7 R 8 、-N(O) m1 、-NR 7 R 8 、-C(O)R 9 、-C(O)-OR 9 、-C(O)NR 7 R 8 、-OR 10 、-NR 7 SO 2 R 10 、-NR 7 C=(O)R 9 、-NR 7 C(O)-OR 9 、-NR 7 OR 9 、-OCX 1 3 、-OCHX 1 2 、-OCH 2 X 1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent Rs 1 The substituents may optionally be joined to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -CN, -SO n1 R 10 , -SO v1 NR 7 R 8 , -NHNH 2 , -ONR 7 R 8 , -NHC=(O)NHNH 2 , -NHC=(O)NR 7 R 8 , -N(O) m1 , -NR 7 R 8 , -C(O)R 9 , -C(O)-OR 9 , -C(O)NR 7 R 8 , -OR 10 , -NR 7 SO 2 R 10 , -NR 7 C=(O)R 9 , -NR 7 C(O)-OR 9 , -NR 7 OR 9 , -OCX 1 3 , -OCHX 1 2 , -OCH 2 X 1、is a 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 adjacent Rs 1 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. When z1 is 0, R 1 is understood to be hydrogen.

[0108] R 2 are independently hydrogen, halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 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, -OCX 2 3 、-OCHX 2 2 、-OCH 2 X 2 、is a 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.

[0109] R 3 are independently hydrogen, halogen, -CX 3 3, -CHX 3 2 , -CH 2 X 3 , -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, -OCX 3 3 , -OCHX 3 2 , -OCH 2 X 3 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0110] R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, -CX A 3 , -CHX A 2 , -CH 2 X A , -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, -OCX A 3 , -OCHX A 2 , -OCH 2 X A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R and R substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. 7 and R 8 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0111] The symbol z1 is an integer from 0 to 4. The symbols m1 and v1 are independently the integer 1 or 2. The symbol n1 is an integer from 0 to 4. The symbols X, X, X, and X are independently -Cl, -Br, -I, or -F. 1 , X 2 , X 3 , and X A are independently -Cl, -Br, -I, or -F.

[0112] In an embodiment, the compound has the following formula:

Chemical formula

[0113] R 4 is independently halogen, -CX 4 3 -CHX 4 2 -CH 2 X 4 -CN, -SO 2 Cl, -SO n4 R 14 -SO v4 NR 11 R 12 -NHNR 11 R 12 -ONR 11 R 12 -NHC=(O)NHNR 11 R 12 -NHC=(O)NR 11 R 12 -N(O) m4 -NR 11 R 12 -C(O)R 13 -C(O)-OR 13 -C(O)NR 11 R 12 -OR 14 -NR 11 SO 2 R 14 -NR 11 C=(O)R 13 -NR 11 C(O)-OR 13 -NR 11 OR 13 -OCX 4 3 -OCHX 4 2 -OCH 2 X 4 is a 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 adjacent R 4 substituents may optionally combine to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R4 is independently halogen, -CX 4 3 、-CHX 4 2 、-CH 2 X 4 、-CN, -SO n4 R 14 、-SO v4 NR 11 R 12 、-NHNR 11 R 12 、-ONR 11 R 12 、-NHC=(O)NHNR 11 R 12 、-NHC=(O)NR 11 R 12 、-N(O) m4 、-NR 11 R 12 、-C(O)R 13 、-C(O)-OR 13 、-C(O)NR 11 R 12 、-OR 14 、-NR 11 SO 2 R 14 、-NR 11 C=(O)R 13 、-NR 11 C(O)-OR 13 、-NR 11 OR 13 、-OCX 4 3 、-OCHX 4 2 、-OCH 2 X 4 、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 adjacent R 4 substituents may optionally combine to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. When z2 is 0, R 4 is understood to be hydrogen.

[0114] R 5 is independently halogen, -CX 5 3 -CHX 5 2 -CH 2 X 5 -CN, -SO 2 Cl, -SO n5 R 18 -SO v5 NR 15 R 16 -NHNR 15 R 16 -ONR 15 R 16 -NHC=(O)NHNR 15 R 16 -NHC=(O)NR 15 R 16 -N(O) m5 -NR 15 R 16 -C(O)R 17 -C(O)-OR 17 -C(O)NR 15 R 16 -OR 18 -NR 15 SO 2 R 18 -NR 15 C=(O)R 17 -NR 15 C(O)-OR 17 -NR 15 OR 17 -OCX 5 3 -OCHX 5 2 -OCH 2 X 5 is a 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 adjacent Rs 5The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In an embodiment, R 5 is independently halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -CN, -SO n5 R 18 , -SO v5 NR 15 R 16 , -NHNR 15 R 16 , -ONR 15 R 16 , -NHC=(O)NHNR 15 R 16 , -NHC=(O)NR 15 R 16 , -N(O) m5 , -NR 15 R 16 , -C(O)R 17 , -C(O)-OR 17 , -C(O)NR 15 R 16 , -OR 18 , -NR 15 SO 2 R 18 , -NR 15 C=(O)R 17 , -NR 15 C(O)-OR 17 , -NR 15 OR 17 , -OCX 5 3 , -OCHX 5 2 , -OCH 2 X 5 is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; two adjacent R 5The substituents may optionally combine to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. When z3 is 0, R 5 is understood to be hydrogen.

[0115] R 11 , R 12 , R 13 , and R 14 are independently hydrogen, halogen, -CX B 3 , -CHX B 2 , -CH 2 X B , -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, -OCX B 3 , -OCHX B 2 , -OCH 2 X B , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R 11 and R 12 substituents attached to the same nitrogen atom may optionally combine to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0116] R 15 , R 16 , R17 and R 18 each independently is hydrogen, halogen, -CX C 3 -CHX C 2 -CH 2 X C -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, -OCX C 3 -OCHX C 2 -OCH 2 X C 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 and R substituents bonded to the same nitrogen atom 15 and R 16 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0117] The symbol z2 is an integer from 0 to 5. The symbol z3 is an integer from 0 to 7. The symbols m4, m5, v4 and v5 are each independently the integer 1 or 2. The symbols n4 and n5 are each independently an integer from 0 to 4. The symbols X 4 X 5 X B and X C each independently is -Cl, -Br, -I, or -F.

[0118] In an embodiment, ring A is a substituted phenyl. In an embodiment, ring A is an unsubstituted phenyl. In an embodiment, ring A is a phenyl. In an embodiment, ring A is a substituted 5- to 6-membered heteroaryl. In an embodiment, ring A is an unsubstituted 5- to 6-membered heteroaryl. In an embodiment, ring A is a 5- to 6-membered heteroaryl. In an embodiment, ring A is a substituted thienyl. In an embodiment, ring A is an unsubstituted thienyl. In an embodiment, ring A is a thienyl. In an embodiment, ring A is 2-thienyl. In an embodiment, ring A is 3-thienyl. In an embodiment, ring A is a substituted pyridyl. In an embodiment, ring A is an unsubstituted pyridyl. In an embodiment, ring A is a pyridyl. In an embodiment, ring A is 2-pyridyl. In an embodiment, ring A is 3-pyridyl. In an embodiment, ring A is 4-pyridyl. In an embodiment, ring A is an unsubstituted pyrrolyl. In an embodiment, ring A is a substituted pyrrolyl. In an embodiment, ring A is a pyrrolyl. In an embodiment, ring A is an unsubstituted furanyl. In an embodiment, ring A is a substituted furanyl. In an embodiment, ring A is a furanyl. In an embodiment, ring A is an unsubstituted pyrazolyl. In an embodiment, ring A is a substituted pyrazolyl. In an embodiment, ring A is a pyrazolyl. In an embodiment, ring A is an unsubstituted imidazolyl. In an embodiment, ring A is a substituted imidazolyl. In an embodiment, ring A is an imidazolyl. In an embodiment, ring A is an unsubstituted oxazolyl. In an embodiment, ring A is a substituted oxazolyl. In an embodiment, ring A is an oxazolyl. In an embodiment, ring A is an unsubstituted isoxazolyl. In an embodiment, ring A is a substituted isoxazolyl. In an embodiment, ring A is an isoxazolyl. In an embodiment, ring A is an unsubstituted thiazolyl. In an embodiment, ring A is a substituted thiazolyl. In an embodiment, ring A is a thiazolyl. In an embodiment, ring A is an unsubstituted triazolyl. In an embodiment, ring A is a substituted triazolyl. In an embodiment, ring A is a triazolyl. In an embodiment, ring B is a substituted naphthyl. In an embodiment, ring B is an unsubstituted naphthyl. In an embodiment, ring B is a naphthyl. In an embodiment, ring B is 1-naphthyl.In an embodiment, ring B is 2-naphthyl. In an embodiment, ring B is quinolinyl. In an embodiment, ring B is a substituted quinolinyl. In an embodiment, ring B is an unsubstituted quinolinyl. In an embodiment, ring B is isoquinolinyl. In an embodiment, ring B is a substituted isoquinolinyl. In an embodiment, ring B is an unsubstituted isoquinolinyl. In an embodiment, ring B is 1-isoquinolinyl. In an embodiment, ring B is 3-isoquinolinyl. In an embodiment, ring B is 4-isoquinolinyl.

[0119] In an embodiment, R 1 is independently halogen, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , a substituted or unsubstituted C 1 -C 8 alkyl, a substituted or unsubstituted 2- to 8-membered heteroalkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted C 6 -C 10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl. In an embodiment, R 1 is independently halogen, -CF 3 , -OH, -NH 2 , -SH, a substituted or unsubstituted C 1 -C 4 alkyl, a substituted or unsubstituted 2- to 4-membered heteroalkyl, a substituted or unsubstituted C 3 -C 6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 1 is independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. In an embodiment, R 1 is independently halogen. In an embodiment, R 1 is independently -CF 3 In an embodiment, R 1 is independently -CHF 2 In an embodiment, R 1 is independently -CH 2 F. In an embodiment, R 1 is independently -OCF 3 In an embodiment, R 1 is independently -OCHF 2 In an embodiment, R 1 is independently -OCH 2 F. In an embodiment, R 1 is independently substituted or unsubstituted C 1 -C 8 alkyl. In an embodiment, R 1 is independently substituted or unsubstituted 2- to 8-membered heteroalkyl. In an embodiment, R 1 is independently substituted or unsubstituted C 3 -C 8 cycloalkyl. In an embodiment, R 1 is independently substituted or unsubstituted 3- to 8-membered heterocycloalkyl. In an embodiment, R 1 is independently substituted or unsubstituted C 6 -C 10 aryl. In an embodiment, R 1 is independently substituted or unsubstituted 5- to 10-membered heteroaryl. In an embodiment, R 1 is independently -OH. In an embodiment, R 1 is independently -NH 2 In an embodiment, R 1 is independently -SH. In an embodiment, R 1 is independently substituted or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1 is independently substituted or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1is independently a substituted or unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1 is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1 is independently a substituted or unsubstituted phenyl. In an embodiment, R 1 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0120] In an embodiment, R 1 is independently a substituted C 1 -C 8 alkyl. In an embodiment, R 1 is independently a substituted 2- to 8-membered heteroalkyl. In an embodiment, R 1 is independently a substituted C 3 -C 8 cycloalkyl. In an embodiment, R 1 is independently a substituted 3- to 8-membered heterocycloalkyl. In an embodiment, R 1 is independently a substituted C 6 -C 10 aryl. In an embodiment, R 1 is independently a substituted 5- to 10-membered heteroaryl. In an embodiment, R 1 is independently a substituted C 1 -C 4 alkyl. In an embodiment, R 1 is independently a substituted 4-membered heteroalkyl. In an embodiment, R 1 is independently a substituted C 3 -C 6 cycloalkyl. In an embodiment, R 1 is independently a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1 is independently a substituted phenyl. In an embodiment, R 1 is independently a substituted 5- to 6-membered heteroaryl. In an embodiment, R 1 is independently an unsubstituted C 1 -C 8 alkyl. In an embodiment, R 1is independently an unsubstituted 2- to 8-membered heteroalkyl. In an embodiment, R 1 is independently an unsubstituted C 3 -C 8 cycloalkyl. In an embodiment, R 1 is independently an unsubstituted 3- to 8-membered heterocycloalkyl. In an embodiment, R 1 is independently an unsubstituted C 6 -C 10 aryl. In an embodiment, R 1 is independently an unsubstituted 5- to 10-membered heteroaryl. In an embodiment, R 1 is independently an unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1 is independently an unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1 is independently an unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1 is independently an unsubstituted phenyl. In an embodiment, R 1 is independently an unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 1 is independently an unsubstituted methyl. In an embodiment, R 1 is independently an unsubstituted ethyl. In an embodiment, R 1 is independently an unsubstituted isopropyl. In an embodiment, R 1 is independently an unsubstituted tert-butyl. In an embodiment, R 1 is independently an unsubstituted methoxy. In an embodiment, R 1 is independently an unsubstituted ethoxy. In an embodiment, R 1 is independently -F. In an embodiment, R 1 is independently -Cl. In an embodiment, R 1 is independently -Br. In an embodiment, R 1 is independently -I. In an embodiment, R 1 is independently hydrogen. In an embodiment, R 1is independently a halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2-4 membered heteroalkyl.

[0121] In embodiments, z1 is 1. In embodiments, z1 is 0. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4.

[0122] In embodiments, R 2 is independently hydrogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -CN, -C(O)H, -C(O)OH, -C(O)NH 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. In embodiments, R 2 is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments, R 2 is independently hydrogen. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently unsubstituted isopropyl. In embodiments, R 2 is independently unsubstituted tert-butyl.

[0123] In embodiments, R2 is independently hydrogen, halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0124] In an embodiment, R 3 is independently hydrogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -CN, -C(O)H, -C(O)OH, -C(O)NH 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 3 is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. In an embodiment, R 3 is independently hydrogen. In an embodiment, R 3 is independently unsubstituted methyl. In an embodiment, R 3 is independently unsubstituted ethyl. In an embodiment, R 3 is independently unsubstituted isopropyl. In an embodiment, R 3 is independently unsubstituted tert-butyl. In an embodiment, R 3 is independently hydrogen, halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X3 、 -CN, -COOH, -CONH 2 、 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0125] In an embodiment, R 4 is independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, a substituted or unsubstituted C 1 -C 8 alkyl, a substituted or unsubstituted 2- to 8-membered heteroalkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted C 6 -C 10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl. In an embodiment, R 4 is independently halogen, -CF 3 , -OH, -NH 2 , -SH, a substituted or unsubstituted C 1 -C 4 alkyl, a substituted or unsubstituted 2- to 4-membered heteroalkyl, a substituted or unsubstituted C 3 -C 6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 4 is independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R4 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. In an embodiment, R 4 is independently halogen. In an embodiment, R 4 is independently -OH. In an embodiment, R 4 is independently unsubstituted methyl. In an embodiment, R 4 is independently unsubstituted methoxy. In an embodiment, R 4 is independently unsubstituted ethyl. In an embodiment, R 4 is independently -F. In an embodiment, R 4 is independently -Cl. In an embodiment, R 4 is independently -Br. In an embodiment, R 4 is independently -I. In an embodiment, R 4 is independently -CF 3 In an embodiment, R 4 is independently -NH 2 In an embodiment, R 4 is independently -SH. In an embodiment, R 4 is independently unsubstituted isopropyl. In an embodiment, R 4 is independently unsubstituted tert-butyl. In an embodiment, R 4 is independently unsubstituted ethoxy. In an embodiment, R 4 is independently unsubstituted propoxy.

[0126] In an embodiment, R 4 is independently halogen. In an embodiment, R 4 is independently -CX 4 3 In an embodiment, R 4 is independently -CHX 4 2 In an embodiment, R 4 is independently -CH 2 X 4 In an embodiment, R 4 is independently -CN. In an embodiment, R 4 is independently -SO n4 R 14is. In an embodiment, R 4 is independently, -SR 14 is. In an embodiment, R 4 is independently, -SO v4 NR 11 R 12 is. In an embodiment, R 4 is independently, -NHNR 11 R 12 is. In an embodiment, R 4 is independently, -ONR 11 R 12 is. In an embodiment, R 4 is independently, -NHC=(O)NHNR 11 R 12 is. In an embodiment, R 4 is independently, -NHC=(O)NR 11 R 12 is. In an embodiment, R 4 is independently, -N(O) m4 is. In an embodiment, R 4 is independently, -NR 11 R 12 is. In an embodiment, R 4 is independently, -C(O)R 13 is. In an embodiment, R 4 is independently, -C(O)-OR 13 is. In an embodiment, R 4 is independently, -C(O)NR 11 R 12 is. In an embodiment, R 4 is independently, -OR 14 is. In an embodiment, R 4 is independently, -NR 11 SO 2 R 14 is. In an embodiment, R 4 is independently, -NR 11 C=(O)R 13 is. In an embodiment, R 4 is independently, -NR 11 C(O)-OR 13 is. In an embodiment, R 4 is independently, -NR 11 OR 13 is. In an embodiment, R4 is independently, -OCX 4 3 It is. In an embodiment, R 4 is independently, -OCHX 4 2 It is. In an embodiment, R 4 is independently, -OCH 2 X 4 It is. In an embodiment, R 4 is independently, -CF 3 It is. In an embodiment, R 4 is independently, -CHF 2 It is. In an embodiment, R 4 is independently, -CH 2 F. In an embodiment, R 4 is independently, -SO 2 CH 3 It is. In an embodiment, R 4 is independently, -SO 2 NH 2 It is. In an embodiment, R 4 is independently, -SH. In an embodiment, R 4 is independently, -N(O) 2 It is. In an embodiment, R 4 is independently, -NH 2 It is. In an embodiment, R 4 is independently, -C(O)CH 3 It is. In an embodiment, R 4 is independently, -C(O)OH. In an embodiment, R 4 is independently, -C(O)NH 2 It is. In an embodiment, R 4 is independently, -OH. In an embodiment, R 4 is independently, -OCF 3 It is. In an embodiment, R 4 is independently, -OCHF 2 It is. In an embodiment, R 4 is independently, -OCH 2 F.

[0127] In an embodiment, R 4 is independently, halogen, -CF 3 , -CHF 2 , -CH2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl. In embodiments, R 4 is independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. In embodiments, R 4 is independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2-4 membered heteroalkyl.

[0128] In embodiments, R 4 is independently substituted or unsubstituted alkyl. In embodiments, R 4 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 4is independently a substituted or unsubstituted cycloalkyl. In an embodiment, R 4 is independently a substituted or unsubstituted heterocycloalkyl. In an embodiment, R 4 is independently a substituted or unsubstituted aryl. In an embodiment, R 4 is independently a substituted or unsubstituted heteroaryl. In an embodiment, two adjacent R 4 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl. In an embodiment, two adjacent R 4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In an embodiment, two adjacent R 4 substituents may optionally be joined to form a substituted or unsubstituted aryl. In an embodiment, two adjacent R 4 substituents may optionally be joined to form a substituted or unsubstituted heteroaryl.

[0129] In an embodiment, R 4 is independently a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), a substituted or unsubstituted heteroalkyl (e.g., a 2- to 10-membered heteroalkyl, a 2- to 8-membered heteroalkyl, a 4- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl), a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 4- to 8-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl), a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6is aryl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 4 is independently substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), substituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 4 is independently 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 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- 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 4 -C 8 cycloalkyl, or C 5 -C 6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0130] In embodiments, R 14 is independently hydrogen, -CX B 3 , -CHX B 2 , -CH 2 X B , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R 14 is independently hydrogen. In embodiments, R 14 is independently -CX B 3 . In embodiments, R 14 is independently -CHX B 2 . In embodiments, R 14 is independently -CH 2 X B . In embodiments, R 14 is independently -CN. In embodiments, R 14 is independently -COOH. In embodiments, R 14 is independently -CONH 2 . In embodiments, R 14 is independently substituted or unsubstituted alkyl. In embodiments, R 14 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 14 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 14is independently a substituted or unsubstituted heterocycloalkyl. In an embodiment, R 14 is independently a substituted or unsubstituted aryl. In an embodiment, R 14 is independently a substituted or unsubstituted heteroaryl. In an embodiment, R 14 is independently a substituted alkyl. In an embodiment, R 14 is independently a substituted heteroalkyl. In an embodiment, R 14 is independently a substituted cycloalkyl. In an embodiment, R 14 is independently a substituted heterocycloalkyl. In an embodiment, R 14 is independently a substituted aryl. In an embodiment, R 14 is independently a substituted heteroaryl. In an embodiment, R 14 is independently an unsubstituted alkyl. In an embodiment, R 14 is independently an unsubstituted heteroalkyl. In an embodiment, R 14 is independently an unsubstituted cycloalkyl. In an embodiment, R 14 is independently an unsubstituted heterocycloalkyl. In an embodiment, R 14 is independently an unsubstituted aryl. In an embodiment, R 14 is independently an unsubstituted heteroaryl. In an embodiment, R 14 is independently a substituted or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 14 is independently a substituted or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 14 is independently a substituted or unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 14 is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 14 is independently a substituted or unsubstituted phenyl. In an embodiment, R 14 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 14 is independently a substituted C 1 -C4 is alkyl. In an embodiment, R 14 is independently a substituted 2- to 4-membered heteroalkyl. In an embodiment, R 14 is independently a substituted C 3 -C 6 cycloalkyl. In an embodiment, R 14 is independently a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 14 is independently a substituted phenyl. In an embodiment, R 14 is independently a substituted 5- to 6-membered heteroaryl. In an embodiment, R 14 is independently an unsubstituted C 1 -C 4 alkyl. In an embodiment, R 14 is independently an unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 14 is independently an unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 14 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 14 is independently an unsubstituted phenyl. In an embodiment, R 14 is independently an unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 14 is hydrogen or unsubstituted methyl.

[0131] In an embodiment, R 14 is a substituted or unsubstituted pyrazolyl. In an embodiment, R 14 is a substituted or unsubstituted pyridyl. In an embodiment, R 14 is a substituted or unsubstituted imidazolyl. In an embodiment, R 14 is a substituted or unsubstituted oxazolyl. In an embodiment, R 14 is a substituted or unsubstituted isoxazolyl. In an embodiment, R 14 is a substituted or unsubstituted thiazolyl. In an embodiment, R 14 is a substituted or unsubstituted furanyl. In an embodiment, R 14 is a substituted or unsubstituted pyrrolyl. In an embodiment, R 14is a substituted or unsubstituted thienyl. In an embodiment, R 14 is a substituted pyrazolyl. In an embodiment, R 14 is a substituted pyridyl. In an embodiment, R 14 is a substituted imidazolyl. In an embodiment, R 14 is a substituted oxazolyl. In an embodiment, R 14 is a substituted isoxazolyl. In an embodiment, R 14 is a substituted thiazolyl. In an embodiment, R 14 is a substituted furanyl. In an embodiment, R 14 is a substituted pyrrolyl. In an embodiment, R 14 is a substituted thienyl. In an embodiment, R 14 is an unsubstituted pyrazolyl. In an embodiment, R 14 is an unsubstituted pyridyl. In an embodiment, R 14 is an unsubstituted imidazolyl. In an embodiment, R 14 is an unsubstituted oxazolyl. In an embodiment, R 14 is an unsubstituted isoxazolyl. In an embodiment, R 14 is an unsubstituted thiazolyl. In an embodiment, R 14 is an unsubstituted furanyl. In an embodiment, R 14 is an unsubstituted pyrrolyl. In an embodiment, R 14 is an unsubstituted thienyl.

[0132] In an embodiment, R 14 are independently hydrogen or unsubstituted alkyl. In an embodiment, R 14 are independently hydrogen or unsubstituted C 1 -C 6 alkyl. In an embodiment, R 14 are independently hydrogen or unsubstituted C 1 -C 5 alkyl. In an embodiment, R 14 are independently hydrogen or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 14 are independently hydrogen or unsubstituted C 1 -C3 is alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 1 -C 2 is alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 2 -C 6 is alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 2 -C 5 is alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 2 -C 4 is alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 2 -C 3 is alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 4 -C 6 is alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 5 -C 6 is alkyl. In an embodiment, R 14 is independently hydrogen. In an embodiment, R 14 is independently unsubstituted alkyl. In an embodiment, R 14 is independently unsubstituted C 1 -C 6 is alkyl. In an embodiment, R 14 is independently unsubstituted C 1 -C 5 is alkyl. In an embodiment, R 14 is independently unsubstituted C 1 -C 4 is alkyl. In an embodiment, R 14 is independently unsubstituted C 1 -C 3 is alkyl. In an embodiment, R 14 is independently unsubstituted C 1 -C 2is alkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 6 is alkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 5 is alkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 4 is alkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 3 is alkyl. In an embodiment, R 14 is independently unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 14 is independently unsubstituted C 4 -C 6 is alkyl. In an embodiment, R 14 is independently unsubstituted C 5 -C 6 is alkyl. In an embodiment, R 14 is independently -CF 3 In an embodiment, R 14 is independently -CHF 2 In an embodiment, R 14 is independently -CH 2 F. In an embodiment, R 14 is independently -CCl 3 In an embodiment, R 14 is independently -CHCl 2 In an embodiment, R 14 is independently -CH 2 Cl. In an embodiment, R 14 is independently -CBr 3 In an embodiment, R 14 is independently -CHBr 2 In an embodiment, R 14 is independently -CH 2 Br. In an embodiment, R 14 is independently -CI 3 In an embodiment, R 14 is independently -CHI 2It is. In an embodiment, R 14 is independently -CH 2 I. In an embodiment, R 14 is independently unsubstituted C 1 -C 4 haloalkyl. In an embodiment, R 14 is independently unsubstituted C 1 -C 3 haloalkyl. In an embodiment, R 14 is independently unsubstituted C 1 -C 2 haloalkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 6 haloalkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 5 haloalkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 4 haloalkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 3 haloalkyl. In an embodiment, R 14 is independently unsubstituted methyl. In an embodiment, R 14 is independently unsubstituted ethyl. In an embodiment, R 14 is independently unsubstituted propyl. In an embodiment, R 14 is independently unsubstituted isopropyl. In an embodiment, R 14 is independently unsubstituted butyl. In an embodiment, R 14 is independently unsubstituted isobutyl. In an embodiment, R 14 is independently unsubstituted tert-butyl.

[0133] In an embodiment, z2 is 1. In an embodiment, z2 is 0. In an embodiment, z2 is 2. In an embodiment, z2 is 3. In an embodiment, z2 is 4. In an embodiment, z2 is 5.

[0134] In an embodiment, R 5is independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl. In embodiments, R 5 is independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 -C 8 alkyl or substituted or unsubstituted 2-8 membered heteroalkyl.

[0135] In embodiments, R 5 is independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. In embodiments, R 5is independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 5 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. In an embodiment, R 5 is independently halogen. In an embodiment, R 5 is independently -OH. In an embodiment, R 5 is independently unsubstituted methyl. In an embodiment, R 5 is independently unsubstituted methoxy. In an embodiment, R 5 is independently unsubstituted ethyl. In an embodiment, R 5 is independently -F. In an embodiment, R 5 is independently -Cl. In an embodiment, R 5 is independently -Br. In an embodiment, R 5 is independently -I. In an embodiment, R 5 is independently -CF 3 . In an embodiment, R 5 is independently -NH 2 . In an embodiment, R 5 is independently -SH. In an embodiment, R 5 is independently unsubstituted isopropyl. In an embodiment, R 5 is independently unsubstituted tert-butyl. In an embodiment, R 5 is independently unsubstituted ethoxy. In an embodiment, R 5 is independently unsubstituted propoxy.

[0136] In an embodiment, R 5 is independently substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4(alkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R 5 is independently substituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), substituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted aryl (e.g., C 6 -C 10 aryl or C 6is aryl), or substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R 5 is independently 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 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- 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 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R 5 is independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2- to 4-membered heteroalkyl. In embodiments, R 5 is unsubstituted C 1 -C 4 alkyl, or unsubstituted 2- to 4-membered heteroalkyl. In embodiments, R 5 is unsubstituted C 1 -C 4 alkyl. In embodiments, R5 is an unsubstituted 2- to 4-membered heteroalkyl.

[0137] In an embodiment, R 5 is independently an unsubstituted alkyl. In an embodiment, R 5 is independently an unsubstituted C 1 -C 6 alkyl. In an embodiment, R 5 is independently an unsubstituted C 1 -C 5 alkyl. In an embodiment, R 5 is independently an unsubstituted C 1 -C 4 alkyl. In an embodiment, R 5 is independently an unsubstituted C 1 -C 3 alkyl. In an embodiment, R 5 is independently an unsubstituted C 1 -C 2 alkyl. In an embodiment, R 5 is independently an unsubstituted C 2 -C 6 alkyl. In an embodiment, R 5 is independently an unsubstituted C 2 -C 5 alkyl. In an embodiment, R 5 is independently an unsubstituted C 2 -C 4 alkyl. In an embodiment, R 5 is independently an unsubstituted C 2 -C 3 alkyl. In an embodiment, R 5 is independently an unsubstituted C 3 -C 6 alkyl. In an embodiment, R 5 is independently an unsubstituted C 4 -C 6 alkyl. In an embodiment, R 5 is independently an unsubstituted C 5 -C 6 alkyl.

[0138] In an embodiment, z3 is 1. In an embodiment, z3 is 0. In an embodiment, z3 is 2. In an embodiment, z3 is 3. In an embodiment, z3 is 4. In an embodiment, z3 is 5. In an embodiment, z3 is 6. In an embodiment, z3 is 7.

[0139] In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently hydrogen, -CX B 3 , -CHX B 2 , -CH 2 X B , -CN, -COOH, -CONH 2 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently hydrogen. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently -CX B 3 . In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently -CHX B 2 . In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently -CH 2 X B . In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently -CN. In an embodiment, R 11 , R 12, R 13 or R 14 is independently -COOH. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently -CONH 2 . In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted or unsubstituted alkyl. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted or unsubstituted heteroalkyl. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted or unsubstituted cycloalkyl. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted or unsubstituted heterocycloalkyl. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted or unsubstituted aryl. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted or unsubstituted heteroaryl. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted alkyl. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted heteroalkyl. In an embodiment, R 11 , R 12 , R 13 or R 14 is independently substituted cycloalkyl. In an embodiment, R 11 , R12 、R 13 、 or R 14 is independently a substituted heterocycloalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted aryl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted heteroaryl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently an unsubstituted alkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently an unsubstituted heteroalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently an unsubstituted cycloalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently an unsubstituted heterocycloalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently an unsubstituted aryl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently an unsubstituted heteroaryl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R11 、R 12 、R 13 、 or R 14 is independently a substituted or unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted or unsubstituted phenyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted C 1 -C 4 alkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted 2- to 4-membered heteroalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted C 3 -C 6 cycloalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14 is independently a substituted phenyl. In an embodiment, R 11 、R 12 、R 13 、 or R 14is independently a substituted 5- to 6-membered heteroaryl. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted C 1 -C 4 alkyl. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted phenyl. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently a substituted 5- to 6-membered heteroaryl.

[0140] In an embodiment, the R 11 and R 12 substituents attached to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In an embodiment, the R 11 and R 12 substituents attached to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heteroaryl. In an embodiment, the R 11 and R 12 substituents attached to the same nitrogen atom may optionally be joined to form a substituted heterocycloalkyl. In an embodiment, the R 11 and R 12The substituents may optionally be joined to form a substituted heteroaryl. In an embodiment, R and R bonded to the same nitrogen atom 11 and R 12 The substituents may optionally be joined to form an unsubstituted heterocycloalkyl. In an embodiment, R and R bonded to the same nitrogen atom 11 and R 12 The substituents may optionally be joined to form an unsubstituted heteroaryl. In an embodiment, R and R bonded to the same nitrogen atom 11 and R 12 The substituents may optionally be joined to form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R and R bonded to the same nitrogen atom 11 and R 12 The substituents may optionally be joined to form a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R and R bonded to the same nitrogen atom 11 and R 12 The substituents may optionally be joined to form a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R and R bonded to the same nitrogen atom 11 and R 12 The substituents may optionally be joined to form a substituted 5- to 6-membered heteroaryl. In an embodiment, R and R bonded to the same nitrogen atom 11 and R 12 The substituents may optionally be joined to form an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R and R bonded to the same nitrogen atom 11 and R 12 The substituents may optionally be joined to form an unsubstituted 5- to 6-membered heteroaryl.

[0141] In an embodiment, R, R, R, or R is independently hydrogen, -CX, 15 , R 16 , R 17 , or R 18 is independently hydrogen, -CX, C 3 , -CHX, C 2 , -CH, 2 X C , -CN, -COOH, -CONH, 2, is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently hydrogen. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently -CX C 3 . In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently -CHX C 2 . In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently -CH 2 X C . In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently -CN. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently -COOH. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently -CONH 2 . In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted alkyl. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted heteroalkyl. In an embodiment, R 15 , R16 , R 17 or R 18 is independently a substituted or unsubstituted cycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted or unsubstituted heterocycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted or unsubstituted aryl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted or unsubstituted heteroaryl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted alkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted heteroalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted cycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted heterocycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted aryl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted heteroaryl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently an unsubstituted alkyl. In an embodiment, R 15 , R 16, R 17 or R 18 is independently unsubstituted heteroalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently unsubstituted cycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently unsubstituted heterocycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently unsubstituted aryl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently unsubstituted heteroaryl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently substituted or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently substituted or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently substituted or unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently substituted or unsubstituted phenyl. In an embodiment, R 15 , R 16 , R 17or R 18 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted C 1 -C 4 alkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted 2- to 4-membered heteroalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted C 3 -C 6 cycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted phenyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently a substituted 5- to 6-membered heteroaryl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently an unsubstituted C 1 -C 4 alkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently an unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 15 , R 16 , R 17 or R 18 is independently an unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 15 , R16 , R 17 , or R 18 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently an unsubstituted phenyl. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently an unsubstituted 5- to 6-membered heteroaryl.

[0142] In an embodiment, the R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In an embodiment, the R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heteroaryl. In an embodiment, the R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted heterocycloalkyl. In an embodiment, the R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted heteroaryl. In an embodiment, the R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heterocycloalkyl. In an embodiment, the R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form an unsubstituted heteroaryl. In an embodiment, the R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, the R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, the R 15and R 16 The substituents may optionally be joined to form a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R attached to the same nitrogen atom 15 and R 16 The substituents may optionally be joined to form a substituted 5- to 6-membered heteroaryl. In an embodiment, R attached to the same nitrogen atom 15 and R 16 The substituents may optionally be joined to form an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R attached to the same nitrogen atom 15 and R 16 The substituents may optionally be joined to form an unsubstituted 5- to 6-membered heteroaryl.

[0143] In an embodiment, m1 is 1. In an embodiment, m1 is 2. In an embodiment, v1 is 1. In an embodiment, v1 is 2. In an embodiment, m4 is 1. In an embodiment, m4 is 2. In an embodiment, m5 is 1. In an embodiment, m5 is 2. In an embodiment, v4 is 1. In an embodiment, v4 is 2. In an embodiment, v5 is 1. In an embodiment, v5 is 2. In an embodiment, n1 is 0. In an embodiment, n1 is 1. In an embodiment, n1 is 2. In an embodiment, n1 is 3. In an embodiment, n1 is 4. In an embodiment, n4 is 0. In an embodiment, n4 is 1. In an embodiment, n4 is 2. In an embodiment, n4 is 3. In an embodiment, n4 is 4. In an embodiment, n5 is 0. In an embodiment, n5 is 1. In an embodiment, n5 is 2. In an embodiment, n5 is 3. In an embodiment, n5 is 4.

[0144] In an embodiment, X 1 is independently -Cl. In an embodiment, X 1 is independently -Br. In an embodiment, X 1 is independently -I. In an embodiment, X 1 is independently -F. In an embodiment, X 2 is independently -Cl. In an embodiment, X2 is independently -Br. In an embodiment, X 2 is independently -I. In an embodiment, X 2 is independently -F. In an embodiment, X 3 is independently -Cl. In an embodiment, X 3 is independently -Br. In an embodiment, X 3 is independently -I. In an embodiment, X 3 is independently -F. In an embodiment, X 4 is independently -Cl. In an embodiment, X 4 is independently -Br. In an embodiment, X 4 is independently -I. In an embodiment, X 4 is independently -F. In an embodiment, X 5 is independently -Cl. In an embodiment, X 5 is independently -Br. In an embodiment, X 5 is independently -I. In an embodiment, X 5 is independently -F. In an embodiment, X A is independently -Cl. In an embodiment, X A is independently -Br. In an embodiment, X A is independently -I. In an embodiment, X A is independently -F. In an embodiment, X B is independently -Cl. In an embodiment, X B is independently -Br. In an embodiment, X B is independently -I. In an embodiment, X B is independently -F. In an embodiment, X C is independently -Cl. In an embodiment, X C is independently -Br. In an embodiment, X C is independently -I. In an embodiment, X C is independently -F.

[0145] In an embodiment, the compound has the following formula:

Chemical formula

[0146] In embodiments, the compound has the following formula:

Chemical formula

[0147] In embodiments, the compound has the following formula:

Chemical formula

[0148] In embodiments, the compound has the following formula:

Chemical formula

[0149] In an embodiment, the compound has the following formula:

Chemical formula

[0150] In an embodiment, the compound has the following formula:

Chemical formula

[0151] In an embodiment, the compound has the following formula:

Chemical formula

[0152] In an embodiment, the compound has the following formula:

Chemical formula

[0153] In an embodiment, the compound has the following formula: [Chemical formula] . R 2 , R 3 , and R 4 are as described herein, including those in the compounds of formulas (I) - (V).

[0154] In an embodiment, the compound has the following formula: [Chemical formula] . R 4 is as described herein, including those in the compounds of formulas (I) - (V). In an embodiment, R 4 is independently -OR 14 . In an embodiment, R 4 is independently -SR 14 . In an embodiment, R 14 is independently hydrogen or unsubstituted alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 1 -C 6 alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 1 -C 5 alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 1 -C 3 alkyl. In an embodiment, R 14 is independently hydrogen or unsubstituted C 1 -C 2 alkyl. In an embodiment, R14 is independently hydrogen or unsubstituted C 2 -C 6 alkyl. In embodiments, R 14 is independently hydrogen or unsubstituted C 2 -C 5 alkyl. In embodiments, R 14 is independently hydrogen or unsubstituted C 2 -C 4 alkyl. In embodiments, R 14 is independently hydrogen or unsubstituted C 2 -C 3 alkyl. In embodiments, R 14 is independently hydrogen or unsubstituted C 3 -C 6 alkyl. In embodiments, R 14 is independently hydrogen or unsubstituted C 4 -C 6 alkyl. In embodiments, R 14 is independently hydrogen or unsubstituted C 5 -C 6 alkyl. In embodiments, R 14 is independently hydrogen. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 is independently unsubstituted C 1 -C 6 alkyl. In embodiments, R 14 is independently unsubstituted C 1 -C 5 alkyl. In embodiments, R 14 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 14 is independently unsubstituted C 1 -C 3 alkyl. In embodiments, R 14 is independently unsubstituted C 1 -C 2 alkyl. In embodiments, R 14 is independently unsubstituted C 2 -C 6 alkyl. In embodiments, R 14 is independently unsubstituted C2 -C 5 is alkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 4 is alkyl. In an embodiment, R 14 is independently unsubstituted C 2 -C 3 is alkyl. In an embodiment, R 14 is independently unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 14 is independently unsubstituted C 4 -C 6 is alkyl. In an embodiment, R 14 is independently unsubstituted C 5 -C 6 is alkyl. In an embodiment, R 14 is independently unsubstituted methyl. In an embodiment, R 14 is independently unsubstituted ethyl. In an embodiment, R 14 is independently unsubstituted propyl. In an embodiment, R 14 is independently unsubstituted isopropyl. In an embodiment, R 14 is independently unsubstituted tert-butyl.

[0155] In an embodiment, the compound has the following formula:

Chemical formula

[0156] In embodiments, the compound has the following formula:

Chemical formula

[0157] In an embodiment, the compound has the following formula:

Chemical formula

[0158] In an embodiment, the compound has the following formula:

Chemical formula

[0159] In an embodiment, the compound has the following formula:

Chemical formula

[0160] In an embodiment, the compound has the following formula:

Chemical formula

[0161] In an embodiment, the compound has the following formula:

Chemical formula

[0162] In an embodiment, the compound has the following formula:

Chemical formula

[0163] In an embodiment, the compound has the following formula:

Chemical formula

[0164] In an embodiment, R 1 independently is hydrogen, oxo, halogen, -CX 1 3 , -CHX 1 2 , -OCH 2 X 1 , -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, -OCX 1 3 , -OCHX 1 2 , -OCH 2 X 1 , R 30 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 30 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 30 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 30A substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 30 A substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 30 A substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 1 is a halogen. In an embodiment, X 1 is F. In an embodiment, R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -OCH 2 X 1 , -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, -OCX 1 3 , -OCHX 1 2 , -OCH 2 X 1 , R 30 A substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 30A substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 30 A substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 30 A substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 30 A substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 30 A substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0165] R 30 is independently oxo, halogen, -CX 30 3 , -CHX 30 2 , -CH 2 X 30 , -OCH 2 X 30 , -OCHX 30 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, -OCX30 3 , R 31 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 31 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 31 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 31 is a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 31 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 31 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 30 is a halogen. In an embodiment, X 30 is F.

[0166] R 31 is independently oxo, halogen, -CX 31 3 , -CHX 31 2 , -CH 2 X 31 , -OCH 2 X 31 , -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, -OCX 31 3 , -OCHX 31 2 , R 32 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 32 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 32 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 32 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 32 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 32 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 31 is halogen. In an embodiment, X 31 is F.

[0167] In an embodiment, R 2 independently is hydrogen, oxo, halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCH 2 X 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, -OCX 2 3 , -OCHX 2 2 , R 33 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 33 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 33 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 33 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 33A substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 33 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 2 is a halogen. In an embodiment, X 2 is F.

[0168] In an embodiment, R 2 is independently halogen, -CX 2 3 -, -CHX 2 2 -, -OCH 2 X 2 -, -CH 2 X 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, -OCX 2 3 -, -OCHX 2 2 -, R 33 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 33 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 33A substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 -cycloalkyl, C 4 -C 8 -cycloalkyl, or C 5 -C 6 -cycloalkyl), R 33 a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 33 a substituted or unsubstituted aryl (e.g., C 6 -C 10 -aryl or C 6 -aryl), or R 33 a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 2 is hydrogen.

[0169] R 33 is independently oxo, halogen, -CX 33 3 -, -CHX 33 2 -, -CHX 33 2 -, -OCH 2 X 33 -, -OCHX 33 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, -OCX 33 3 -, -OCHX 33 2 -, R 34Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 34 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 34 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 34 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 34 substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 34 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 33 is halogen. In an embodiment, X 33 is F.

[0170] R 34 is independently oxo, halogen, -CX 34 3 , -CHX 34 2 , -CH 2 X 34 2 , -OCH 2 X 34 , -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, -OCX 34 3 , -OCHX 34 2 , R 35 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 35 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 35 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 35 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 35 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 35 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 34 is halogen. In an embodiment, X 34 is F.

[0171] In an embodiment, R 3independently, hydrogen, oxo, halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -OCH 2 X 3 , -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, -OCX 3 3 , -OCHX 3 2 , R 36 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 36 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 36 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 36 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 36 substituted or unsubstituted aryl (e.g., C6 -C 10 Aryl or C 6 aryl), or R 36 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 3 is a halogen. In an embodiment, X 3 is F. In an embodiment, R 3 is independently halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -OCH 2 X 3 , -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, -OCX 3 3 , -OCHX 3 2 , R 36 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 36 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 36 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 36 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 36 substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 36 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 3 is hydrogen.

[0172] R 36 is independently oxo, halogen, -CX 36 3 , -CHX 36 2 , -CH 2 X 36 , -OCH 2 X 36 , -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, -OCX 36 3 , -OCHX 36 2 , R 37 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C1 -C 4 alkyl), R 37 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 37 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 37 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 37 substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 37 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 36 is halogen. In embodiments, X 36 is F.

[0173] R 37 is independently oxo, halogen, -CX 37 3 , -CHX 37 2 , -CH 2 X 37 , -OCH 2 X 37 , -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, -NHOH, -OCX 37 3 、 -OCHX 37 2 、 R 38 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 38 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 38 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 38 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 38 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 38 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 37 is halogen. In an embodiment, X 37 is F.

[0174] In an embodiment, R 4 is independently hydrogen, oxo, halogen, -CX 4 3 、 -CHX 4 2 、 -CH 2 X 4 、 -OCH2 X 4 、 -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, -OCX 4 3 、 -OCHX 4 2 、 R 39 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 39 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 39 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 39 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 39 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 39It is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 4 is a halogen. In an embodiment, X 4 is F. In an embodiment, R 4 is independently halogen, -CX 4 3 -, -CHX 4 2 -, -CH 2 X 4 -, -OCH 2 X 4 -, -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, -OCX 4 3 -, -OCHX 4 2 -, R 39 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 39 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 39 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6Cycloalkyl), R 39 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 39 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 39 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0175] R 39 Is independently oxo, halogen, -CX 39 3 -CHX 39 2 -CH 2 X 39 -OCH 2 X 39 -OCHX 39 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, -OCX 39 3 -OCHX 39 2 R 40 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl, or C 1 -C 4 Alkyl), R 40A substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 40 A substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 40 A substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 40 A substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 40 A substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 39 is halogen. In an embodiment, X 39 is F.

[0176] R 40 is independently oxo, halogen, -CX 40 3 , -CHX 40 2 , -CH 2 X 40 , -OCH 2 X 40 , -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, -OCX 40 3 , -OCHX 40 2 , R 41 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 41 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 41 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 41 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 41 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 41 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 40 is halogen. In an embodiment, X 40 is F.

[0177] In an embodiment, R 5 is independently hydrogen, oxo, halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCH 2 X 5, -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, -OCX 5 3 , -OCHX 5 2 , R 42 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 42 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 42 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 42 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 42 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 42 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 5is a halogen. In an embodiment, X 5 is F. In an embodiment, R 5 is independently halogen, -CX 5 3 -, -CHX 5 2 -, -CH 2 X 5 -, -OCH 2 X 5 -, -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, -OCX 5 3 -, -OCHX 5 2 -, R 42 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 42 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 42 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 42A substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 42 A substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 42 A substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0178] R 42 is independently oxo, halogen, -CX 42 3 , -CHX 42 2 , -CH 2 X 42 , -OCH 2 X 42 , -OCHX 42 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, -OCX 42 3 , -OCHX 42 2 , R 43 A substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 43A substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 43 A substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 43 A substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 43 A substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 43 A substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 42 is a halogen. In an embodiment, X 42 is F.

[0179] R 43 is independently oxo, halogen, -CX 43 3 , -CHX 43 2 , -CH 2 X 43 , -OCH 2 X 43 , -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, -OCX 43 3 , -OCHX 43 2 , R 44 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 44 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 44 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 44 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 44 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 44 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 43 is halogen. In an embodiment, X 43 is F.

[0180] In an embodiment, R 7 is independently hydrogen, oxo, halogen, -CX 7 3 , -CHX 7 2 , -CH 2 X 7 , -OCH 2 X 7, -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, -OCX 7 3 , -OCHX 7 2 , R 48 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 48 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 48 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 48 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 48 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 48 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 7is a halogen. In an embodiment, X 7 is F. In an embodiment, R bonded to the same nitrogen atom 7 and R 8 substituents may optionally be joined to form an R 48 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), or an R 48 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0181] In an embodiment, R 7 is independently hydrogen or unsubstituted alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 1 -C 6 alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 1 -C 5 alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 1 -C 3 alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 1 -C 2 alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 2 -C 6 alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 2 -C 5 alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 2 -C 4 alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 2 -C 3is alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 4 -C 6 is alkyl. In an embodiment, R 7 is independently hydrogen or unsubstituted C 5 -C 6 is alkyl. In an embodiment, R 7 is independently hydrogen. In an embodiment, R 7 is independently unsubstituted alkyl. In an embodiment, R 7 is independently unsubstituted C 1 -C 6 is alkyl. In an embodiment, R 7 is independently unsubstituted C 1 -C 5 is alkyl. In an embodiment, R 7 is independently unsubstituted C 1 -C 4 is alkyl. In an embodiment, R 7 is independently unsubstituted C 1 -C 3 is alkyl. In an embodiment, R 7 is independently unsubstituted C 1 -C 2 is alkyl. In an embodiment, R 7 is independently unsubstituted C 2 -C 6 is alkyl. In an embodiment, R 7 is independently unsubstituted C 2 -C 5 is alkyl. In an embodiment, R 7 is independently unsubstituted C 2 -C 4 is alkyl. In an embodiment, R 7 is independently unsubstituted C 2 -C 3 is alkyl. In an embodiment, R 7 is independently unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 7 is independently unsubstituted C4 -C 6 is alkyl. In an embodiment, R 7 is independently unsubstituted C 5 -C 6 is alkyl. In an embodiment, R 7 is hydrogen. In an embodiment, R 7 is independently hydrogen, halogen, -CX 7 3 , -CHX 7 2 , -CH 2 X 7 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7 and R 8 substituents optionally bonded together may form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0182] R 48 is independently oxo, halogen, -CX 48 3 , -CHX 48 2 , -CH 2 X 48 , -OCH 2 X 48 , -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, -OCX 48 3 , -OCHX48 2 , R 49 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 49 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 49 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 49 is a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 49 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 49 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 48 is a halogen. In an embodiment, X 48 is F.

[0183] R 49 is independently oxo, halogen, -CX 49 3 , -CHX 49 2 , -CH 2 X 49 , -OCH 2 X 49 , -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, -OCX 49 3 , -OCHX 49 2 , R 50 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 50 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 50 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 50 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 50 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 50 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 49 is halogen. In an embodiment, X 49 is F.

[0184] In the embodiment, R 8 independently is hydrogen, oxo, halogen, -CX 8 3 , -CHX 8 2 , -CH 2 X 8 , -OCH 2 X 8 , -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, -OCX 8 3 , -OCHX 8 2 , R 51 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 51 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 51 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 51 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 51Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 51 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 8 is halogen. In an embodiment, X 8 is F. In an embodiment, X 7 is F. In an embodiment, R 7 and R 8 substituents bonded to the same nitrogen atom may optionally be joined to form R 51 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 51 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0185] In an embodiment, R 8 is independently hydrogen or unsubstituted alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 1 -C 6 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 1 -C 5 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 1 -C 3 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 1 -C 2 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 2 -C 6 alkyl. In an embodiment, R8 is independently hydrogen or unsubstituted C 2 -C 5 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 2 -C 4 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 2 -C 3 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 3 -C 6 alkyl. In an embodiment, R 8 is independently hydrogen or unsubstituted C 4 -C 6 alkyl. In an embodiment, R 8 is independently hydrogen. In an embodiment, R 5 -C 6 alkyl. In an embodiment, R 8 is independently hydrogen. In an embodiment, R 8 is independently unsubstituted alkyl. In an embodiment, R 8 is independently unsubstituted C 1 -C 6 alkyl. In an embodiment, R 8 is independently unsubstituted C 1 -C 5 alkyl. In an embodiment, R 8 is independently unsubstituted C 1 -C 4 alkyl. In an embodiment, R 8 is independently unsubstituted C 1 -C 3 alkyl. In an embodiment, R 8 is independently unsubstituted C 1 -C 2 alkyl. In an embodiment, R 8 is independently unsubstituted C 2 -C 6 alkyl. In an embodiment, R 8 is independently unsubstituted C 2 -C 5 alkyl. In an embodiment, R 8 is independently unsubstituted C2 -C 4 is alkyl. In an embodiment, R 8 is independently unsubstituted C 2 -C 3 is alkyl. In an embodiment, R 8 is independently unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 8 is independently unsubstituted C 4 -C 6 is alkyl. In an embodiment, R 8 is independently unsubstituted C 5 -C 6 is alkyl. In an embodiment, R 8 is hydrogen. In an embodiment, R 8 is independently hydrogen, halogen, -CX 8 3 , -CHX 8 2 , -CH 2 X 8 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0186] R 51 is independently oxo, halogen, -CX 51 3 , -CHX 51 2 , -CH 2 X 51 , -OCH 2 X 51 , -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, -OCX 51 3 , -OCHX 51 2 , R 52 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 52 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 52 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 52 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 52 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 52 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 51 is halogen. In an embodiment, X 51 is F.

[0187] R 52 is independently oxo, halogen, -CX 52 3 , -CHX 52 2 , -CH 2 X 52, -OCH 2 X 52 , -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, -OCX 52 3 , -OCHX 52 2 , R 53 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 53 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 53 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 53 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 53 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 53It is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 52 is a halogen. In an embodiment, X 52 is F.

[0188] In an embodiment, R 9 is independently hydrogen, oxo, halogen, -CX 9 3 , -CHX 9 2 , -CH 2 X 9 , -OCH 2 X 9 , -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, -OCX 9 3 , -OCHX 9 2 , R 54 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 54 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 54 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8Cycloalkyl, or C 5 -C 6 cycloalkyl), R 54 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 54 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 54 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 9 is halogen. In an embodiment, X 9 is F. In an embodiment, R 9 is hydrogen. In an embodiment, R 9 are independently hydrogen, halogen, -CX 9 3 -CHX 9 2 -CH 2 X 9 -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0189] R 54 are independently oxo, halogen, -CX 54 3 -CHX 54 2 -CH 2 X 54 -OCH 2 X 54 -OCHX 54 2 -CN, -OH, -NH 2 -COOH, -CONH 2 -NO 2 -SH, -SO 3 H, -SO 4 H, -SO2 NH 2 、 -NHNH 2 、 -ONH 2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H、 -NHC=(O)H、 -NHC(O)-OH、 -NHOH、 -OCX 54 3 、 -OCHX 54 2 、 R 55 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 55 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 55 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 55 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 55 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 55 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 54 is halogen. In an embodiment, X 54 is F.

[0190] R 55 is independently oxo, halogen, -CX55 3 ,-CHX 55 2 ,-CH 2 X 55 ,-OCH 2 X 55 ,-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, -OCX 55 3 ,-OCHX 55 2 ,R 56 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 56 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 56 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 56 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 56 Substituted or unsubstituted aryl (e.g., C 6 -C 10Aryl or C 6 aryl), or R 56 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 55 is a halogen. In an embodiment, X 55 is F.

[0191] In an embodiment, R 10 is independently hydrogen, oxo, halogen, -CX 10 3 -, -CHX 10 2 -, -CH 2 X 10 -, -OCH 2 X 10 -, -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, -OCX 10 3 -, -OCHX 10 2 -, R 57 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 57 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 57 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 57 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 57 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 57 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 10 is halogen. In an embodiment, X 10 is F. In an embodiment, R 10 is hydrogen. In an embodiment, R 10 is independently hydrogen, halogen, -CX 10 3 , -CHX 10 2 , -CH 2 X 10 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0192] R 57 is independently oxo, halogen, -CX 57 3 , -CHX 57 2 , -CH 2 X 57 , -OCH 2 X 57 , -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, -OCX 57 3 , -OCHX 57 2 , R 58 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 58 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 58 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 58 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 58 substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 58 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 57 is halogen. In an embodiment, X 57 is F.

[0193] R 58independently, oxo, halogen, -CX 58 3 , -CHX 58 2 , -CH 2 X 58 , -OCH 2 X 58 , -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, -OCX 58 3 , -OCHX 58 2 , R 59 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 59 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 59 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 59 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 59 substituted or unsubstituted aryl (e.g., C 6-C 10 Aryl or C 6 aryl), or R 59 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 58 is a halogen. In an embodiment, X 58 is F.

[0194] In an embodiment, R 11 is independently hydrogen, oxo, halogen, -CX 11 3 -, -CHX 11 2 -, -CH 2 X 11 -, -OCH 2 X 11 -, -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, -OCX 11 3 -, -OCHX 11 2 -, R 60 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 60 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 60 is a substituted or unsubstituted cycloalkyl (e.g., C3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 60 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 60 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 60 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 11 is halogen. In an embodiment, X 11 is F. In an embodiment, R 11 and R 12 substituents bonded to the same nitrogen atom may optionally be joined to form R 60 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 60 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 11 is hydrogen. In an embodiment, R 11 is independently hydrogen, halogen, -CX 11 3 , -CHX 11 2 , -CH 2 X 11 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0195] R60 is independently oxo, halogen, -CX 60 3 、-CHX 60 2 、-CH 2 X 60 、-OCH 2 X 60 、-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, -OCX 60 3 、-OCHX 60 2 、R 61 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 61 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 61 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 61 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 61 substituted or unsubstituted aryl (e.g., C6 -C 10 Aryl or C 6 Aryl), or R 61 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 60 Is halogen. In an embodiment, X 60 Is F.

[0196] R 61 Is independently oxo, halogen, -CX 61 3 -CHX 61 2 -CH 2 X 61 -OCH 2 X 61 -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, -OCX 61 3 -OCHX 61 2 R 62 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl, or C 1 -C 4 Alkyl), R 62 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 62 Substituted or unsubstituted cycloalkyl (e.g., C3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 62 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 62 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 62 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 61 is halogen. In an embodiment, X 61 is F.

[0197] In an embodiment, R 12 is independently hydrogen, oxo, halogen, -CX 12 3 -CHX 12 2 -CH 2 X 12 -OCH 2 X 12 -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, -OCX 12 3 -OCHX 12 2 -R 63 Substituted or unsubstituted alkyl (e.g., C1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 63 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 63 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 63 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 63 substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 63 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 12 is halogen. In embodiments, X 12 is F. In embodiments, R 11 and R 12 substituents bonded to the same nitrogen atom may optionally be joined to form R 63 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 63 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R 12 is hydrogen. In embodiments, R 12 are independently hydrogen, halogen, -CX 12 3 , -CHX12 2 、 -CH 2 X 12 、 -CN, -COOH, -CONH 2 、 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0198] R 63 is independently oxo, halogen, -CX 63 3 、 -CHX 63 2 、 -CH 2 X 63 、 -OCH 2 X 63 、 -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, -OCX 63 3 、 -OCHX 63 2 、 R 64 a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 64 a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 64 a substituted or unsubstituted cycloalkyl (e.g., C3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 64 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 64 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 64 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 63 is halogen. In embodiments, X 63 is F.

[0199] R 64 is independently oxo, halogen, -CX 64 3 , -CHX 64 2 , -CH 2 X 64 , -OCH 2 X 64 , -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, -OCX 64 3 , -OCHX 64 2 , R 65 Substituted or unsubstituted alkyl (e.g., C 1 -C8 Alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 65 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 65 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 65 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 65 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 65 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 64 is halogen. In an embodiment, X 64 is F.

[0200] In an embodiment, R 13 is independently hydrogen, oxo, halogen, -CX 13 3 , -CHX 13 2 , -CH 2 X 13 , -OCH 2 X 13 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH2 、 -ONH 2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H、 -NHC=(O)H、 -NHC(O)-OH、 -NHOH、 -OCX 13 3 、 -OCHX 13 2 、 R 66 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 66 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 66 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 66 is a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 66 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 66 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 13 is a halogen. In an embodiment, X 13 is F. In an embodiment, R 13 is hydrogen. In an embodiment, R 13 is independently hydrogen, halogen, -CX 13 3 、 -CHX13 2 ,-CH 2 X 13 ,-CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0201] R 66 is independently oxo, halogen, -CX 66 3 , -CHX 66 2 , -CH 2 X 66 , -OCH 2 X 66 , -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, -OCX 66 3 , -OCHX 66 2 , R 67 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 67 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 67 substituted or unsubstituted cycloalkyl (e.g., C3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 67 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 67 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 67 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 66 is halogen. In embodiments, X 66 is F.

[0202] R 67 is independently oxo, halogen, -CX 67 3 -CHX 67 2 -CH 2 X 67 -OCH 2 X 67 -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, -OCX 67 3 -OCHX 67 2 -R 68 Substituted or unsubstituted alkyl (e.g., C 1 -C8 Alkyl, C 1 -C 6 Alkyl, or C 1 -C 4 Alkyl), R 68 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 68 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 68 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 68 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 68 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 67 is halogen. In embodiments, X 67 is F.

[0203] In embodiments, R 14 is independently hydrogen, oxo, halogen, -CX 14 3 , -CHX 14 2 , -CH 2 X 14 , -OCH 2 X 14 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH2 、 -ONH 2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H、 -NHC=(O)H、 -NHC(O)-OH、 -NHOH、 -OCX 14 3 、 -OCHX 14 2 、 R 69 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 69 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 69 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 69 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 69 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 69 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 14 is halogen. In an embodiment, X 14 is F. In an embodiment, R 14 is hydrogen. In an embodiment, R 14 is independently hydrogen, halogen, -CX 14 3 、 -CHX14 2 ,-CH 2 X 14 ,-CN, -COOH, -CONH 2 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0204] R 69 is independently oxo, halogen, -CX 69 3 , -CHX 69 2 , -CH 2 X 69 , -OCH 2 X 69 , -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, -OCX 69 3 , -OCHX 69 2 , R 70 a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 70 a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 70 a substituted or unsubstituted cycloalkyl (e.g., C3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 70 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 70 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 70 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 69 is halogen. In an embodiment, X 69 is F.

[0205] R 70 is independently oxo, halogen, -CX 70 3 , -CHX 70 2 , -CH 2 X 70 , -OCH 2 X 70 , -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, -OCX 70 3 , -OCHX 70 2 , R 71 Substituted or unsubstituted alkyl (e.g., C 1 -C8 Alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 71 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 71 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 71 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 71 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 71 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 70 is halogen. In embodiments, X 70 is F.

[0206] In embodiments, R 15 is independently hydrogen, oxo, halogen, -CX 15 3 , -CHX 15 2 , -CH 2 X 15 , -OCH 2 X 15 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH2 、 -ONH 2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H、 -NHC=(O)H、 -NHC(O)-OH、 -NHOH、 -OCX 15 3 、 -OCHX 15 2 、 R 72 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 72 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 72 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 72 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 72 substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 72 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 15 is halogen. In an embodiment, X 15 is F. In an embodiment, R 15 and R 16 substituents attached to the same nitrogen atom are optionally joined to form R 72A substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 72 May form a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R 15 Is hydrogen. In embodiments, R 15 Independently is hydrogen, halogen, -CX 15 3 , -CHX 15 2 , -CH 2 X 15 , -CN, -COOH, -CONH 2 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0207] In embodiments, R 15 Independently is hydrogen or unsubstituted alkyl. In embodiments, R 15 Independently is hydrogen or unsubstituted C 1 -C 6 alkyl. In embodiments, R 15 Independently is hydrogen or unsubstituted C 1 -C 5 alkyl. In embodiments, R 15 Independently is hydrogen or unsubstituted C 1 -C 4 alkyl. In embodiments, R 15 Independently is hydrogen or unsubstituted C 1 -C 3 alkyl. In embodiments, R 15 Independently is hydrogen or unsubstituted C 1 -C 2 alkyl. In embodiments, R 15 Independently is hydrogen or unsubstituted C 2 -C 6 alkyl. In embodiments, R 15is independently hydrogen or unsubstituted C 2 -C 5 alkyl. In embodiments, R 15 is independently hydrogen or unsubstituted C 2 -C 4 alkyl. In embodiments, R 15 is independently hydrogen or unsubstituted C 2 -C 3 alkyl. In embodiments, R 15 is independently hydrogen or unsubstituted C 3 -C 6 alkyl. In embodiments, R 15 is independently hydrogen or unsubstituted C 4 -C 6 alkyl. In embodiments, R 15 is independently hydrogen or unsubstituted C 5 -C 6 alkyl. In embodiments, R 15 is independently hydrogen. In embodiments, R 15 is independently unsubstituted alkyl. In embodiments, R 15 is independently unsubstituted C 1 -C 6 alkyl. In embodiments, R 15 is independently unsubstituted C 1 -C 5 alkyl. In embodiments, R 15 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 15 is independently unsubstituted C 1 -C 3 alkyl. In embodiments, R 15 is independently unsubstituted C 1 -C 2 alkyl. In embodiments, R 15 is independently unsubstituted C 2 -C 6 alkyl. In embodiments, R 15 is independently unsubstituted C 2 -C 5 alkyl. In embodiments, R 15 is independently unsubstituted C 2 -C4 is alkyl. In an embodiment, R 15 is independently unsubstituted C 2 -C 3 is alkyl. In an embodiment, R 15 is independently unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 15 is independently unsubstituted C 4 -C 6 is alkyl. In an embodiment, R 15 is independently unsubstituted C 5 -C 6 is alkyl.

[0208] R 72 is independently oxo, halogen, -CX 72 3 , -CHX 72 2 , -CH 2 X 72 , -OCH 2 X 72 , -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, -OCX 72 3 , -OCHX 72 2 , R 73 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 73Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 73 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 73 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 73 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 73 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 72 is halogen. In an embodiment, X 72 is F.

[0209] R 73 is independently oxo, halogen, -CX 73 3 , -CHX 73 2 , -CH 2 X 73 , -OCH 2 X 73 , -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, -OCX 73 3 , -OCHX 73 2 , R 74 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 74 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 74 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 74 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 74 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 74 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 73 is halogen. In an embodiment, X 73 is F.

[0210] In an embodiment, R 16 is independently hydrogen, oxo, halogen, -CX 16 3 , -CHX 16 2 , -CH 2 X 16 , -OCH 2 X 16, -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, -OCX 16 3 , -OCHX 16 2 , R 75 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 75 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 75 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 75 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 75 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 75 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 16is a halogen. In an embodiment, X 16 is F. In an embodiment, R bonded to the same nitrogen atom 15 and R 16 substituents may optionally be joined to form an R 75 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or an R 75 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In an embodiment, R 16 is hydrogen. In an embodiment, R 16 is independently hydrogen, halogen, -CX 16 3 , -CHX 16 2 , -CH 2 X 16 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0211] In an embodiment, R 16 is independently hydrogen or unsubstituted alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 1 -C 6 alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 1 -C 5 alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 1 -C 3 alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 1 -C2 is alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 2 -C 6 is alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 2 -C 5 is alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 2 -C 4 is alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 2 -C 3 is alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 4 -C 6 is alkyl. In an embodiment, R 16 is independently hydrogen or unsubstituted C 5 -C 6 is alkyl. In an embodiment, R 16 is independently hydrogen. In an embodiment, R 16 is independently unsubstituted alkyl. In an embodiment, R 16 is independently unsubstituted C 1 -C 6 is alkyl. In an embodiment, R 16 is independently unsubstituted C 1 -C 5 is alkyl. In an embodiment, R 16 is independently unsubstituted C 1 -C 4 is alkyl. In an embodiment, R 16 is independently unsubstituted C 1 -C 3 is alkyl. In an embodiment, R 16 is independently unsubstituted C 1 -C 2 is alkyl. In an embodiment, R 16 is independently unsubstituted C 2 -C 6is alkyl. In an embodiment, R 16 is independently unsubstituted C 2 -C 5 is alkyl. In an embodiment, R 16 is independently unsubstituted C 2 -C 4 is alkyl. In an embodiment, R 16 is independently unsubstituted C 2 -C 3 is alkyl. In an embodiment, R 16 is independently unsubstituted C 3 -C 6 is alkyl. In an embodiment, R 16 is independently unsubstituted C 4 -C 6 is alkyl. In an embodiment, R 16 is independently unsubstituted C 5 -C 6 is alkyl.

[0212] R 75 is independently oxo, halogen, -CX 75 3 、-CHX 75 2 、-CH 2 X 75 、-OCH 2 X 75 、-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, -OCX 75 3 、-OCHX 75 2 、R 76 substituted or unsubstituted alkyl (e.g., C 1 -C 8Alkyl, C 1 -C 6 Alkyl, or C 1 -C 4 Alkyl), R 76 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 76 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 4 -C 8 Cycloalkyl, or C 5 -C 6 Cycloalkyl), R 76 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 76 Substituted or unsubstituted aryl (e.g., C 6 -C 10 Aryl or C 6 Aryl), or R 76 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 75 Is halogen. In an embodiment, X 75 Is F.

[0213] R 76 Are independently oxo, halogen, -CX 76 3 -, -CHX 76 2 -, -CH 2 X 76 -, -OCH 2 X 76 -, -CN, -OH, -NH 2 -, -COOH, -CONH 2 -, -NO 2 -, -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 -, -NHNH 2 -, -ONH2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 76 3 、 -OCHX 76 2 、 R 77 is a substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 77 is a substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 77 is a substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 77 is a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 77 is a substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 77 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 76 is a halogen. In an embodiment, X 76 is F.

[0214] In an embodiment, R 17 are independently hydrogen, oxo, halogen, -CX 17 3 、 -CHX 172 , -CH 2 X 17 , -OCH 2 X 17 , -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, -OCX 17 3 , -OCHX 17 2 , R 78 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 78 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 78 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 78 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 78 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 78It is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 17 is a halogen. In an embodiment, X 17 is F. In an embodiment, R 17 is hydrogen. In an embodiment, R 17 is independently hydrogen, halogen, -CX 17 3 , -CHX 17 2 , -CH 2 X 17 , -CN, -COOH, -CONH 2 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0215] R 78 is independently oxo, halogen, -CX 78 3 , -CHX 78 2 , -CH 2 X 78 , -OCH 2 X 78 , -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, -OCX 78 3 , -OCHX 78 2 , R 79 a substituted or unsubstituted alkyl (e.g., C 1 -C8 Alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 79 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 79 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 79 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 79 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 79 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 78 is halogen. In an embodiment, X 78 is F.

[0216] R 79 is independently oxo, halogen, -CX 79 3 , -CHX 79 2 , -CH 2 X 79 , -OCH 2 X 79 , -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, -OCX 79 3 , -OCHX 79 2 , R 80 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 80 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 80 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 80 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 80 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 80 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 79 is halogen. In an embodiment, X 79 is F.

[0217] In an embodiment, R 18 is independently hydrogen, oxo, halogen, -CX 18 3 , -CHX18 2 , -CH 2 X 18 , -OCH 2 X 18 , -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, -OCX 18 3 , -OCHX 18 2 , R 81 substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 81 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 81 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 81 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 81 substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R81 is a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 18 is a halogen. In an embodiment, X 18 is F. In an embodiment, R 18 is hydrogen. In an embodiment, R 18 is independently hydrogen, halogen, -CX 18 3 -, -CHX 18 2 -, -CH 2 X 18 -, -CN, -COOH, -CONH 2 -, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0218] R 81 is independently oxo, halogen, -CX 81 3 -, -CHX 81 2 -, -CH 2 X 81 -, -OCH 2 X 81 -, -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, -OCX 81 3 -, -OCHX 81 2 -, R 82 a substituted or unsubstituted alkyl (e.g., C 1-C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 82 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 82 substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 82 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 82 substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 82 substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 81 is halogen. In an embodiment, X 81 is F.

[0219] R 82 is independently oxo, halogen, -CX 82 3 , -CHX 82 2 , -CH 2 X 82 , -OCH 2 X 82 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH2 、 -ONH 2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H、 -NHC=(O)H、 -NHC(O)-OH、 -NHOH、 -OCX 82 3 、 -OCHX 82 2 、 R 83 Substituted or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), R 83 Substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 83 Substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 83 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 83 Substituted or unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or R 83 Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). X 82 is halogen. In an embodiment, X 82 is F.

[0220] R 32 、 R 35 、 R 38 、 R 41 、 R44 , R 50 , R 53 , R 56 , R 59 , R 62 , R 65 , R 68 , R 71 , R 74 , R 77 , R 80 , and R 83 are independently hydrogen, oxo, halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCF 3 , -OCHF 2 , -CCl 3 , -CHCl 2 , -CH 2 Cl, -OCH 2 Cl, -OCCl 3 , -OCHCl 2 , -CBr 3 , -CHBr 2 , -CH 2 Br, -OCH 2 Br, -OCBr 3 , -OCHBr 2 , -CI 3 , -CHI 2 , -CH 2 I, -OCH 2 I, -OCI 3 , -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, unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- 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 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, R 32 , R 35 , R 38 , R 41 , R 44 , R 50 , R 53 , R 56 , R 59 , R 62 , R 65 , R 68 , R 71 , R 74 , R 77 , R 80 , and R 83 are independently oxo, halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCF 3 , -OCHF 2 , -CCl 3 , -CHCl 2 , -CH 2 Cl, -OCH 2 Cl, -OCCl 3 , -OCHCl 2 , -CBr 3 , -CHBr 2, -CH 2 Br, -OCH 2 Br, -OCBr 3 , -OCHBr 2 , -CI 3 , -CHI 2 , -CH 2 I, -OCH 2 I, -OCI 3 , -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, 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 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- 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 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl or C 6 aryl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0221] In some embodiments, the compound is any one of the compounds described herein (e.g., in the aspects, embodiments, claims, figures, tables, or examples).

[0222] In some embodiments, the compounds described herein are R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and / or other variables. In such embodiments, each variable may optionally be different, and each group may be appropriately labeled to more clearly distinguish them. For example, each R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and / or R 19 are different, they may each be, for example, R 1.1 , R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 5.1 , R 5.2 , R 5.3 , R 5.4 , R 5.5 , R 5.6 , R5.7 , R 7.1 , R 7.2 , R 7.3 , R 7.4 , R 7.5 , R 7.6 , R 7.7 , R 7.8 , R 7.9 , R 7.10 , R 7.11 , R 7.12 , R 7.13 , R 7.14 , R 7.15 , R 7.16 , R 7.17 , R 7.18 , R 7.19 , R 7.20 , R 7.21 , R 7.22 , R 7.23 , R 7.24 , R 7.25 , R 7.26 , R 7.27 , R 7.28 , R 7.29 , R 7.30 , R 7.31 , R 7.32 , R 7.33 , R 7.34 , R 7.35 , R 7.36 , R 7.37 , R 7.38 , R 7.39 , R 7.40 , R 7.41 , R 7.42 , R 8.1 , R 8.2 , R 8.3 , R 8.4 , R 8.5 , R 8.6 , R 8.7 , R 8.8 , R 8.9 , R 8.10 , R 8.11 , R 8.12 , R 8.13 , R 8.14 , R 8.15 , R 8.16 , R 8.17 , R 8.18 , R 8.19 , R 8.20 , R 8.21 , R 8.22 , R 8.23 , R 8.24, R 8.25 , R 8.26 , R 8.27 , R 8.28 , R 8.29 , R 8.30 , R 8.31 , R 8.32 , R 8.33 , R 8.34 , R 8.35 , R 8.36 , R 8.37 , R 8.38 , R 8.39 , R 8.40 , R 8.41 , R 8.42 , R 9.1 , R 9.2 , R 9.3 , R 9.4 , R 9.5 , R 9.6 , R 9.7 , R 9.8 , R 9.9 , R 9.10 , R 9.11 , R 9.12 , R 9.13 , R 9.14 , R 9.15 , R 9.16 , R 9.17 , R 9.18 , R 9.19 , R 9.20 , R 9.21 , R 9.22 , R 9.23 , R 9.24 , R 9.25 , R 9.26 , R 9.27 , R 9.28 , R 9.29 , R 9.30 , R 9.31 , R 9.32 , R 9.33 , R 9.34 , R 9.35 , R 9.36 , R 9.37 , R 9.38 , R 9.39 , R 9.40 , R 9.41 , R 9.42 , R 10.1 , R 10.2 , R 10.3 , R 10.4 , R 10.5 , R 10.6 , R10.7 , R 10.8 , R 10.9 , R 10.10 , R 10.11 , R 10.12 , R 10.13 , R 10.14 , R 10.15 , R 10.16 , R 10.17 , R 10.18 , R 10.19 , R 10.20 , R 10.21 , R 10.22 , R 10.23 , R 10.24 , R 10.25 , R 10.26 , R 10.27 , R 10.28 , R 10.29 , R 10.30 , R 10.31 , R 10.32 , R 10.33 , R 10.34 , R 10.35 , R 10.36 , R 10.37 , R 10.38 , R 10.39 , R 10.40 , R 10.41 , R 10.42 , R 11.1 , R 11.2 , R 11.3 , R 11.4 , R 11.5 , R 11.6 , R 11.7 , R 11.8 , R 11.9 , R 11.10 , R 11.11 , R 11.12 , R 11.13 , R 11.14 , R 11.15 , R 11.16 , R 11.17 , R 11.18 , R 11.19 , R 11.20 , R 11.21 , R 11.22 , R 11.23 , R 11.24 , R 11.25 , R 11.26 , R 11.27 , R 11.28 , R 11.29 , R 11.30 , R 11.31, R 11.32 , R 11.33 , R 11.34 , R 11.35 , R 11.36 , R 11.37 , R 11.38 , R 11.39 , R 11.40 , R 11.41 , R 11.42 , R 12.1 , R 12.2 , R 12.3 , R 12.4 , R 12.5 , R 12.6 , R 12.7 , R 12.8 , R 12.9 , R 12.10 , R 12.11 , R 12.12 , R 12.13 , R 12.14 , R 12.15 , R 12.16 , R 12.17 , R 12.18 , R 12.19 , R 12.20 , R 12.21 , R 12.22 , R 12.23 , R 12.24 , R 12.25 , R 12.26 , R 12.27 , R 12.28 , R 12.29 , R 12.30 , R 12.31 , R 12.32 , R 12.33 , R 12.34 , R 12.35 , R 12.36 , R 12.37 , R 12.38 , R 12.39 , R 12.40 , R 12.41 , R 12.42 , R 13.1 , R 13.2 , R 13.3 , R 13.4 , R 13.5 , R 13.6 , R 13.7 , R 13.8 , R 13.9 , R 13.10 , R 13.11 , R 13.12 , R 13.13 , R13.14 , R 13.15 , R 13.16 , R 13.17 , R 13.18 , R 13.19 , R 13.20 , R 13.21 , R 13.22 , R 13.23 , R 13.24 , R 13.25 , R 13.26 , R 13.27 , R 13.28 , R 13.29 , R 13.30 , R 13.31 , R 13.32 , R 13.33 , R 13.34 , R 13.35 , R 13.36 , R 13.37 , R 13.38 , R 13.39 , R 13.40 , R 13.41 , R 13.42 , R 14.1 , R 14.2 , R 14.3 , R 14.4 , R 14.5 , R 14.6 , R 14.7 , R 14.8 , R 14.9 , R 14.10 , R 14.11 , R 14.12 , R 14.13 , R 14.14 , R 14.15 , R 14.16 , R 14.17 , R 14.18 , R 14.19 , R 14.20 , R 14.21 , R 14.22 , R 14.23 , R 14.24 , R 14.25 , R 14.26 , R 14.27 , R 14.28 , R 14.29 , R 14.30 , R 14.31 , R 14.32 , R 14.33 , R 14.34 , R 14.35 , R 14.36 , R 14.37 , R 14.38, R 14.39 , R 14.40 , R 14.41 , R 14.42 , R 15.1 , R 15.2 , R 15.3 , R 15.4 , R 15.5 , R 15.6 , R 15.7 , R 15.8 , R 15.9 , R 15.10 , R 15.11 , R 15.12 , R 15.13 , R 15.14 , R 15.15 , R 15.16 , R 15.17 , R 15.18 , R 15.19 , R 15.20 , R 15.21 , R 15.22 , R 15.23 , R 15.24 , R 15.25 , R 15.26 , R 15.27 , R 15.28 , R 15.29 , R 15.30 , R 15.31 , R 15.32 , R 15.33 , R 15.34 , R 15.35 , R 15.36 , R 15.37 , R 15.38 , R 15.39 , R 15.40 , R 15.41 , R 15.42 , R 16.1 , R 16.2 , R 16.3 , R 16.4 , R 16.5 , R 16.6 , R 16.7 , R 16.8 , R 16.9 , R 16.10 , R 16.11 , R 16.12 , R 16.13 , R 16.14 , R 16.15 , R 16.16 , R 16.17 , R 16.18 , R 16.19 , R 16.20, R 16.21 , R 16.22 , R 16.23 , R 16.24 , R 16.25 , R 16.26 , R 16.27 , R 16.28 , R 16.29 , R 16.30 , R 16.31 , R 16.32 , R 16.33 , R 16.34 , R 16.35 , R 16.36 , R 16.37 , R 16.38 , R 16.39 , R 16.40 , R 16.41 , R 16.42 , R 17.1 , R 17.2 , R 17.3 , R 17.4 , R 17.5 , R 17.6 , R 17.7 , R 17.8 , R 17.9 , R 17.10 , R 17.11 , R 17.12 , R 17.13 , R 17.14 , R 17.15 , R 17.16 , R 17.17 , R 17.18 , R 17.19 , R 17.20 , R 17.21 , R 17.22 , R 17.23 , R 17.24 , R 17.25 , R 17.26 , R 17.27 , R 17.28 , R 17.29 , R 17.30 , R 17.31 , R 17.32 , R 17.33 , R 17.34 , R 17.35 , R 17.36 , R 17.37 , R 17.38 , R 17.39 , R 17.40 , R 17.41 , R 17.42 , R 18.1 , R 18.2 , R18.3 , R 18.4 , R 18.5 , R 18.6 , R 18.7 , R 18.8 , R 18.9 , R 18.10 , R 18.11 , R 18.12 , R 18.13 , R 18.14 , R 18.15 , R 18.16 , R 18.17 , R 18.18 , R 18.19 , R 18.20 , R 18.21 , R 18.22 , R 18.23 , R 18.24 , R 18.25 , R 18.26 , R 18.27 , R 18.28 , R 18.29 , R 18.30 , R 18.31 , R 18.32 , R 18.33 , R 18.34 , R 18.35 , R 18.36 , R 18.37 , R 18.38 , R 18.39 , R 18.40 , R 18.41 , R 18.42 may be referred to as, R 1 's definition is that of R 1.1 , R 1.2 , R 1.3 , R 1.4 , R 1.5 is assumed; R 4 is R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 is assumed; R 5 is R 5.1 , R 5.2 , R 5.3 , R 5.4 , R 5.5 , R 5.6 , R 5.7 is assumed; R 7 is R 7.1 , R 7.2 , R 7.3 , R 7.4, R 7.5 , R 7.6 , R 7.7 , R 7.8 , R 7.9 , R 7.10 , R 7.11 , R 7.12 , R 7.13 , R 7.14 , R 7.15 , R 7.16 , R 7.17 , R 7.18 , R 7.19 , R 7.20 , R 7.21 , R 7.22 , R 7.23 , R 7.24 , R 7.25 , R 7.26 , R 7.27 , R 7.28 , R 7.29 , R 7.30 , R 7.31 , R 7.32 , R 7.33 , R 7.34 , R 7.35 , R 7.36 , R 7.37 , R 7.38 , R 7.39 , R 7.40 , R 7.41 , R 7.42 is assumed; R 8 is R 8.1 , R 8.2 , R 8.3 , R 8.4 , R 8.5 , R 8.6 , R 8.7 , R 8.8 , R 8.9 , R 8.10 , R 8.11 , R 8.12 , R 8.13 , R 8.14 , R 8.15 , R 8.16 , R 8.17 , R 8.18 , R 8.19 , R 8.20 , R 8.21 , R 8.22 , R 8.23 , R 8.24 , R 8.25 , R 8.26 , R 8.27 , R8.28 , R 8.29 , R 8.30 , R 8.31 , R 8.32 , R 8.33 , R 8.34 , R 8.35 , R 8.36 , R 8.37 , R 8.38 , R 8.39 , R 8.40 , R 8.41 , R 8.42 is assumed; R 9 is, R 9.1 , R 9.2 , R 9.3 , R 9.4 , R 9.5 , R 9.6 , R 9.7 , R 9.8 , R 9.9 , R 9.10 , R 9.11 , R 9.12 , R 9.13 , R 9.14 , R 9.15 , R 9.16 , R 9.17 , R 9.18 , R 9.19 , R 9.20 , R 9.21 , R 9.22 , R 9.23 , R 9.24 , R 9.25 , R 9.26 , R 9.27 , R 9.28 , R 9.29 , R 9.30 , R 9.31 , R 9.32 , R 9.33 , R 9.34 , R 9.35 , R 9.36 , R 9.37 , R 9.38 , R 9.39 , R 9.40 , R 9.41 , R 9.42 is assumed; R 10 is, R 10.1 , R 10.2 , R 10.3 , R 10.4 , R 10.5 , R 10.6 , R 10.7 , R10.8 and R 10.9 and R 10.10 and R 10.11 and R 10.12 and R 10.13 and R 10.14 and R 10.15 and R 10.16 and R 10.17 and R 10.18 and R 10.19 and R 10.20 and R 10.21 and R 10.22 and R 10.23 and R 10.24 and R 10.25 and R 10.26 and R 10.27 and R 10.28 and R 10.29 and R 10.30 and R 10.31 and R 10.32 and R 10.33 and R 10.34 and R 10.35 and R 10.36 and R 10.37 and R 10.38 and R 10.39 and R 10.40 and R 10.41 and R 10.42 is assumed; and R 11 is R 11.1 and R 11.2 and R 11.3 and R 11.4 and R 11.5 and R 11.6 and R 11.7 and R 11.8 and R 11.9 and R 11.10 and R 11.11 and R 11.12 and R 11.13 and R 11.14 and R 11.15 and R 11.16 and R 11.17 and R 11.18 and R 11.19 and R 11.20 and R 11.21 and R 11.22 and R 11.23 and R 11.24 and R 11.25 and R 11.26 and R 11.27 and R 11.28 and R 11.29 and R 11.30 and R11.31 and R 11.32 and R 11.33 and R 11.34 and R 11.35 and R 11.36 and R 11.37 and R 11.38 and R 11.39 and R 11.40 and R 11.41 and R 11.42 is assumed; R 12 is R 12.1 and R 12.2 and R 12.3 and R 12.4 and R 12.5 and R 12.6 and R 12.7 and R 12.8 and R 12.9 and R 12.10 and R 12.11 and R 12.12 and R 12.13 and R 12.14 and R 12.15 and R 12.16 and R 12.17 and R 12.18 and R 12.19 and R 12.20 and R 12.21 and R 12.22 and R 12.23 and R 12.24 and R 12.25 and R 12.26 and R 12.27 and R 12.28 and R 12.29 and R 12.30 and R 12.31 and R 12.32 and R 12.33 and R 12.34 and R 12.35 and R 12.36 and R 12.37 and R 12.38 and R 12.39 and R 12.40 and R 12.41 and R 12.42 is assumed; R 13 is R 13.1 and R 13.2 and R 13.3 and R 13.4 and R 13.5 and R 13.6 and R 13.7 and R 13.8 and R 13.9 and R 13.10 and R13.11 , R 13.12 , R 13.13 , R 13.14 , R 13.15 , R 13.16 , R 13.17 , R 13.18 , R 13.19 , R 13.20 , R 13.21 , R 13.2 2 , R 13.23 , R 13.24 , R 13.25 , R 13.26 , R 13.27 , R 13.28 , R 13.29 , R 13.30 , R 13.31 , R 13.32 , R 13.33 , R 13.34 , R 13.35 , R 13.36 , R 13.37 , R 13.38 , R 13.39 , R 13.40 , R 13.41 , R 13.42 is assumed; R 14 is R 14.1 , R 14.2 , R 14.3 , R 14.4 , R 14.5 , R 14.6 , R 14.7 , R 14.8 , R 14.9 , R 14.10 , R 14.11 , R 14.12 , R 14.13 , R 14.14 , R 14.15 , R 14.16 , R 14.17 , R 14.18 , R 14.19 , R 14.20 , R 14.21 , R 14.22 , R 14.23 , R 14.24 , R 14.25 , R 14.26 , R 14.27 , R 14.28 , R 14.29 , R 14.30 , R 14.31 , R 14.32, R 14.33 , R 14.34 , R 14.35 , R 14.36 , R 14.37 , R 14.38 , R 14.39 , R 14.40 , R 14.41 , R 14.42 is assumed; R 15 is R 15.1 , R 15.2 , R 15.3 , R 15.4 , R 15.5 , R 15.6 , R 15.7 , R 15.8 , R 15.9 , R 15.10 , R 15.11 , R 15.12 , R 15.13 , R 15.14 , R 15.15 , R 15.16 , R 15.17 , R 15.18 , R 15.19 , R 15.20 , R 15.21 , R 15.22 , R 15.23 , R 15.24 , R 15.25 , R 15.26 , R 15.27 , R 15.28 , R 15.29 , R 15.30 , R 15.31 , R 15.32 , R 15.33 , R 15.34 , R 15.35 , R 15.36 , R 15.37 , R 15.38 , R 15.39 , R 15.40 , R 15.41 , R 15.42 is assumed; R 16 is R 16.1 , R 16.2 , R 16.3 , R 16.4 , R 16.5 , R 16.6 , R 16.7 , R 16.8 , R 16.9 , R 16.10 , R 16.11 , R 16.12, R 16.13 , R 16.14 , R 16.15 , R 16.16 , R 16.17 , R 16.18 , R 16.19 , R 16.20 , R 16.21 , R 16.22 , R 16.23 , R 16.24 , R 16.25 , R 16.26 , R 16.27 , R 16.28 , R 16.29 , R 16.30 , R 16.31 , R 16.32 , R 16.33 , R 16.34 , R 16.35 , R 16.36 , R 16.37 , R 16.38 , R 16.39 , R 16.40 , R 16.41 , R 16.42 is assumed; R 17 is R 17.1 , R 17.2 , R 17.3 , R 17.4 , R 17.5 , R 17.6 , R 17.7 , R 17.8 , R 17.9 , R 17.10 , R 17.11 , R 17.12 , R 17.13 , R 17.14 , R 17.15 , R 17.16 , R 17.17 , R 17.18 , R 17.19 , R 17.20 , R 17.21 , R 17.22 , R 17.23 , R 17.24 , R 17.25 , R 17.26 , R 17.27 , R 17.28 , R 17.29 , R 17.30 , R 17.31 , R 17.32 , R 17.33 , R 17.34 , R 17.35 , R17.36 , R 17.37 , R 17.38 , R 17.39 , R 17.40 , R 17.41 , R 17.42 is assumed; and / or R 18 is 18.1 , R 18.2 , R 18.3 , R 18.4 , R 18.5 , R 18.6 , R 18.7 , R 18.8 , R 18.9 , R 18.10 , R 18.11 , R 18.12 , R 18.13 , R 18.14 , R 18.15 , R 18.16 , R 18.17 , R 18.18 , R 18.19 , R 18.20 , R 18.21 , R 18.22 , R 18.23 , R 18.24 , R 18.25 , R 18.26 , R 18.27 , R 18.28 , R 18.29 , R 18.30 , R 18.31 , R 18.32 , R 18.33 , R 18.34 , R 18.35 , R 18.36 , R 18.37 , R 18.38 , R 18.39 , R 18.40 , R 18.41 , R 18.42 is assumed. R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R19 Variables used within the definition of [[ID=]], and / or appearing in multiple instances and being different from other variables, may be similarly appropriately labeled to more clearly distinguish each group. In some embodiments, the compound is a compound described herein (e.g., in the aspects, embodiments, examples, claims, tables, schemes, figures, or diagrams).

[0223] In an embodiment, the compound has the following formula:

Chemical Formula

[0224] In an embodiment, the compound has the following formula:

Chemical formula

[0225] W 1 is N or C(R 4.2 ). W 2 is N or C(R 5.1 ). W 3 is N or C(R 5.2 ). R 5.1 and R 5.2 are each independently the R 5is the part of R 4.2 independently, is the R described in this specification, including those in the embodiments 4 is the part of. In the embodiment, W 1 is N. In the embodiment, W 2 is N. In the embodiment, W 3 is N. In the embodiment, W 1 is C(R 4.2 ). In the embodiment, W 2 is C(R 5.1 ). In the embodiment, W 3 is C(R 5.2 ). In the embodiment, W 1 is CH. In the embodiment, W 2 is CH. In the embodiment, W 3 is CH.

[0226] In the embodiment, the compound has the following formula:

Chemical formula

[0227] In the embodiment, the compound has the following formula:

Chemical formula

[0228] In an embodiment, the compound has the following formula:

Chemical formula

[0229] W 1 is N or C(R 4.2 ). W 2 is N or C(R 5.1 ). W 3 is N or C(R 5.2 ). R 5.1 and R 5.2 are each independently a moiety of R as described herein, including those in the embodiments. R 5 is a moiety of R as described herein, including those in the embodiments. R4.2 is independently, including those in the embodiments, R as described herein 4 is a part of. In an embodiment, W 1 is N. In an embodiment, W 2 is N. In an embodiment, W 3 is N. In an embodiment, W 1 is C(R 4.2 ). In an embodiment, W 2 is C(R 5.1 ). In an embodiment, W 3 is C(R 5.2 ). In an embodiment, W 1 is CH. In an embodiment, W 2 is CH. In an embodiment, W 3 is CH.

[0230] In an embodiment of the compounds of formula (VI)-(X), R 2 is hydrogen. In an embodiment of the compounds of formula (VI)-(X), R 3 is hydrogen. In an embodiment of the compounds of formula (VI)-(X), R 2 and R 3 are hydrogen.

[0231] In an embodiment, R 1.1 is independently halogen. In an embodiment, R 1.1 is independently -CF 3 . In an embodiment, R 1.1 is independently -CHF 2 . In an embodiment, R 1.1 is independently -CH 2 F. In an embodiment, R 1.1 is independently -OCF 3 . In an embodiment, R 1.1 is independently -OCHF 2 . In an embodiment, R 1.1 is independently -OCH 2 F. In an embodiment, R 1.1 is independently -OH. In an embodiment, R 1.1 is independently -NH 2 . In an embodiment, R1.1 is independently -SH. In an embodiment, R 1.1 is independently a substituted or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1.1 is independently a substituted or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1.1 is independently a substituted or unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.1 is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.1 is independently a substituted or unsubstituted phenyl. In an embodiment, R 1.1 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 1.1 is independently a substituted C 1 -C 4 alkyl. In an embodiment, R 1.1 is independently a substituted 4-membered heteroalkyl. In an embodiment, R 1.1 is independently a substituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.1 is independently a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.1 is independently a substituted phenyl. In an embodiment, R 1.1 is independently a substituted 5- to 6-membered heteroaryl. In an embodiment, R 1.1 is independently an unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1.1 is independently an unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1.1 is independently an unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.1 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.1 is independently an unsubstituted phenyl. In an embodiment, R 1.1 is independently an unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R1.1 is independently unsubstituted methyl. In an embodiment, R 1.1 is independently unsubstituted ethyl. In an embodiment, R 1.1 is independently unsubstituted isopropyl. In an embodiment, R 1.1 is independently unsubstituted tert-butyl. In an embodiment, R 1.1 is independently unsubstituted methoxy. In an embodiment, R 1.1 is independently unsubstituted ethoxy. In an embodiment, R 1.1 is independently -F. In an embodiment, R 1.1 is independently -Cl. In an embodiment, R 1.1 is independently -Br. In an embodiment, R 1.1 is independently -I. In an embodiment, R 1.1 is independently hydrogen.

[0232] In an embodiment, R 1.2 is independently halogen. In an embodiment, R 1.2 is independently -CF 3 . In an embodiment, R 1.2 is independently -CHF 2 . In an embodiment, R 1.2 is independently -CH 2 F. In an embodiment, R 1.2 is independently -OCF 3 . In an embodiment, R 1.2 is independently -OCHF 2 . In an embodiment, R 1.2 is independently -OCH 2 F. In an embodiment, R 1.2 is independently -OH. In an embodiment, R 1.2 is independently -NH 2 . In an embodiment, R 1.2 is independently -SH. In an embodiment, R 1.2 is independently substituted or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1.2 is independently substituted or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R1.2 is independently a substituted or unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.2 is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.2 is independently a substituted or unsubstituted phenyl. In an embodiment, R 1.2 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 1.2 is independently a substituted C 1 -C 4 alkyl. In an embodiment, R 1.2 is independently a substituted 4-membered heteroalkyl. In an embodiment, R 1.2 is independently a substituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.2 is independently a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.2 is independently a substituted phenyl. In an embodiment, R 1.2 is independently a substituted 5- to 6-membered heteroaryl. In an embodiment, R 1.2 is independently an unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1.2 is independently an unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1.2 is independently an unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.2 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.2 is independently an unsubstituted phenyl. In an embodiment, R 1.2 is independently an unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 1.2 is independently an unsubstituted methyl. In an embodiment, R 1.2 is independently an unsubstituted ethyl. In an embodiment, R 1.2 is independently an unsubstituted isopropyl. In an embodiment, R 1.2 is independently an unsubstituted tert-butyl. In an embodiment, R1.2 is independently an unsubstituted methoxy. In an embodiment, R 1.2 is independently an unsubstituted ethoxy. In an embodiment, R 1.2 is independently -F. In an embodiment, R 1.2 is independently -Cl. In an embodiment, R 1.2 is independently -Br. In an embodiment, R 1.2 is independently -I. In an embodiment, R 1.2 is independently hydrogen.

[0233] In an embodiment, R 1.3 is independently a halogen. In an embodiment, R 1.3 is independently -CF 3 . In an embodiment, R 1.3 is independently -CHF 2 . In an embodiment, R 1.3 is independently -CH 2 F. In an embodiment, R 1.3 is independently -OCF 3 . In an embodiment, R 1.3 is independently -OCHF 2 . In an embodiment, R 1.3 is independently -OCH 2 F. In an embodiment, R 1.3 is independently -OH. In an embodiment, R 1.3 is independently -NH 2 . In an embodiment, R 1.3 is independently -SH. In an embodiment, R 1.3 is independently a substituted or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1.3 is independently a substituted or unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1.3 is independently a substituted or unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.3 is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.3is independently a substituted or unsubstituted phenyl. In an embodiment, R 1.3 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 1.3 is independently a substituted C 1 -C 4 alkyl. In an embodiment, R 1.3 is independently a substituted 4-membered heteroalkyl. In an embodiment, R 1.3 is independently a substituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.3 is independently a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.3 is independently a substituted phenyl. In an embodiment, R 1.3 is independently a substituted 5- to 6-membered heteroaryl. In an embodiment, R 1.3 is independently an unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1.3 is independently an unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1.3 is independently an unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.3 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.3 is independently an unsubstituted phenyl. In an embodiment, R 1.3 is independently an unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 1.3 is independently an unsubstituted methyl. In an embodiment, R 1.3 is independently an unsubstituted ethyl. In an embodiment, R 1.3 is independently an unsubstituted isopropyl. In an embodiment, R 1.3 is independently an unsubstituted tert-butyl. In an embodiment, R 1.3 is independently an unsubstituted methoxy. In an embodiment, R 1.3 is independently an unsubstituted ethoxy. In an embodiment, R 1.3 is independently -F. In an embodiment, R 1.3 is independently -Cl. In an embodiment, R1.3 is independently -Br. In an embodiment, R 1.3 is independently -I. In an embodiment, R 1.3 is independently hydrogen.

[0234] In an embodiment, R 1.4 is independently halogen. In an embodiment, R 1.4 is independently -CF 3 In an embodiment, R 1.4 is independently -CHF 2 In an embodiment, R 1.4 is independently -CH 2 F. In an embodiment, R 1.4 is independently -OCF 3 In an embodiment, R 1.4 is independently -OCHF 2 In an embodiment, R 1.4 is independently -OCH 2 F. In an embodiment, R 1.4 is independently -OH. In an embodiment, R 1.4 is independently -NH 2 In an embodiment, R 1.4 is independently -SH. In an embodiment, R 1.4 is independently a substituted or unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1.4 is independently a substituted or unsubstituted 2 - 4 membered heteroalkyl. In an embodiment, R 1.4 is independently a substituted or unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.4 is independently a substituted or unsubstituted 3 - 6 membered heterocycloalkyl. In an embodiment, R 1.4 is independently a substituted or unsubstituted phenyl. In an embodiment, R 1.4 is independently a substituted or unsubstituted 5 - 6 membered heteroaryl. In an embodiment, R 1.4 is independently a substituted C 1 -C 4 alkyl. In an embodiment, R1.4 is independently a substituted 4-membered heteroalkyl. In an embodiment, R 1.4 is independently a substituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.4 is independently a substituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.4 is independently a substituted phenyl. In an embodiment, R 1.4 is independently a substituted 5- to 6-membered heteroaryl. In an embodiment, R 1.4 is independently an unsubstituted C 1 -C 4 alkyl. In an embodiment, R 1.4 is independently an unsubstituted 2- to 4-membered heteroalkyl. In an embodiment, R 1.4 is independently an unsubstituted C 3 -C 6 cycloalkyl. In an embodiment, R 1.4 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.4 is independently an unsubstituted phenyl. In an embodiment, R 1.4 is independently an unsubstituted 5- to 6-membered heteroaryl. In an embodiment, R 1.4 is independently an unsubstituted methyl. In an embodiment, R 1.4 is independently an unsubstituted ethyl. In an embodiment, R 1.4 is independently an unsubstituted isopropyl. In an embodiment, R 1.4 is independently an unsubstituted tert-butyl. In an embodiment, R 1.4 is independently an unsubstituted methoxy. In an embodiment, R 1.4 is independently an unsubstituted ethoxy. In an embodiment, R 1.4 is independently -F. In an embodiment, R 1.4 is independently -Cl. In an embodiment, R 1.4 is independently -Br. In an embodiment, R 1.4 is independently -I. In an embodiment, R 1.4 is independently hydrogen.

[0235] In an embodiment, R 4.1is independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. In embodiments, R 4.1 is independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2- to 4-membered heteroalkyl. In embodiments, R 4.1 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. In embodiments, R 4.1 is independently halogen. In embodiments, R 4.1 is independently -OH. In embodiments, R 4.1 is independently unsubstituted methyl. In embodiments, R 4.1 is independently unsubstituted methoxy. In embodiments, R 4.1 is independently unsubstituted ethyl. In embodiments, R 4.1 is independently -F. In embodiments, R 4.1 is independently -Cl. In embodiments, R 4.1 is independently -Br. In embodiments, R 4.1 is independently -I. In embodiments, R 4.1 is independently -CF 3 . In embodiments, R 4.1 is independently -NH 2 . In embodiments, R 4.1 is independently -SH. In embodiments, R 4.1 is independently hydrogen. In embodiments, R 4.1 is independently unsubstituted isopropyl. In embodiments, R 4.1 is independently unsubstituted ethoxy. I...

Claims

1. A pharmaceutical composition comprising a compound and / or an anticancer agent and a pharmaceutically acceptable excipient, wherein the compound is administered to a subject in combination with the anticancer agent, the anticancer agent is an EGFR inhibitor, and the compound has the following formula: 【Chemical 1】 wherein Ring A is phenyl or a 5- to 6-membered heteroaryl; Ring B is 1-naphthyl or isoquinolinyl; R １ independently represents halogen, -CX １ ３ , -CHX １ ２ , -CH ２ X １ , -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, -NHCOH, -NHCO-OH, -NHOH, -OCX １ ３ , -OCHX １ ２ , -OCH ２ X １ , R ３０ substituted or unsubstituted C １ -C ８ alkyl, R ３０ substituted or unsubstituted 2- to 8-membered heteroalkyl, R ３０ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ３０ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ３０ substituted or unsubstituted C ６ -C １０ aryl, or R ３０ is substituted or unsubstituted 5- to 10-membered heteroaryl; R ３０ is independently oxo, halogen, -CX ３０ ３ -, -CHX ３０ ２ -, -CH ２ X ３０ -, -OCH ２ X ３０ -, -OCHX ３０ 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 -, -NH-C(=O)NHNH ２ -, -NH-C(=O)NH ２ -, -NHSO ２ H, -NH-C(=O)H, -NH-C(O)-OH, -NHOH, -OCX ３０ ３ R ３１ substituted or unsubstituted C １ -C ８ alkyl, R ３１ substituted or unsubstituted 2- to 10-membered heteroalkyl, R ３１ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ３１ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ３１ substituted or unsubstituted C ６ -C １０ aryl, or R ３１ substituted or unsubstituted 5- to 10-membered heteroaryl; R ３１ is independently oxo, halogen, -CX ３１ ３ , -CHX ３１ ２ , -CH ２ X ３１ , -OCH ２ X ３１ , -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, -NHCOH, -NHCO-OH, -NHOH, -OCX ３１ ３ , -OCHX ３１ ２ , R ３２ substituted or unsubstituted C １ -C ８ alkyl, R ３２ substituted or unsubstituted 2- to 10-membered heteroalkyl, R ３２ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ３２ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ３２ substituted or unsubstituted C ６ -C １０ aryl, or R ３２ substituted or unsubstituted 5- to 10-membered heteroaryl; R ２ is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl, or unsubstituted tert-butyl; R ３ is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl, or unsubstituted tert-butyl; R ４ is independently halogen, -CX ４ ３ -, -CHX ４ ２ -, -CH ２ X ４ -, -OCH ２ X ４ -, -CN, -OH, -NH ２ -, -COOH, -CONH ２ -, -NO ２ -, -SH, -SO ３ H, -SO ４ H, -SO ２ NH ２ -, -NHNH ２ -, -ONH ２ -, -NH-C(=O)NHNH ２ -, -NH-C(=O)NH ２ -, -NHSO ２ H, -NH-C(=O)H, -NH-C(O)-OH, -NHOH, -OCX ４ ３ -, -OCHX ４ ２ -, R ３９ substituted or unsubstituted C １ -C ８ alkyl, R ３９ substituted or unsubstituted 2- to 10-membered heteroalkyl, R ３９ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ３９ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ３９ substituted or unsubstituted C ６ -C １０ aryl, or R ３９ is substituted or unsubstituted 5- to 10-membered heteroaryl; R ３９ is independently oxo, halogen, -CX ３９ ３ , -CHX ３９ ２ , -CH ２ X ３９ , -OCH ２ X ３９ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -SO ４ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NH C=(O)NHNH ２ , -NH C=(O)NH ２ , -NHSO ２ H, -NH C=(O)H, -NH C(O)-OH, -NHOH, -OCX ３９ ３ , -OCHX ３９ ２ , R ４０ substituted or unsubstituted C １ -C ８ alkyl, R ４０ substituted or unsubstituted 2- to 10-membered heteroalkyl, R ４０ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ４０ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ４０ substituted or unsubstituted C ６ -C １０ aryl, or R ４０ substituted or unsubstituted 5- to 10-membered heteroaryl; R ４０ is independently oxo, halogen, -CX ４０ ３ , -CHX ４０ ２ , -CH ２ X ４０ , -OCH ２ X ４０ , -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, -NHCOH, -NHCO-OH, -NHOH, -OCX ４０ ３ , -OCHX ４０ ２ , R ４１ substituted or unsubstituted C １ -C ８ alkyl, R ４１ substituted or unsubstituted 2- to 10-membered heteroalkyl, R ４１ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ４１ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ４１ substituted or unsubstituted C ６ -C １０ aryl, or R ４１ substituted or unsubstituted 5- to 10-membered heteroaryl; R ５ is independently halogen, -CX ５ ３ , -CHX ５ ２ , -CH ２ X ５ , -OCH ２ X ５ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -SO ４ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NH-C(=O)NHNH ２ , -NH-C(=O)NH ２ , -NHSO ２ H, -NH-C(=O)H, -NH-C(O)-OH, -NHOH, -OCX ５ ３ , -OCHX ５ ２ , R ４２ substituted or unsubstituted C １ -C ８ alkyl, R ４２ substituted or unsubstituted 2- to 10-membered heteroalkyl, R ４２ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ４２ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ４２ substituted or unsubstituted C ６ -C １０ aryl, or R ４２ substituted or unsubstituted 5- to 10-membered heteroaryl; R ４２ is independently oxo, halogen, -CX ４２ ３ , -CHX ４２ ２ , -CH ２ X ４２ , -OCH ２ X ４２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -SO ４ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NH-C(=O)NHNH ２ , -NH-C(=O)NH ２ , -NHSO ２ H, -NH-C(=O)H, -NH-C(O)-OH, -NHOH, -OCX ４２ ３ , -OCHX ４２ ２ , R ４３ substituted or unsubstituted C １ -C ８ alkyl, R ４３ substituted or unsubstituted 2- to 10-membered heteroalkyl, R ４３ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ４３ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ４３ substituted or unsubstituted C ６ -C １０ aryl, or R ４３ is substituted or unsubstituted 5- to 10-membered heteroaryl; R ４３ is independently oxo, halogen, -CX ４３ ３ , -CHX ４３ ２ , -CH ２ X ４３ , -OCH ２ X ４３ , -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, -NHOC=(O)H, -NHOC(O)-OH, -NHOH, -OCX ４３ ３ , -OCHX ４３ ２ , R ４４ substituted or unsubstituted C １ -C ８ alkyl, R ４４ substituted or unsubstituted 2- to 10-membered heteroalkyl, R ４４ substituted or unsubstituted C ３ -C ８ cycloalkyl, R ４４ substituted or unsubstituted 3- to 8-membered heterocycloalkyl, R ４４ substituted or unsubstituted C ６ -C １０ aryl, or R ４４ is substituted or unsubstituted 5- to 10-membered heteroaryl; R ３２ 、 R ４１ 、 and R ４４ are, independently, oxo, halogen, -CF ３ 、 -CHF ２ 、 -CH ２ F, -OCH ２ F, -OCF ３ 、 -OCHF ２ 、 -CCl ３ 、 -CHCl ２ 、 -CH ２ Cl, -OCH ２ Cl, -OCl ３ 、 -OCHCl ２ 、 -CBr ３ 、 -CHBr ２ 、 -CH ２ Br, -OCH ２ Br, -OBr ３ 、 -OCHBr ２ 、 -CI ３ 、 -CHI ２ 、 -CH ２ I, -OCH ２ I, -OCI ３ 、 -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 、 -NH-C(=O)NHNH ２ 、 -NH-C(=O)NH ２ 、 -NHSO ２ H, -NH-C(=O)H, -NH-C(O)-OH, -NHOH, unsubstituted C １ -C ８ alkyl, unsubstituted 2-10 membered heteroalkyl, unsubstituted C ３ -C ８ cycloalkyl, unsubstituted 3-8 membered heterocycloalkyl, unsubstituted C ６ -C １０ aryl, or unsubstituted 5-10 membered heteroaryl; z1 is an integer from 0 to 4; z2 is an integer from 0 to 5; z3 is an integer from 0 to 7; and X １ , X ４ , X ５ , X ３０ , X ３１ , X ３９ , X ４０ , X ４２ , and X ４３ are independently, -Cl, -Br, -I, or -F, said pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the compound has the following formula: [Chemical 2]

3. The pharmaceutical composition according to claim 1, wherein the compound of formula (II) has the following formula:

4. 【Chemical Formula 3】

5.

6. R １ is independently halogen, -CF ３ , -OH, -NH ２ , -SH, unsubstituted C １ -C ４ alkyl, unsubstituted 2-4 membered heteroalkyl, unsubstituted C ３ -C ６ cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-6 membered heteroaryl, the pharmaceutical composition according to any one of claims 1 to 3. The pharmaceutical composition according to any one of claims 1 to 5, wherein z1 is 1. R １ is independently halogen, -OH, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, unsubstituted methyl, or unsubstituted methoxy, the pharmaceutical composition according to any one of claims 1 to 3.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein z1 is 0.

8.

9.

10. R ４ is independently halogen, -CF ３ , -OH, -NH ２ , -SH, unsubstituted C １ -C ４ alkyl, unsubstituted 2-4 membered heteroalkyl, unsubstituted C ３ -C ６ cycloalkyl, unsubstituted 3-6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-6 membered heteroaryl, the pharmaceutical composition according to any one of claims 1 to 7.

11. R ４ is independently halogen, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, -OH, -OR １４ , unsubstituted methyl, or unsubstituted methoxy, and R １４ is hydrogen or unsubstituted C １ -C ３ alkyl, the pharmaceutical composition according to any one of claims 1 to 7. The pharmaceutical composition according to any one of claims 1 to 10, wherein z2 is 1. R １４ The pharmaceutical composition according to claim 9, wherein R is unsubstituted methyl.

12. The pharmaceutical composition according to any one of claims 1 to 7, wherein z2 is 0.

13.

14.

15. R ５ is independently halogen, -CF ３ , -OH, -NH ２ , -SH, unsubstituted C １ -C ４ alkyl, unsubstituted 2- to 4-membered heteroalkyl, unsubstituted C ３ -C ６ cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5- to 6-membered heteroaryl, the pharmaceutical composition according to any one of claims 1 to 12. The pharmaceutical composition according to any one of claims 1 to 14, wherein z3 is 1. R ５ is independently halogen, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, -OH, unsubstituted methyl, or unsubstituted methoxy, the pharmaceutical composition according to any one of claims 1 to 12.

16. The pharmaceutical composition according to any one of claims 1 to 12, wherein z3 is 0.

17.

18.

19. R ２ The pharmaceutical composition according to any one of claims 1 to 16, wherein R is hydrogen. The pharmaceutical composition according to any one of claims 1 to 18, wherein Ring A is phenyl. R ３ The pharmaceutical composition according to any one of claims 1 to 17, wherein R is hydrogen.

20. The pharmaceutical composition according to any one of claims 1 to 18, wherein Ring A is a 5- to 6-membered heteroaryl.

21. The pharmaceutical composition according to any one of claims 1 to 18, wherein Ring A is pyridyl.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein Ring B is 1-naphthyl.

23. The pharmaceutical composition according to any one of claims 1 to 21, wherein Ring B is isoquinolinyl.

24. The pharmaceutical composition according to any one of claims 1 to 21, wherein Ring B is 1-isoquinolinyl or 4-isoquinolinyl.

25. The pharmaceutical composition according to claim 1, wherein the compound has the following formula:

26. The pharmaceutical composition according to claim 1, wherein the compound has the following formula: 【Chemical Formula 4】

27. The pharmaceutical composition according to claim 1, wherein the compound has the following formula:

28. 【Chemical Formula 5】 ​ ​ ​ 【Chemical Formula 6】 ​ ​ The compound has the following formula: 【Chemical Formula 7】 【Chem.】 【Chem.】 The pharmaceutical composition according to claim 1, wherein the compound has the following formula:

29. The compound has the following formula: 【Chemical Formula 8】 The pharmaceutical composition according to claim 1, wherein the compound has the following formula:

30. The pharmaceutical composition according to any one of claims 1 to 29, wherein the compound and the anticancer agent are formulated separately.

31. The pharmaceutical composition according to any one of claims 1 to 30, for inhibiting PCNA activity and treating a disease related to PCNA activity.

32. The pharmaceutical composition according to any one of claims 1 to 30, for inhibiting PCNA activity and treating cancer.

33. The pharmaceutical composition according to claim 32, wherein the cancer is sarcoma, adenocarcinoma, leukemia, or lymphoma.

34. The pharmaceutical composition according to claim 32, wherein the cancer is lung cancer, colon cancer, central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, breast cancer, mesothelioma, liver cancer, stomach cancer, esophageal cancer, bladder cancer, cervical cancer, osteosarcoma, pancreatic cancer, adrenocortical cancer, adrenal cancer, colorectal cancer, testicular cancer, myeloma, B acute lymphoblastic lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, chronic leukemia, acute leukemia, adenocarcinoma, hematoid carcinoma, or thyroid cancer.

35. The pharmaceutical composition according to any one of claims 32 to 34, wherein the treatment further includes radiation therapy.

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