Bicyclic compounds for restoring mutant p53 function

Abstract

Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. The present disclosure describes compounds and methods to recover wild-type function to p53 mutants. The compounds of the present disclosure can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA and activate downstream effectors involved in tumor suppression. The disclosed compounds can be used to reduce the progression of cancers that contain a p53 mutation.

Description

Atty. Docket No.44727-732601 BICYCLIC COMPOUNDS FOR RESTORING MUTANT P53 FUNCTION CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application Number 63 / 537,612, filed September 11, 2023, and U.S. Provisional Patent Application Number 63 / 642,398, filed May 3, 2024, each of which is incorporated by reference herein in its entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 10, 2024, is named PMV_44727-732601.xml and is 3,842 bytes in size. BACKGROUND

[0003] Cancer, an uncontrolled proliferation of cells, is a multifactorial disease characterized by tumor formation, growth, and in some instances, metastasis. Cells carrying an activated oncogene, damaged genome, or other cancer-promoting alterations can be prevented from replicating through an elaborate tumor suppression network. A central component of this tumor suppression network is p53, one of the most potent tumor suppressors in the cell. Both the wild type and mutant conformations of p53 are implicated in the progression of cancer. INCORPORATION BY REFERENCE

[0004] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually. SUMMARY OF THE INVENTION

[0005] In some embodiments, the present disclosure provides a compound of the formula:or a pharmaceutically-acceptable salt thereof, wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5or CR5R6; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S;Atty. Docket No.44727-732601 - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19, CR19R20, N, NR19, O, or S; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - RMand RNare each independentlyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R19, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R24and R25is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halogen, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0006] In some embodiments, disclosed herein is a method of inducing apoptosis in a cell, the method comprising contacting the cell with a therapeutically-effective amount of a compound of the disclosure that binds a p53 mutant, wherein the compound increases the ability of the p53 mutant to bind DNA, wherein the cell expresses the p53 mutant.

[0007] In some embodiments, disclosed herein is a method of treating a cancer, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of the disclosure.Atty. Docket No.44727-732601 DETAILED DESCRIPTION

[0008] The present disclosure provides compounds and methods for restoring wild-type function to mutant p53. The compounds of the present disclosure can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA. The restoration of activity of the p53 mutant can allow for the activation of downstream effectors of p53 leading to inhibition of cancer progression. The disclosure further provides methods of treatment of a cancerous lesion or a tumor harboring a p53 mutation.

[0009] Cancer is a collection of related diseases characterized by uncontrolled proliferation of cells with the potential to metastasize throughout the body. Cancer can be classified into five broad categories including, for example: carcinomas, which can arise from cells that cover internal and external parts of the body such as the lung, breast, and colon; sarcomas, which can arise from cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues; lymphomas, which can arise in the lymph nodes and immune system tissues; leukemia, which can arise in the bone marrow and accumulate in the bloodstream; and adenomas, which can arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.

[0010] Although different cancers can develop in virtually any of the body's tissues, and contain unique features, the basic processes that cause cancer can be similar in all forms of the disease. Cancer begins when a cell breaks free from the normal restraints on cell division and begins to grow and divide out of control. Genetic mutations in the cell can preclude the ability of the cell to repair damaged DNA or initiate apoptosis and can result in uncontrolled growth and division of cells.

[0011] The ability of tumor cell populations to multiply is determined not only by the rate of cell proliferation but also by the rate of cell attrition. Programmed cell death, or apoptosis, represents a major mechanism of cellular attrition. Cancer cells can evade apoptosis through a variety of strategies, for example, through the suppression of p53 function, thereby suppressing expression of pro-apoptotic proteins.

[0012] Oncogenes and tumor suppressor genes can regulate the proliferation of cells. Genetic mutations can affect oncogenes and tumor suppressors, potentially activating or suppressing activity abnormally, further facilitating uncontrolled cell division. Whereas oncogenes assist in cellular growth, tumor suppressor genes slow cell division by repairing damaged DNA and activating apoptosis. Cellular oncogenes that can be mutated in cancer include, for example, Cdk1, Cdk2, Cdk3, Cdk4, Cdk6, EGFR, PDGFR, VEGF, HER2, Raf kinase, K-Ras, and myc. Tumor suppressor genes that can be mutated in cancer include, for example, BRCA1, BRCA2, cyclin-dependent kinase inhibitor 1C, Retinoblastoma protein (pRb), PTEN, p16, p27, p53, and p73. Tumor suppressor p53.

[0013] The tumor suppressor protein p53 is a 393 amino acid transcription factor that can regulate cell growth in response to cellular stresses including, for example, UV radiation, hypoxia, oncogene activation, and DNA damage. p53 has various mechanisms for inhibiting the progression of cancer including, for example, initiation of apoptosis, maintenance of genomic stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis. Due to the critical role of p53 in tumorAtty. Docket No.44727-732601 suppression, p53 is inactivated in almost all cancers either by direct mutation or through perturbation of associated signaling pathways involved in tumor suppression. Homozygous loss of the p53 gene occurs in almost all types of cancer, including carcinomas of the breast, colon, and lung. The presence of certain p53 mutations in several types of human cancer can correlate with less favorable patient prognosis.

[0014] In the absence of stress signals, p53 levels are maintained at low levels via the interaction of p53 with Mdm2, an E3 ubiquitin ligase. In an unstressed cell, Mdm2 can target p53 for degradation by the proteasome. Under stress conditions, the interaction between Mdm2 and p53 is disrupted, and p53 accumulates. The critical event leading to the activation of p53 is phosphorylation of the N-terminal domain of p53 by protein kinases, thereby transducing upstream stress signals. The phosphorylation of p53 leads to a conformational change, which can promote DNA binding by p53 and allow transcription of downstream effectors. The activation of p53 can induce, for example, the intrinsic apoptotic pathway, the extrinsic apoptotic pathway, cell cycle arrest, senescence, and DNA repair. p53 can activate proteins involved in the above pathways including, for example, Fas / Apo1, KILLER / DR5, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and p21 (WAF1). Additionally, p53 can repress the transcription of a variety of genes including, for example, c-MYC, Cyclin B, VEGF, RAD51, and hTERT.

[0015] Each chain of the p53 tetramer is composed of several functional domains including the transactivation domain (amino acids 1-100), the DNA-binding domain (amino acids 101-306), and the tetramerization domain (amino acids 307-355), which are highly mobile and largely unstructured. Most p53 cancer mutations are located in the DNA-binding core domain of the protein, which contains a central β-sandwich of anti-parallel β-sheets that serves as a basic scaffold for the DNA-binding surface. The DNA-binding surface is composed of two β-turn loops, L2 and L3, which are stabilized by a zinc ion, for example, at Arg175 and Arg248, and a loop-sheet-helix motif. Altogether, these structural elements form an extended DNA-binding surface that is rich in positively-charged amino acids and makes specific contact with various p53 response elements.

[0016] Due to the prevalence of p53 mutations in virtually every type of cancer, the reactivation of wild type p53 function in a cancerous cell can be an effective therapy. Mutations in p53 located in the DNA- binding domain of the protein or periphery of the DNA-binding surface result in aberrant protein folding required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. p53 mutations that can abrogate the activity of p53 include, for example, R175H, Y220C, G245S, R248Q, R248W, R273H, and R282H. These p53 mutations can either distort the structure of the DNA-binding site or thermodynamically destabilize the folded protein at body temperature. Wild-type function of p53 mutants can be recovered by binding of the p53 mutant to a compound that can shift the folding- unfolding equilibrium towards the folded state, thereby reducing the rate of unfolding and destabilization.

[0017] Non-limiting examples of amino acids include: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lys); methionine (M, Met);Atty. Docket No.44727-732601 phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); and valine (V, Val). Mechanism of compounds of the disclosure.

[0018] The compounds of the present disclosure can selectively bind to a p53 mutant and can recover wild-type activity of the p53 mutant including, for example, DNA binding function and activation of downstream targets involved in tumor suppression. In some embodiments, a compound of the disclosure selectively binds to the p53 Y220C mutant. The Y220C mutant is a temperature sensitive mutant, which binds to DNA at lower temperature and is denatured at body temperature. A compound of the disclosure can stabilize the Y220C mutant to reduce the likelihood of denaturation of the protein at body temperature.

[0019] Located in the periphery of the p53 β-sandwich connecting β-strands S7 and S8, the aromatic ring of Y220 is an integral part of the hydrophobic core of the β-sandwich. The Y220C mutation can be highly destabilizing due to the formation of an internal surface cavity. A compound of the disclosure can bind to and occupy this surface crevice to stabilize the β-sandwich, thereby restoring wild-type p53 DNA- binding activity.

[0020] To determine the ability of a compound of the disclosure to bind and stabilize mutant p53, assays can be employed to detect, for example, a conformational change in the p53 mutant or activation of wild- type p53 targets. Conformational changes in p53 can be measured by, for example, differential scanning fluorimetry (DSF), isothermal titration calorimetry (ITC), nuclear magnetic resonance spectrometry (NMR), or X-ray crystallography. Additionally, antibodies specific for the wild type of mutant conformation of p53 can be used to detect a conformational change via, for example, immunoprecipitation (IP), immunofluorescence (IF), or immunoblotting.

[0021] Methods used to detect the ability of the p53 mutant to bind DNA can include, for example, DNA affinity immunoblotting, modified enzyme-linked immunosorbent assay (ELISA), electrophoretic mobility shift assay (EMSA), fluorescence resonance energy transfer (FRET), homogeneous time- resolved fluorescence (HTRF), and a chromatin immunoprecipitation (ChIP) assay.

[0022] To determine whether a compound described herein is able to reactivate the transcriptional activity of p53, the activation of downstream targets in the p53 signaling cascade can be measured. Activation of p53 effector proteins can be detected by, for example, immunohistochemistry (IHC-P), reverse transcription polymerase chain reaction (RT-PCR), and western blotting. The activation of p53 can also be measured by the induction of apoptosis via the caspase cascade and using methods including, for example, Annexin V staining, TUNEL assays, pro-caspase and caspase levels, and cytochrome c levels. Another consequence of p53 activation is senescence, which can be measured using methods such as β-galactosidase staining.

[0023] A p53 mutant that can be used to determine the effectiveness of a compound of the disclosure to increase the DNA binding ability of a p53 mutant is a p53 truncation mutant, which contains only amino acids 94-312, encompassing the DNA-binding domain of p53. For example, the sequence of the p53 Y220C mutant used for testing compound efficacy can be:Atty. Docket No.44727-732601 SSSVPSQ KTYQGSYGFR LGFLHSGTAK SVTCTYSPAL NKMFCQLAKT CPVQLWVDST PPPGTRVRAM AIYKQSQHMT EVVRRCPHHE RCSDSDGLAP PQHLIRVEGN LRVEYLDDRN TFRHSVVVPC EPPEVGSDCT TIHYNYMCNS SCMGGMNRRP ILTIITLEDS SGNLLGRNSF EVHVCACPGR DRRTEEENLR KKGEPHHELP PGSTKRALSN NT (SEQ ID NO.1)

[0024] A compound of the disclosure can increase the ability of a p53 mutant to bind DNA by at least or up to about 0.1%, at least or up to about 0.2%, at least or up to about 0.3%, at least or up to about 0.4%, at least or up to about 0.5%, at least or up to about 0.6%, at least or up to about 0.7%, at least or up to about 0.8%, at least or up to about 0.9%, at least or up to about 1%, at least or up to about 2%, at least or up to about 3%, at least or up to about 4%, at least or up to about 5%, at least or up to about 6%, at least or up to about 7%, at least or up to about 8%, at least or up to about 9%, at least or up to about 10%, at least or up to about 11%, at least or up to about 12%, at least or up to about 13%, at least or up to about 14%, at least or up to about 15%, at least or up to about 16%, at least or up to about 17%, at least or up to about 18%, at least or up to about 19%, at least or up to about 20%, at least or up to about 21%, at least or up to about 22%, at least or up to about 23%, at least or up to about 24%, at least or up to about 25%, at least or up to about 26%, at least or up to about 27%, at least or up to about 28%, at least or up to about 29%, at least or up to about 30%, at least or up to about 31%, at least or up to about 32%, at least or up to about 33%, at least or up to about 34%, at least or up to about 35%, at least or up to about 36%, at least or up to about 37%, at least or up to about 38%, at least or up to about 39%, at least or up to about 40%, at least or up to about 41%, at least or up to about 42%, at least or up to about 43%, at least or up to about 44%, at least or up to about 45%, at least or up to about 46%, at least or up to about 47%, at least or up to about 48%, at least or up to about 49%, at least or up to about 50%, at least or up to about 51%, at least or up to about 52%, at least or up to about 53%, at least or up to about 54%, at least or up to about 55%, at least or up to about 56%, at least or up to about 57%, at least or up to about 58%, at least or up to about 59%, at least or up to about 60%, at least or up to about 61%, at least or up to about 62%, at least or up to about 63%, at least or up to about 64%, at least or up to about 65%, at least or up to about 66%, at least or up to about 67%, at least or up to about 68%, at least or up to about 69%, at least or up to about 70%, at least or up to about 71%, at least or up to about 72%, at least or up to about 73%, at least or up to about 74%, at least or up to about 75%, at least or up to about 76%, at least or up to about 77%, at least or up to about 78%, at least or up to about 79%, at least or up to about 80%, at least or up to about 81%, at least or up to about 82%, at least or up to about 83%, at least or up to about 84%, at least or up to about 85%, at least or up to about 86%, at least or up to about 87%, at least or up to about 88%, at least or up to about 89%, at least or up to about 90%, at least or up to about 91%, at least or up to about 92%, at least or up to about 93%, at least or up to about 94%, at least or up to about 95%, at least or up to about 96%, at least or up to about 97%, at least or up to about 98%, at least or up to about 99%, at least or up to about 100%, at least or up to about 125%, at least or up to about 150%, at least or up to about 175%, at least or up toAtty. Docket No.44727-732601 about 200%, at least or up to about 225%, or at least or up to about 250% as compared to the ability of the p53 mutant to bind DNA in the absence of a compound of the disclosure.

[0025] A compound described herein can increase the activity of the p53 mutant that is, for example, at least or up to about 2-fold, at least or up to about 3-fold, at least or up to about 4-fold, at least or up to about 5-fold, at least or up to about 6-fold, at least or up to about 7-fold, at least or up to about 8-fold, at least or up to about 9-fold, at least or up to about 10-fold, at least or up to about 11-fold, at least or up to about 12-fold, at least or up to about 13-fold, at least or up to about 14-fold, at least or up to about 15- fold, at least or up to about 16-fold, at least or up to about 17-fold, at least or up to about 18-fold, at least or up to about 19-fold, at least or up to about 20-fold, at least or up to about 25-fold, at least or up to about 30-fold, at least or up to about 35-fold, at least or up to about 40-fold, at least or up to about 45- fold, at least or up to about 50-fold, at least or up to about 55-fold, at least or up to about 60-fold, at least or up to about 65-fold, at least or up to about 70-fold, at least or up to about 75-fold, at least or up to about 80-fold, at least or up to about 85-fold, at least or up to about 90-fold, at least or up to about 95- fold, at least or up to about 100-fold, at least or up to about 110-fold, at least or up to about 120-fold, at least or up to about 130-fold, at least or up to about 140-fold, at least or up to about 150-fold, at least or up to about 160-fold, at least or up to about 170-fold, at least or up to about 180-fold, at least or up to about 190-fold, at least or up to about 200-fold, at least or up to about 250-fold, at least or up to about 300-fold, at least or up to about 350-fold, at least or up to about 400-fold, at least or up to about 450-fold, at least or up to about 500-fold, at least or up to about 550-fold, at least or up to about 600-fold, at least or up to about 650-fold, at least or up to about 700-fold, at least or up to about 750-fold, at least or up to about 800-fold, at least or up to about 850-fold, at least or up to about 900-fold, at least or up to about 950-fold, at least or up to about 1,000-fold, at least or up to about 1,500-fold, at least or up to about 2,000-fold, at least or up to about 3,000-fold, at least or up to about 4,000-fold, at least or up to about 5,000-fold, at least or up to about 6,000-fold, at least or up to about 7,000-fold, at least or up to about 8,000-fold, at least or up to about 9,000-fold, or at least or up to about 10,000-fold greater than the activity of the p53 mutant in the absence of the compound.

[0026] A compound of the disclosure can be used, for example, to induce apoptosis, cell cycle arrest, or senescence in a cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cell carries a mutation in p53. Compounds of the disclosure.

[0027] In some embodiments, the disclosure provides a compound of formula Ia, or a pharmaceutically- acceptable salt thereof:Atty. Docket No.44727-732601 wherein: each is independently a single bond or a double bond; X1is CR5, CR5R6, N, NR5, O, S, or a carbon atom connected to A or Q; X2is CR7, CR7R8, N, NR7, O, S, or a carbon atom connected to A or Q; X3is CR9, CR9R10, N, NR9, O, S, or a carbon atom connected to A or Q; X4is CR11, CR11R12, N, NR11, O, S, or a carbon atom connected to A or Q; X5is CR13, CR13R14, N, NR13, or a carbon atom connected to Q; X6is CR15, CR15R16, N, NR2, O, S, or a carbon atom connected to Q; X7is C, CR17, or N; X8is C, CR18, or N; X9is CR19, CR19R20, N, NR19, O, S, or a carbon atom connected to Q; wherein one of X1, X2, X3, and X4is a carbon atom connected to A, and wherein one of X1, X2, X3, X4, X5, and X6is a carbon atom connected to Q; A is ethyndiyl or a substituted or unsubstituted 5-membered, 6-membered, 7-membered, or 8- membered monocyclic heteroaryl ring comprising 1, 2, or 3 heteroatoms as ring members, wherein each heteroatom is independently selected from O, N, and S; Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; each R19and R20is H or substituted or unsubstituted C1-6alkyl; R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, - NR21R22, -NR21C(O)R22, -OC(O)R21, -P(O)R21R22, or -SiR21R22R23; R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - NR26R27, -NR26C(O)R27, or -OC(O)R26; each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; each R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.Atty. Docket No.44727-732601

[0028] In some embodiments, the disclosure provides a compound of formula Ib, or a pharmaceutically- acceptable salt thereof:wherein: each is independently a single bond or a double bond; X1is CR5, CR5R6, N, NR5, O, S, C-A-R1, or C-Q-NR3R4; X2is CR7, CR7R8, N, NR7, O, S, C-A-R1, or C-Q-NR3R4; X3is CR9, CR9R10, N, NR9, O, S, C-A-R1, or C-Q-NR3R4; X4is CR11, CR11R12, N, NR11, O, S, C-A-R1, or C-Q-NR3R4; X5is CR13, CR13R14, N, NR13, or C-Q-NR3R4; X6is CR15, CR15R16, N, NR2, O, S, or C-Q-NR3R4; X7is C, CR17, or N; X8is C, CR18, or N; X9is CR19, CR19R20, N, NR19, O, S, or C-Q-NR3R4; wherein one of X1, X2, X3, and X4is C-A-R1, and wherein one of X1, X2, X3, X4, X5, and X6is C-Q- NR3R4; A is ethyndiyl or a substituted or unsubstituted 5-membered, 6-membered, 7-membered, or 8- membered monocyclic heteroaryl ring comprising 1, 2, or 3 heteroatoms as ring members, wherein each heteroatom is independently selected from O, N, and S; Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; each R19and R20is H or substituted or unsubstituted C1-6alkyl; R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, - NR21R22, -NR21C(O)R22, -OC(O)R21, -P(O)R21R22, or -SiR21R22R23; R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - NR26R27, -NR26C(O)R27, or -OC(O)R26; each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; each R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27,Atty. Docket No.44727-732601 -NR26C(O)R27, or -OC(O)R26; each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0029] In some embodiments, when X5is N, X6is NR2, A is ethyndiyl, R1is 2-hydroxybutyl, Q is a bond and R3is 3-chlorophenyl, then R2is not isopropyl.

[0030] In some embodiments, each is selected from a single bond and a double bond to form a 10 pi electron system.

[0031] In some embodiments, A is an aromatic 5-membered, or 6-membered monocyclic ring comprising 1, 2, or 3 heteroatoms as ring members, wherein each heteroatom is independently selected from O, N, and S, wherein the ring is substituted or unsubstituted.

[0032] In some embodiments, A is an aromatic nitrogen containing 5-membered ring comprising 0, 1 or 2 additional heteroatoms as ring members, wherein each additional heteroatom is independently selected from O, N, and S, which is substituted or unsubstituted. In some embodiments, A is selected from thiadiazolyl, thiazolyl, pyrazolyl and oxadiazolyl, each of which is independently substituted or unsubstituted. In some embodiments, A is 1,3,5-thiadiazol-2,4-diyl, 1,3,4-oxadiazol-2,5-diyl or 1,2,4- oxadiazol-3,5-diyl. In some embodiments, A is 1,2,4-oxadiazol-3,5-diyl.

[0033] In some embodiments, A is ethyndiyl.

[0034] In some embodiments, R2is substituted or unsubstituted alkyl. In some embodiments, R2is substituted or unsubstituted methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl. In some embodiments, R2is C1-2haloalkyl. In some embodiments, R2is trifluoroethyl or difluoroethyl.

[0035] In some embodiments, R1is selected from alkyl, alkoxy, aryl, heteroaryl, and heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, R1is substituted alkyl. In some embodiments, R1is alkyl substituted with -NR21C(O)R22. In some embodiments, R1is C1-3alkyl substituted with -NR21C(O)R22. In some embodiments, R1is -CH2-NHC(O)R21, wherein R22is C3-6cycloalkyl or 5 membered heteroaryl, each of which is independently substituted or unsubstituted. In some embodiments, R1is -CH2-NHC(O)R21, wherein R22is cyclopropyl or pyrazolyl; each of which is independently substituted or unsubstituted. In some embodiments, R22is pyrazolyl substituted with one or more substituents independently selected from C1-4alkyl.

[0036] In some embodiments, R1is a substituted alkyl or alkylene. In some embodiments, R1can be substituted by one or more substituents selected from a hydroxyl group, sulfhydryl group, halogen, amino group, nitro group, nitroso group, cyano group, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halo-alkyl group, cyclic alkyl group, alkenyl group, halo-alkenyl group, alkynyl group, halo-alkynyl group, alkoxy group, aryl group, aryloxy group, aralkyl group, arylalkoxy group, heterocyclyl group, acyl group, acyloxy group, carbamate group, amide group, urethane group, and ester group.Atty. Docket No.44727-732601

[0037] In some embodiments, R1is alkyl substituted with an amino group. In some embodiments, R1is methyl substituted with NR21R22. In some embodiments, R1is alkyl substituted with -C(O)NR21R22. In some embodiments, R1is methyl substituted with -C(O)NR21R22. In some embodiments, R1is alkyl substituted with -C(O)OR21. In some embodiments, R1is methyl substituted with COOH.

[0038] In some embodiments, R1is C1-3 alkyl substituted with NR21R22. In some embodiments, R1is methyl substituted with NR21R22, wherein R21is hydrogen, and R22is a substituted phenyl. In some embodiments, R1is methyl substituted with -NHR22, and R22is substituted phenyl. In some embodiments, R22is phenyl substituted with one or more substituents independently selected from OR26, -C(O)NR26R27, and -SO2R26.

[0039] In some embodiments, R1is selected from -C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -NR21R22, -NR21C(O)R22, and -OC(O)R21.

[0040] In some embodiments, R1is alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H or halo.

[0041] In some embodiments, Q is a bond. In some embodiments, Q is -C(=O)- .

[0042] In some embodiments, R3is 5-10 membered monocyclic or polycyclic nitrogen-containing heterocyclyl, each of which is independently substituted or unsubstituted.

[0043] In some embodiments, R3is 5-6 membered nitrogen containing heterocyclyl substituted at least with C1-4alkyl or halo. In some embodiments, R3is 6 membered nitrogen-containing heterocyclyl substituted at least with methyl or fluoro.

[0044] In some embodiments, R3is selected from 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 1- piperazinyl, tetrahydro-2H-pyran-4-yl, 4-azepanyl and 8-azabicyclo[3.2.1]oct-3-yl. In some embodiments, R3is piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl, each of which is independently substituted or unsubstituted.

[0045] In some embodiments, R3is piperidinyl unsubstituted or substituted with methyl or fluoro.

[0046] In some embodiments, R3is a ring that is:,.

[0047] In some embodiments, Rais methyl. In some embodiments, R4is H, and R3is a ring that isAtty. Docket No.44727-732601 ring is substituted or unsubstituted. In some embodiments, R4is H, and R3is a, wherein the ring is substituted or unsubstituted.

[0048] In some embodiments, R3is C6-10 aryl, 5-6 membered nitrogen containing heteroaryl, each of which is independently substituted or unsubstituted.

[0049] In some embodiments, R3is selected from -C(O)R24, -C(O)OR24, -C(O)NR24R25, -OR24, -SR24, - NR24R25, -NR24C(O)R25, -OC(O)R24. In some embodiments, R3is selected from C2-4 alkenyl, C2-4 alkynyl, and phenyl, each of which is independently substituted or unsubstituted, or H.

[0050] In some embodiments, R13is C1-4 alkyl, C2-4 alkenyl, each of which is independently substituted or unsubstituted, or H, or halo. In some embodiments, R13is substituted or unsubstituted methyl, ethyl, propyl, iso-propyl, butyl or tert-butyl. In some embodiments, R13is C1-2 haloalkyl. In some embodiments, R13is 2,2,2-trifluoroethyl. In some embodiments, R13is H.

[0051] In some embodiments, each R21and R22is independently alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxy, carboxyl group, amino group, acyl group, acyloxy group, or an amide group, any of which is unsubstituted or substituted, or hydrogen. In some embodiments, R21is hydrogen, and R22is a substituted carboxyl group.

[0052] In some embodiments, the pattern of dashed bonds can be chosen to provide an aromatic or partially aromatic ring, for example, indoles, benzimidazoles, and azaindoles. In some embodiments, X1is CR5or a carbon atom connected to Q. In some embodiments, X2is CR7or a carbon atom connected to A. In some embodiments, X3is a carbon atom connected to A. In some embodiments, X4is CR11, or a carbon atom connected to A. In some embodiments, X5is CR13, or a carbon atom connected to Q. In some embodiments, X1is a carbon atom connected to Q; X2is CR7, X3is a carbon atom connected to A; X4is CR11, X5is N, and X6is NR2. In some embodiments, X1is CR5, X2is CR7, X3is a carbon atom connected to A; X4is CR11, X5is a carbon atom connected to Q, and X6is NR2. In some embodiments, X1is a carbon atom connected to Q; X2is CR7, X3is a carbon atom connected to A; and X4is CR11, X5is CR13 ,and X6is NR2. In some embodiments, X5is CR13, and X6is S. In some embodiments, X5is CR13, X6is N, X7is C, and X8is N. In some embodiments, X9is CR19. In some embodiments, X9is CR19, wherein R19is methyl, ethyl, or hydrogen. In some embodiments, X9is CH.

[0053] One embodiment relates to compounds of formula IIa and IIbAtty. Docket No.44727-732601wherein Q is alkylene, which is substituted or unsubstituted; or C=O or a bond.

[0054] One embodiment relates to compounds of Formula III, or a pharmaceutically acceptable salt thereof:wherein X5is CR13or N; and Q is alkylene, which is substituted or unsubstituted; or C=O or a bond.

[0055] One embodiment relates to compounds of Formula IV, or a pharmaceutically acceptable salt thereof:wherein Q is alkylene, which is substituted or unsubstituted; or C=O or a bond; R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, - NR21R22, -NR21C(O)R22, -OC(O)R21, -P(O)R21R22, or -SiR21R22R23; R2is substituted or unsubstituted C1-6alkyl; R3is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; each R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -Atty. Docket No.44727-732601 OC(O)R26; each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0056] One embodiment relates to compounds of Formula V, or a pharmaceutically acceptable salt thereof:wherein Q is alkylene, which is substituted or unsubstituted; or C=O or a bond.

[0057] One embodiment relates to compounds of Formula VI, or a pharmaceutically acceptable salt thereof:

[0058] In some embodiments, the compound is of the formula:wherein Ryis alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; and Rzis alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -OR26, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -Atty. Docket No.44727-732601 SOR26, or -SO2R26, or a pharmaceutically-acceptable salt thereof, wherein the variables are as defined above.

[0059] In some embodiments, provided herein is a compound of formula Ia or Ia′, or a pharmaceutically- acceptable salt thereof:wherein: each is independently a single bond or a double bond; X1is CR5, CR5R6, N, NR5, O, S, a carbon atom connected to Q, or a carbon atom connected to A; X2is CR7, CR7R8, N, NR7, O, S or a carbon atom connected to A or Q; X3is CR9, CR9R10, N, NR9, O, S, or a carbon atom connected to A or Q; X4is CR11, CR11R12, N, NR11, O, S, or a carbon atom connected to A or Q; X5is CR13, CR13R14, N, NR13, or a carbon atom connected to Q; X6is CR15, CR15R16, N, NR2, O, S, or a carbon atom connected to Q; X7is C, CR17, or N; X8is C, CR18, or N; wherein one of X1, X2, X3and X4is a carbon atom connected to A or Q; A is ethyndiyl or a substituted or unsubstituted aromatic 5-membered, 6-membered, 7-membered, or 8-membered monocyclic ring system comprising 1, 2, or 3 heteroatoms as ring members, wherein each heteroatom is independently selected from O, N, and S; Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; R is H or substituted or unsubstituted C1-6alkyl; R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, - NR21R22, -NR21C(O)R22, -OC(O)R21, -P(O)R21R22, or -SiR21R22R23;Atty. Docket No.44727-732601 R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - NR26R27, -NR26C(O)R27, or -OC(O)R26; each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; each R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; each R26and R27is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H; and each R28and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, provided that when X5is N, X6is NR2, A is ethyndiyl, R1is 2-hydroxybut-2-yl, Q is a bond and R3is 3-chlorophenyl, then R2is not isopropyl.

[0060] In some embodiments, provided herein is a method of treating cancer or a p53-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula Ia or Ia′, or a pharmaceutically-acceptable salt thereof:wherein:Atty. Docket No.44727-732601 each is independently a single bond or a double bond; X1is CR5, CR5R6, N, NR5, O, S, a carbon atom connected to Q, or a carbon atom connected to A; X2is CR7, CR7R8, N, NR7, O, S or a carbon atom connected to A or Q; X3is CR9, CR9R10, N, NR9, O, S, or a carbon atom connected to A or Q; X4is CR11, CR11R12, N, NR11, O, S, or a carbon atom connected to A or Q; X5is CR13, CR13R14, N, NR13, or a carbon atom connected to Q; X6is CR15, CR15R16, N, NR2, O, S, or a carbon atom connected to Q; X7is C, CR17, or N; X8is C, CR18, or N; wherein one of X1, X2, X3and X4is a carbon atom connected to A or Q; A is ethyndiyl or a substituted or unsubstituted aromatic 5-membered, 6-membered, 7-membered, or 8-membered monocyclic ring system comprising 1, 2, or 3 heteroatoms as ring members, wherein each heteroatom is independently selected from O, N, and S; Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; R is H or substituted or unsubstituted C1-6 alkyl; R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, - NR21R22, -NR21C(O)R22, -OC(O)R21, -P(O)R21R22, or -SiR21R22R23; R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - NR26R27, -NR26C(O)R27, or -OC(O)R26; each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; each R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; each R26and R27is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H; and each R28and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0061] Non-limiting examples of compounds of the disclosure include any of the following compounds,Atty. Docket No.44727-732601 or a pharmaceutically-acceptable salt thereof:.

[0062] In some embodiments, the present disclosure provides a compound of formula VII, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; - X1is CR5, CR5R6, N, NR5, O, S, or a carbon atom connected to Q; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, S, or a carbon atom connected to Q; - X4is CR11, CR11R12, N, NR11, O, S, or a carbon atom connected to Q; - X5is CR13, CR13R14, N, NR13, O, S, or a carbon atom connected to Q; - X6is CR15, CR15R16, N, NR2, O, S, or a carbon atom connected to Q; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19, CR19R20, N, NR19, O, S, or a carbon atom connected to Q; wherein one of X1, X2, X3, X4, X5, X6and X9is a carbon atom connected to Q; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond;Atty. Docket No.44727-732601 - Y is -NR3R4, SR3, or OR3; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27-NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, - SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0063] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0064] In some embodiments, the present disclosure provides a compound of formula VII-1, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; - X1is CR5, CR5R6, N, NR5, or a carbon atom connected to Q; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, or a carbon atom connected to Q; - X4is CR11, CR11R12, N, NR11, or a carbon atom connected to Q; - X5is CR13, CR13R14, N, NR13, O, S, or a carbon atom connected to Q; - X6is CR15, CR15R16, N, NR2, O, S, or a carbon atom connected to Q; - X7is C, CR17, or N;Atty. Docket No.44727-732601 - X8is C, CR18, or N; - X9is C, CR19, or N; wherein one of X1, X3, X4, X5, and X6is a carbon atom connected to Q; - Q is C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - R3is heteroaryl or heterocyclyl, each of which is substituted with at least halo; - R4is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0065] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0066] In some embodiments, the present disclosure provides a compound of formula VII-2, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; - X1is CR5or CR5R6, X2is C or CR7, and X3is CR9or CR9R10; or X1is N or NR5; X2is C or CR7, and X3is CR9or CR9R10; or X1is CR5or CR5R6, X2is C or CR7, and X3is N or NR9;Atty. Docket No.44727-732601 - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR2, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27-NR26R27, - NR26C(O)R27, or -OC(O)R26; - R3is heteroaryl or heterocyclyl; - R4is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0067] In some embodiments, the compound is of formula VII-3, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0068] In some embodiments, the compound is of formula VII-4, or a pharmaceutically-acceptable salt thereof:

[0069] In some embodiments, the compound is of formula VII-5, or a pharmaceutically-acceptable salt thereof:

[0070] In some embodiments, the compound is of formula VII-6, or a pharmaceutically-acceptable salt thereof:

[0071] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0072] In some embodiments, each R5, R9, and R2is independently substituted or unsubstituted alkyl, H, halo, -SO2R26, or -NR26R27. In some embodiments, each R5, R9, and R19is independently substituted or unsubstituted alkyl, H, or halo. In some embodiments, each R2, R5, R9, and R19is independently unsubstituted alkyl, H, or halo. In some embodiments, each R2, R5, R9, and R19is independently H or halo. In some embodiments, each R2, R5, R9, and R19is H.

[0073] In some embodiments, each R15is independently substituted or unsubstituted alkyl, H, halo, - SO2R26, or -NR26R27. In some embodiments, each R15is independently substituted or unsubstituted alkyl, H, or halo. In some embodiments, each R15is independently unsubstituted alkyl, H, or halo. In some embodiments, each R15is independently H or halo. In some embodiments, each R15is H.

[0074] In some embodiments, the present disclosure provides a compound of formula VIII or formula IX, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601wherein: each is independently a single bond or a double bond; - X1is CR5or CR5R6, X2is C or CR7, and X3is CR9or CR9R10; or X1is N or NR5; X2is C or CR7, and X3is CR9or CR9R10; or X1is CR5or CR5R6, X2is C or CR7, and X3is N or NR9; - X4is CR11, CR11R12, N, NR11, O, S, or a carbon atom connected to Q; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR2, O, S, or a carbon atom connected to Q; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - R3is heteroaryl or heterocyclyl; - R4is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R13is independently alkyl, alkenyl, alkynyl, or aryl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6alkyl;Atty. Docket No.44727-732601 - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0075] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0076] In some embodiments, the compound is of formula VIII-1, or a pharmaceutically-acceptable salt thereof:wherein X1is CR5and X3is CR9, or X1is N and X3is CR9, or X1is CR5and X3is N; and X4is CR11or N.

[0077] In some embodiments, the compound is of formula VIII-2, or a pharmaceutically-acceptable salt thereof:

[0078] In some embodiments, the compound is of formula VIII-3, or a pharmaceutically-acceptable salt thereof:unsubstituted alkyl, H, or halo. In some embodiments, each R5, R9, R11, and R19is independently H or halo. In some embodiments, each R5, R9, R11, and R2is H.Atty. Docket No.44727-732601

[0080] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0081] In some embodiments, the present disclosure provides a compound of formula VIII-4, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; - X1is CR5or N; - X3is CR9or N; - X4is CR11or N; - A is a substituted or unsubstituted heterocyclylene; - Y is -NR3R4, SR3, or OR3; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - R3is heteroaryl or heterocyclyl, each of which is substituted with at least halo; - R4is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R5, R9, R11, R13, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6 alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0082] In some embodiments, Y is -NR3R4.Atty. Docket No.44727-732601

[0083] In some embodiments, the present disclosure provides a compound of formula VIII-5, or a pharmaceutically-acceptable salt thereof:- A is a substituted or unsubstituted heteroarylene; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - R3is heteroaryl or heterocyclyl; - R4is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R5, R9, R11, R13, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - R13is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or -C(O)R26, -C(O)OR26, -C(O)NR26R27, or -SO2R26; - each R19is H or substituted or unsubstituted C1-6 alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0084] In some embodiments, Y is -NR3R4.

[0085] In some embodiments, each R5, R9, R11, and R2is independently substituted or unsubstituted alkyl, H, halo, -SO2R26, or -NR26R27. In some embodiments, each R5, R9, R11, and R2is independently substituted or unsubstituted alkyl, H, or halo. In some embodiments, R5, R9, R11, and R2is independently unsubstituted alkyl, H, or halo. In some embodiments, each R5, R9, R11, and R2is independently H or halo. In some embodiments, each R5, R9, R11, and R2is H.Atty. Docket No.44727-732601

[0086] In some embodiments, the present disclosure provides a compound of formula IX-1, or a pharmaceutically-acceptable salt thereof:each is independently a single bond or a double bond; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR2, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - Q is C=O or a bond; - A is a substituted or unsubstituted heterocyclylene; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - R3is heteroaryl or heterocyclyl, each of which is substituted with at least halo; - R4is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R5, R9, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; - each R19is H or substituted or unsubstituted C1-6alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; andAtty. Docket No.44727-732601 - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0087] In some embodiments, Q is C=O or a bond. In some embodiments, Q is C=O. In some embodiments, Q is a bond.

[0088] In some embodiments, the present disclosure provides a compound of formula IX-2, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; - X5is NR14, O, or S; - X6is CR15or N; - Q is C=O or a bond; - A is a substituted or unsubstituted heterocyclylene; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - R3is substituted or unsubstituted heterocyclylalkyl; - R4is alkyl that is substituted or unsubstituted, or H; - each R5, R9, R14, R15, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.Atty. Docket No.44727-732601

[0089] In some embodiments, Q is C=O or a bond. In some embodiments, Q is C=O. In some embodiments, Q is a bond.

[0090] In some embodiments, the present disclosure provides a compound of formula IX-3, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; - X5is CR13or N; - X6is NR2, O, or S; - Q is C=O or a bond; - A is a substituted or unsubstituted heterocyclylene; - R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -(CH2)wC(O)R21, -(CH2)wC(O)OR21, -(CH2)wC(O)NR21R22, - (CH2)wOR21, -(CH2)wSR21, -(CH2)wNR21R22, -(CH2)wNR21C(O)R22, -(CH2)wOC(O)R21, - (CH2)wP(O)R21R22, or -(CH2)wSiR21R22R23, wherein w is 0, 1, 2, or 3; - R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - R3is substituted or unsubstituted heterocyclylalkyl; - R4is alkyl that is substituted or unsubstituted, or H; - each R5, R9, R13, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; ; - each R19is H or substituted or unsubstituted C1-6alkyl - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.Atty. Docket No.44727-732601

[0091] In some embodiments, Q is C=O or a bond. In some embodiments, Q is C=O. In some embodiments, Q is a bond.

[0092] In some embodiments, R1is selected from alkyl, alkoxy, aryl, heteroaryl, and heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, R1is substituted alkyl. In some embodiments, R1is alkyl substituted with -NR28C(O)R29. In some embodiments, R1is C1-3 alkyl substituted with -NR28C(O)R29. In some embodiments, R1is -CH2-NHC(O)R29, wherein R29is C3-6 cycloalkyl or 5 membered heteroaryl, each of which is independently substituted or unsubstituted. In some embodiments, R1is -CH2-NHC(O)R29, wherein R29is cyclopropyl or pyrazolyl; each of which is independently substituted or unsubstituted. In some embodiments, R29is pyrazolyl substituted with one or more substituents independently selected from C1-4 alkyl

[0093] In some embodiments, R1is a substituted alkyl or alkylene. In some embodiments, R1can be substituted by one or more substituents selected from a hydroxyl group, sulfhydryl group, halogen, amino group, nitro group, nitroso group, cyano group, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halo-alkyl group, cyclic alkyl group, alkenyl group, halo-alkenyl group, alkynyl group, halo-alkynyl group, alkoxy group, aryl group, aryloxy group, aralkyl group, arylalkoxy group, heterocyclyl group, acyl group, acyloxy group, carbamate group, amide group, urethane group, and ester group.

[0094] In some embodiments, R1is alkyl substituted with an amino group. In some embodiments, R1is methyl substituted with NR21R22. In some embodiments, R1is alkyl substituted with -C(O)NR21R22. In some embodiments, R1is methyl substituted with -C(O)NR21R22. In some embodiments, R1is alkyl substituted with -C(O)OR21. In some embodiments, R1is methyl substituted with COOH.

[0095] In some embodiments, R1is C1-3alkyl substituted with NR21R22. In some embodiments, R1is methyl substituted with NR21R22, wherein R21is hydrogen, and R22is a substituted phenyl. In some embodiments, R1is methyl substituted with -NHR22, and R22is substituted phenyl. In some embodiments, R22is phenyl substituted with one or more substituents independently selected from OR24, -C(O)NR24R25, and -SO2R24.

[0096] In some embodiments, each R24and R25that are geminal to one another are joined to form a 4, 5, 6, 7, or 8 membered ring.

[0097] In some embodiments, R1is selected from -C(O)R21, -C(O)OR21, -C(O)NR21R22, -S(O)2NR21R22- OR21, -NR21R22, -NR21C(O)R21, and -OC(O)R21.

[0098] In some embodiments, R1is alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H or halo.

[0099] In some embodiments, each R5, and R9, is independently substituted or unsubstituted alkyl, H, halo, -SO2R26, or -NR26R27. In some embodiments, each R5, R9, and R19is independently substituted or unsubstituted alkyl, H, or halo. In some embodiments, R5, R9, and R19is independently unsubstituted alkyl, H, or halo. In some embodiments, each R5, R9, and R19is independently H or halo. In some embodiments, each R5, R9, and R19is H.Atty. Docket No.44727-732601

[0100] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3.

[0101] In some embodiments, R22is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, R22is 5 or 6-membered aryl that is substituted or unsubstituted. In some embodiments, R22is 5 or 6-membered heteroaryl that is substituted or unsubstituted. In some embodiments, R22is 5 or 6-membered heterocyclyl that is substituted or unsubstituted. In some embodiments, R22is aryl, heteroaryl, or heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, - SO2R24, -NSOR24, and -NSO2R24. In some embodiments, R22is aryl, heteroaryl, or heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -SOR24, -SO2R24, -NSOR24, and -NSO2R24. In some embodiments, R22is aryl, heteroaryl, or heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, - S(O)2NR24R25, -SOR24, -SO2R24, -NR24S(O)R25, and -NR24S(O)2R25.

[0102] In some embodiments, R22is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently substituted. In some embodiments, R22is 5 or 6- membered aryl that is substituted. In some embodiments, R22is 5 or 6-membered heteroaryl that is substituted. In some embodiments, R22is 5 or 6-membered heterocyclyl that is substituted. In some embodiments, R22is aryl, heteroaryl, or heterocyclyl, each of which is substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, - OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, -SO2R24, -NSOR24, and -NSO2R24. In some embodiments, R22is aryl, heteroaryl, or heterocyclyl, each of which is substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, - OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-SOR24, -SO2R24, -NSOR24, and -NSO2R24. In some embodiments, R22is aryl, heteroaryl, or heterocyclyl, each of which is substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, - CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-SOR24, - SO2R24, -NR24S(O)R25, and -NR24S(O)2R25.

[0103] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, - OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, -SO2R24, -NSOR24, and -NSO2R24. InAtty. Docket No.44727-732601 some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, - C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-SOR24, -SO2R24, -NSOR24, and - NSO2R24.In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, - OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-SOR24, -SO2R24, -NR24S(O)R25, and -NR24S(O)2R25.

[0104] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NS(O)R24, and - NS(O)2R24.In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25.

[0105] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from C1-6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R24.

[0106] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1- C6alkyl. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and - NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0107] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with 1, 2, or 3Atty. Docket No.44727-732601 substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6 alkyl. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0108] In some embodiments, R22is phenyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6 alkyl. In some embodiments, R22is phenyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is phenyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and - NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0109] In some embodiments, R22is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, - C(O)NR24R25, -S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, - C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NS(O)R24, and - NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0110] In some embodiments, R22is pyridyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6 alkyl. In some embodiments, R22is pyridyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is pyridyl that is unsubstituted or substitutedAtty. Docket No.44727-732601 with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and - NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0111] In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6 alkyl. In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and - NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0112] In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or methyl. In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, - S(O)2NR24R25-S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or methyl. In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and - NR24S(O)2R25, wherein each R24and R25is independently H or methyl.

[0113] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, - C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25.

[0114] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from C1-6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R24.

[0115] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H orAtty. Docket No.44727-732601 C1-C6alkyl. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0116] In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R254, wherein each R24and R25is independently H or C1-C6 alkyl. In some embodiments, R22is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0117] In some embodiments, R22is phenyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is phenyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0118] In some embodiments, R22is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, - C(O)NR24R25, -S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, - C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0119] In some embodiments, R22is pyridyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, R22is pyridyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0120] In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H orAtty. Docket No.44727-732601 C1-C6 alkyl. In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0121] In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or methyl. In some embodiments, R22is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25-S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or methyl.

[0122] In some embodiments, each R24and R25is independently H or C1-C6alkyl. In some embodiments, each R24and R25is independently H or methyl.

[0123] In some embodiments, the present disclosure provides a compound of formula X, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; - X1is CR5, CR5R6, N, NR5, O, or S; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C, CR11, or N; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - A is ethynylene or substituted or unsubstituted heterocyclylene; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, -N(R26)-, - NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3;Atty. Docket No.44727-732601 - each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R19, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0124] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0125] In some embodiments, a compound herein is of formula X-1′, or a pharmaceutically-acceptable salt thereof:wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5or CR5R6; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - A is ethenylene, arylene, cycloalkylene, or heterocyclylene, each of which is independently substituted or unsubstituted, or ethynylene; - U is -L1-J, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -Atty. Docket No.44727-732601 C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; - RMand RNare each independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R19is hydrogen, halogen, or substituted or unsubstituted alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28, or R24and R25together with the nitrogen atom to which R24and R25are bound form a ring, wherein the ring is substituted or unsubstituted; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0126] In some embodiments, U is -L1-J, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with one, two, or three groups independently selected from 1, 2, or 3 RX; or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

[0127] In some embodiments, U is -L1-J or C1-6alkyl that is unsubstituted or substituted with one, two, orAtty. Docket No.44727-732601 three groups independently selected from 1, 2, or 3 RX, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1- 6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

[0128] In some embodiments, U is -L1-J or substituted or unsubstituted alkyl.

[0129] In some embodiments, U is -L1-J.

[0130] In some embodiments, a compound herein is of formula X-1′′, or a pharmaceutically-acceptable salt thereof:wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5, CR5R6, or N; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19, CR19R20, N, NR19, O, or S; - A is ethenylene, arylene, cycloalkylene, or heterocyclylene, each of which is independently substituted or unsubstituted, or ethynylene; - RMand RNare each independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3;Atty. Docket No.44727-732601 - each R3is independently heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R4is independently heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - R13is haloethyl, CH2-CN, CH2-haloalkyl, O-haloalkyl, S-haloalkyl, CH2-heterocyclyl, O- heterocyclyl, or S-heterocyclyl; - each R19and R20is hydrogen, halogen, or substituted or unsubstituted alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28, or R24and R25together with the nitrogen atom to which R24and R25are bound form a ring, wherein the ring is substituted or unsubstituted; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0131] In some embodiments, a compound herein is of formula X-1′′′, or a pharmaceutically-acceptable salt thereof:wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5, CR5R6, or N; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19, CR19R20, N, NR19, O, or S;Atty. Docket No.44727-732601 - A is ethenylene, arylene, cycloalkylene, or heterocyclylene, each of which is independently substituted or unsubstituted, or ethynylene; - RMand RNare each independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - R13is CH2-CN, CH2-CF3, O-CF3, S-CF3, or CH2CF3; - each R19and R20is hydrogen, halogen, or substituted or unsubstituted alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28, or R24and R25together with the nitrogen atom to which R24and R25are bound form a ring, wherein the ring is substituted or unsubstituted; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0132] In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0133] In some embodiments,Atty. Docket No.44727-732601

[0134] In some embodiments,

[0135] In some embodiments, A is arylene or heterocyclylene, each of which is substituted or unsubstituted, or ethynylene.

[0136] In some embodiments, RMand RNare each independently substituted or unsubstituted alkyl, - OR26, -SR26, -NR26R27, halogen, or hydrogen.

[0137] In some embodiments, RMand RNare each methyl, -OH, or hydrogen.

[0138] In some embodiments, each RMand RNis hydrogen.

[0139] In some embodiments, A is C3-9cycloalkylene, C6-10arylene, C1-9heterocyclylene, each of which is independently unsubstituted or substituted with 1 to 7 RX; or ethynylene, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

[0140] In some embodiments, A is C6-10arylene or C1-9heterocyclylene, each of which is independently unsubstituted or substituted with 1 to 7 RX; or ethynylene.

[0141] In some embodiments, A is cyclobutylene.

[0142] In some embodiments, A is ethenylene.

[0143] In some embodiments, RMand RNare each independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with one, two, or three groups independently selected from 1, 2, or 3 RX; or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

[0144] In some embodiments, RMand RNare each independently C1-6alkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with one, two, or three groups independently selected from 1, 2, or 3 RX; or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C3-10cycloalkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

[0145] In some embodiments, the present disclosure provides a compound of formula X-1, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601wherein: each is independently a single bond or a double bond; - X1is CR5or CR5R6; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - A is ethynylene or substituted or unsubstituted heterocyclylene; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, -N(R26)-, - NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0146] In some embodiments, the present disclosure provides a compound of formula X-1a, or aAtty. Docket No.44727-732601 pharmaceutically-acceptable salt thereof:1a), wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5or CR5R6; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - A is ethynylene or substituted or unsubstituted heterocyclylene; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R19is hydrogen, halogen, or substituted or unsubstituted alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, -Atty. Docket No.44727-732601 C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28, or R24and R25together with the nitrogen atom to which R24and R25are bound form a ring, wherein the ring is substituted or unsubstituted; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0147] In some embodiments, X1is CR5, X2is C, X3is CR9, and X4is C.

[0148] In some embodiments, X2is C and X4is C. In some embodiments, X1is CR5and X3is CR9.

[0149] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0150] In some embodiments, the compound is of formula X-A, or a pharmaceutically-acceptable salt thereof:

[0151] In some embodiments, the compound is of formula X-A-1, or a pharmaceutically-acceptable salt thereof:

[0152] In some embodiments, X5is NR13, X6is N, and X7is C; or X5is NR13, X6is CR15, and X7is C; or X5is CR13, X6is N, and X7is N. In some embodiments, R5, R9, R15, and R19are each hydrogen.

[0153] In some embodiments, the compound is of formula X-2, or a pharmaceutically-acceptable salt thereof:

[0154] In some embodiments, the compound is of formula X-3, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0155] In some embodiments, the compound is of formula X-4, or a pharmaceutically-acceptable salt thereof:

[0156] In some embodiments, the compound is of formula X-5, or a pharmaceutically-acceptable salt thereof:

[0157] In some embodiments, the compound is of formula X-6, or a pharmaceutically-acceptable salt thereof:

[0158] In some embodiments, the compound is of formula X-7, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0159] In some embodiments, the compound is of formula X-8, or a pharmaceutically-acceptable salt thereof:

[0160] In some embodiments, the compound is of formula X-9, or a pharmaceutically-acceptable salt thereof:

[0161] In some embodiments, the compound is of formula X-10, or a pharmaceutically-acceptable salt thereof:

[0162] In some embodiments, the compound is of formula X-10a, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0164] In some embodiments, the compound is of formula X-12, or a pharmaceutically-acceptable salt thereof:

[0165] In some embodiments, the compound is of formula X-13, or a pharmaceutically-acceptable salt thereof:

[0166] In some embodiments, the present disclosure provides a compound of formula XI, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601wherein: each is independently a single bond or a double bond; - X1is CR5, CR5R6, N, NR5, O, or S; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C, CR11, or N; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - A is ethynylene or substituted or unsubstituted heterocyclylene; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, -N(R26)-, - NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0167] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.Atty. Docket No.44727-732601

[0168] In some embodiments, the compound is of formula XI-1, or a pharmaceutically-acceptable salt thereof:

[0169] In some embodiments, the compound is of formula XI-2, or a pharmaceutically-acceptable salt thereof:

[0170] In some embodiments, the compound is of formula XI-3, or a pharmaceutically-acceptable salt thereof:

[0171] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0172] In some embodiments, each R5, R9, and R11, and R19is independently substituted or unsubstituted alkyl, H, halo, -SO2R26, or -NR26R27. In some embodiments, each R5, R9, R11, and R19is independently substituted or unsubstituted alkyl, H, or halo. In some embodiments, R5, R9, R11, and R19is independently unsubstituted alkyl, H, or halo. In some embodiments, each R5, R9, R11, and R19is independently H or halo. In some embodiments, each R5, R9, R11, and R19is H.

[0173] In some embodiments, A is a substituted or unsubstituted 4, 5, 6, 7, or 8-membered monocyclic ring. In some embodiments, A is a substituted or unsubstituted 5, 6, 7, or 8-membered monocyclic ring. In some embodiments, A is a substituted or unsubstituted 5 or 6-membered monocyclic ring.

[0174] In some embodiments, A is substituted or unsubstituted heterocyclylene. In some embodiments, A is a substituted or unsubstituted 5, 6, 7, or 8-membered heterocyclylene. In some embodiments, A is a substituted or unsubstituted 5 or 6-membered heterocyclylene.Atty. Docket No.44727-732601

[0175] In some embodiments, A is substituted or unsubstituted heteroarylene. In some embodiments, A is a substituted or unsubstituted 5 or 6-membered heteroarylene. In some embodiments, A is thiadiazoldiyl, thiazoldiyl, pyrazoldiyl or oxadiazoldiyl, each of which is independently substituted or unsubstituted. In some embodiments, A is 1,3,5-thiadiazol-2,4-diyl, 1,3,4-oxadiazol-2,5-diyl or 1,2,4-oxadiazol-3,5-diyl. In some embodiments, A is 1,2,4-oxadiazol-3,5-diyl. In some embodiments, A is pyridinediyl. In some embodiments, A is pyridine-2,4-diyl. In some embodiments, A is pyridine-2,5-diyl. In some embodiments, A is pyridine-2,6-diyl. In some embodiments, A is pyridine-3,5-diyl. In some embodiments, A is pyridine-3,6-diyl. In some embodiments, A is pyridine-4,6-diyl.

[0176] In some embodiments, the present disclosure provides a compound of formula XII, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; - X1is CR5, CR5R6, N, NR5, O, or S; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C, CR11, or N; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, -N(R26)-, - NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted;Atty. Docket No.44727-732601 - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6 alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H. In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0177] In some embodiments, the present disclosure provides a compound of formula XII-1, or a pharmaceutically-acceptable salt thereof:each is independently a single bond or a double bond; - X1is CR5, CR5R6, N, NR5, O, or S; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C, CR11, or N; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, -N(R26)-, - NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3;Atty. Docket No.44727-732601 - each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6 alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0178] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0179] In some embodiments, a compound herein is of formula XII-1′, or a pharmaceutically-acceptable salt thereof:wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5, CR5R6, or N; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19, CR19R20, N, NR19, O, or S; - A is ethenylene, arylene, cycloalkylene, or heterocyclylene, each of which is independently substituted or unsubstituted, or ethynylene;Atty. Docket No.44727-732601 - E is J, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, - OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - RMand RNare each independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3is independently heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R4is independently heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - R13is haloethyl, CH2-CN, CH2-haloalkyl, O-haloalkyl, S-haloalkyl, CH2-heterocyclyl, O- heterocyclyl, or S-heterocyclyl; - each R19is hydrogen, halogen, or substituted or unsubstituted alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28, or R24and R25together with the nitrogen atom to which R24and R25are bound form a ring, wherein the ring is substituted or unsubstituted; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0180] In some embodiments, X1is CR5or N; X2and X4are each C; X3is CR9or N; X5is CR13, N, NR13, O, or S; X6is CR15, N, NR15, O, or S; X7and X8are each independently C or N; and X9is CR19, N, NR19, O, or S. In some embodiments, X5is CR13, N, NR13, or S; X6is CR15, N, NR15, O, or S; X7is C or N; X8is C or N; and X9is CR19, N, NR19, or O. In some embodiments, X5is CR13, N, or NR13; X6is CR15, N, O, or S; X7is C or N; X8is C or N; and X9is CR19, N, or NR19.Atty. Docket No.44727-732601

[0181] In some embodiments, the present disclosure provides a compound of formula XII-2, or a pharmaceutically-acceptable salt thereof:each is independently a single bond or a double bond; - X1is CR5, CR5R6, N or NR5, and X3is CR9or CR9R10; or X1is CR5or CR5R6, and X3is CR9, CR9R10, N, or NR9; - X2is C, CR7, or N; - X4is C, CR11, or N; - X5is CR13, CR13R14, N, NR14, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, -N(R26)-, - NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6 alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; andAtty. Docket No.44727-732601 - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0182] In some embodiments, Q is C=O or a bond. In some embodiments, Y is -NR3R4. In some embodiments, Y is -NR3R4and Q is C=O. In some embodiments, Y is -NR3R4and Q is a bond.

[0183] In some embodiments, the present disclosure provides a compound of formula XII-2′, or a pharmaceutically-acceptable salt thereof:wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5or CR5R6; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19, CR19R20, N, NR19, O, or S; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - RMand RNare each independentlyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -Atty. Docket No.44727-732601 C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R19, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R24and R25is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halogen, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H .

[0184] In some embodiments, X5is CR13, N, NR13, or S; X6is CR15, N, NR15, O, or S; X7is C or N; X8is C or N; and X9is CR19, N, NR19, or O. In some embodiments, X5is CR13, N, or NR13; X6is CR15, N, O, or S; X7is C or N; X8is C or N; and X9is CR19, N, or NR19.

[0185] In some embodiments, the compound is of formula XII-3, or a pharmaceutically-acceptable salt thereof:embodiments, X5is CR13, N, or NR13; X6is CR15, N, O, or S; X7is C or N; X8is C or N; and X9is CR19, N, or NR19.

[0186] In some embodiments, the compound is of formula XII-3′, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601Atty. Docket No.44727-732601.

[0187] In some embodiments, the present disclosure provides a compound of formula XII′, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5, CR5R6, N, NR5, O, or S; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C, CR11, or N; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19, CR19R20, N, NR19, O, or S; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, -N(R26)-, - NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - RMand RNare each independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26;Atty. Docket No.44727-732601 - E is J, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, - SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3is independently heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; - each R4is independently heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - each R19is H or substituted or unsubstituted C1-6alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0188] In some embodiments, the compound is of formula XII-3a, or a pharmaceutically-acceptable salt thereof:wherein each RZis independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, - NS(O)R24, -NS(O)2R24, -S(O)NR24R25, and -S(O)2NR24R25, and n is 1, 2, 3, 4, or 5.

[0189] In some embodiments, the compound is of formula XII-3a, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601wherein each RZis independently selected from alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, and -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25, and n is 1, 2, 3, 4, or 5.

[0190] In some embodiments, each RZis independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NS(O)R24, -NS(O)2R24, -S(O)NR24R25, and - S(O)2NR24R25. In some embodiments, each RZis independently selected from -OR24, -C(O)NR24R25, - SO2R24, and -S(O)2NR24R25.

[0191] In some embodiments, each RZis independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halogen, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, and - NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, each RZis independently selected from halogen, -OR24, -C(O)NR24R25, -SO2R24, and -S(O)2NR24R25.

[0192] In some embodiments, the compound is of formula XII-4, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0194] In some embodiments, the compound is of formula XII-6, or a pharmaceutically-acceptable salt thereof:

[0195] In some embodiments, the compound is of formula XII-7, or a pharmaceutically-acceptable salt thereof:

[0196] In some embodiments, the compound is of formula XII-8, or a pharmaceutically-acceptable salt thereof:

[0197] In some embodiments, the compound is of formula XII-9, or a pharmaceutically-acceptable salt thereof:

[0198] In some embodiments, the compound is of formula XII-10, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0199] In some embodiments, the compound is of formula XII-11, or a pharmaceutically-acceptable salt thereof:

[0200] In some embodiments, the compound is of formula XII-12, or a pharmaceutically-acceptable salt thereof:

[0201] In some embodiments, the compound is of formula XII-12a, or a pharmaceutically-acceptable salt thereof:

[0202] In some embodiments, the compound is of formula XII-13, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0203] In some embodiments, the compound is of formula XII-14, or a pharmaceutically-acceptable salt thereof:

[0204] In some embodiments, the compound is of formula XII-15, or a pharmaceutically-acceptable salt thereof:, wherein each RZis independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, - C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NS(O)R24, -NS(O)2R24, - S(O)NR24R25, and -S(O)2NR24R25, and n is 1, 2, 3, 4, or 5.

[0206] In some embodiments,, wherein each RZis independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, - C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, and -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25, and n is 1, 2, 3, 4, or 5.Atty. Docket No.44727-732601

[0207] In some embodiments, each R5, R9, and R19is independently substituted or unsubstituted alkyl, H, halo, -SO2R26, or -NR26R27. In some embodiments, each R5, R9, and R19is independently substituted or unsubstituted alkyl, H, or halo. In some embodiments, R5, R9, and R19is independently unsubstituted alkyl, H, or halo. In some embodiments, each R5, R9, and R19is independently H or halo. In some embodiments, each R5, R9, and R19is H.

[0208] In some embodiments, R5and R13, together with the atoms to which R5and R13are attached, are joined to form a 5-, 6-, 7-, 8-, or 9-membered ring.

[0209] In some embodiments, R13and R19, together with the atoms to which R5and R13are attached, are joined to form a 5-, 6-, 7-, 8-, or 9-membered ring.

[0210] In some embodiments, R15and R19, together with the atoms to which R5and R13are attached, are joined to form a 5-, 6-, 7-, 8-, or 9-membered ring.

[0211] In some embodiments, Q is a bond. In some embodiments, Q is a bond. In some embodiments, Q is C1-6alkylene, C2-6alkenylene, or C2-6alkynylene, each of which is independently unsubstituted or substituted with one or two groups selected from C1-3alkyl or halogen; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond. In some embodiments, Q is C1-6alkylene. In some embodiments, Q is C1-3alkylene. In some embodiments, Q is methylene. In some embodiments, Q is C=O. Q is C1-6alkylene. In some embodiments, Q is methylene. In some embodiments, Q is –C(O)– or a bond. In some embodiments, Q is –C(O)–.

[0212] In some embodiments, Q is C=O and Y is NR3R4. In some embodiments, Q is C=O and Y is OR3. In some embodiments, Q is C=O and Y is NR3R4. In some embodiments, Q is a bond and Y is OR3. In some embodiments, Q is a bond and Y is NR3R4.

[0213] In some embodiments, Y is

[0215] In some embodiments, Y is:Atty. Docket No.44727-732601.

[0216] In some embodiments, Y is:.

[0217] In some embodiments, Y is:.

[0218] In some embodiments, Y is:

[0219] In some embodiments, Y is:

[0220] In some embodiments, Y is:.

[0221] In some embodiments, Y is:Atty. Docket No.44727-732601

[0222] In some embodiments, Y is:

[0223] In some embodiments, Y is:

[0228] In some embodiments, Y is:.

[0229] In some embodiments, Y is:.

[0230] In some embodiments, Y is:Atty. Docket No.44727-732601

[0231] In some embodiments,

[0232] In some embodiments,

[0233] In some embodiments,

[0234] In some embodiments,

[0235] In some embodiments, each RXis, independently:

[0236] In some embodiments, each RXis, independently:Atty. Docket No.44727-732601 .

[0238] In some embodiments, Y is:.

[0239] In some embodiments, Y is:Atty. Docket No.44727-732601 ,

[0240] In some embodiments, Y is:Atty. Docket No.44727-732601

[0242] In some embodiments, Y is:Atty. Docket No.44727-732601

[0246] In some embodiments, Y is:

[0248] In some embodiments, Y is:Atty. Docket No.44727-732601

[0250] In some embodiments, Y is. In some embodiments, Y is. In some embodiments,some embodiments,

[0251] In some embodiments, L1is -C(O)N(R26)-, -N(R26)-, or -NR26C(O)-. In some embodiments, R26is alkyl. In some embodiments, R26is C1-6alkyl. In some embodiments, R26is methyl. In some embodiments, R26is hydrogen. In some embodiments, L1is -C(O)N(R26)-. In some embodiments, L1is -C(O)N(Me)-. In some embodiments, L1is -N(R26)-. In some embodiments, L1is -N(Me)-. In some embodiments, L1is -NR26C(O)-.

[0252] In some embodiments, R3is substituted or unsubstituted heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 5, 6, 7, or 8-membered heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 5 or 6-membered heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 5-membered heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 6-membered heterocyclylalkyl.

[0253] In some embodiments, R3is 5-10 membered monocyclic or polycyclic nitrogen-containing heterocyclyl, each of which is independently substituted or unsubstituted.

[0254] In some embodiments, R3is 5-6 membered nitrogen containing heterocyclyl substituted at least with halo. In some embodiments, R3is 6 membered nitrogen-containing heterocyclyl substituted at least with fluoro.

[0255] In some embodiments, R3is selected from 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 1- piperazinyl, tetrahydro-2H-pyran-4-yl, 4-azepanyl and 8-azabicyclo[3.2.1]oct-3-yl. In some embodiments, R3is piperidinyl, piperazinyl, morpholinyl, or pyrrolidinyl, each of which is independently substituted or unsubstituted.

[0256] In some embodiments, R3is piperidinyl unsubstituted or substituted with methyl or fluoro.

[0257] In some embodiments,some embodiments,Atty. Docket No.44727-732601

[0258] In some embodiments,some embodiments,someembodiments,

[0259] In some embodiments, R3is cycloalkyl, heterocyclylalkyl, or heteroalkyl, each of which is substituted or unsubstituted.

[0260] In some embodiments, R3is substituted or unsubstituted cycloalkyl. In some embodiments, R3is substituted or unsubstituted 4-, 5-, or 6-membered cycloalkyl. In some embodiments, R3is substituted or unsubstituted cyclohexyl. In some embodiments, R3is substituted cyclohexyl.

[0261] In some embodiments, R3is substituted or unsubstituted heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 4-, 5-, 6-, 7-, or 8-membered heterocyclylalkyl.

[0262] In some embodiments, R3is a substituted or unsubstituted 4-, 5-, or 6-membered heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 5-membered heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 6-membered heterocyclylalkyl.

[0263] In some embodiments, R3is substituted or unsubstituted nitrogen-containing heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 4-, 5-, 6-, 7-, or 8-membered nitrogen-containing heterocyclylalkyl.

[0264] In some embodiments, R3is substituted or unsubstituted piperidinyl. In some embodiments, R3is piperidinyl that is unsubstituted or substituted with one, two, or three groups independently selected from alkyl, heteroalkyl, halogen, and heterocyclylalkyl. In some embodiments, R3is piperidinyl that isAtty. Docket No.44727-732601 unsubstituted or substituted with one, two, or three groups independently selected from alkyl, cycloalkyl, heteroalkyl, halogen, and heterocyclylalkyl, each of which is independently substituted or unsubstituted.

[0265] In some embodiments, R4is substituted or unsubstituted alkyl, or hydrogen. In some embodiments, R4is substituted or unsubstituted alkyl. In some embodiments, R4is C1-C6alkyl or hydrogen. In some embodiments, R4is methyl, ethyl, isopropyl, n-propyl, or hydrogen. In some embodiments, R4is hydrogen.

[0266] In some embodiments, R3is substituted or unsubstituted nitrogen-containing heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 5, 6, 7, or 8-membered nitrogen-containing heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 5-membered nitrogen- containing heterocyclylalkyl. In some embodiments, R3is a substituted or unsubstituted 6-membered nitrogen-containing heterocyclylalkyl.

[0267] In some embodiments, R3is heterocyclyl substituted with at least halogen. In some embodiments, R3is a 5, 6, 7, or 8-membered heterocyclyl substituted with at least halogen. In some embodiments, R3is a 5 or 6-membered heterocyclyl substituted with at least halogen.

[0268] In some embodiments, R3is heterocyclyl substituted with alkyl, heteroalkyl, heterocyclyl, or halogen. In some embodiments, R3is a 5, 6, 7, or 8-membered heterocyclyl substituted with at least halogen. In some embodiments, R3is a 5 or 6-membered heterocyclyl substituted with at least halogen.

[0269] In some embodiments, R3is heterocyclylalkyl substituted with at least halogen. In some embodiments, R3is a 5, 6, 7, or 8-membered heterocyclylalkyl substituted with at least halogen. In some embodiments, R3is a 5 or 6-membered heterocyclylalkyl substituted with at least halogen.

[0270] In some embodiments, R3is heterocyclyl substituted with halogen and C1-C6alkyl. In some embodiments, R3is a 5, 6, 7, or 8-membered heterocyclyl substituted with halogen and C1-C6alkyl. In some embodiments, R3is a 5 or 6-membered heterocyclyl substituted with halogen and C1-C6alkyl.

[0271] In some embodiments, R3is heterocyclyl substituted with halogen and alkyl. In some embodiments, R3is a 5, 6, 7, or 8-membered heterocyclyl substituted with halogen and alkyl. In some embodiments, R3is a 5 or 6-membered heterocyclyl substituted with halogen and alkyl.

[0272] In some embodiments, R3is nitrogen-containing heterocyclylalkyl substituted with halogen and alkyl. In some embodiments, R3is a 5, 6, 7, or 8-membered nitrogen-containing heterocyclylalkyl substituted with halogen and alkyl. In some embodiments, R3is a 5-membered nitrogen-containing heterocyclylalkyl substituted with halogen and alkyl. In some embodiments, R3is a 6-membered nitrogen-containing heterocyclylalkyl substituted with halogen and alkyl.

[0273] In some embodiments, R3is nitrogen-containing heterocyclylalkyl substituted with halogen and C1-C6alkyl. In some embodiments, R3is a 5, 6, 7, or 8-membered nitrogen-containing heterocyclylalkyl substituted with halogen and C1-C6alkyl. In some embodiments, R3is a 5-membered nitrogen-containing heterocyclylalkyl substituted with halogen and C1-C6alkyl. In some embodiments, R3is a 6-membered nitrogen-containing heterocyclylalkyl substituted with halogen and C1-C6alkyl.

[0274] In some embodiments, each R3and R4is independently:Atty. Docket No.44727-732601 - C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-9cycloalkyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with 1 to 7 RX; or - H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or - R3and R4together with the nitrogen atom to which R3and R4are bound form C1- 9heterocyclyl, that is unsubstituted or substituted with 1 to 7 RX; wherein each RXis independently selected from halogen, C(O)R24, -C(O)OR24, -NR24R25, -OR24, -C(O)NR24R25, -SR24, -S(O)R24, -SO2R24, -NR24C(O)R25, or -OC(O)R24; or C1-6alkyl, C1-6heteroalkyl, or C1- 9heterocyclyl, each of which is independently unsubstituted or substituted with halogen, methyl, ethyl, propyl, butyl, C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -S(O)R28, - SO2R28, -NR28R29, -NR28C(O)R29, or -OC(O)R28.

[0275] In some embodiments, each R3and R4is independently: - C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-9cycloalkyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with 1 to 7 RX; or - H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or - R3and R4together with the nitrogen atom to which R3and R4are bound form C1-9heterocyclyl, that is unsubstituted or substituted with 1 to 7 RX; wherein each RXis independently selected from -CN, halogen, -C(O)R24, -C(O)OR24, -NR24R25, - OR24, -C(O)NR24R25, -SR24, -S(O)R24, -SO2R24, -NR24C(O)R25, and-OC(O)R24; or C1-6alkyl, C1-6heteroalkyl C6-10aryl, and C1-9heterocyclyl, C1-6alkylene-C6-10aryl, and C1-6alkylene-C1-9heterocyclyl, each of which is independently unsubstituted or substituted with -CN, halogen, methyl, ethyl, propyl, butyl, -C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -S(O)R28, - SO2R28, -NR28R29, -NR28C(O)R29, or -OC(O)R28.

[0276] In some embodiments, R3is C3-9cycloalkyl, C1-9heterocyclylalkyl, or C1-6heteroalkyl, each of which is independently unsubstituted or substituted with 1 to 7 RX. The compound of claim 97 or 98, wherein R3is cyclohexyl that is unsubstituted or substituted with 1 to 7 RX.

[0277] In some embodiments, R3is C1-9heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX. In some embodiments, R3is a 4-, 5-, 6-, 7-, or 8-membered heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX. In some embodiments, R3is a 4-, 5-, or 6-membered heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX. In some embodiments, R3is a 5-membered heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX. In some embodiments, R3is a 6-membered heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX. In some embodiments, R3is a 4-, 5-, 6-, 7-, or 8-membered nitrogen-containing heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX.

[0278] In some embodiments, each RXis independently selected from halogen, NR24R25, -C(O)R25, - NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl. In some embodiments,Atty. Docket No.44727-732601 each RXis independently selected from fluoro, methyl, ethyl, tetrahydropyranyl, 2-methoxyethyl, 2- hydroxy-3-methoxypropyl, 2,3-dihydroxypropyl, N-tetrahydro-2H-pyran-4-yl(carbamoyl)methyl, 2- mesylethyl, methoxy, N-methyl(carbamoyl)methyl, carbamoylmethyl, dimethylamino, or 2-amino-2- oxoeth-1-yl.

[0279] In some embodiments, each RXis independently selected from -CN, halogen, -NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with halogen, -CN, -OR28, -C(O)NR28R29, -C(O)OR28, - SO2R28, methyl, ethyl, or propyl.

[0280] In some embodiments, each RXis independently selected from -CN, halogen, -NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with halogen, -CN, -C(O)NR28R29, -C(O)OR28, -SO2R28, methyl, ethyl, or propyl.

[0281] In some embodiments, each RXis independently selected from fluoro, methyl, ethyl, methoxy, 3,3-difluorocyclopentyl, 3,4-difluorocyclopentyl, 4-cyanocyclohexyl, 4-hydroxycyclohexyl, 4- fluorocyclohexyl, 4,4-difluorocyclohexyl, tetrahydro-3-furyl, tetrahydropyranyl, 2- methyltetrahydropyranyl, 2,4-dimethyltetrahydropyranyl, 2-fluorotetrahydropyranyl, 2,2- dimethyltetrahydro-2H-pyran-4-yl, 4-methyltetrahydro-2H-pyran-4-yl, 4-oxepanyl, 2-oxa-6- spiro[3.3]heptyl, 8-oxabicyclo[3.2.1]oct-3-yl 3,4-dihydroxycyclopentyl, 8-oxabicyclo[3.2.1]oct-3-yl, bicyclo[1.1.1]pent-1-yl, 2-methoxy-1-methylethyl, 2-methoxy-2-methylpropyl, 3-fluoropropyl, 3,3- difluoropropyl, 3,3,3-trifluoropropyl, 3-fluoro-3-methylbutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 2,2-difluorocyclopropyl, 2-methoxyethyl, 2-hydroxy-3-methoxypropyl, 2,3-dihydroxypropyl, N- tetrahydro-2H-pyran-4-yl(carbamoyl)methyl, 2-mesylethyl, methoxy, N-methyl(carbamoyl)methyl, carbamoylmathyl, methylamino, dimethylamino, or 2-amino-2-oxoeth-1-yl.

[0282] In some embodiments, R5is substituted or unsubstituted alkyl, haloalkyl, halogen, or hydrogen. In some embodiments, R5is C1-6alkyl, C1-6haloalkyl, halogen, or hydrogen. In some embodiments, R5is hydrogen.

[0283] In some embodiments, R9is substituted or unsubstituted alkyl, haloalkyl, halogen, or hydrogen. In some embodiments, R9is C1-6alkyl, C1-6haloalkyl, halogen, or hydrogen. In some embodiments, R9is hydrogen.

[0284] In some embodiments, R13is cyanomethyl, alkyl, alkoxy, alkylthio, heterocyclyl, or heterocyclylalkyl that is substituted or unsubstituted. In some embodiments, R13is cyanomethyl, alkyl, alkoxy, alkylthio, or heterocyclylalkyl that is substituted or unsubstituted. In some embodiments, R13is cyanomethyl, alkyl, alkylthio, or heterocyclylalkyl that is substituted or unsubstituted. In some embodiments, R13is alkyl or heterocyclyl that is substituted or unsubstituted. In some embodiments, R13is alkyl that is substituted or unsubstituted. In some embodiments, R13is haloalkyl. In some embodiments, R13is C1-C6haloalkyl. In some embodiments, R13is heterocyclylalkyl that is substituted or unsubstituted. In some embodiments, R13is CH2-heterocyclyl that is substituted or unsubstituted. In some embodiments, R13is -CH2-heteroaryl that is substituted or unsubstituted. In some embodiments, R13isAtty. Docket No.44727-732601 thiophenylmethyl. In some embodiments, R13is cyanomethyl. In some embodiments, R13is C1-6alkyl or C1-6haloalkyl. In some embodiments, R13is C1-4 alkyl, C2-4 alkenyl, each of which is independently substituted or unsubstituted, or H, or halo. In some embodiments, R13is substituted or unsubstituted methyl, ethyl, propyl, iso-propyl, butyl or tert-butyl. In some embodiments, R13is C1-2 haloalkyl. In some embodiments, R13is 2,2,2-trifluoroethyl. In some embodiments, R13is cyclopropylmethyl. In some embodiments, R13is H. In some embodiments, R13is 2,2,2-trifluoroethyl, 2,2-difluoroethyl, S-CF3, 2,2- difluoroethenyl, cyanomethyl, thiophenylmethyl, isopropyl, or cyclopropylmethyl. In some embodiments, R13is 2,2,2-trifluoroethyl, 2,2-difluoroethyl, isopropyl, or cyclopropylmethyl. In some embodiments, R13is -OR26. In some embodiments, R13is -SR26. In some embodiments, R13is -O-alkyl. In some embodiments, R13is -S-alkyl. In some embodiments, R13is -O-haloalkyl. In some embodiments, R13is - S-haloalkyl. In some embodiments, R13is -O-C1-6alkyl. In some embodiments, R13is -S-C1-6alkyl. In some embodiments, R13is -O-C1-6haloalkyl. In some embodiments, R13is -S-C1-6haloalkyl. In some embodiments, R13is -OCF3. In some embodiments, R13is -SCF3.

[0285] In some embodiments, R15is alkyl or hydrogen. In some embodiments, R15is C1-6alkyl or hydrogen. In some embodiments, R15is methyl. In some embodiments, R15is hydrogen.

[0286] In some embodiments, R19is substituted or unsubstituted alkyl, haloalkyl, halogen, or hydrogen. In some embodiments, R19is C1-6alkyl, C1-6haloalkyl, halogen, or hydrogen. In some embodiments, R19is hydrogen. In some embodiments, R19is C1-6haloalkyl. In some embodiments, R19is hydrogen. In some embodiments, R19is 2,2,2-trifluoroethyl.

[0287] In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently substituted or unsubstituted. In some embodiments, J is aryl or heteroaryl, each of which is independently substituted or unsubstituted. In some embodiments, J is 5 or 6-membered aryl that is substituted or unsubstituted. In some embodiments, J is 5 or 6-membered heteroaryl that is substituted or unsubstituted. In some embodiments, J is 5 or 6-membered heterocyclyl that is substituted or unsubstituted. In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, - OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -SOR24, -SO2R24, -NSOR24, and -NSO2R24. In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -P(=NR26)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -SOR24, -SO2R24, -S(=NR24)(=O)R25, S(=NR24)(=NR25)R26, -S(=NR24)(=O)NR25R26, -S(=NR24)(=NR25)R26R27, -NR24S(O)R25, and - NR24SO2R25. In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents independently selected from -OMe, -OEt, isopropyloxy, -OCD3, -OCF3, -OH, halogen, cyano, methyl, ethyl, isopropyl, tert-butyl, dufluoromethyl, trifluoromethyl, 1-cyano-1-methylethyl, methylsulfonyl, ethylsulfonyl, N-morpholinylsulfonyl, 3,3,3-Atty. Docket No.44727-732601 trifluoropropylsulfonyl, sulfonamide, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 2- methoxyethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, isopropylcarbamoyl, tert-butylcarbamoyl, 2,2-difluorocyclopropylcarbamoyl, 3,3-difluorocyclobutylcarbamoyl, carboxy, 2,2,2- trifluoroethylcarbamoyl, dimethylphosphoryl, N-morpholinylcarbonyl, and (2,6-dimethyl-N- morpholinyl)carbonyl,

[0288] In some embodiments, J is 5- or 6-membered aryl, 5- or 6-membered heteroaryl, or 5- or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1- 9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, - SO2R24, -NS(O)R24, -NS(O)2R24, -S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, J is 5- or 6- membered aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, -NR24S(O)2R25, - S(=NR24)(=O)R25, -S(O)NR24R25, and -S(O)2NR24R25.

[0289] In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted. In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently substituted. In some embodiments, J is 5 or 6- membered aryl that is substituted. In some embodiments, J is 5 or 6-membered heteroaryl that is substituted. In some embodiments, J is 5 or 6-membered heterocyclyl that is substituted. In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, - OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -SOR24, -SO2R24, -NSOR24, and -NSO2R24. In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, - NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -SOR24, -SO2R24, - S(=NR24)(=O)R25, -NR24S(O)R25, and -NR24S(O)2R25. In some embodiments, J is aryl, heteroaryl, or heterocyclyl, each of which is substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25, -SOR24, -SO2R24, -S(=NR24)(=O)R25, -NR24S(O)R25, and -NR24S(O)2R25.

[0290] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, - OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -SOR24, -SO2R24, -NSOR24, and -NSO2R24.In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -Atty. Docket No.44727-732601 OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -SOR24, -SO2R24, - S(=NR24)(=O)R25, -NR24S(O)R25, and -NR24S(O)2R25.

[0291] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24. In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, - NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -S(=NR24)(=O)R25, -NR24S(O)R25, and -NR24S(O)2R25.

[0292] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -S(=NR24)(=O)R25, - NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0293] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -S(=NR24)(=O)R25, -NR24S(O)R25, and - NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0294] In some embodiments, J is phenyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, J is phenyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -S(=NR24)(=O)R25, - NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0295] In some embodiments, J is C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with one to six groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24,Atty. Docket No.44727-732601 -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NS(O)R24, -NS(O)2R24, -S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, J is C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with one to six groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, -NR24S(O)2R25, - S(=NR24)(=O)R25, -S(O)NR24R25, and -S(O)2NR24R25.

[0296] In some embodiments, J is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)2NR24R25,-S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl.In some embodiments, J is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, - C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25,-S(O)R24, -S(O)2R24, - S(=NR24)(=O)R25, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1- C6alkyl.

[0297] In some embodiments, J is 5- or 6-membered aryl, 5- or 6-membered heteroaryl, or 5- or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one to five groups independently selected from alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -SO2R24, -NR24S(O)R25, and -NR24S(O)2R25, -S(=NR24)(=O)R25, -S(O)NR24R25, and - S(O)2NR24R25.

[0298] In some embodiments, J is phenyl that is unsubstituted or substituted. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five substituents, or 5-membered heteroaryl that is unsubstituted or substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, - NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NS(O)R24, - NS(O)2R24, -S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five substituents, or 5-membered heteroaryl that is unsubstituted or substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -S(=NR24)(=O)R25, -NR24S(O)R25, and - NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25.

[0299] In some embodiments, J is pyridyl that is unsubstituted or substituted. In some embodiments, J is pyridyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, - NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, J is pyridyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -Atty. Docket No.44727-732601 S(O)R24, -S(O)2R24, -S(=NR24)(=O)R25, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0300] In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, - NS(O)R24, -NS(O)2R24, -S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from -OR24, -C(O)NR24R25, - SO2R24, and -S(O)2NR24R25.In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1- 9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, -NR24S(O)2R25, -S(=NR24)(=O)R25, -S(O)NR24R25, and - S(O)2NR24R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from -OR24, -C(O)NR24R25, -SO2R24, and -S(O)2NR24R25.

[0301] In some embodiments, J is pyrazolyl that is unsubstituted or substituted. In some embodiments, J is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, - NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -NS(O)R24, and -NS(O)2R24, wherein each R24and R25is independently H or C1-C6alkyl. In some embodiments, J is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, - S(O)R24, -S(O)2R24, -S(=NR24)(=O)R25, -NR24S(O)R25, -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0302] In some embodiments, J is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR19R25, -OR19, -C(O)R19, -P(O)R19R25, -C(O)OR19, - C(O)NR19R25, -S(O)2NR24R25, -S(O)R19, -S(O)2R19, -NS(O)R19, and -NS(O)2R19, wherein each R19and R25is independently H or methyl. In some embodiments, J is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, -NR19R25, -OR19, -C(O)R19, - P(O)R19R25, -C(O)OR19, -C(O)NR19R25, -S(O)2NR24R25, -S(O)R19, -S(O)2R19, -S(=NR24)(=O)R25, - NR24S(O)R25, and -NR24S(O)2R25, wherein each R19and R25is independently H or methyl.

[0303] In some embodiments, J is thiophenyl that is unsubstituted or substituted. In some embodiments, J is thiophenyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, - NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24, -NR24S(O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1-C6alkyl.

[0304] In some embodiments, J is imidazolyl that is unsubstituted or substituted. In some embodiments, J is imidazolyl that is unsubstituted or substituted with one or more substituents selected from halo, -CN, - NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(O)R24, -S(O)2R24- NR24S(O)R25, -S(=NR24)(=O)R25, and -NR24S(O)2R25, wherein each R24and R25is independently H or C1- C6alkyl.Atty. Docket No.44727-732601

[0305] In some embodiments, J is 5- or 6-membered aryl, 5- or 6-membered heteroaryl, or 5- or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6- 10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, and -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, J is 5- or 6-membered aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, - NR24S(O)R25, and -NR24S(O)2R25, -S(=NR24)(=O)R25, -S(O)NR24R25, and -S(O)2NR24R25.

[0306] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R19.

[0307] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(=NR24)(=O)R25, and -S(O)2R19.

[0308] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, C1-C6deuteroalkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, - S(=NR24)(=O)R25, and -S(O)2R19.

[0309] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R19.

[0310] In some embodiments, J is 5 or 6-membered aryl, 5 or 6-membered heteroaryl, or 5 or 6- membered heterocyclyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R19.

[0311] In some embodiments, J is phenyl that is unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R19. In some embodiments, J is phenyl that is unsubstituted or substituted with one or more substituents selected from C1-C6haloalkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R19. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from halogen, -OR24, -C(O)NR24R25, -SO2R24, and -S(O)2NR24R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from halogen, -OR24, - C(O)NR24R25, -SO2R24, -P(O)R24R25, and -S(O)2NR24R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from -OR24, -C(O)NR24R25, - SO2R24, and -S(O)2NR24R25.

[0312] In some embodiments, J is phenyl that is unsubstituted or substituted with one to five substituents,Atty. Docket No.44727-732601 or 5-membered heteroaryl that is unsubstituted or substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2- 6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, and -NR24S(O)2R25, - S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five substituents, or 5-membered heteroaryl that is unsubstituted or substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -S(=NR24)(=O)R25, -NR24S(O)R25, and - NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25.

[0313] In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, and -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, - S(=NR24)(=O)R25,-NR24S(O)R25, and -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five substituents, or 5- membered heteroaryl that is unsubstituted or substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, - P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, -NR24S(O)2R25, - S(O)2NR24R25, and -S(=NR24)(=O)R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NSR24(O)R25, -NR24S(O)2R25, - S(O)2NR24R25, and -S(=NR24)(=O)R25. In some embodiments, J is phenyl that is unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C1-C6deuteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NSR24(O)R25, - NR24S(O)2R25, -S(O)2NR24R25, and -S(=NR24)(=O)R25.

[0314] In some embodiments, J is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and - S(O)2R19. In some embodiments, J is 5 or 6-membered heteroaryl that is unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, - S(=NR24)(=O)R25, and -S(O)2R19.Atty. Docket No.44727-732601

[0315] In some embodiments, J is pyridyl that is unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R19. In some embodiments, J is pyridyl that is unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, -S(=NR24)(=O)R25, and -S(O)2R19.

[0316] In some embodiments, J is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R19.

[0317] In some embodiments, J is pyrazolyl that is unsubstituted or substituted with one or more substituents selected from C1-C6alkyl, halo, -OR24, -C(O)NR24R25, -S(O)2NR24R25, and -S(O)2R19.

[0318] In some embodiments, J is, wherein T1is hydrogen or halogen, T2is NR24R25, - OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, -NS R24(O)2R25, -S(O)NR24R25, -S(O)2NR24R25, and -S(=NR24)(=O)R25; and T3is C1-C6alkyl, C1-6haloalkyl, or OR24. In some embodiments, J is, wherein T1is hydrogen or halogen, T2is NR24R25, - OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, -NS R24(O)2R25, -S(O)NR24R25, -S(O)2NR24R25, and -S(=NR24)(=O)R25; and T3is C1-C6alkyl, C1- C6deuteroalkyl, C1-6haloalkyl, or OR24.

[0319] In some embodiments, J is

[0321] In some embodiments, each R24and R25that are geminal to one another are joined to form a 4, 5, 6, 7, or 8 membered ring.Atty. Docket No.44727-732601

[0322] In some embodiments, each R19and R25is independently H or C1-C6alkyl. In some embodiments, each R19and R25is independently H or methyl.

[0323] R24and R25are each independently selected from alkyl and hydrogen. In some embodiments, R24and R25are each independently selected from haloalkyl, alkyl, and hydrogen.

[0324] In some embodiments, R26and R27are each independently selected from alkyl and hydrogen.

[0325] In some embodiments, R28and R29are each independently selected from alkyl and hydrogen.

[0326] In some embodiments, R24and R25are each independently selected from methyl, ethyl, propyl, butyl, and hydrogen. In some embodiments, R24and R25are each independently selected from -CD3, methyl, ethyl, propyl, butyl, and hydrogen.

[0327] In some embodiments, R26and R27are each independently selected from methyl, ethyl, propyl, butyl, and hydrogen. In some embodiments, R26and R27are each independently selected from -CD3, methyl, ethyl, propyl, butyl, and hydrogen.

[0328] In some embodiments, R28and R29are each independently selected from methyl, ethyl, propyl, butyl, and hydrogen. In some embodiments, R28and R29are each independently selected from -CD3, methyl, ethyl, propyl, butyl, and hydrogen.

[0329] In some embodiments, each R19is hydrogen, halogen, or C1-6alkyl that is unsubstituted or substituted with halogen.

[0330] In some embodiments, each R24and R25is independently C1-6alkyl, C3-10cyclolkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is unsubstituted or substituted with halogen, methyl or ethyl; or H, -C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, - NR28C(O)R29, or -OC(O)R28; or R24and R25together with the nitrogen atom to which R24and R25are bound form a 5- or 6-membered ring, wherein the ring is unsubstituted or substituted with halogen, methyl, or ethyl.

[0331] In some embodiments, each R24and R25is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is unsubstituted or substituted with halogen, methyl or ethyl; or H, -C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or - OC(O)R28; or R24and R25together with the nitrogen atom to which R24and R25are bound form a 5- or 6- membered ring, wherein the ring is unsubstituted or substituted with halogen, methyl, or ethyl.

[0332] In some embodiments, each R26, R27, R28, and R29is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, C1-6alkyleneC6-10aryl, C1-6alkyleneC1-9heteroaryl, or C1-6alkyleneC1-9heterocyclyl, each of which is independently unsubstituted or substituted with halogen, cyano, hydroxy, amino, methyl, ethyl, propyl, or butyl; or hydrogen.

[0333] In some embodiments, each R26, R27, R28, and R29is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with halogen, cyano, hydroxy, amino, methyl, ethyl, propyl, or butyl; or hydrogen.

[0334] In some embodiments, each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with halogen, methyl, ethyl, propyl, or butyl; or H,Atty. Docket No.44727-732601 halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26.

[0335] Compounds herein can include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.

[0336] Non-limiting examples of optional substituents include a hydroxyl group, an oxo group, sulfhydryl group, halogen, amino group, nitro group, nitroso group, cyano group, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxaldehyde group, imine group, alkyl group, halo-alkyl group, alkenyl group, halo-alkenyl group, alkynyl group, halo-alkynyl group, alkoxy group, aryl group, aryloxy group, aralkyl group, arylalkoxy group, heterocyclyl group, acyl group, acyloxy group, carbamate group, carbamoyl group, amide group, phosphine group, phosphine oxide group, ureido group, epoxy group, and ester group.

[0337] Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups. An alkyl or alkylene group can be, for example, a C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. In some embodiments, each alkyl is independently C1-10alkyl. In some embodiments, each alkyl is independently C1-6alkyl. In some embodiments, each alkyl is independently C1-4alkyl.

[0338] Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0339] Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t- butyl.

[0340] Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, trifluoroethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3- carboxypropyl.

[0341] Non-limiting examples of cyclic alkyl groups (also referred to as “cycloalkyl") include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups. Non- limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cycloprop-1-yl, cycloprop-2-en- 1-yl, cyclobutyl, 2,3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopenta-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctanyl, 2,5- dimethylcyclopent-1-yl, 3,5-dichlorocyclohex-1-yl, 4-hydroxycyclohex-1-yl, 3,3,5-trimethylcyclohex-1- yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3- dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. In some embodiments, each cycloalkyl is independently C3-10cycloalkyl. In some embodiments, each cycloalkyl is independentlyAtty. Docket No.44727-732601 C3-8cycloalkyl.

[0342] Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups. The olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. An alkenyl or alkenylene group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. Non-limiting examples of alkenyl and alkenylene groups include ethenyl, prop-1-en-1-yl, isopropenyl, but-1-en-4-yl; 2-chloroethenyl, 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7-hydroxy-7-methyloct-3,5-dien-2-yl. In some embodiments, each alkenyl is independently C2-10alkenyl. In some embodiments, each alkenyl is independently C2-6alkenyl.

[0343] Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkynyl or alkynylene group can be internal or terminal. An alkynyl or alkynylene group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. Non- limiting examples of alkynyl or alkynylene groups include ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, and 2-methyl-hex-4-yn-1-yl; 5-hydroxy-5-methylhex-3-yn-1-yl, 6-hydroxy-6-methylhept-3-yn-2-yl, and 5- hydroxy-5-ethylhept-3-yn-1-yl. In some embodiments, each alkynyl is independently C2-10alkynyl. In some embodiments, each alkynyl is independently C2-6alkynyl.

[0344] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms. In some embodiments, each haloalkyl is independently C1-10haloalkyl. In some embodiments, each haloalkyl is independently C1-6haloalkyl.

[0345] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or an ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy. In some embodiments, each alkoxy is independently C1-10alkoxy. In some embodiments, each alkoxy is independently C1-6alkoxy.

[0346] An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be monocyclic or polycyclic. An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl. Non- limiting examples of substituted aryl groups include 3,4-dimethylphenyl, 4-tert-butylphenyl, 4- cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)-phenyl, 4- (trifluoromethoxy)phenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 2- chlorophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-fluorophenyl, 3- methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-Atty. Docket No.44727-732601 hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6- trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6- dichlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3-dimethylphenyl, 2,4- dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4- ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4- diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6- triethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-methoxyphenyl, 4- (dimethylphosphoryl)-2-methoxyphenyl, 2-methoxy-4-(methylcarbamoyl)phenyl, 2-methoxy-4- (methylsulfonyl)phenyl, and 2-methoxy-4-sulfamoylphenyl.

[0347] Non-limiting examples of substituted aryl groups include 2-aminophenyl, 2-(N- methylamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl, 2-(N,N- diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl, 3-(N,N-dimethylamino)phenyl, 3-(N- ethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 4-aminophenyl, 4-(N-methylamino)phenyl, 4-(N,N- dimethylamino)phenyl, 4-(N-ethylamino)phenyl, 4-(N,N-diethylamino)phenyl, 2-methoxyphenyl, 4- (dimethylphosphoryl)-2-methoxyphenyl, 2-methoxy-4-(methylcarbamoyl)phenyl, 2-methoxy-4- (methylsulfonyl)phenyl, and 2-methoxy-4-sulfamoylphenyl.

[0348] In some embodiments, each aryl is independently C4-12aryl.In some embodiments, each aryl is independently C4-10aryl. In some embodiments, each aryl is independently C6-10aryl.

[0349] A heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.

[0350] Non-limiting examples of heterocycles include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, sultam rings, phospholyl, phosphininyl, azaphospholyl, azaphosphininyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4- tetrahydroquinoline; and ii) heterocyclic units having 2 or more rings one of which is a heterocyclic ring, non-limiting examples of which include hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro- 1H-cycloocta[b]pyrrolyl. In some embodiments, each heterocyclyl is independently C1-9heterocyclyl. In some embodiments, each heterocyclyl is independently a 3-10 membered ring containing 1-5 heteroatomsAtty. Docket No.44727-732601 selected from N, O, S, or P. In some embodiments, each heterocyclyl is independently a 3-10 membered monocyclic, bicyclic, or spirocyclic ring containing 1-5 heteroatoms selected from N, O, S, or P. In some embodiments, each heterocyclyl is independently a 3-8 membered ring containing 1-5 heteroatoms selected from N, O, S, or P. A heterocyclyl group can also be a heterocyclylalkyl group.

[0351] A heterocyclylalkyl group (e.g. “heterocyclylalkyl”) can be a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclylalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocyclylalkyl is bonded through a non-aromatic ring atom), spirocyclic, or bridged ring systems. The nitrogen, phosphorous, carbon, or sulfur atoms in the heterocyclylalkyl radical may be optionally oxidized. For example, a cyclic phosphane group (e.g., 1-methylphospinane) can be substituted with an oxo group to afford the corresponding phosphine oxide (e.g.1-methylphospinane 1-oxide), or substituted with a =N-RNradical to afford the corresponding phosphinanimine (e.g.1-methyl-1-phosphinan-1- imine), where RNis any suitable monovalent radical. The nitrogen atom in the heterocyclylalkyl radical can be optionally quaternized.

[0352] Representative heterocyclylalkyls include, but are not limited to, heterocyclylalkyls having from two to fifteen carbon atoms (C2-C15heterocyclylalkyl), from two to ten carbon atoms (C2-C10heterocyclylalkyl), from two to eight carbon atoms (C2-C8heterocyclylalkyl), from two to six carbon atoms (C2-C6heterocyclylalkyl), from two to five carbon atoms (C2-C5heterocyclylalkyl), or two to four carbon atoms (C2-C4heterocyclylalkyl). In some embodiments, the heterocyclylalkyl is a 3- to 6- membered heterocyclylalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocyclylalkyl. Examples of such heterocyclylalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3- oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocyclylalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocyclylalkyl, the number of carbon atoms in the heterocyclylalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocyclylalkyl (i.e. skeletal atoms of the heterocyclylalkyl ring). Unless stated otherwise specifically in the specification, a heterocyclylalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, a heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocyclylalkyl is optionallyAtty. Docket No.44727-732601 substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclylalkyl is optionally substituted with halogen. In some embodiments, each heterocyclylalkyl is independently a 3-10 membered ring containing 1-5 heteroatoms selected from N, O, S, or P. In some embodiments, each heterocyclylalkyl is independently a 3-10 membered ring containing 1-5 heteroatoms selected from N, O, or S. In some embodiments, each heterocyclylalkyl is independently a 3-10 membered monocyclic, bicyclic, or spirocyclic ring containing 1-5 heteroatoms selected from N, O, S, or P. In some embodiments, each heterocyclylalkyl is independently a 3-8 membered ring containing 1-5 heteroatoms selected from N, O, S, or P. In some embodiments, each heterocyclylalkyl is independently a 3-8 membered ring containing 1-5 heteroatoms selected from N, O, or S.

[0353] Non-limiting examples of heteroaryl include: i) heteroaryl rings containing a single ring, non- limiting examples of which include, 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2- phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non-limiting examples of which include: 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl. In some embodiments, each heteroaryl is independently C1-9heteroaryl. In some embodiments, each heteroaryl is independently C5-9heteroaryl. In some embodiments, each heteroaryl is independently a 4-10 membered aromatic ring containing 1-5 heteroatoms selected from N, O, S, or P. In some embodiments, each heteroaryl is independently a 4-10 membered monocyclic or bicyclic aromatic ring containing 1-5 heteroatoms selected from N, O, S, or P. In some embodiments, each heteroaryl is independently a 4-8 membered aromatic ring containing 1-5 heteroatoms selected from N, O, S, or P.

[0354] As used herein, the term “hydrogen”, the atomic symbol “H”, implicit hydrogen atoms in chemical structures, and hydrogen atoms encompassed by specific and generic chemical radical terms shall be understood to include all atoms with atomic number 1, including1H (i.e. “protium”),2H (i.e. “deuterium” or “D”), and3H (i.e. “tritium”). For example, the terms “alkoxy” and “methoxy” shall be understood to be inclusive of the radical -OCD3, and the term “C1-C6alykl” shall be inclusive of the term “C1-C6deuteroalkyl”. Likewise, all references to a given atomic element shall be understood to include all natural and unnatural isotopes of that element.

[0355] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In:Atty. Docket No.44727-732601 Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0356] Compositions comprising the compounds disclosed herein, in some embodiments, can be prepared whereby a proportion of atoms at a given position are of a specific isotope, and said proportion differs from the natural abundance of said isotope. In some embodiments, the present disclosure provides a composition comprising a population of molecules, wherein each molecule has a structure according to a compound provided herein, wherein the population of molecules has a mass of at least 1 μg, wherein at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 97%, at least 99%, at least 99%, at least 99.9%, or at least 99.99%, of the molecules in the population of molecules each independently comprise a deuterium atom.

[0357] In some embodiments, the present disclosure provides a composition comprising a population of molecules having a mass of at least 1 μg, wherein each molecule has a structure according to a compound provided herein, wherein if, in a mass spectrometry experiment, a mass spectrum of the population is obtained, the mass spectrometry experiment determines that at least 10% of the molecules in the population of molecules each independently comprise a deuterium atom.

[0358] Reference to the formulas expressly depicts all divisions thereof, e.g. formula X in the description expressly includes, for example, formulas X-1, X-2, X-3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-11, and X-12.

[0359] Any compound herein can be purified. A compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at leastAtty. Docket No.44727-732601 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.

[0360] In some embodiments, compounds of the disclosure can be used to treat cancer in a subject. A compound of the disclosure can, for example, slow the proliferation of cancer cell lines, or kill cancer cells. In some embodiments, the present disclosure provides a method of treating cancer or a p53 meditated disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound provided herein.

[0361] Non-limiting examples of cancer that can be treated by a compound of the disclosure include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas, Burkitt lymphoma, carcinoma of unknown primary origin, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, germ cell tumors, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gliomas, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, Hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liposarcoma, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, lymphomas, leukemias, macroglobulinemia, malignant fibrous histiocytoma of bone / osteosarcoma, medulloblastoma, melanomas, mesothelioma, metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndromes, myeloid leukemia, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pituitary adenoma, pleuropulmonary blastoma, plasma cell neoplasia, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, skin cancers, skin carcinoma merkel cell, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, T-cell lymphoma, throat cancer, thymoma, thymic carcinoma, thyroid cancer, trophoblastic tumor (gestational), cancers of unknown primary site, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, WaldenströmAtty. Docket No.44727-732601 macroglobulinemia, and Wilms tumor.

[0362] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer expresses a mutant p53 protein. In some embodiments, the mutant p53 protein has a mutation at amino acid 220. In some embodiments, the mutant p53 protein is p53 Y220C.

[0363] In some embodiments, compounds of the disclosure can be used to treat small cell lung cancer, pancreatic cancer, prostate cancer, colon cancer, breast cancer, endometrial cancer, ovarian cancer, head and neck cancer, and germ cell cancer.

[0364] In some embodiments, the compounds of the disclosure show non-lethal toxicity. Pharmaceutically-acceptable salts.

[0365] The present disclosure provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt.

[0366] Metal salts can arise from the addition of an inorganic base to a compound of the invention. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0367] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0368] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.

[0369] In some embodiments, an ammonium salt is a triethyl amine salt, a trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.

[0370] Acid addition salts can arise from the addition of an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid,Atty. Docket No.44727-732601 sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0371] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt.

[0372] In some embodiments, one or more of the compounds of the disclosure is in the form of a salt protonated on a nitrogen atom, including salts formed with organic and inorganic anions and cations discussed herein. Non-limiting examples of such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D- glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, and cinnamic acid. Pharmaceutical Compositions of the disclosure.

[0373] A pharmaceutical composition of the disclosure can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.

[0374] Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient.

[0375] A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.

[0376] A pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release.

[0377] For oral administration, pharmaceutical compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used toAtty. Docket No.44727-732601 formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject. Non- limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N′-bis(2- ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremaphor, DMSO, and potassium phosphate buffer.

[0378] Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0379] The active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0380] The compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject. The compounds of the disclosure can be applied to an accessible body cavity.

[0381] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, and PEG. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.

[0382] In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0383] Pharmaceutical compositions can be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds intoAtty. Docket No.44727-732601 preparations that can be used pharmaceutically. Formulations can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.

[0384] The pharmaceutical compositions can include at least one pharmaceutically-acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form. Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0385] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.

[0386] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.

[0387] Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.

[0388] A composition of the disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel- forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.

[0389] In some, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can beAtty. Docket No.44727-732601 formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.

[0390] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.

[0391] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams and Wilkins 1999), each of which is incorporated by reference in its entirety.

[0392] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The agents can be packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month.

[0393] Therapeutic agents described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary. For example, the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition. The compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein.

[0394] A compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months,Atty. Docket No.44727-732601 about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years. The length of treatment can vary for each subject.

[0395] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged injectables, vials, or ampoules. Aqueous suspension compositions can be packaged in single-dose non- reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative. Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.

[0396] Pharmaceutical compositions provided herein, can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins. The other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.

[0397] Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage.

[0398] For solid compositions, nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.

[0399] Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics / antispasmodics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.

[0400] Compounds can be delivered via liposomal technology. The use of liposomes as drug carriers can increase the therapeutic index of the compounds. Liposomes are composed of natural phospholipids and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine). A liposome design can employ surface ligands for attaching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues. Optimal liposomalAtty. Docket No.44727-732601 properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells. Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.

[0401] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti- adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.

[0402] Compositions of the disclosure can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration / use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. The written material can be a label. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies. Combinations

[0403] Combination therapy with a compound of the disclosure and at least one additional therapeutic agent, for example, any additional therapeutic agent described herein, can be used to treat a condition. In some embodiments, the combination therapy can produce a significantly better therapeutic result than the additive effects achieved by each individual constituent when administered alone at a therapeutic dose. In some embodiments, the dosage of the compound or additional therapeutic agent, for example, any additional therapeutic agent described herein, in combination therapy can be reduced as compared to monotherapy with each agent, while still achieving an overall therapeutic effect. In some embodiments, a compound and an additional therapeutic agent, for example, any additional therapeutic agent described herein, can exhibit a synergistic effect. In some embodiments, the synergistic effect of a compound and additional therapeutic agent, for example, any additional therapeutic agent described herein, can be used to reduce the total amount drugs administered to a subject, which decrease side effects experienced by the subject.

[0404] The compounds of the disclosure can be used in combination with at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein. In some embodiments, the at least one additional pharmaceutically-active agent, for example, any additionalAtty. Docket No.44727-732601 therapeutic agent described herein, can modulate the same or a different target as the compounds of the disclosure. In some embodiments, the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, can modulate the same target as the compounds of the disclosure, or other components of the same pathway, or overlapping sets of target enzymes. In some embodiments, the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, can modulate a different target from the compounds of the disclosure.

[0405] Accordingly, in one aspect, the present disclosure provides a method for treating cancer, the method comprising administering to a subject in need thereof (a) an effective amount of a compound of the disclosure and (b) an effective amount of at least one additional pharmaceutically active agent, for example, any additional therapeutic agent described herein, to provide a combination therapy. In some embodiments, the combination therapy may have an enhanced therapeutic effect compared to the effect of the compound and the at least one additional pharmaceutically active agent each administered alone. According to certain exemplary embodiments, the combination therapy has a synergistic therapeutic effect. According to this embodiment, the combination therapy produces a significantly better therapeutic result (e.g., anti-cancer, cell growth arrest, apoptosis, induction of differentiation, cell death, etc.) than the additive effects achieved by each individual constituent when administered alone at a therapeutic dose.

[0406] Combination therapy includes but is not limited to the combination of compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, or radiation treatment, to provide a synergistic therapeutic effect. In some embodiments, the compounds of the disclosure are used in combination with one or more anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Suitable chemotherapeutic agents for use in the combinations of the present disclosure include, but are not limited to, alkylating agents, antibiotic agents, antimetabolic agents, hormonal agents, plant-derived agents, anti- angiogenic agents, differentiation inducing agents, cell growth arrest inducing agents, apoptosis inducing agents, cytotoxic agents, agents affecting cell bioenergetics, biologic agents, e.g., monoclonal antibodies, kinase inhibitors and inhibitors of growth factors and their receptors, gene therapy agents, cell therapy, or any combination thereof. a. Combination treatment with estrogen receptor antagonists

[0407] In some embodiments, a compound of the disclosure is used in combination with an estrogen receptor antagonist. In some embodiments, a compound of the disclosure is used in combination with toremifene (Fareston®), fulvestrant (Faslodex®), or tamoxifen citrate (Soltamox®).

[0408] Fulvestrant is a selective estrogen receptor degrader (SERD) and is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. Fulvestrant is a complete estrogen receptor antagonist with little to no agonist effects and accelerates the proteasomal degradation of the estrogen receptor. Fulvestrant has poor oral bioavailability and is administered via intramuscular injection. Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes estrogen receptor-positive breast cancer cells to heregulin beta1. In some embodiments, a compound of the disclosure is used in combination with fulvestrant. b. Combination treatment with aromatase inhibitorsAtty. Docket No.44727-732601

[0409] In some embodiments, a compound of the disclosure is used in combination with an aromatase inhibitor. Aromatase inhibitors are used in the treatment of breast cancer in post-menopausal women and gynecomastia in men. Aromatase inhibitors can be used off-label to reduce estrogen conversion when using external testosterone. Aromatase inhibitors can also be used for chemoprevention in high-risk women.

[0410] In some embodiments, a compound of the disclosure is used in combination with a non-selective aromatase inhibitor. In some embodiments, a compound of the disclosure is used in combination with a non-selective aromatase inhibitor, such as aminoglutethimide or testolactone (Teslac®). In some embodiments, a compound of the disclosure is used in combination with a selective aromatase inhibitor. In some embodiments, a compound of the disclosure is used in combination with a selective aromatase inhibitor, such as anastrozole (Arimidex®), letrozole (Femara®), exemestane (Aromasin®), vorozole (Rivizor®), formestane (Lentaron®), or fadrozole (Afema®). In some embodiments, a compound of the disclosure is used in combination with exemestane. In some embodiments, a compound of the disclosure is used in combination with an aromatase inhibitor such as 1,4,6-androstatrien-3,17-dione (ATD) or 4- androstene-3,6,17-trione. c. Combination treatment with mTOR inhibitors

[0411] In some embodiments, a compound of the disclosure is used in combination with an mTOR inhibitor. mTOR inhibitors are drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine / threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K)-related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through the protein complexes mTORC1 and mTORC2.

[0412] In some embodiments, a compound of the disclosure is used in combination with an mTOR inhibitor, such as rapamycin, temsirolimus (CCI-779), everolimus (RAD001), ridaforolimus (AP-23573). In some embodiments, a compound of the disclosure is used in combination with everolimus (Afinitor®). Everolimus affects the mTORC1 protein complex and can lead to hyper-activation of the kinase AKT, which can lead to longer survival in some cell types. Everolimus binds to FKBP12, a protein receptor which directly interacts with mTORC1 and inhibits downstream signaling. mRNAs that codify proteins implicated in the cell cycle and in the glycolysis process are impaired or altered as a result, inhibiting tumor growth and proliferation.

[0413] In some embodiments, a compound of the disclosure is used in combination with a mTOR inhibitor and an aromatase inhibitor. For example, a compound of the disclosure is used in combination with everolimus and exemestane. d. Combination treatment with antimetabolites

[0414] Antimetabolites are chemotherapy treatments that are similar to normal substances within the cell. When cells incorporate the antimetabolites into the cellular metabolism, the cells are unable to divide. Antimetabolites are cell-cycle specific and attack cells at specific phases in the cell cycle.

[0415] In some examples, a compound of the disclosure is used in combination with one or more antimetabolites, such as a folic acid antagonist, pyrimidine antagonist, purine antagonist, or an adenosineAtty. Docket No.44727-732601 deaminase inhibitor. In some embodiments, a compound of the disclosure is used in combination with an antimetabolite, such as methotrexate, 5-fluorouracil, foxuridine, cytarabine, capecitabine, gemcitabine, 6- mercaptopurine, 6-thioguanine, cladribine, fludarabine, nelarabine, or pentostatin. In some embodiments, a compound of the disclosure is used in combination with capecitabine (Xeloda®), gemcitabine (Gemzar®), or cytarabine (Cytosar-U®). e. Combination treatment with plant alkaloids

[0416] In some embodiments, a compound of the disclosure is used in combination with a plant alkaloid. In some embodiments, a compound of the disclosure is used in combination with a plant alkaloid, such as vinca alkaloids, taxanes, podophyllotoxins, or camptothecan analogues. In some embodiments, a compound of the disclosure is used in combination with plant alkaloids, such as vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, tenisopide, irinotecan, or topotecan.

[0417] In some embodiments, a compound of the disclosure is used in combination with a taxane, such as paclitaxel (Abraxane® or Taxol®) and docetaxel (Taxotere®). In some embodiments, a compound of the disclosure is used in combination with paclitaxel. In some embodiments, a compound of the disclosure is used in combination with docetaxel. f. Combination treatment with therapeutic antibodies

[0418] In some embodiments, a compound of the disclosure is used in combination with therapeutic antibodies. In some embodiments, a compound of the disclosure is used in combination with naked monoclonal antibodies, such as alemtuzumab (Campath®) or trastuzumab (Herceptin®). In some embodiments, a compound of the disclosure is used in combination with conjugated monoclonal antibodies, such as radiolabeled antibodies or chemolabeled antibodies. In some embodiments, a compound of the disclosure is used in combination with conjugated monoclonal antibodies, such as ibritumomab tiuxetan (Zevalin®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (Kadcyla®), or denileukin diftitox (Ontak®). In some embodiments, a compound of the disclosure is used in combination with bispecific monoclonal antibodies, such as blinatumomab (Blincyto®).

[0419] In some embodiments, a compound of the disclosure is used in combination with an anti-CD20 antibody, such as rituximab (Mabthera® / Rituxan®), obinutuzumab (Gazyva®), ibritumomab tiuxetan, tositumomab, ofatumumab (Genmab®), ocaratuzumab, ocrelizumab, TRU-015, or veltuzumab. Other antibodies that can be used in combination with a compound of the disclosure include antibodies against the programed cell death (PD-1) receptor, for example pembrolizumab (Keytruda®) or nivolumba (Opdivo®). g. Combination treatment with PD-L1 and / or PD-1 antagonists

[0420] The PD-1 pathway comprises the immune cell co-receptor Programmed Death-1 (PD-1) and the PD-1 ligands PD-L1 and PD-L2. The PD-1 pathway mediates local immunosuppression in the tumor microenvironment. PD-1 and PD-L1 antagonists suppress the immune system. In some embodiments, a PD-1 or PD-L1 antagonist is a monoclonal antibody or antigen binding fragment thereof that specifically binds to, blocks, or downregulates PD-1 or PD-L1, respectively. In some embodiments, a PD-1 or PD-L1 antagonist is a compound or biological molecule that specifically binds to, blocks, or downregulates PD-1Atty. Docket No.44727-732601 or PD-L1, respectively.

[0421] In some embodiments, the compounds of the disclosure are used in combination with a PD-1 or PD-L1 antagonist. In some embodiments, the compounds of the disclosure are used in combination with a PD-1 / PD-L1 antagonist, for example, MK-3475, nivolumab (Opdivo®), pembrolizumab (Keytruda®), humanized antibodies (i.e., h409Al l, h409A16 and h409A17), AMP-514, BMS-936559, MEDI0680, MEDI4736, MPDL3280A, MSB0010718C, MDX-1105, MDX-1106, or pidilzumab. In some embodiments, the compounds of the disclosure are used in combination with a PD-1 / PD-L1 antagonist that is an immunoadhesion molecule, such as AMP-224. In some embodiments, the compounds of the disclosure are used in combination with a PD-1 / PD-L1 antagonist to treat cancer cells or a tumor that overexpresses PD-1 or PD-L1. In some embodiments, the compounds of the disclosure are used in combination with a PD-1 / PD-L1 antagonist to treat cancer cells or a tumor that overexpresses miR-34. h. Combination treatment with anti-hormone therapy

[0422] Anti-hormone therapy uses an agent to suppress selected hormones or the effects. Anti-hormone therapy is achieved by antagonizing the function of hormones with a hormone antagonist and / or by preventing the production of hormones. In some embodiments, the suppression of hormones can be beneficial to subjects with certain cancers that grow in response to the presence of specific hormones. In some embodiments, a compound of the disclosure is used in combination with a hormone antagonist.

[0423] In some embodiments, a compound of the disclosure is used in combination with anti-androgens, anti-estrogens, aromatase inhibitors, or luteinizing hormone-releasing hormone (LHRH) agonists. In some embodiments, a compound of the disclosure is used in combination with anti-androgens, such as bicalutamide (Casodex®), cyproterone (Androcur®), flutamide (Euflex®), or nilutamide (Anandron®). In some embodiments, a compound of the disclosure is used in combination with anti-estrogens, such as fulvestrant (Faslodex®), raloxifene (Evista®), or tamoxifen (Novaladex®, Tamofen®). In some embodiments, a compound of the disclosure is used in combination with LHRH agonists, such as buserelin (Suprefact®), goserelin (Zoladex®), or leuprolide (Lupron®, Lupron Depot®, Eligard®). i. Combination treatment with hypomethylating (demethylating) agents (HMAs)

[0424] Treatment of these and other types of cancer may be improved by examining combinations that increase anti-tumor activities and may allow for similar activity at reduced doses compared to single agent treatment, leading to improved patient outcomes, and limiting adverse events. Hypomethylating (demethylating) agents inhibit DNA methylation, which affects cellular function through successive generations of cells without changing the underlying DNA sequence. Hypomethylating agents can block the activity of DNA methyltransferase. Two examples of HMAs for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients are decitabine and azacitidine. In some embodiments, a compound of the disclosure is used in combination with hypomethylating agents, such as azacitidine (Vidaza®, Azadine®) or decitabine (Dacogen®). j. Combination treatment with anti-inflammatory agents

[0425] In some embodiments, a compound of the disclosure is used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), specific COX-2 inhibitors, or corticosteroids. In some embodiments,Atty. Docket No.44727-732601 a compound of the disclosure is used in combination with NSAIDs, such as aspirin, ibuprofen, naproxen, celecoxib, ketorolac, or diclofenac. In some embodiments, a compound of the disclosure is used in combination with specific COX-2 inhibitors, such as celecoxib (Celebrex®), rofecoxib, or etoricoxib. In some embodiments, a compound of the disclosure is used in combination with corticosteroids, such as dexamethasone or glucosteroids (e.g., hydrocortisone and prednisone). k. Combination treatment with HDAC inhibitors

[0426] Histone deacetylase (HDAC) inhibitors are chemical compounds that inhibit histone deacetylase. HDAC inhibitors can induce p21 expression, a regulator of p53 activity. In some embodiments, a compound of the disclosure is used in combination with an HDAC inhibitor. In some embodiments, a compound of the disclosure is used in combination with an HDAC inhibitor, such as vorinostat, romidepsin (Istodax®), chidamide, panobinostat (Farydak®), belinostat (PDX101), panobinostat (LBH589), valproic acid, mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), SB939, resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), HBI-8000, kevetrin, CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, or trichostatin A. l. Combination treatment with platinum-based antineoplastic drugs

[0427] Platinum-based antineoplastic drugs are coordinated complex of platinum. In some embodiments, a compound of the disclosure is used in combination with a platinum-based antineoplastic drug, such as cisplatin, oxaliplatin, carboplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin. In some embodiments, a compound of the disclosure is used in combination with cisplatin or carboplatin. In some embodiments, a compound of the disclosure is used in combination with cisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloroplatinum(II), or CDDP; Platinol®) and carboplatin (also known as cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II); tradenames Paraplatin® and Paraplatin-AQ®). m. Combination treatment with kinase inhibitors

[0428] Abnormal activation of protein phosphorylation is frequently either a driver of direct consequence of cancer. Kinase signaling pathways are involved in the phenotypes of tumor biology, including proliferation, survival, motility, metabolism, angiogenesis, and evasion of antitumor immune responses.

[0429] MEK inhibitors: MEK inhibitors are drugs that inhibit the mitogen-activated protein kinase enzymes MEK1 and / or MEK2. In some embodiments, a compound of the disclosure is used in combination with a MEK1 inhibitor. In some embodiments, a compound of the disclosure is used in combination with a MEK2 inhibitor. In some embodiments, a compound of the disclosure is used in combination with an agent that can inhibit MEK1 and MEK2. In some embodiments, a compound of the disclosure is used in combination with a MEK1 / MEK2 inhibitor, such as trametinib (Mekinist®), cobimetinib, binimetinib, selumetinib (AZD6244), pimasertibe (AS-703026), PD-325901, CI-1040, PD035901, or TAK-733. In some embodiments, a compound of the disclosure is used in combination with trametinib. In some embodiments, a compound of the disclosure is used in combination with cobimetinib.Atty. Docket No.44727-732601

[0430] BRAF inhibitors: BRAF inhibitors are drugs that inhibit the serine / threonine-protein kinase B-raf (BRAF) protein. In some embodiments, a compound of the disclosure is used in combination with a BRAF inhibitor. In some embodiments, a compound of the disclosure is used in combination with a BRAF inhibitor that can inhibit wild type BRAF. In some embodiments, a compound of the disclosure is used in combination with a BRAF inhibitor that can inhibit mutated BRAF. In some embodiments, a compound of the disclosure is used in combination with a BRAF inhibitor that can inhibit V600E mutated BRAF. In some embodiments, a compound of the disclosure is used in combination with a BRAF inhibitor, such as vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), C-1, NVP-LGX818, or sorafenib (Nexavar®).

[0431] KRAS inhibitors: KRAS is a gene that acts as an on / off switch in cell signaling. In some embodiments, a compound of the disclosure is used in combination with a KRAS inhibitor. In some embodiments, a compound of the disclosure is used in combination with a wild type KRAS inhibitor. In some embodiments, a compound of the disclosure is used in combination with a mutated KRAS inhibitor.

[0432] BTK inhibitors: Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase of the Tec kinase family that is involved in B-cell receptor signaling. In some embodiments, a compound of the disclosure is used in combination with a BTK inhibitor. In some embodiments, a compound of the disclosure is used in combination with a BTK inhibitor, such as ibrutinib or acalabrutinib.

[0433] CDK inhibitors: CDK4 and CDK6 are cyclin-dependent kinases that control the transition between the G1 and S phases of the cell cycle. CDK4 / CDK6 activity is deregulated and overactive in cancer cells. Selective CDK4 / CDK6 inhibitors can block cell-cycle progression in the mid-G1 phase of the cell cycle, causing arrest and preventing the proliferation of cancer cells. In some embodiments, a compound of the disclosure is used in combination with a CDK4 / CDK6 inhibitor. In some embodiments, a compound of the disclosure is used in combination with a CDK4 / CDK6 inhibitor, such as palbociclib (Ibrance®), ribociclib, trilaciclib, seliciclib, dinaciclib, milciclib, roniciclib, atuveciclib, briciclib, riviciclib, voruciclib, or abemaciclib. In some embodiments, a compound of the disclosure is used in combination with palbociclib. In some embodiments, a compound of the disclosure is used in combination with ribociclib. In some embodiments, a compound of the disclosure is used in combination with abemaciclib.

[0434] In some examples, a compound of the disclosure is used in combination with an inhibitor of CDK4 and / or CDK6 and with an agent that reinforces the cytostatic activity of CDK4 / 6 inhibitors and / or with an agent that converts reversible cytostasis into irreversible growth arrest or cell death. Examples of cancer subtypes include NSCLC, melanoma, neuroblastoma, glioblastoma, liposarcoma, and mantle cell lymphoma. In some examples, a compound of the disclosure is used in combination with at least one additional pharmaceutically active agent that alleviates CDKN2A (cyclin-dependent kinase inhibitor 2A) deletion. In some examples, a compound of the disclosure is used in combination with at least one additional pharmaceutically active agent that alleviates CDK9 (cyclin-dependent kinase 9) abnormality.

[0435] In some embodiments, a compound of the disclosure is used in combination with a CDK2, CDK7, and / or CDK9 inhibitor. In some embodiments, a compound of the disclosure is used in combination withAtty. Docket No.44727-732601 a CDK2, CDK7, or CDK9 inhibitor, such as seliciclib, voruciclib, or milciclib. In some embodiments, a compound of the disclosure is used in combination with a CDK inhibitor, such as dinaciclib, roniciclib (Kisqali®), or briciclib. In some examples, a compound of the disclosure is used in combination with at least one additional pharmaceutically-active agent that alleviates CDKN2A (cyclin-dependent kinase inhibitor 2A) deletion.

[0436] ATM regulators: A compound of the disclosure can be used in combination with one or more pharmaceutically-active agent that regulates the ATM (upregulate or downregulate). In some embodiments the compounds described herein can synergize with one or more ATM regulators. In some embodiments one or more of the compounds described herein can synergize with all ATM regulators.

[0437] AKT inhibitors: In some embodiments, a compound of the disclosure is used in combination with one or more pharmaceutically-active agent that inhibits the AKT (protein kinase B (PKB)). In some embodiments the compounds described herein can synergize with one or more AKT inhibitors. In some embodiments, the AKT inhibitor is selected from the AKT inhibitor is selected from the group consisting of A6730, B2311, 124018, GSK2110183 (afuresertib), Perifosine (KRX-0401), GDC-0068 (ipatasertib), RX-0201, VQD-002, LY294002, A-443654, A-674563, Akti-1, Akti-2, Akti-1 / 2, AR-42, API-59CJ- OMe, ATI-13148, AZD-5363, erucylphosphocholine, GSK-2141795 (GSK795), MK2206 (CAS # 1032349-93-1), KP372-1, L-418, NL-71-101, PBI-05204, PIA5, PX-316, SR13668, triciribine, GSK 690693 (CAS # 937174-76-0), FPA 124 (CAS # 902779-59-3), Miltefosine, capivasertib, PHT-427 (CAS # 1191951-57-1), 10-DEBC hydrochloride, Akt inhibitor III, Akt inhibitor VIII, MK-2206 dihydrochloride (CAS # 1032350-13-2), SC79, AT7867 (CAS # 857531 -00-1), CCT128930 (CAS # 885499-61-6), A-674563 (CAS # 552325-73-2), AGL 2263, AS-041164 (5-benzo[1,3]dioxol-5- ylmethylene-thiazolidine-2,4-dione), BML-257 (CAS # 32387-96-5), XL-418, CAS # 612847-09-3, CAS # 98510-80-6, H-89 (CAS # 127243-85-0), OXY-111 A, and 3-[1-[[4-(7-phenyl-3H-imidazo[4,5- g]quinoxalin-6-yl)phenyl]methyl]piperidin-4-yl]-1H-benzimidazol-2-one. Also disclosed herein are methods of treating a condition in a subject in need thereof comprising administering an AKT inhibitor. In some embodiments, the AKT inhibitor is selected from MK2206, ipatasertib, and capivasertib, or a pharmaceutically-acceptable salt thereof. In some embodiments, the AKT inhibitor is an inhibitor of Akt1.

[0438] In some embodiments, the AKT inhibitor is:

[0439] In some embodiments, the AKT inhibitor is:Atty. Docket No.44727-732601,

[0441] PI3K inhibitors: In some embodiments, a compound of the disclosure is used in combination with one or more pharmaceutically-active agent that inhibits a phosphoinositide 3-kinase protein. In some embodiments, the PI3K inhibitor is selected from idelalisib, copanlisib, duvelisib, alpelisib, seletalisib, gedatolisib, inavolisib, rigosertib sodium, leniolisib, umbralisib, buparlisib (AN2025), AMG-319, GM - 604, acalisib, bimiralisib, GDC-0084, ACP-319, tenalisib, serabelisib, SF-1126, nemiralisib, fimepinostat, LY-3023414, voxtalisib, dactolisib, eganelisib, parsaclisib, GSK2636771, AZD-8186, and ASN-003. In some embodiments, the PI3K inhibitor is selected from a PI3Kα, PI3Kβ, PI3Kγ, or PI3Kδ inhibitor. Also disclosed herein are methods of treating a condition in a subject in need thereof comprising administering a PI3K110α inhibitor. In some embodiments, the PI3K inhibitor is selected from alpelisib, inavolisib, serabelisib, GSK2636771, eganelisib, idelalisib, or duvelisib.

[0442] In some embodiments, the PI3K inhibitor is:(inavolisib), or a pharmaceutically-acceptable salt thereof.

[0443] In some embodiments, the PI3K inhibitor is:(serabelisib), or a pharmaceutically-acceptable salt thereof.

[0444] In some embodiments, the PI3K inhibitor is:Atty. Docket No.44727-732601pharmaceutically-acceptable salt thereof.

[0445] In some embodiments, the PI3K inhibitor is: (eganelisib), or a pharmaceutically-acceptable salt thereof. the PI3K inhibitor is:, or a pharmaceutically-acceptable salt thereof.

[0447] In some embodiments, the PI3K inhibitor is:(duvelisib), or a pharmaceutically-acceptable salt thereof.

[0448] In some embodiments, the PI3K inhibitor is(alpelisib), or a pharmaceutically-acceptable salt thereof. n. MDM2 inhibitors.

[0449] In some embodiments, a compound of the disclosure is used in combination with one or moreAtty. Docket No.44727-732601 pharmaceutically-active agent that inhibits mouse double minute 2 homolog (MDM2). In some embodiments, the MDM2 inhibitor is Nutlin-1, Nutlin-2, Nutlin-3, RG7112 (RO5045337), idasanutlin (RG7388), AMG-232 (KRT-232), APG-115, BI-907828, CGM097, siremadlin (HDM201), SAR405838 (MI-77301), MK-8242 (SCH 900242), RAIN-32, or milademetan (DS-3032b), or a pharmaceutically- acceptable salt of any of the foregoing:Atty. Docket No.44727-732601milademetanBI-907828.

[0450] MDM2 inhibitors of the present disclosure also include stereoisomers of MDM2 inhibiting structures disclosed herein, including diastereomers, epimers, and enantiomers thereof. For example, Nutlin-3 includes Nutlin-3a (i.e., ((-)-Nutlin-3), or 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-Atty. Docket No.44727-732601 propan-2-yloxyphenyl)-4,5-dihydroimidazol-1-yl]-oxomethyl]-2-piperazinone) and Nutlin-3b (i.e., ((+)- Nutlin-3), or 4-[[(4R,5S)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5- dihydroimidazol-1-yl]-oxomethyl]-2-piperazinone). o. Combination treatment with other pharmaceutically-active agents

[0451] In some examples, a compound of the disclosure is used in combination with at least one additional pharmaceutically-active agent that alleviates PTEN (phosphatase and tensin homolog) deletion. In some examples, a compound of the disclosure is used in combination with at least one additional pharmaceutically-active agent that alleviates Wip-1Alpha over expression. In some examples, a compound of the disclosure is used in combination with at least one additional pharmaceutically-active agent that is a Nucleoside metabolic inhibitor. Examples of nucleoside metabolic inhibitors include capecitabine, gemcitabine and cytarabine (Arac).

[0452] TABLE 1 below lists suitable additional pharmaceutically-active agents for use with the methods described herein. TABLE 1Atty. Docket No.44727-732601Atty. Docket No.44727-732601Administration of Combination Treatment

[0453] A compound of the disclosure or a pharmaceutical composition comprising a compound of the disclosure and at least one additional pharmaceutically-active agent or a pharmaceutical composition comprising at least one additional pharmaceutically-active agent can be administered simultaneously (i.e., simultaneous administration) or sequentially (i.e., sequential administration).

[0454] In some embodiments, a compound of the disclosure and the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, are administered simultaneously, either in the same composition or in separate compositions. When the drugs are administered simultaneously, the compound and the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, may be contained in the same composition (e.g., a composition comprising both the compound and the at least additional pharmaceutically-active agent) or in separate compositions (e.g., the compound is contained in one composition and the at least additional pharmaceutically-active agent is contained in another composition).

[0455] In some embodiments, the compound and the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, are administered sequentially, i.e., the compound is administered either prior to or after the administration of the additional pharmaceutically-active agent. In some embodiments, the compound is administered before the additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein. In some embodiments, the pharmaceutically-active agent, for example, any additional therapeutic agent described herein, is administered before the compound. The compound and the additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, are contained in separate compositions, which may be contained in the same or different packages.

[0456] In some embodiments, the administration of the compounds and the additional pharmaceutically- active agent, for example, any additional therapeutic agent described herein, are concurrent, i.e., the administration period of the compounds and that of the agent overlap with each other. In some embodiments, the administration of the compounds and the additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, are non-concurrent. For example, in some embodiments, the administration of the compound is terminated before the additional pharmaceutically- active agent, for example, any additional therapeutic agent described herein, is administered. In some embodiments, the administration of the additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, is terminated before the compound is administered. The time period between these two non-concurrent administrations can range from being days apart to being weeks apart.Atty. Docket No.44727-732601

[0457] The dosing frequency of the compound and the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, may be adjusted over the course of the treatment, based on the judgment of the administering physician. When administered separately, the compound and the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, can be administered at different dosing frequency or intervals. For example, the compound can be administered weekly, while the at least one additional pharmaceutically- active agent, for example, any additional therapeutic agent described herein, can be administered more or less frequently. Or, the compound can be administered twice weekly, while the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, can be administered more or less frequently. In addition, the compound and the at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, can be administered using the same route of administration or using different routes of administration.

[0458] A therapeutically-effective amount of a compound and / or the additional pharmaceutically- active agent, for example, any additional therapeutic agent described herein, for use in therapy can vary with the nature of the condition being treated, the length of treatment time desired, the age and the condition of the patient, and can be determined by the attending physician.

[0459] In some embodiments, when a compound of the disclosure is administered in combination with at least one additional pharmaceutically-active agent, for example, any additional therapeutic agent described herein, the dosage of the compound can be given a lower dosage than when the compound is administered alone. Dosing

[0460] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are liquids in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with a preservative. Formulations for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.

[0461] A compound described herein can be present in a composition in a range of from about 1 mg to about 5000 mg; from about 100 mg to about 4000 mg; from about 10 mg to about 3500 mg; from about 5 mg to about 3000 mg, from about 10 mg to about 2500 mg, from about 50 mg to about 2000 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, fromAtty. Docket No.44727-732601 about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg. In some embodiments, the therapeutically- effective amount of the compound is from about 250 mg to about 2500 mg. In some embodiments, the therapeutically-effective amount of the compound is from about 500 mg to about 2000 mg. In some embodiments, the therapeutically-effective amount of the compound is from about 500 mg to about 1000 mg. In some embodiments, the therapeutically-effective amount of the compound is from about 500 mg to about 1500 mg. In some embodiments, the therapeutically-effective amount of the compound is from about 500 mg to about 3000 mg In some embodiments, the therapeutically-effective amount of the compound is from about 1000 mg to about 3000 mg. In some embodiments, the therapeutically-effective amount of the compound is from about 2000 mg to about 3000 mg.

[0462] A compound described herein can be present in a composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg. In some embodiments, the therapeutically-effective amount of the compound is about 2250 mg, about 2500 mg, or about 3000 mg. In some embodiments, the therapeutically-effective amount of the compound is about 1,200 mg. In some embodiments, the therapeutically-effective amount of the compound is about 1,500 m. In some embodiments, the therapeutically-effective amount of the compound is about 2,000 mg. In some embodiments, the therapeutically-effective amount of the compound is about 2,500 mg. In some embodiments, the therapeutically-effective amount of the compound is about 3,000 mg. In some embodiments, the therapeutically-effective amount of the compound is about 3,500 mg.

[0463] In some embodiments, a dose can be expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drug per kilograms of subject body mass. In some embodiments, a compound is administered in an amount ranging from about 5 mg / kg to about 50 mg / kg, 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg. In some embodiments, the therapeutically-effective amount of the compound is about 50 mg / kg. In some embodiments, the therapeutically-effective amount of the compound is about 40 mg / kg. In some embodiments, the therapeutically-effective amount of the compound is about 30 mg / kg.Atty. Docket No.44727-732601

[0464] In some embodiments, a dose can be expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drug per kilograms of subject body mass. In some embodiments, a compound is administered in an amount ranging from about 5 mg / kg to about 50 mg / kg, 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg. GENERAL SYNTHETIC SCHEMES

[0465] The compounds of this invention can be synthesized according to the following procedure of Schemes I-IV, wherein the substituents are as defined for Formulas I-XII, above, except where further noted. Some of the compounds can be synthesized using chemistry described in WO2017143291, WO2021061643 and WO2021231474.

[0466] The following abbreviations are used: RT, rt room temperature, ambient temperature DCM, CH2C12 dichloromethane DIEA, DIPEA, EtNiPr2 diisopropylethylamine, Hünig's base i-PrNH2isopropylamine H2O water D2O deuterated water DMF dimethylformamide DMSO dimethylsulfoxide DMSO-d6 deuterated dimethylsulfoxide AcCN, MeCN, ACN acetonitrile TFA trifluoroacetic acid AcOH acetic acid H2SO4sulfuric acid FA formic acid TsOH p-toluenesulfonic acid HCl hydrochloric acid THF tetrahydrofuran EtOAc, EA ethyl acetate Na2SO4sodium sulfate Na2CO3sodium carbonate Na2HCO3sodium bicarbonate mg milligram g gram ml, mL milliliter h, hr hourAtty. Docket No.44727-732601 min minutes KCl potassium chloride NH4Cl ammonium chloride NH4HCO3 ammonium bicarbonate NH3 ammonia H2O water MeOH methanol EtOH ethanol HCHO formaldehyde N2 nitrogen Pd(PPh3)4 tetrakis(triphenylphosphine) palladium HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate Cs2CO3 cesium carbonate K2CO3 potassium carbonate NaH sodium hydride PE petroleum ether LiOH, LiOH-H2O lithium hydroxide, lithium hydroxide hydrate SiO2silica CuI copper iodide Fe iron NIS N-iodosuccinimide PMHS Polymethylhydrosiloxane EDTA ethylenediamine tetraacetic acid KF potassium fluoride NaHBH3CN sodium cyanoborohydride Sn(Oth)2Tin(II) trifluoromethanesulfonate CF3CH2OTf 2,2,2-Trifluoroethyl trifluoromethanesulfonate Eq., equiv. equivalentsAtty. Docket No.44727-732601 SCHEME I

[0467] The 6-substituted indoles of the disclosure (where R4is H) can be synthesized according to Scheme I from corresponding 4-amino-6-halo-indoles. 6-Iodo-1H-indol-4-ylamine is treated with a base, such as NaH, at a temperature below RT, such as at about 0 °C and optionally substituted alkyl trifluoromethanesulfonate is added to provide 6-iodo-1-( optionally substituted alkyl)indol-4-ylamine. The 6-iodo-1-( optionally substituted alkyl)indol-4-ylamine is coupled with substituted ketones or aldehydes, such as substituted piperidinones, in the presence of acid, such as AcOH, and NaBH3CN, at a temperature above RT, such as at about 60 °C to provide the 6-iodo-N-(optionally substituted piperidyl)- 1-(optionally substituted alkyl)indol-4-ylamine. The 6-iodo-N-(optionally substituted piperidyl)-1- (optionally substituted alkyl)indol-4-ylamines are coupled with substituted alkynes, such as with CuI in the presence of Pd(PPh3)4to give the desired 1,4,6-substituted-indoles. SCHEME II

[0468] The benzimidazole compounds of the disclosure (where R4is H, and where Q is C=O) can be synthesized according to Scheme II from corresponding anilines. The anilines are halogenated, such as with NIS, in acid, e.g. AcOH, to afford 4-iodo-2-nitroanilines. The 4-iodo-2-nitroaniline is reduced, suchAtty. Docket No.44727-732601 as with NH4Cl and Fe, at a temperature above RT, e.g. at about 80 °C to afford the corresponding diaminobenzoates. The 1H-benzimidazole-4-carboxylates are prepared by treating the diaminobenzoates with trimethoxymethane and an acid, such as H2SO4. The 1H-benzimidazoles are alkylated, such as with alkyl-OTf and Cs2CO3 to provide the 1-substituted 1H-benzimidazoles. The 6-iodo-1-(optionally substituted alkyl)benzimidazoles are coupled with substituted alkynes, such as with CuI in the presence of Pd(PPh3)4 to give the corresponding methyl 6-substituted alkynyl-benzimidazole-4-carboxylates. 6- Substituted alkynyl- benzimidazole-4-carboxylic acids are prepared from the corresponding esters by treatment with base, such as LiOH. The 6-substituted alkynyl-benzimidazole-4-carboxylic acids are converted to the corresponding amides such as by treatment with HATU, DIEA and amines, such as at a temperature at or below RT, e.g. about 0 °C.

[0469] The azaindole compounds of the disclosure (where R4is H) can be synthesized according to Scheme III from corresponding aldehydes. The optionally substituted aldehyde in dioxane is halogenated, such as with Br2 at a temperature below RT, such as at about 0 °C, to afford the bromoaldehyde. The bromoaldehyde is cyclized, such as in the presence of 3-nitropyridin-2-amine and TsOH, at a temperature above RT, such as at about 100 °C to afford imidazo[1,2-a]pyridines. The imidazo[1,2-a]pyridines are halogenated, such as with NIS in the presence of acid, e.g. AcOH, at aAtty. Docket No.44727-732601 temperature about RT, such as at about 30 °C, to afford the 6-iodo-imidazo[1,2-a]pyridines. The 6-iodo- 8-nitro-3-imidazo[1,2-a]pyridine is reduced, such as with NH4Cl and Fe, at a temperature above RT, e.g. at about 80 °C to afford the corresponding imidazo[1,2-a]pyridin-8-amines. The imidazo[1,2-a]pyridin- 8-amines are coupled with optionally substituted ketones or aldehydes, such as optionally substituted piperidinones, in the presence of PMHS and Sn(OTf)2 , at a temperature above 50 °C, such as at about 130 °C, to provide the 6-iodo-N-(substituted piperidyl)-1-(substituted alkyl) imidazo[1,2-a]pyridin-8-yl)- amine. The 6-iodo-N-(substituted piperidyl)-1-(substituted alkyl) imidazo[1,2-a]pyridin-8-yl)-amine are coupled with substituted alkynes, such as with CuI in the presence of Pd(PPh3)4 to give the desired 3,6,8- substituted imidazo[1,2-a]pyridin-8-ylamines. SCHEME IV

[0470] 1-Halolkyl-substituted indoles of the disclosure (where R4 is H) can be synthesized according to Scheme IV from corresponding 4-nitro-6-halo-indoles. 6-Bromo-4-nitro-1H-indoles are iodinated, such as with CuI and NaI. The indole is treated with a base, such as NaH, at a temperature below RT, such as at about 0 °C and haloalkyl trifluoromethanesulfonate is added to provide 6-iodo-1-( haloalkyl)-4-nitro- indoles. The 6-iodo-1-( haloalkyl)-4-nitro-indoles are reduced, such as with iron and ammonium chloride to yield the corresponding amines. The 6-iodo-1-(haloalkyl)indol-4-ylamines are coupled with substituted alkynes, such as with CuI in the presence of Pd(PPh3)4 to give the corresponding 4-amino-6- substituted-indoles. The 4-amino-6-substituted-indoles are coupled with substituted ketones, acids or aldehydes, such as substituted piperidinones, in the presence of BH3, at a temperature about RT, such as at about 0-25 °C to provide the desired indoles.Atty. Docket No.44727-732601 EMBODIMENTS

[0471] Embodiment A1. A compound of formula Ia, or a pharmaceutically-acceptable salt thereof:wherein: each is independently a single bond or a double bond; X1is CR5, CR5R6, N, NR5, O, S, or a carbon atom connected to A or Q; X2is CR7, CR7R8, N, NR7, O, S, or a carbon atom connected to A or Q; X3is CR9, CR9R10, N, NR9, O, S, or a carbon atom connected to A or Q; X4is CR11, CR11R12, N, NR11, O, S, or a carbon atom connected to A or Q; X5is CR13, CR13R14, N, NR13, or a carbon atom connected to Q; X6is CR15, CR15R16, N, NR2, O, S, or a carbon atom connected to Q; X7is C, CR17, or N; X8is C, CR18, or N; X9is CR19, CR19R20, N, NR19, O, S, or a carbon atom connected to Q; wherein one of X1, X2, X3, and X4is a carbon atom connected to A, and wherein one of X1, X2, X3, X4, X5, and X6is a carbon atom connected to Q; A is ethyndiyl or a substituted or unsubstituted 5-membered, 6-membered, 7-membered, or 8- membered monocyclic heteroaryl ring comprising 1, 2, or 3 heteroatoms as ring members, wherein each heteroatom is independently selected from O, N, and S; Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or C=O, C=S, or a bond; each R19and R20is H or substituted or unsubstituted C1-6alkyl; R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, - NR21R22, -NR21C(O)R22, -OC(O)R21, -P(O)R21R22, or -SiR21R22R23; R2is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - NR26R27, -NR26C(O)R27, or -OC(O)R26; each R3and R4is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, - SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted;Atty. Docket No.44727-732601 each R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0472] Embodiment A2. The compound of embodiment A1, wherein A is an aromatic 5-membered, or 6- membered monocyclic ring comprising 1, 2, or 3 heteroatoms as ring members, wherein each heteroatom is independently selected from O, N, and S.

[0473] Embodiment A3. The compound of embodiment A1, wherein A is selected from an aromatic nitrogen containing 5-membered ring comprising 0, 1 or 2 additional heteroatoms as ring members, wherein each additional heteroatom is independently selected from O, N, and S.

[0474] Embodiment A4. The compound of embodiment A1, wherein A is selected from thiadiazolyl, thiazolyl, pyrazolyl, and oxadiazolyl, each of which is independently substituted or unsubstituted.

[0475] Embodiment A5. The compound of embodiment A1, wherein A is selected from 1,3,5-thiadiazol- 2,4-diyl, 1,3,4-oxadiazol-2,5-diyl and 1,2,4-oxadiazol-3,5-diyl.

[0476] Embodiment A6. The compound of embodiment A1, wherein A is ethyndiyl.

[0477] Embodiment A7. The compound of embodiment A1, wherein R2is substituted or unsubstituted alkyl.

[0478] Embodiment A8. The compound of embodiment A7, wherein R2is C1-2haloalkyl.

[0479] Embodiment A9. The compound of embodiment A7, wherein R2is trifluoroethyl.

[0480] Embodiment A10. The compound of embodiment A1, wherein R1is alkyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0481] Embodiment A11. The compound of embodiment A1, wherein R1is substituted alkyl.

[0482] Embodiment A12. The compound of embodiment A11, wherein R1is C1-3alkyl substituted with - NR23C(O)R24.

[0483] Embodiment A13. The compound of embodiment A11, wherein R1is -CH2-NHC(O)R21, wherein R21is C3-6cycloalkyl or 5 membered heteroaryl, each of which is independently substituted or unsubstituted.

[0484] Embodiment A14. The compound of embodiment A13, wherein R21is cyclopropyl or pyrazolyl; each of which is independently substituted or unsubstituted.

[0485] Embodiment A15. The compound of embodiment A13, wherein R21is pyrazolyl substituted with one or more substituents independently selected from C1-4 alkyl.

[0486] Embodiment A16. The compound of embodiment A11, wherein R1is methyl substituted with - NHR22, wherein R22is substituted phenyl or -SO2- C1-4 alkyl.Atty. Docket No.44727-732601

[0487] Embodiment A17. The compound of embodiment A16, wherein R22is phenyl substituted with one or more R16substituents.

[0488] Embodiment A18. The compound of embodiment A16, wherein R22is phenyl substituted with one or more substituents independently selected from halo, -OR24, -C(O)NR24R25, and -SO2R24.

[0489] Embodiment A19. The compound of embodiment A1, wherein Q is a bond.

[0490] Embodiment A20. The compound of embodiment A1, wherein Q is C=O.

[0491] Embodiment A21. The compound of embodiment A1, wherein R3is 4-10 membered monocyclic or polycyclic heterocyclyl, each of which is independently substituted or unsubstituted.

[0492] Embodiment A22. The compound of embodiment A21, wherein R3is independently C6-10 aryl, 5- 6 membered nitrogen-containing heteroaryl, or 4-6 membered monocyclic or polycyclic oxygen- containing heterocyclyl, 4-10 membered monocyclic or polycyclic nitrogen-containing heterocyclyl, each of which is independently substituted or unsubstituted.

[0493] Embodiment A23. The compound of embodiment a1, wherein R3is 4-6 membered nitrogen containing heterocyclyl substituted at least with methyl or halo.

[0494] Embodiment A24. The compound of embodiment A1, wherein R3is selected from 3-azetidinyl, 3- pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, tetrahydro-2H-pyran-4-yl, 4-azepanyl and 8- azabicyclo[3.2.1]oct-3-yl.

[0495] Embodiment A25. The compound of embodiment A1, wherein R3is piperidinyl unsubstituted or substituted with methyl, ethyl, or fluoro. Ra N

[0496] Embodiment A26. The compound of embodiment A1, wherein R3is , wherein Rais C1-4alkyl.

[0497] Embodiment A27. The compound of embodiment A1, wherein R is H or methyl.

[0498] Embodiment A28. The compound of embodiment A1, wherein R3is -C(O)R26, -C(O)OR26, - C(O)NR26R27, -SOR26, or -SO2R26.

[0499] Embodiment A29. The compound of embodiment A1, wherein X1is a carbon atom connected to Q; X2is CR7, X3is a carbon atom connected to A; X4is CR11, and X5is N.

[0500] Embodiment A30. The compound of embodiment A1, wherein X1is CR5, X2is CR7, X3is a carbon atom connected to A; X4is CR11, and X5is a carbon atom connected to Q.

[0501] Embodiment A31. The compound of embodiment A1, wherein X1is a carbon atom connected to Q; X2is CR7, X3is a carbon atom connected to A; and X4is CR11, and X5is CR13.

[0502] Embodiment A32. The compound of embodiment A1, wherein the compound is of formula IIa or IIb:(IIa)Atty. Docket No.44727-732601wherein Q is alkylene, which is substituted or unsubstituted; or C=O or a bond. Embodiment A33. The compound of embodiment A1, wherein the compound is of formula IIIwherein X5is CR13or N; and Q is alkylene, which is substituted or unsubstituted; or C=O or a bond.

[0503] Embodiment A34. The compound of embodiment A1, wherein the compound is of formula IVwherein Q is alkylene, which is substituted or unsubstituted; or C=O or a bond; R1is alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, -C(O)R21, -C(O)OR21, -C(O)NR21R22, -OR21, -SR21, - NR21R22, -NR21C(O)R22, -OC(O)R21, -P(O)R21R22, or -SiR21R22R23; R2is substituted or unsubstituted C1-6alkyl; R3is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24; each R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halo, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -Atty. Docket No.44727-732601 OC(O)R26; each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0504] Embodiment A35. The compound of embodiment A34, wherein when R1is 2-hydroxybut-2-yl, Q is a bond, and R3is 3-chlorophenyl, then R2is not isopropyl.

[0505] Embodiment A36. The compound of embodiment A1, wherein the compound is of formula Vwherein Q is alkylene, which is substituted or unsubstituted; or C=O or a bond.

[0506] Embodiment A37. The compound of embodiment A1, wherein the compound is of formula VIII(VI).

[0507] Embodiment 1. A compound of formula X-1′, or a pharmaceutically-acceptable salt thereof:wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5or CR5R6; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N;Atty. Docket No.44727-732601 - X9is C, CR19, or N; - A is ethenylene, arylene, cycloalkylene, or heterocyclylene, each of which is independently substituted or unsubstituted, or ethynylene; - U is -L1-J, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; - RMand RNare each independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, - C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or - OC(O)R26; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R19is hydrogen, halogen, or substituted or unsubstituted alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28, or R24and R25together with the nitrogen atom to which R24and R25are bound form a ring, wherein the ring is substituted or unsubstituted; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0508] Embodiment 2. The compound of embodiment 1, wherein U is -L1-J or substituted or unsubstituted alkyl.

[0509] Embodiment 3. The compound of embodiment 1, wherein U is -L1-J.Atty. Docket No.44727-732601

[0510] Embodiment 4. The compound of any one of embodiments 1-3, wherein J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. R27R26

[0511] Embodiment 5. The compound of any one of embodiments 1-4, wherein A is or.

[0512] Embodiment 6. The compound of any one of embodiments 1-4, wherein A isor.

[0513] Embodiment 7. The compound of any one of embodiments 1-4, wherein A is arylene or heterocyclylene, each of which is substituted or unsubstituted, or ethynylene.

[0514] Embodiment 8. The compound of any one of embodiments 1-7, wherein RMand RNare each independently substituted or unsubstituted alkyl, -OR26, -SR26, -NR26R27, halogen, or hydrogen.

[0515] Embodiment 9. The compound of any one of embodiments 1-7, wherein RMand RNare each methyl, -OH, or hydrogen.

[0516] Embodiment 10. The compound of any one of embodiments 1-7, wherein each RMand RNis hydrogen.

[0517] Embodiment 11. The compound of embodiment 1, wherein A is C3-9cycloalkylene, C6-10arylene, C1-9heterocyclylene, each of which is independently unsubstituted or substituted with 1 to 7 RX; or ethynylene, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

[0518] Embodiment 12. The compound of embodiment 11, wherein A is C6-10arylene or C1- 9heterocyclylene, each of which is independently unsubstituted or substituted with 1 to 7 RX; or ethynylene.

[0519] Embodiment 13. The compound of embodiment 1 or embodiment 11, wherein A is cyclobutylene.

[0520] Embodiment 14. The compound of embodiment 1 or embodiment 11, wherein A is ethenylene.

[0521] Embodiment 15. The compound of any one of embodiments 1 and 11-14, wherein U is -L1-J, C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with one, two, or three groups independently selected from 1, 2, or 3 RX; or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26, wherein each RXis independently selected from halogen, NR24R25, - C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.Atty. Docket No.44727-732601

[0522] Embodiment 16. The compound of any one of embodiments 1 and 11-14, wherein U is -L1-J or C1-6alkyl that is unsubstituted or substituted with one, two, or three groups independently selected from 1, 2, or 3 RX, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

[0523] Embodiment 17. The compound of any one of embodiments 1 and 11-17, wherein RM, and RNare each independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with one, two, or three groups independently selected from 1, 2, or 3 RX; or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1- 6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

[0524] Embodiment 18. The compound of embodiment 1, wherein the compound is of formula X-1a, or a pharmaceutically-acceptable salt thereof:1a), wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5or CR5R6; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9, O, or S; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is C, CR19, or N; - A is ethynylene or substituted or unsubstituted heterocyclylene; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted;Atty. Docket No.44727-732601 - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R19is hydrogen, halogen, or substituted or unsubstituted alkyl; - each R24and R25is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halo, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28, or R24and R25together with the nitrogen atom to which R24and R25are bound form a ring, wherein the ring is substituted or unsubstituted; and - each R26, R27, R28, and R29is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

[0525] Embodiment 19. The compound of embodiment 1 or embodiment 18, wherein X1is CR5, X2is C, X3is CR9, and X4is C.

[0526] Embodiment 20. The compound of embodiment 1 or embodiment 18, wherein the compound is of formula X-A, or a pharmaceutically-acceptable salt thereof:

[0527] Embodiment 21. The compound of any one of embodiments 1 and 18-20, wherein X8is C and X9is CR19.

[0528] Embodiment 22. The compound of any one of embodiments 1 and 18-21, wherein the compound is of formula X-3, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0529] Embodiment 23. The compound of any one of embodiments 1 and 18-21, wherein the compound is of formula X-4, or a pharmaceutically-acceptable salt thereof:

[0530] Embodiment 24. The compound of any one of embodiments 1 and 18-21, wherein the compound is of formula X-5, or a pharmaceutically-acceptable salt thereof:

[0531] Embodiment 25. The compound of any one of embodiments 1 and 18-21, wherein the compound is of formula X-6, or a pharmaceutically-acceptable salt thereof:

[0532] Embodiment 26. The compound of any one of embodiments 1 and 18-21, wherein the compound is of formula X-8, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0533] Embodiment 27. The compound of any one of embodiments 1 and 18-20, wherein the compound is of formula X-10, or a pharmaceutically-acceptable salt thereof:

[0534] Embodiment 28. The compound of any one of embodiments 1 and 18-27, wherein A is substituted or unsubstituted heterocyclylene.

[0535] Embodiment 29. The compound of any one of embodiments 1 and 18-28, wherein A is five- membered heterocyclylene having 1-4 ring members that are heteroatoms selected from N, O, and S that is unsubstituted or substituted with methyl or ethyl.

[0536] Embodiment 30. The compound of any one of embodiments 1 and 18-29, wherein A is 1,2,4- oxadiazoldiyl.

[0537] Embodiment 31. The compound of any one of embodiments 1 and 18-27, wherein A is ethynylene.

[0538] Embodiment 32. The compound of embodiment 1 or embodiment 18, wherein the compound is of formula XII-3, or a pharmaceutically-acceptable salt thereof:

[0539] Embodiment 33. The compound of embodiment 1 or embodiment 18, wherein the compound is of formula XII-4, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0540] Embodiment 34. The compound of embodiment 1 or embodiment 18, wherein the compound is of formula XII-5, or a pharmaceutically-acceptable salt thereof:

[0541] Embodiment 35. The compound of embodiment 1 or embodiment 18, wherein the compound is of formula XII-7, or a pharmaceutically-acceptable salt thereof:

[0542] Embodiment 36. The compound of embodiment 1 or embodiment 18, wherein the compound is of formula XII-9, or a pharmaceutically-acceptable salt thereof:

[0543] Embodiment 37. The compound of embodiment 1 or embodiment 18, wherein the compound is of formula XII-10, or a pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601

[0544] Embodiment 38. The compound of embodiment 1 or embodiment 18, wherein the compound is of

[0545] Embodiment 39. The compound of any one of embodiments 1 and 18-38, wherein L1is -C(O)N(R26)-, -N(R26)-, or -NR26C(O)-.

[0546] Embodiment 40. The compound of any one of embodiments 1 and 18-38, wherein L1is -C(O)N(R26)-.

[0547] Embodiment 41. The compound of any one of embodiments 1 and 18-38, wherein L1is -C(O)N(H)-.

[0548] Embodiment 42. The compound of any one of embodiments 1 and 18-38, wherein L1is -N(R26)-.

[0549] Embodiment 43. The compound of any one of embodiments 1 and 18-38, wherein L1is -N(H)-.

[0550] Embodiment 44. The compound of any one of embodiments 1 and 18-43, wherein J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted.

[0551] Embodiment 45. The compound of any one of embodiments 1 and 18-44, wherein J is 5- or 6- membered aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is independently substituted or unsubstituted.

[0552] Embodiment 46. The compound of any one of embodiments 1 and 18-45, wherein J is phenyl that is substituted or unsubstituted.

[0553] Embodiment 47. The compound of any one of embodiments 1 and 18-45, wherein J is pyrazolyl that is substituted or unsubstituted.

[0554] Embodiment 48. The compound of any one of embodiments 1 and 18-43, wherein J is 5- or 6- membered aryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one to five groups independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, - SO2R24, -NS(O)R24, -NS(O)2R24, -S(O)NR24R25, and -S(O)2NR24R25.Atty. Docket No.44727-732601

[0555] Embodiment 49. The compound of embodiment 1 or embodiment 18, wherein the compound is of formula XII-3a, or a pharmaceutically-acceptable salt thereof:wherein each RZis independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,...

Claims

Atty. Docket No.44727-732601 CLAIMS What is claimed is:or a pharmaceutically-acceptable salt thereof, wherein: - each is independently a single bond or a double bond such that all valences are satisfied; - X1is CR5or CR5R6; - X2is C, CR7, or N; - X3is CR9, CR9R10, N, NR9; - X4is C or CR11; - X5is CR13, CR13R14, N, NR13, O, or S; - X6is CR15, CR15R16, N, NR15, O, or S; - X7is C, CR17, or N; - X8is C, CR18, or N; - X9is CR19, CR19R20, N, NR19, O, or S; - L1is -C(O)-, -S(O)-, -C(O)O-, -C(O)N(R26)-, -S(O)N(R26)-, -S(O)2N(R26)-, -O-, -S-, -SO2-, - N(R26)-, -NR26C(O)-, -NR26S(O)-, -NR26S(O)2-, or -OC(O)-; - J is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; - RMand RNare each independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, - NR26C(O)R27, or -OC(O)R26; - Q is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond; - Y is -NR3R4, SR3, or OR3; - each R3and R4is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, - C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or R3and R4together with theAtty. Docket No.44727-732601 nitrogen atom to which R3and R4are bound form a ring, wherein the ring is substituted or unsubstituted; - each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R19, R21, R22, and R23is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, -SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26; - each R24and R25is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted; or H, halogen, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; and - each R26, R27, R28, and R29is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or H.

2. The compound of claim 1, wherein RMand RNare each independently substituted or unsubstituted alkyl, -OR26, -SR26, -NR26R27, halogen, or hydrogen.

3. The compound of claim 1, wherein RMand RNare each methyl, -OH, or hydrogen.

4. The compound of claim 1, wherein each RMand RNis hydrogen.

5. The compound of claim 1, wherein RMand RNare each independently C1-6alkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with one, two, or three groups independently selected from 1, 2, or 3 RX; or hydrogen, halogen, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26, wherein each RXis independently selected from halogen, NR24R25, -C(O)R25, -NR25C(O)R26, and -OR24; or C1-6alkyl, C3-10cycloalkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with C(O)NR28R29, -SO2R28, methyl, ethyl, or propyl.

6. The compound of claim 1, wherein X2is C and X4is C.

7. The compound of claim 1, wherein X1is CR5and X3is CR9.

8. The compound of claim 1, wherein the compound is of formula XII-3, or a pharmaceutically- acceptable salt thereof:Atty. Docket No.44727-732601 9. The compound of claim 1 or claim 8, wherein the compound is of formula XII-4, or a pharmaceutically-acceptable salt thereof:10.pharmaceutically-acceptable salt thereof:11.pharmaceutically-acceptable salt thereof:12.pharmaceutically-acceptable salt thereof:Atty. Docket No.44727-732601 13. The compound of claim 1 or claim 8, wherein the compound is of formula XII-10, or a pharmaceutically-acceptable salt thereof:14.pharmaceutically-acceptable salt thereof:pharmaceutically-acceptable salt thereof:pharmaceutically-acceptable salt thereof:

18. The compound of any one of claims 1 and 8-16, wherein L1is -C(O)N(R26)-. . The compound of any one of claims 1 and 8-16, wherein L1is -C(O)N(Me)-.

20. The compound of any one of claims 1 and 8-16, wherein L1is -C(O)N(H)-.

21. The compound of any one of claims 1 and 8-16, wherein L1is -N(R26)-.Atty. Docket No.44727-732601 22. The compound of any one of claims 1 and 8-16, wherein L1is -N(Me)-.

23. The compound of any one of claims 1 and 8-16, wherein L1is -N(H)-.

24. The compound of any one of claims 1 and 8-23, wherein J is aryl or heteroaryl, each of which is independently substituted or unsubstituted.

25. The compound of any one of claims 1 and 8-24, wherein J is 5- or 6-membered aryl, 5- or 6- membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is independently substituted or unsubstituted.

26. The compound of any one of claims 1 and 8-25, wherein J is phenyl that is substituted or unsubstituted.

27. The compound of any one of claims 1 and 8-25, wherein J is pyrazolyl that is substituted or unsubstituted.

28. The compound of any one of claims 1 and 8-25, wherein J is thiophenyl that is substituted or unsubstituted.

29. The compound of any one of claims 1 and 8-25, wherein J is pyridyl that is substituted or unsubstituted.

30. The compound of any one of claims 1 and 8-25, wherein J is imidazolyl that is substituted or unsubstituted.

31. The compound of any one of claims 1 and 8-24, wherein J is 5- or 6-membered aryl, 5- or 6- membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one to five groups independently selected from alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, -CN, -NR24R25, -OR24, - C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, - NR24S(O)2R25, -S(=NR24)(=O)R25, -S(O)NR24R25, and -S(O)2NR24R25.

32. The compound of claim 1 or claim 8, wherein the compound is of formula XII-3a, or a pharmaceutically-acceptable salt thereof:wherein each RZis independently selected from alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, - C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, -NR25S(O)2R25, -S(=NR24)(=O)R25, - S(O)NR24R25, and -S(O)2NR24R25, and n is 1, 2, 3, 4, or 5.

33. The compound of claim 32, wherein each RZis independently selected from C1-6alkyl, C1- 6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl,Atty. Docket No.44727-732601 halogen, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, - SO2R24, -NR24S(O)R25, -NSR24(O)2R25, -S(=NR24)(=O)R25, -S(O)NR24R25, and -S(O)2NR24R25.

34. The compound of claim 32, wherein each RZis independently selected from halogen, -OR24, - C(O)NR24R25, -SO2R24, P(O)R24R25, and -S(O)2NR24R25.

35. The compound of any one of claims 1 and 8-34, wherein R13is alkyl or -S-alkyl that is substituted or unsubstituted.

36. The compound of any one of claims 1 and 8-35, wherein R13is R13is cyanomethyl.

37. The compound of any one of claims 1 and 8-35, wherein R13is -S-C1-6haloalkyl.

38. The compound of any one of claims 1 and 8-35, wherein R13is -SCF3.

39. The compound of any one of claims 1 and 8-34, wherein R13is alkyl that is substituted or unsubstituted.

40. The compound of any one of claims 1 and 8-35, wherein R13is alkyl, haloalkyl, or -CH2- heterocyclyl.

41. The compound of any one of claims 1, 8-35, and 40, wherein R13is thiophenylmethyl.

42. The compound of any one of claims 1 and 8-35, wherein R13is alkyl or haloalkyl.

43. The compound of any one of claims 1 and 8-35, wherein R13is C1-6alkyl or C1-6haloalkyl.

44. The compound of any one of claims 1 and 8-35, wherein R13is 2,2,2-trifluoroethyl, 2,2- difluoroethyl, isopropyl, or cyclopropylmethyl.

45. The compound of any one of claims 1 and 8-35, wherein R13is haloalkyl.

46. The compound of any one of claims 1 and 8-35, wherein R13is C1-2haloalkyl.

47. The compound of any one of claims 1 and 8-35, wherein R13is 2,2,2-trifluoroethyl, or 2,2- difluoroethyl.

48. The compound of any one of claims 1 and 8-35, wherein R13is 2,2,2-trifluoroethyl.

49. The compound of any one of claims 1, 8, 9, 10, and 15, wherein R15is alkyl or hydrogen.

50. The compound of any one of claims 1, 8, 9, 10, and 15, wherein R15is C1-6alkyl or hydrogen.

51. The compound of any one of claims 1, 8, 9, 10, and 15, wherein R15is methyl.

52. The compound of any one of claims 1, 8, 9, 10, and 15, wherein R15is hydrogen.

53. The compound of any one of claims 1 and 8-52, wherein Q is alkylene.

54. The compound of any one of claims 1 and 8-52, wherein Q is C1-6alkylene.

55. The compound of any one of claims 1 and 8-52, wherein Q is methylene.

56. The compound of any one of claims 1 and 8-52, wherein Q is –C(O)– or a bond.

57. The compound of any one of claims 1 and 8-52, wherein Q is –C(O)–.

58. The compound of any one of claims 1 and 8-52, wherein Q is a bond.

59. The compound of any one of claims 1 and 8-58, wherein Y is -NR3R4.

60. The compound of any one of claims 1 and 8-59, wherein R4is hydrogen or substituted or unsubstituted alkyl.

61. The compound of any one of claims 1 and 8-59, wherein R4is methyl, ethyl, isopropyl, n-propyl, or hydrogen.Atty. Docket No.44727-732601 62. The compound of any one of claims 1 and 8-59, wherein R4is hydrogen.

63. The compound of any one of claims 1 and 8-62, wherein R3is cycloalkyl, heterocyclylalkyl, or heteroalkyl, each of which is substituted or unsubstituted.

64. The compound of any one of claims 1 and 8-62, wherein R3is substituted or unsubstituted cycloalkyl.

65. The compound of any one of claims 1 and 8-62, wherein R3is substituted or unsubstituted 4-, 5-, or 6-membered cycloalkyl.

66. The compound of any one of claims 1 and 8-62, wherein R3is substituted or unsubstituted cyclohexyl.

67. The compound of any one of claims 1 and 8-62, wherein R3is substituted cyclohexyl.

68. The compound of any one of claims 1 and 8-62, wherein R3is substituted or unsubstituted heterocyclylalkyl.

69. The compound of any one of claims 1 and 8-62, wherein R3is a substituted or unsubstituted 4-, 5-, 6-, 7-, or 8-membered heterocyclylalkyl.

70. The compound of any one of claims 1 and 8-62, wherein R3is a substituted or unsubstituted 4-, 5-, or 6-membered heterocyclylalkyl.

71. The compound of any one of claims 1 and 8-62, wherein R3is a substituted or unsubstituted 5- membered heterocyclylalkyl.

72. The compound of any one of claims 1 and 8-62, wherein R3is a substituted or unsubstituted 6- membered heterocyclylalkyl.

73. The compound of any one of claims 1 and 8-62, wherein R3is substituted or unsubstituted nitrogen-containing heterocyclylalkyl.

74. The compound of any one of claims 1 and 8-62, wherein R3is a substituted or unsubstituted 4-, 5-, 6-, 7-, or 8-membered nitrogen-containing heterocyclylalkyl.

75. The compound of any one of claims 1 and 8-62, wherein R3is substituted or unsubstituted piperidinyl.

76. The compound of any one of claims 1 and 8-62, wherein R3is piperidinyl that is unsubstituted or substituted with one, two, or three groups independently selected from alkyl, cycloalkyl, heteroalkyl, halogen, and heterocyclylalkyl, each of which is independently substituted or unsubstituted.

77. The compound of any one of claims 1 and 8-25, wherein J is 5- or 6-membered aryl, 5- or 6- membered heteroaryl, or 5- or 6-membered heterocyclyl, each of which is independently unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, -NR24S(O)R25, -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25.

78. The compound of any one of claims 1 and 8-25, wherein J is phenyl that is unsubstituted or substituted with one to five substituents, or 5-membered heteroaryl that is unsubstituted orAtty. Docket No.44727-732601 substituted with one to four substituents, wherein each substituent is independently selected from C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1- 9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -SO2R24, -NR24S(O)R25, -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25.

79. The compound of any one of claims 1 and 8-25, wherein J is phenyl that is unsubstituted or substituted with one to five groups independently selected from C1-6alkyl, C1-6haloalkyl, C3- 10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1-9heterocyclyl, halo, -CN, - NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, -S(O)R24, -SO2R24, - NR24S(O)R25, -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25.

80. The compound of any one of claims 1 and 8-25, wherein J is phenyl that is unsubstituted or substituted with one to five groups independently selected from halogen, -OR24, -C(O)NR24R25, - SO2R24, and -S(O)2NR24R25.

81. The compound of any one of claims 1 and 8-80, wherein R24and R25are each independently selected from haloalkyl, alkyl and hydrogen.

82. The compound of any one of claims 1 and 8-80, wherein R24and R25are each independently selected from alkyl and hydrogen.

83. The compound of any one of claims 1 and 8-80, wherein R26and R27are each independently selected from alkyl and hydrogen.

84. The compound of any one of claims 1 and 8-80, wherein R28and R29are each independently selected from alkyl and hydrogen.

85. The compound of any one of claims 1 and 8-80, wherein R24and R25are each independently selected from methyl, ethyl, propyl, butyl, and hydrogen.

86. The compound of any one of claims 1, 8-80 and 85, wherein R26and R27are each independently selected from methyl, ethyl, propyl, butyl, and hydrogen.

87. The compound of any one of claims 1 and 8-86, wherein R28and R29are each independently selected from methyl, ethyl, propyl, butyl, and hydrogen.

88. The compound of any one of claims 1 and 8-14, wherein R19is substituted or unsubstituted alkyl, haloalkyl, halogen, or hydrogen.

89. The compound of any one of claims 1 and 8-14, wherein R19is C1-6alkyl, C1-6haloalkyl, halogen, or hydrogen.

90. The compound of any one of claims 1 and 8-14, wherein R19is hydrogen.

91. The compound of any one of claims 1 and 8-90, wherein R5is substituted or unsubstituted alkyl, haloalkyl, halogen, or hydrogen.

92. The compound of any one of claims 1 and 8-90, wherein R5is C1-6alkyl, C1-6haloalkyl, halogen, or hydrogen.

93. The compound of any one of claims 1 and 8-90, wherein R5is hydrogen.

94. The compound of any one of claims 1 and 8-93, wherein R9is substituted or unsubstituted alkyl, haloalkyl, halogen, or hydrogen.Atty. Docket No.44727-732601 95. The compound of any one of claims 1 and 8-93, wherein R9is C1-6alkyl, C1-6haloalkyl, halogen, or hydrogen.

96. The compound of any one of claims 1 and 8-93, wherein R9is hydrogen.

97. The compound of claim 1 or claim 8, wherein A is ethynylene or 5- or 6-membered heterocyclylene that is unsubstituted or substituted with one to three R29.

98. The compound of any one of claims 1, 8, and 97, wherein J is C6-10aryl, C1-9heteroaryl, or C1- 9heterocyclyl, each of which is independently unsubstituted or substituted with one to six groups independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, C1- 9heterocyclyl, halo, -CN, -NR24R25, -OR24, -C(O)R24, -P(O)R24R25, -C(O)OR24, -C(O)NR24R25, - S(O)R24, -SO2R24, -NR24S(O)R25, -NR24S(O)2R25, -S(O)NR24R25, and -S(O)2NR24R25.

99. The compound of any one of claims 1, 8, 97, and 98, wherein Q is C1-6alkylene, C2-6alkenylene, or C2-6alkynylene, each of which is independently unsubstituted or substituted with one or two groups selected from C1-3alkyl or halogen; or -C(O)-, -N(R26)C(O)-, -C(S)-, or a bond.

100. The compound of any one of claims 1, 8-59, 77-80, 88-90, and 97-99, wherein each R3and R4is independently: - C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-9cycloalkyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with 1 to 7 RX; or - H, -C(O)R24, -C(O)OR24, -C(O)NR24R25, -SOR24, or -SO2R24, or - R3and R4together with the nitrogen atom to which R3and R4are bound form C1-9heterocyclyl, that is unsubstituted or substituted with 1 to 7 RX; wherein each RXis independently selected from -CN, halogen, -C(O)R24, -C(O)OR24, -NR24R25, - OR24, -C(O)NR24R25, -SR24, -S(O)R24, -SO2R24, -NR24C(O)R25, and-OC(O)R24; or C1-6alkyl, C3-10cycloalkyl, C1-6heteroalkyl, C6-10aryl, and C1-9heterocyclyl, C1-6alkylene-C6-10aryl, C1-6alkylene- C1-9cycloalkyl, and C1-6alkylene-C1-9heterocyclyl, each of which is independently unsubstituted or substituted with -CN, halogen, methyl, ethyl, propyl, butyl, -C(O)R28, -C(O)OR28, -C(O)NR28R29, - OR28, -SR28, -S(O)R28, -SO2R28, -NR28R29, -NR28C(O)R29, or -OC(O)R28.

101. The compound of claim 100, wherein R3is C3-9cycloalkyl, C1-9heterocyclylalkyl, or C1-6heteroalkyl, each of which is independently unsubstituted or substituted with 1 to 7 RX.

102. The compound of claim 100 or 101, wherein R3is cyclohexyl that is unsubstituted or substituted with 1 to 7 RX.

103. The compound of claim 100, wherein R3is C1-9heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX.

104. The compound of claim 100, wherein R3is a 4-, 5-, 6-, 7-, or 8-membered heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX.

105. The compound of claim 100, wherein R3is a 4-, 5-, or 6-membered heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX.

106. The compound of claim 100, wherein R3is a 5-membered heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX.Atty. Docket No.44727-732601 107. The compound of claim 100, wherein R3is a 6-membered heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX.

108. The compound of claim 100, wherein R3is a 4-, 5-, 6-, 7-, or 8-membered nitrogen-containing heterocyclylalkyl that is unsubstituted or substituted with 1 to 7 RX.

109. The compound of any one of claims 100-108, wherein each RXis independently selected from -CN, halogen, -NR24R25, -C(O)R25, -C(O)OR24, -NR25C(O)R26, and -OR24; or C1-6alkyl, C1-9heterocyclyl, and C1-6heteroalkyl, each of which is independently unsubstituted or substituted with halogen, -CN, -OR28, -C(O)NR28R29, -C(O)OR28, -SO2R28, methyl, ethyl, or propyl.

110. The compound of any one of claims 100-108, wherein each RXis independently selected from fluoro, methyl, ethyl, methoxy, 3,3-difluorocyclopentyl, 3,4-difluorocyclopentyl, 4- cyanocyclohexyl, 4-hydroxycyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, tetrahydro-3- furyl, tetrahydropyranyl, 2-methyltetrahydropyranyl, 2,4-dimethyltetrahydropyranyl, 2- fluorotetrahydropyranyl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, 4-methyltetrahydro-2H-pyran-4- yl, 4-oxepanyl, 2-oxa-6-spiro[3.3]heptyl, 8-oxabicyclo[3.2.1]oct-3-yl 3,4-dihydroxycyclopentyl, 8- oxabicyclo[3.2.1]oct-3-yl, bicyclo[1.1.1]pent-1-yl, 2-methoxy-1-methylethyl, 2-methoxy-2- methylpropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 3-fluoro-3-methylbutyl, 3- fluorocyclobutyl, 3,3-difluorocyclobutyl, 2,2-difluorocyclopropyl, 2-methoxyethyl, 2-hydroxy-3- methoxypropyl, 2,3-dihydroxypropyl, N-tetrahydro-2H-pyran-4-yl(carbamoyl)methyl, 2- mesylethyl, methoxy, N-methyl(carbamoyl)methyl, carbamoylmethyl, methylamino, dimethylamino, or 2-amino-2-oxoeth-1-yl.

111. The compound of claim 1 or claim 8, wherein each R5, R6, R7, R9, R10, R11, R13, R14, R15, R16, R17, R18, R21, R22, and R23is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with halogen, methyl, ethyl, propyl, or butyl; or H, halo, -C(O)R26, -C(O)OR26, -C(O)NR26R27, -OR26, -SR26, - SO2R26, -NR26R27, -NR26C(O)R27, or -OC(O)R26.

112. The compound of any one of claims 1, 8, and 97-111, wherein each R19is hydrogen, halogen, or C1-6alkyl that is unsubstituted or substituted with halogen.

113. The compound of claims 1, 8, and 97-112, wherein each R24and R25is independently C1-6alkyl, C3-10cyclolkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is unsubstituted or substituted with halogen, methyl or ethyl; or H, - C(O)R28, -C(O)OR28, -C(O)NR28R29, -OR28, -SR28, -NR28R29, -NR28C(O)R29, or -OC(O)R28; or R24and R25together with the nitrogen atom to which R24and R25are bound form a 5- or 6-membered ring, wherein the ring is unsubstituted or substituted with halogen, methyl, or ethyl.

114. The compound of claims 1, 8, and 97-113, wherein each R26, R27, R28, and R29is independently C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C1-9heteroaryl, or C1-9heterocyclyl, each of which is independently unsubstituted or substituted with halogen, cyano, hydroxy, amino, methyl, ethyl, propyl, or butyl; or hydrogen.

115. The compound of any one of claims 100-105, 107, and 108, wherein Y is:Atty. Docket No.44727-732601.

116. The compound of any one of claims 100-105, 107, and 108, wherein Y is:.

117. The compound of any one of claims 100-105, 107, and 108, wherein Y is:.

118. The compound of any one of claims 100-105, 107, and 108, wherein Y is:.

119. The compound of any one of claims 100-105, 107, and 108, wherein Y is:.

120. The compound of any one of claims 100-105, 107, and 108, wherein Y is:.

121. The compound of any one of claims 100-105, 107, and 108, wherein Y is:.

122. The compound of any one of claims 100-105, 107, and 108, wherein Y is:.

123. The compound of any one of claims 100-105, 107, 108, and 115-122, wherein RXis:Atty. Docket No.44727-732601124. The compound of any one of claims 1-63, 68-70, 72-80, 88-90, 97-101, 103-105, 107-109, 111, 115, and 116, wherein Y is:

125. The compound of any one of claims 1-63, 68-70, 72-80, 88-90, 97-101, 103-105, and 107-110, wherein Y is:Atty. Docket No.44727-732601127. The compound of any one of claims 1-63, 68-70, 72-80, 88-90, 97-101, 103-105, 107-109, and 111, wherein Y is:

128. The compound of any one of claims 1-63, 68-70, 72-80, 88-90, 97-101, 103-105, 107-109, and 111, wherein Y is:.

129. The compound of any one of claims 1-62, wherein Y is:.

130. The compound of any one of claims 1-63, 68-70, 72-80, 88-90, 97-101, 103-105, 107-109, 111, 115, and 116, wherein Y is:Atty. Docket No.44727-732601131. The compound any one of claims 1-63, 68-70, 72-80, 88-90, 97-101, 103-105, 107-109, 111, 115, and 116, wherein Y is:.

132. The compound of any one of claims 1-63, 68-70, 72-80, 88-90, 97-101, 103-105, and 107-109, wherein Y is:

133. The compound of any one of claims 1-63, 68-70, 72-80, 88-90, 97-101, 103-105, and 107-110, wherein Y is:.

134. The compound of any one of claims 1-63, 100, and 101, wherein Y is:

135. The compound of any one of claims 1-63, 68, 73, 74, 77-80, 88-90, 97-101, 103, 104, and 108, wherein Y is:

136. The compound of any one of claims 1-63 and 100, wherein Y is:Atty. Docket No.44727-732601 137. The compound of any one of claims 1-63 and 100, wherein Y is:.

138. The compound of any one of claims 1-63 and 100, wherein Y is:

139. The compound of any one of claims 1-63 and 100, wherein Y is:

140. The compound of any one of claims 1-63 and 100, wherein Y is:.

141. The compound of any one of claims 1-63, 68-70, 72, 77-80, 88-90, 97-101, 103-105, and 107 wherein Y is:.

142. The compound of any one of claims 1-67 and 100, wherein Y is:.

143. The compound of any one of claims 1-63, 68-70, 72, 77-80, 88-90, 97-101, 103-105, and 107, wherein Y is:

144. A pharmaceutical composition comprising a compound of any of claims 1-143, and a pharmaceutically-acceptable salt thereof.

145. A method of treating cancer or a p53 meditated disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1- 143 or a pharmaceutical composition of claim 144.Atty. Docket No.44727-732601 146. The method of claim 145, wherein the cancer is breast cancer.

147. The method of claim 145, wherein the cancer is lung cancer.

148. The method of claim 145, wherein the cancer is ovarian cancer.

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