Tricyclic compounds that break down neosubstrates for medical therapy.

Abstract

The present invention provides neosubstrate-degrading tricyclic compounds for use in the treatment of disorders described herein, including, for example, abnormal cell proliferation, neurodegenerative diseases, and autoimmune diseases.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims the interests of U.S. Provisional Patent Application No. 63 / 091,894, filed on 14 October 2020, which in whole constitutes part of this specification by reference for all purposes.

[0002] The present invention provides a tricyclic compound that degrades the cerebron E3 ubiquitin ligase neosubstrate, which is used in the treatment of disorders described herein, including, for example, abnormal cell proliferation, inflammatory disorders, neurodegenerative diseases, and autoimmune diseases.

[0003] [References] The contents of the text file, named "16010-058WO1_SequenceListing_ST25.txt", created on October 14, 2021, and measuring 3.94KB, constitute part of this specification by quoting its entire contents. [Background technology]

[0004] Proteolysis is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved by the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of virtually all cellular processes, including antigen processing, apoptosis, organelle biosynthesis, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neurodegeneration and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biosynthesis, and viral infection.

[0005] The covalent bonding of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases labels proteins for proteasomal degradation, where the protein is digested into small peptides and ultimately into its constituent amino acids, which become the building blocks of new proteins. Defects in proteasomal degradation have been associated with a variety of clinical disorders, particularly Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0006] Thalidomide, and its analogues lenalidomide and pomalidomide, have attracted attention as immunomodulatory and antineoplastic agents, particularly in the treatment of multiple myeloma (see Non-Patent Documents 1 and 2). Thalidomide, lenalidomide, pomalidomide, and their analogues contain an imide functional group (C(O)-NH-C(O)). Celegene has disclosed a variety of imides and their uses, including those described in Patent Documents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24.

[0007] The phthalimide portion of an imide interacts with specific amino acids in the cereblon receptor of the ligase protein complex, "generating" a thermodynamically favorable site for what is called a "neosubstrate." A neosubstrate is a protein that does not normally bind to the ligase but generates this novel site when a drug binds to cereblon. A major focus of current research is the identification of neosubstrates based on the diverse chemical structures of cereblon-binding ligands. This opens up new avenues for medical therapies, as well as novel means of disrupting biological pathways that cause dysfunctional diseases by relying on protein neosubstrates.

[0008] The rapid ubiquitination and proteasomal degradation of IKZF1 and IKZF3 by thalidomide, lenalidomide, and pomalidomide has become the subject of extensive research. These drugs degrade IKZF1 / 3 through the Cys2-His2 (C2H2) zinc finger (ZF) domains of both IKZF1 and IKZF3, thereby catalyzing CRL4 CRBN Replenish with E3 ubiquitin ligase (Non-Patent Literature 3). Sievers et al. tested numerous proteins with C2H2 zinc finger domains in functional or computational screens and identified 15 individual ZFs and 7 full-length ZF-containing proteins that are degraded by thalidomide derivatives. This study showed that 28 ZFs with diverse amino acid sequences (including IKZF2 and IKZF4) bind to the same drug-CRBN interface. They observed that thalidomide analogs containing chemical modifications at the drug-ZF interface can convert ZFs with weak affinity to the CRBN-pomalidomide complex into targets for degradation. IKZF2 and IKZF4 are not degraded by pomalidomide, lenalidomide, or CC-122, but are efficiently degraded by CC-220, which exemplifies the currently unpredictable nature of proteolysis and the fact that this is uniquely based on the combination of cereblon and the specific chemical structure of the drug, where the neosubstrate-binding motif generates a thermodynamically favorable binding site for the neosubstrate.

[0009] Thalidomide analogs have been reported to degrade structurally unrelated proteins, raising further questions about how cereblon works and how best to utilize it for therapeutic purposes. For example, in addition to IKZF1 / 3, casein kinase 1α (CK1α) and GSPT1 have been reported to be degradable through this mechanism (Non-Patent Documents 4, 5, 6, and 7).

[0010] It has been further reported that ARID2 can be degraded using the CRBN proteasome pathway (Non-Patent Literature 8). ARID2 is a component of the polybromo-associated BAF (PBAF) chromatin remodeling complex. Yamamoto, et al. reported that ARID2 is degradable via CRL4 CRBN It was reported to be a pomalidomide-inducible neosubstrate. Another subunit of PBAF, BRD7, is essential for pomalidomide-inducible ARID2 degradation. ARID2 degradation is an example of cofactor-affected target protein degradation.

[0011] Patent document 25, filed by the Dana Farber Cancer Institute, discloses tricyclic glutarimide-containing compounds. Patent documents 26, 27, and 28, filed by Kymera, also disclose tricyclic glutarimide-containing compounds, respectively.

[0012] Patent documents 29 and 30 filed by C4 Therapeutics, Inc. disclose cereblon binders for the degradation of Ikaros (IKZF1 / 3).

[0013] Patent document 31, filed by Calico Life Sciences LLC and AbbVie Inc., describes PTPN1 and PTPN2 degraders covalently bound to various cereblon ligands.

[0014] Examples of patent applications in zinc finger decomposition spaces include Patent Documents 32, 33, 34, 35, 36, 37, 38, 39, and 40.

[0015] Despite these efforts, there remains a need for novel compounds, uses, and methods of production for medical therapies, including the treatment of abnormal cell proliferation, neurodegenerative diseases, and autoimmune diseases, and this compound causes proteolysis of the neosubstrate CRL4 CRBNIt can bind to the cereblon receptor of E3 ubiquitin ligase, generating a novel binding site for neosubstrates, which are mediators of human diseases. [Prior art documents] [Patent Documents]

[0016] [Patent Document 1] U.S. Patent No. 6,045,501 [Patent Document 2] U.S. Patent No. 6,315,720 [Patent Document 3] U.S. Patent No. 6,395,754 [Patent Document 4] U.S. Patent No. 6,561,976 [Patent Document 5] U.S. Patent No. 6,561,977 [Patent Document 6] U.S. Patent No. 6,755,784 [Patent Document 7] U.S. Patent No. 6,869,399 [Patent Document 8] U.S. Patent No. 6,908,432 [Patent Document 9] U.S. Patent No. 7,141,018 [Patent Document 10] U.S. Patent No. 7,230,012 [Patent Document 11] U.S. Patent No. 7,820,697 [Patent Document 12] U.S. Patent No. 7,874,984 [Patent Document 13] U.S. Patent No. 7,959,566 [Patent Document 14] U.S. Patent No. 8,204,763 [Patent Document 15] U.S. Patent No. 8,315,886 [Patent Document 16] U.S. Patent No. 8,589,188 [Patent Document 17] U.S. Patent No. 8,626,531 [Patent Document 18] U.S. Patent No. 8,673,939 [Patent Document 19] U.S. Patent No. 8,735,428 [Patent Document 20] U.S. Patent No. 8,741,929 [Patent Document 21] U.S. Patent No. 8,828,427 [Patent Document 22] U.S. Patent No. 9,056,120 [Patent Document 23] U.S. Patent No. 9,101,621 [Patent Document 24] U.S. Patent No. 9,101,622 [Patent Document 25] International Publication No. 2020 / 006262 [Patent Document 26] International Publication No. 2020 / 206424 [Patent Document 27] International Publication No. 2020 / 010177 [Patent Document 28] International Publication No. 2020 / 010227 [Patent Document 29] International application PCT / US2019 / 24094 [Patent Document 30] International application PCT / US2020 / 02678 [Patent Document 31] International Publication No. 2021 / 127586 [Patent Document 32] International Publication No. 2020 / 012334 [Patent Document 33] International Publication No. 2020 / 012337 [Patent Document 34] International Publication No. 2019 / 038717 [Patent Document 35] International Publication No. 2020 / 128972 [Patent Document 36] International Publication No. 2020 / 006264 [Patent Document 37] International Publication No. 2020 / 117759

Patent document 38

Patent document 39

Patent document 40

Non-licensed literature

[0017] [Non-licensed document 1] Martiniani, R. et al. "Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma" Adv Hematol, 2012, 2012:842945 [Non-licensed document 2] Terpos, E. et al. "Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma" Oncotargets and Therapy, 2013, 6:531 [Non-licensed document 3] Sievers et.al., Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN, Science 362, 558 (2018) [Non-licensed document 4] Kronke, et al., Lenalidomide induces ubiquitination and degradation of CK1α in de(5q) MDS; Nature, 523, 183-188 (2015)

Non-licensed Document 5

[0018] Novel tricyclic compounds are provided herein, along with their use and manufacture, for the treatment of diseases characterized by abnormal cell proliferation, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases, as described herein.

[0019] The tricyclic compounds provided herein induce proteolytic degradation of the neosubstrate CRL4 CRBNThe tricyclic compounds described herein can bind to the cereblon receptor of E3 ubiquitin ligase, generating novel binding sites for neosubstrates, which are mediators of human diseases. The tricyclic compounds described herein can generate novel surface forms on cereblon, which can directly interact with target proteins or target protein complexes to directly or indirectly reduce protein levels. In various embodiments, the tricyclic compounds described herein can cause a reduction in neosubstrate target protein levels through direct ubiquitination of the target protein, or through ubiquitination of neosubstrate target protein cofactors, target protein complexes, or other proteins involved in regulating target protein homeostasis. The compounds can cause a reduction in target protein levels by degradation of neosubstrate target proteins that directly bind to ligand-bound cereblon, degradation of neosubstrates that are cofactors that bind to ligand-bound cereblon, degradation of the binding site of the complex cofactor and target protein interface to ligand-bound cereblon, degradation of neosubstrate target protein complexes that bind to ligand-bound CRBN, or degradation of proteins that affect the homeostasis level of the target protein but are not present in the target protein complex or cofactor.

[0020] In certain embodiments, the degraded neosubstrate is a protein containing a β-hairpin turn with glycine at a key position ("g-loop protein" or "g-loop degron") that acts as a "structural degron" of cereblon when cereblon is also bound to the tricyclic compound of the present invention, as further described herein. Non-limiting examples of neosubstrates include Sal-like protein 4 (SALL4), GSPT1, IKFZ1, IKFZ3, CK1α, ZFP91, ZNF93, protein kinase, C2H2-containing zinc finger protein, RNA recognition motif-containing protein, zinc beta-ribbon-containing protein, beta-propeller-containing protein, P-loop NTPase-containing protein, really interesting new gene (RING) finger domain-containing protein, SRC homology 3 (SH3) domain-containing protein, immunoglobulin E set domain-containing protein, Tudor domain-containing protein, FAM38, or ARID. In other embodiments, another disease-mediated protein is degraded by a disclosed tricyclic cereblon-binding compound, which may include any of those described herein or otherwise determined.

[0021] In another embodiment, CRL4 CRBN A tricyclic compound that binds to the cereblon receptor of E3 ubiquitin ligase can generate novel binding sites for two or more protein neosubstrates that are mediators of human diseases, thereby causing proteolysis of numerous neosubstrates. In one particular embodiment, both IRAK4 and IKZF are degraded. In another embodiment, both SALL4 and IKZF are degraded. In yet another embodiment, other variants of the numerous proteins described herein are degraded to treat targeted human diseases.

[0022] In the main embodiments, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, or Formula XIV: [ka] (wherein, A is

Chem.

Chem.

[0023] In another embodiment of the present invention, a pharmaceutically acceptable carrier for optionally forming a composition contains formula XV, formula XVI, or formula XVII: [ka] (In the formula, AA is, [ka] Selected from, Ring E is, (a) [ka] (b) If permitted by valence, R 2A fused ring selected from a 5-membered heteroaryl, a 5- to 8-membered heterocycle, a 5- to 8-membered cycloalkyl, or a 5- to 8-membered cycloalkenyl, optionally substituted with one, two, or three substituents independently selected from the above. Selected from, Ring F is, (a)R 1 Phenyl substituted with one, two, or three substituents independently selected from ', (b) If permitted by valence, R 1 A fused ring selected from a 5-membered or 6-membered heteroaryl, a 5- to 8-membered heterocycle, a 5- to 8-membered cycloalkyl, or a 5- to 8-membered cycloalkenyl, optionally substituted with one, two, or three substituents independently selected from the above. Selected from, R 1 'Each of them is independent, (a) alkyl, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 , cyano, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, where each heteroaryl, aryl, and heterocyclic is R 40 Substituting with one, two, three, or four substituents independently selected from the original, (b) [ka] ,and, (c) Divalent parts, e.g., O, S, or =NR, where permitted by valency and stability. 25 , Selected from, Here, R 1’ The base is, arbitrarily, another R 1’ Base or R 2 They may combine with the base to form a fused ring or a biring, which may bridge ring-A and ring-E. R 2' are, independently, alkyl, halogen, haloalkyl, and -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 R is selected from cyano, nitro, heteroaryl, aryl, and heterocyclic compounds, or alternatively, if acceptable by valency and stability. 2’ This is the divalent part, for example, O, S, or =NR 25 It may also be the case that R 2’ The base is, arbitrarily, another R 2’ Base or R 1 They may combine with the base to form a fused ring or a biring, which may bridge ring-A and ring-E. R 2 Each of the elements is independently selected from heteroaryl, aryl, and heterocycles, and each heteroaryl, aryl, and heterocycle is optionally R 40 It is substituted with one, two, three, or four substituents independently selected from R, where R 2’’ The base is arbitrarily R 1 Base or R 2 They may combine with the base to form a fused ring or a biring, which may bridge ring-A and ring-E. R 3a is hydrogen, alkyl, halogen, or haloalkyl, Or, R 3a and R 6a They come together to form a one-carbon linkage or a two-carbon linkage, for example, R 3a and R 6a When forming a single carbon bond, [ka] teeth, [ka] And, Or, R 3a and R 4a These combine to form a 1-carbon linkage, a 2-carbon linkage, a 3-carbon linkage, or a 4-carbon linkage, for example, R3a and R 4a When forming a single carbon bond, [ka] teeth, [ka] And, Or, R 3a and R 3a Adjacent to R 4a The groups come together to form a double bond, R 4a It is selected from hydrogen, alkyl, halogen, and haloalkyl, R 6s and R 7a These are independently hydrogen, alkyl, halogen, haloalkyl, and -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , and -NR 10 R 11 Selected from, Or, R 6a and R 7a They come together to form a 3-membered or 4-membered spiro ring. Here R 3a , R 4a , R 6a and R 7a At least one of them is not hydrogen, R 28 Alkyl, alkene, alkyne, hydroxy, azide, amino, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 Selected from cyano, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, where each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is optionally R 40 Substituted with one, two, three, or four substituents independently selected from, Here R15 , R 16 , R 17 , and R 20 If at least one of them is not a bond, R 28 It may be hydrogen, The present invention provides compounds of (wherein all other variable parts are as defined herein) or pharmaceutically acceptable salts, N-oxides, isotopic derivatives, or prodrugs thereof.

[0024] In several embodiments, compounds and methods are provided for the treatment of disorders including cancer, tumors, or noncancerous or nontumorous conditions, such as those described in more detail below, characterized by any abnormal cell proliferation responsive to this therapy. In certain embodiments, the disorder is, for example, hematopoietic disorders, such as lymphocyte disorders, leukemia, lymphocytic leukemia, lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hematological malignancies, multiple myeloma, myelodysplastic syndromes, such as 5q syndrome, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, AML, or chronic lymphocytic leukemia. In another embodiment, selected compounds of the present invention are administered to achieve immunomodulation and reduce angiogenesis. In other embodiments, but not limited to, compounds and methods described herein are presented for the treatment of disorders including graft-versus-host rejection, viral infection, bacterial infection, amyloid-based proteinopathy, proteinopathy, or fibrous disorders. Furthermore, other disorders that can be treated with an effective amount of the compounds described herein are listed below.

[0025] In certain embodiments, any of the compounds described herein have, i.e., are enriched, at least one desired isotopic substitution of an atom in substantially naturally occurring isotopic abundances. In certain embodiments, the compound contains one or more deuterium atoms.

[0026] Other features and advantages of the present invention will become apparent from the following detailed description and claims.

[0027] Therefore, the present invention includes at least the following features. (a) Compounds of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein, or pharmaceutically acceptable salts, isotopic derivatives (including deuterated derivatives), or prodrugs thereof (b) For the treatment of medical disorders in which patients require treatment, typically in humans, that are responsive to such compounds, such as those described herein, compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or pharmaceutically acceptable salts, isotopes, or prodrugs thereof. (c) Patients having any one of the disorders described herein, typically in the treatment of humans, use in an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof. (d) Use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or their pharmaceutically acceptable salts, isotope derivatives, or prodrugs, in the manufacture of a drug for the treatment of a medical disorder in which the drug is reactive to such compounds, as further described herein. (e) A method for producing a pharmacopoeia for the treatment of a disorder described herein in a host, characterized in that a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII is used in the production. (f) For the treatment of abnormal cell proliferation or cancer in a host, including any of the cancers described herein, compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein, or pharmaceutically acceptable salts, isotopes, or prodrugs thereof. (g) Use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or pharmaceutically acceptable salts, isotopes, or prodrugs thereof, in the manufacture of a drug for the treatment of cancer, including any of the cancers described herein. (h) A method for producing a drug for the treatment of abnormal cell proliferation or cancer, including any of the cancers described herein, in a host, characterized in that a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII is used in the production. (i) For the treatment of tumors in a host, including any of the tumors described herein, compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein, or pharmaceutically acceptable salts, isotopes, or prodrugs thereof, (j) Use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or pharmaceutically acceptable salts, isotopes, or prodrugs thereof, in the manufacture of a drug for the treatment of any tumor, including any of the tumors described herein. (k) A method for producing a drug for the treatment of a tumor in a host, including any of the tumors described herein, characterized in that a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV, formula XVI, or formula XVII is used in the production. (l) Compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein, or pharmaceutically acceptable salts, isotopes, or prodrugs thereof, for the treatment of immune disorders, autoimmune disorders, neurodegenerative disorders, fibrous disorders, or inflammatory disorders in a host. (m) Use of compounds of formulas I, II, III, IV, V, VI, VII, VIII, and IX. (n) Compounds of formula X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein, or pharmaceutically acceptable salts, isotope derivatives, or prodrugs thereof, in the manufacture of drugs for the treatment of immunodeficiency, autoimmune disorder, neurodegenerative disorder, fibrous disorder, or inflammatory disorder. (o) A method for producing a drug for the treatment of an immune disorder, autoimmune disorder, or inflammatory disorder in a host, characterized in that a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV, formula XVI, or formula XVII is used in the production. (p) Compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein, or pharmaceutically acceptable salts, isotope derivatives, or prodrugs thereof, for the treatment of hematological malignancies, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma. (q) Use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or pharmaceutically acceptable salts, isotope derivatives, or prodrugs thereof, in the manufacture of agents for the treatment of hematological malignancies, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma, as described herein. (r) A method for producing a drug for the treatment of hematological malignancies in a host, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma, characterized in that a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII is used in the production. (s) A pharmaceutical composition comprising, in an amount effective for host treatment, a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent. (t) A compound described herein as a mixture of an enantiomer or diastereomer (if appropriate), including a racemic mixture. (u) Compounds described herein in an enantiomerically or diastereomerically concentrated form (where appropriate), including an isolated enantiomer or diastereomer (i.e., purer than about 80%, 85%, 90%, 95%, 97%, or 99%), and (v) A process for producing a therapeutic product containing an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII as described herein. [Brief explanation of the drawing]

[0028] [Figure 1] This is a synthetic diagram showing a non-limiting synthetic example that can be used with the intermediate 3-(5-bromo-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione, which adds a range of R1 and / or R2 groups. [Figure 2] This is a synthetic diagram showing a non-limiting synthetic example that can be used with the intermediate 1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-5-carbaldehyde, which adds a range of R1 and / or R2 groups. [Figure 3] This figure shows a representative formula, not limited to, of the compounds of the present invention. [Modes for carrying out the invention]

[0029] I. Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this application pertains. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Methods and materials similar to or equivalent to those described herein may be used in the implementation and testing of this application, but preferred methods and materials are described below. All publications, patent applications, patents and other references referenced herein constitute part of this specification by reference. References cited herein are not considered prior art to this application. In case of conflict, this specification, including definitions, shall prevail. In addition, materials, methods and examples are illustrative and not intended to be limiting.

[0030] Compounds are described using their formal names. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains.

[0031] In certain embodiments of each compound described herein, the compounds may be in the form of isomers such as racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, or rotational isomers, as each is specifically described, unless otherwise explicitly excluded by the context.

[0032] The terms "a" and "an" do not indicate a limitation of quantity, but rather indicate the presence of at least one of the items mentioned. The term "or" means "and / or". Unless otherwise specified herein, the enumeration of value ranges is intended merely as a simple way to refer individually to each distinct value contained within that range, and each distinct value constitutes part of this specification by reference as if they were individually enumerated herein. The endpoints of all ranges are contained within that range and can be combined independently. All methods described herein can be performed in a preferred order unless otherwise specified herein or clearly rejected by the context. The use of example or illustrative words (e.g., "such as") is intended merely to better illustrate the invention and does not indicate a limitation of the scope of the invention unless otherwise asserted.

[0033] The present invention includes compounds described herein that have isotopic substitution of at least one desired atom in an amount exceeding the natural abundance of the isotope, i.e., enriched. Isotopes are atoms that have the same atomic number but different mass numbers, i.e., the same number of protons but different number of neutrons. When isotopic substitution is used, substitution of hydrogen with at least one deuterium is common.

[0034] More generally, examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, for example. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17O, 18 O, 18 F, 35 S, and 36 Examples include each of Cl. In one non-limiting embodiment, isotope-labeled compounds are used in metabolic studies (e.g., 14 (using C), reaction dynamics studies (for example) 2 H or 3 It can be used in detection or imaging techniques, including drug or substrate tissue distribution assays or radiotherapy for patients, such as positron emission tomography (PET) or single-photon emission tomography (SPECT), using H. Additionally, any hydrogen atom present in the compound of the present invention 18 Substitution with a fluorine atom is also possible, and this substitution may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by replacing the non-isotope-labeled reagent with a readily available isotope-labeled reagent, by following the procedures disclosed in the scheme or in the following examples and preparations.

[0035] As a general example, though not limited to them, hydrogen isotopes, for example, deuterium ( 2 H) and tritium ( 3 H) can be used in any part of the described structure in which the desired result is achieved. Alternatively or additionally, carbon isotopes, for example 13 C and 14 You can use C.

[0036] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is replaced by deuterium. In certain embodiments, isotopes are enriched to 90%, 95%, 99%, or more at any position of interest. In one non-limiting embodiment, deuterium is enriched to 90%, 95%, or 99% at a desired position.

[0037] In one non-limiting embodiment, the substitution of a hydrogen atom with a deuterium atom can occur in any of the compounds described herein. For example, if any of the groups are methyl, ethyl, or methoxy, or contain these by substitution, for example, an alkyl residue may be deuterated (e.g., CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 in a non-limiting embodiment). In certain other embodiments, if two substituents combine to form a ring, an unsubstituted carbon may be deuterated. In certain embodiments, at least one deuterium atom is located on an atom having a bond that is cleaved during the metabolism of the compound in vivo, or on an atom one, two, or three atoms away from the bond that is metabolized (for example, sometimes referred to as the α-isotope effect, β-isotope effect, or γ-isotope effect, or the primary isotope effect, secondary isotope effect, or tertiary isotope effect).

[0038] The compounds of the present invention can form solvates with a solvent (including water). Therefore, in one non-limiting embodiment, the present invention includes compounds in the solvated forms described herein. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent may be isotope-substituted, such as D2O, d6-acetone, and d6-DMSO. Solvates may be in liquid or solid form.

[0039] A dash ("-") without a space between two letters or symbols is used to indicate the attachment point of a substituent. For example, -(C=O)NH2 is attached via the carbon of the keto (C=O) group.

[0040] "Alkyl" refers to a branched or linear saturated aliphatic hydrocarbon group. In one non-limiting embodiment, an alkyl group contains 1 to about 12 carbon atoms, more commonly 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In one non-limiting embodiment, an alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The designations used herein refer to alkyl groups having members in each range that are described as independent species. For example, the term C1-C6 alkyl as used herein refers to linear or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to mean that these are each described as independent species. For example, the term C1-C4 alkyl as used herein refers to linear or branched alkyl groups having 1, 2, 3, or 4 carbon atoms, and is intended to mean that these are each described as independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0041] An "alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable points along the chain. The designated ranges used herein refer to alkenyl groups having each member in the range described above as a separate species for the alkyl moiety. In one non-limiting embodiment, an alkenyl contains 2 to about 12 carbon atoms, more generally 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one unsaturated point.

[0042] An "alkynyl" is a branched or linear aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. The designations used herein refer to alkynyl groups having each member within the range described above as a separate species for the alkyl moiety. In one non-limiting embodiment, an alkynyl contains 2 to about 12 carbon atoms, more generally 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkynyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkynyls include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0043] "Halo" and "halogen" are independently fluorine, chlorine, bromine, or iodine.

[0044] A "haloalkyl" is a branched or linear alkyl group substituted with one or more of the above halo atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A "perhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0045] As used herein, "aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms within the aromatic ring system (e.g., 6, 10, or 14 π electrons shared in a cyclic configuration). 6~14 This refers to "aryl". In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl" (for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl," for example, anthracyl. "Aryl" also includes ring systems in which the above-defined aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the radical or attachment site is on the aryl ring, in which case the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4-membered to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0046] "Arylalkyl" refers to either an alkyl group as defined herein substituted with an aryl group as defined herein, or an aryl group as defined herein substituted with an alkyl group as defined herein.

[0047] The term "heterocyclic" refers to saturated and partially saturated heteroatom-containing ring radicals that contain one, two, three, or four heteroatoms independently selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocyclic rings may include monocyclic rings with 3 to 10 members and bicyclic ring systems with 5 to 16 members (including bridging, fusion, and spirofusion bicyclic ring systems). Heterocyclic rings do not include rings containing -OO-, -OS-, or -SS- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl), saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclic radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanil, chromanil, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, Examples include, but are not limited to, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0048] "Heterocyclic" also includes groups in which a heterocyclic radical fuses / condenses with an aryl or carbocyclic radical and the attachment site is a heterocyclic system. "Heterocyclic" also includes groups in which a heterocyclic radical is an oxo group (i.e., [ka] This also includes groups substituted with ), for example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline or isoindoline; partially unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0049] The term “heterocycle” also includes “bicyclic heterocycle.” The term “bicyclic heterocycle” refers to a heterocycle as defined herein that has one bridging, fusion, or spirocyclic portion of the heterocycle. The bridging, fusion, or spirocyclic portion of the heterocycle can be a carbocyclic, heterocycle, or aryl group, insofar as a stable molecule is formed. Unless otherwise excluded by context, the term “heterocycle” includes bicyclic heterocycles. A bicyclic heterocycle includes a group in which the fusion heterocycle is substituted with an oxo group. Non-restrictive examples of bicyclic heterocycles include: [ka] These are some examples.

[0050] "Heterocyclic alkyl" refers to either an alkyl group as defined herein that is substituted with a heterocyclic group as defined herein, or a heterocyclic group as defined herein that is substituted with an alkyl group as defined herein.

[0051] The term "heteroaryl" refers to a stable aromatic ring system containing one, two, three, or four heteroatoms independently selected from O, N, and S, in which the ring nitrogen and sulfur atoms (or more) are optionally oxidized and the nitrogen atom (or more) is optionally quaternized. Examples include unsaturated 5- or 6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, and triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl; and unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, such as 2-thie. Examples include, but are not limited to, nyl, 3-thienyl; unsaturated 5- or 6-membered heteromonocyclic groups containing one or two oxygen atoms and one to three nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); and unsaturated 5- or 6-membered heteromonocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms, such as thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl). In certain embodiments, the "heteroaryl" group is an 8-, 9-, or 10-membered bicyclic ring system. Examples of 8-membered, 9-membered, or 10-membered bicyclic heteroaryl groups include benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthilidinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, and benzotriazolyl.

[0052] "Heteroarylalkyl" refers to either an alkyl group as defined herein substituted with a heteroaryl group as defined herein, or a heteroaryl group as defined herein substituted with an alkyl group as defined herein.

[0053] As used herein, "carbocyclic," "carbocyclic," or "cycloalkyl" means that the non-aromatic ring system contains all the carbocyclic atoms and 3 to 14 ring carbon atoms ("C"). 3~14 The cycloalkyl group comprises a saturated or partially unsaturated (i.e., non-aromatic) group having 3 to 10 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C"). 3~10 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 9 ring carbon atoms ("C"). 3~9 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3~8 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 7 ring carbon atoms ("C"). 3~7 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C"). 4~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has five or six ring carbon atoms ("C"). 5~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C"). 5~10 Cycloalkyl). Exemplary C 3~6 Examples of cycloalkyl groups, though not limited to them, include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8The cycloalkyl group is not limited to the above C 3~6 Examples include cycloalkyl groups, and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Exemplary C 3~10 The cycloalkyl group is not limited to the above C 3~8 Cycloalkyl groups, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 Examples include the following. As shown in the above examples, in certain embodiments, the cycloalkyl group may be saturated or contain one or more intercarbon double bonds. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring defined above is fused with one heterocycle, aryl, or heteroaryl ring, and the attachment point is on the cycloalkyl ring, in which case the carbon number continues to represent the carbon number in the carbocyclic system. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring defined above has a spirocyclic heterocycle, aryl, or heteroaryl ring, and the attachment point is on the cycloalkyl ring, in which case the carbon number continues to represent the carbon number in the carbocyclic system. The term "cycloalkyl" also includes bicyclic or polycyclic fusions, bridges, or spirocyclic systems containing 5 to 14 carbon atoms and 0 heteroatoms in the non-aromatic ring system. Typical examples of "cycloalkyl" include: [ka] These include, but are not limited to, the following:

[0054] The term "bicyclic" refers to a ring system in which two rings are fused, with each ring independently selected from carbon rings, heterocyclic rings, aryl rings, and heteroaryl rings. Non-restrictive examples of bicyclic groups include: [ka] These are some examples.

[0055] When the term "bicyclic" is used in relation to a divalent residue, the attachment points may be on separate rings or on the same ring. In certain embodiments, both attachment points are on the same ring. In certain embodiments, both attachment points are on different rings. Non-limiting examples of divalent bicyclic groups include: [ka] These are some examples.

[0056] "Aliphatic" refers to saturated or unsaturated linear, branched, or cyclic hydrocarbons. In this specification, "aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and encompasses each of these definitions. In certain embodiments, "aliphatic" is used to refer to an aliphatic group having 1 to 20 carbon atoms. An aliphatic chain may be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated, or alkynyl. An unsaturated aliphatic group may be in a cis or trans configuration. In certain embodiments, an aliphatic group contains 1 to about 12 carbon atoms, more generally 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In certain embodiments, an aliphatic group contains 1 to about 8 carbon atoms. In certain embodiments, an aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The designations used herein refer to aliphatic groups having members in each range described as an independent species. For example, the term C1-C6 aliphatic, as used herein, refers to linear or branched alkyl, alkenyl, or alkynyl groups having one, two, three, four, five, or six carbon atoms, each of which is intended to be described as an independent species. For example, the term C1-C4 aliphatic, as used herein, refers to linear or branched alkyl, alkenyl, or alkynyl groups having one, two, three, or four carbon atoms, each of which is intended to be described as an independent species. In certain embodiments, the aliphatic group is substituted with one or more functional groups so that a stable moiety is formed.

[0057] The term “heteroaliphatic” refers to an aliphatic moiety containing at least one heteroatom in place of carbon atoms in the chain, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atom. In certain embodiments, the heteroatom is nitrogen only. In certain embodiments, the heteroatom is oxygen only. In certain embodiments, the heteroatom is sulfur only. “Heteroaliphatic” is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In certain embodiments, “heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 20 carbon atoms. In certain embodiments, the heteroaliphatic group is optionally substituted to form a stable moiety. Non-exclusive examples of heteroaliphatic moieties include polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocyclic-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0058] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, oral forms, sublingual forms, topical forms, gels, and mucosal forms. "Dosage form" may also include implants, such as optical implants.

[0059] As used herein, “endogenous” means any substance that originates from or is produced within an organism, cell, tissue, or system.

[0060] As used herein, the term “exogenous” refers to any substance introduced from or produced outside of an organism, cell, tissue, or system.

[0061] As used herein, the term "modulate" means mediating a detectable increase or decrease in the level of response in a subject compared to the level of response in the subject in the absence of the treatment or compound, and / or otherwise identical, compared to the level of response in an untreated subject. This term encompasses mediating a beneficial therapeutic response in a subject, preferably a human, by disrupting and / or affecting an inherent signal or response.

[0062] Parenteral administration of compounds includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection, or infusion methods.

[0063] As used herein, “pharmaceutical composition” is a composition comprising at least one activator, such as a selective active compound described herein, and at least one other substance, such as a carrier. “Pharmaceutical combinations” is a combination of at least two activators, which may be combined into a single dosage form or administered together in separate dosage forms, and which are indicated to be used in combination to treat any of the disorders described herein.

[0064] As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound obtained by modifying the parent compound to produce its inorganic and organic salts, acid addition salts, or base addition salts, with the loss of bioacidic toxicity. Salts of the compound can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid form with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K) or by reacting these compounds in their free base form with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical when practical. Salts of the compound further include solvates of the compound and salts of the compound.

[0065] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, ecylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nExamples of salts prepared from organic acids such as -COOH (where n is 0 to 4) or using different acids that produce the same counterion. A further list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0066] The term "carrier" means a diluent, additive, or vehicle in which the activator is used or delivered.

[0067] "Pharmacologically acceptable additives" mean additives that are generally safe and not inappropriate for administration to a host (usually a human), either biologically or otherwise, and that are useful in the preparation of a pharmaceutical composition / combination. In certain embodiments, additives acceptable for veterinary use are used.

[0068] "Patient," "host," or "subject" is a human or non-human animal requiring treatment for any of the disorders specifically described herein. Typically, the host is human. "Host" may also alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0069] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention means an amount that is effective in producing a therapeutic effect such as improvement of symptoms or reduction or mitigation of the disease itself when administered to a host.

[0070] In certain embodiments, a “prodrug” is a parent molecule in a form that is metabolized or chemically converted to the parent molecule in vivo, for example, in mammals or humans. Non-limiting examples of prodrugs include esters, such as amides, carbonates, carbamates, phosphates, ketals, imines, oxazolidines, and thiazolidins of primary or secondary amines. Prodrugs may be designed to release the parent molecule upon a change in pH (e.g., in the stomach or intestines) or upon the action of an enzyme (e.g., esterase or amidase).

[0071] In certain embodiments, “stable” means that less than 10%, less than 5%, less than 3%, or less than 1% of the compound decomposes under ambient conditions and has a shelf life of at least 3 months, 4 months, 5 months, or 6 months. In certain embodiments, compounds stored under ambient conditions are stored at approximately room temperature and exposed to air and relative humidity of less than about 40%, less than 50%, less than 60%, or less than 70%. In certain embodiments, compounds stored under ambient conditions are stored at approximately room temperature under an inert gas (such as argon or nitrogen). Typically, the parts described herein do not have more than one or two heteroatoms directly bonded to each other, unless the part is heteroaromatic.

[0072] Throughout this disclosure, various aspects of the present invention may be presented in range form. It should be understood that range form is merely for convenience and should not be interpreted as a limitation of the scope of the invention. Range descriptions should be considered to specifically disclose all conceivable subranges and the individual numerical values ​​within those ranges. For example, a range description such as 1-6 should be considered to specifically disclose subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and the individual numbers within those ranges, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0073] II. Compounds of the present invention In a particular embodiment, the compound of formula (I) is formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula (Il), formula (Im), and formula (In): [ka] Selected from TIFF0007863101000025.tif182170 or a pharmaceutically acceptable salt thereof.

[0074] In a particular embodiment, the compound of formula (II) is formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), and formula (IIf): [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0075] In a particular embodiment, the compound of formula (III) is formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IIIe), formula (IIIf), formula (IIIg), formula (IIIh), formula (IIIi), formula (IIIj), formula (IIIk), formula (IIIl), formula (IIIm), and formula (IIIn): [ka] Selected from TIFF0007863101000028.tif136170 or a pharmaceutically acceptable salt thereof.

[0076] In a particular embodiment, the compound of formula (IV) is formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (IVe), formula (IVf), formula (IVg), formula (IVh), formula (IVi), formula (IVj), formula (IVk), formula (IVl), formula (IVm), and formula (IVn): [ka] Selected from TIFF0007863101000030.tif224170, TIFF0007863101000031.tif44170, or a pharmaceutically acceptable salt thereof.

[0077] In a particular embodiment, the compound of formula (V) is formula (Va), formula (Vb), formula (Vc), formula (Vd), formula (Ve), formula (Vf), formula (Vg), formula (Vh), formula (Vi), formula (Vj), formula (Vk), formula (Vl), formula (Vm), and formula (Vn): [ka] Selected from TIFF0007863101000033.tif181170 or a pharmaceutically acceptable salt thereof.

[0078] In a particular embodiment, the compound of formula (VI) is formula (VIa), formula (VIb), formula (VIc), formula (VId), formula (VIf), formula (VIg), formula (VIh), formula (VIi), formula (VIj), formula (VIk), formula (VIl), formula (VIm), and formula (VIn): [ka] Selected from TIFF0007863101000035.tif129170 or a pharmaceutically acceptable salt thereof.

[0079] In a particular embodiment, the compound of formula (VII) is formula (VIIa), formula (VIIb), formula (VIIc), formula (VIId), formula (VIIe), formula (VIIf), formula (VIIg), formula (VIIh), formula (VIIi), formula (VIIj), formula (VIIk), formula (VIIl), formula (VIIm), and formula (VIIn): [ka] Selected from TIFF0007863101000037.tif222170, TIFF0007863101000038.tif43170, or a pharmaceutically acceptable salt thereof.

[0080] In a particular embodiment, the compound of formula (VIII) is formula (VIIIa), formula (VIIIb), formula (VIIIc), formula (VIIId), formula (VIIIe), formula (VIIIf), formula (VIIIg), formula (VIIIh), formula (VIIIi), formula (VIIIj), formula (VIIIk), formula (VIIIl), formula (VIIIm), and formula (VIIIn): [ka] Selected from TIFF0007863101000040.tif198170, TIFF0007863101000041.tif45170, or a pharmaceutically acceptable salt thereof.

[0081] In a particular embodiment, the compound of formula (IX) is formula (IXa), formula (IXb), formula (IXc), formula (IXd), formula (IXe), formula (IXf), formula (IXg), formula (IXh), formula (IXi), formula (IXj), formula (IXk), formula (IXl), formula (IXm), and formula (IXn): [ka] Selected from TIFF0007863101000043.tif190170, TIFF0007863101000044.tif45170, or a pharmaceutically acceptable salt thereof.

[0082] In a particular embodiment, the compound of formula (X) is formula (Xa), formula (Xb), formula (Xc), formula (Xd), formula (Xe), formula (Xf), formula (Xg), formula (Xh), formula (Xi), formula (Xj), formula (Xk), formula (Xl), formula (Xm), and formula (Xn): [ka] Selected from TIFF0007863101000046.tif186170 or a pharmaceutically acceptable salt thereof.

[0083] In a particular embodiment, the compound of formula (XI) is formula (XIa), formula (XIb), formula (XIc), formula (XId), formula (XIe), formula (XIf), formula (XIg), formula (XIh), formula (XIi), formula (XIj), formula (XIl), formula (XIm), and formula (XIn): [ka] Selected from TIFF0007863101000048.tif132170 or a pharmaceutically acceptable salt thereof.

[0084] In a particular embodiment, the compound of formula (XII) is formula (XIIa), formula (XIIb), formula (XIIc), formula (XIId), formula (XIIe), formula (XIIf), formula (XIIg), formula (XIIh), formula (XIIi), formula (XIIj), formula (XIIk), formula (XIIl), formula (XIIm), and formula (XIIn): [ka] Selected from TIFF0007863101000050.tif219170, TIFF0007863101000051.tif41170, or a pharmaceutically acceptable salt thereof.

[0085] In certain embodiments, the compound of formula (XIII) is formula (XIIIa), formula (XIIIb), formula (XIIIc), formula (XIIId), formula (XIIIe), formula (XIIIf), formula (XIIIg), formula (XIIIh), formula (XIIIi), formula (XIIIj), formula (XIIIk), formula (XIIIl), formula (XIIIm), and formula (XIIIn): [ka] Selected from TIFF0007863101000053.tif187170 or a pharmaceutically acceptable salt thereof.

[0086] In a particular embodiment, the compound of formula (XIV) is formula (XIVa), formula (XIVb), formula (XIVc), formula (XIVd), formula (XIVe), formula (XIVf), formula (XIVg), formula (XIVh), formula (XIVi), formula (XIVj), formula (XIVk), formula (XIVl), formula (XIVm), and formula (XIVn): [ka] Selected from TIFF0007863101000055.tif202170 or a pharmaceutically acceptable salt thereof.

[0087] In a particular embodiment, the compounds of formula (XVII) are formulas (XVIIa), (XVIIb), (XVIIc), (XVIId), (XVIIe), (XVIIf), (XVIIg), (XVIIh), (XVIIi), (XVIIj), (XVIIk), (XVIIl), (XVIIm), and (XVIIn): [ka] Selected from TIFF0007863101000057.tif134170 or a pharmaceutically acceptable salt thereof.

[0088] Non-limiting examples of compounds of formula I include: [ka] It includes.

[0089] Non-limiting examples of compounds of formula II include: [ka] It includes.

[0090] Non-limiting examples of compounds of formula III include: [ka] This includes TIFF0007863101000061.tif209170.

[0091] Non-limiting examples of compounds of formula IV include: [ka] It includes.

[0092] Non-limiting examples of compounds of formula V include: [ka] It includes.

[0093] Non-limiting examples of compounds of formula VI include: [ka] It includes.

[0094] Non-limiting examples of compounds of formula VII include: [ka] It includes.

[0095] Non-limiting examples of compounds of formula VIII include: [ka] It includes.

[0096] Non-limiting examples of compounds of formula IX include: [ka] It includes.

[0097] Non-restrictive examples of compounds of formula X include: [ka] It includes.

[0098] Non-limiting examples of compounds of formula XI include: [ka] This includes TIFF0007863101000070.tif64170.

[0099] Non-limiting examples of compounds of formula XII include: [ka] This includes TIFF0007863101000072.tif194170 and TIFF0007863101000073.tif90170.

[0100] Non-limiting examples of compounds of formula XIII include: [ka] It includes.

[0101] Non-limiting examples of compounds of formula XIV include: [ka] It includes.

[0102] Non-limiting examples of compounds of formula XV include: [ka] It includes.

[0103] Further non-limiting examples of compounds of formula XV include: [ka] It includes.

[0104] Further non-limiting examples of compounds of formula XV include: [ka] It includes.

[0105] Further non-limiting examples of compounds of formula XV include: [ka] It includes.

[0106] Non-limiting examples of compounds of formula XVI include: [ka] It includes.

[0107] Further non-limiting examples of compounds of formula XVI include: [ka] The formulas include TIFF0007863101000082.tif217170TIFF0007863101000083.tif218170TIFF0007863101000084.tif237170 (where m is an integer selected from 0, 1, 2, 3, 4, or 5).

[0108] Further non-limiting examples of compounds of formula XVI include: [ka] TIFF0007863101000086.tif211170TIFF0007863101000087.tif205170TIFF0007863101000088.tif193170TIFF0007863101000089.tif207170TIFF0007863101000090.tif58170 (wherein m is an integer selected from 0, 1, 2, 3, 4, or 5) are included.

[0109] Non-limiting examples of compounds of formula XVII include: [ka] This includes TIFF0007863101000092.tif254170.

[0110] Further non-limiting examples of compounds of formula XVII include: [ka] This includes TIFF0007863101000094.tif123170.

[0111] In the structure described herein, hydroxyl (for example, R 1 Base or R 2 The base is located on a heteroaryl ring carbon adjacent to nitrogen, and unless otherwise specified herein, only one tautomer is shown as a concise way of referring individually to each distinct tautomer or mixture thereof, and each distinct tautomer or mixture thereof is incorporated herein as if it were listed individually. This is, [ka] This is explained by a non-restrictive example, which includes, [ka] It includes both.

[0112] When a bond is enclosed in square brackets, it indicates that the bond can be located in any position permitted by its valence and stability. The following compound enclosed in square brackets is a non-restrictive example illustrating the meaning of square brackets: [ka] They appear to be depicted separately, independently. [ka] Includes.

[0113] Non-limiting examples of the compounds of the present invention include: [ka] This includes TIFF0007863101000100.tif231170TIFF0007863101000101.tif231170TIFF0007863101000102.tif207170TIFF0007863101000103.tif203170TIFF0007863101000104.tif100170.

[0114] R 1 and R 2 Embodiment: In a particular embodiment, R 1 It is hydrogen.

[0115] In a particular embodiment, R 1 It is alkyl.

[0116] In a particular embodiment, R 1 It is a halogen.

[0117] In a particular embodiment, R 1 It is a haloalkyl.

[0118] In a particular embodiment, R 1 は-OR 10 That is the case.

[0119] In a particular embodiment, R 1 Ha-SR 10 That is the case.

[0120] In a particular embodiment, R 1 -S(O)R 12 That is the case.

[0121] In a particular embodiment, R 1 ha-SO2R 12 That is the case.

[0122] In a particular embodiment, R 1 -NR 10 R 11 That is the case.

[0123] In a particular embodiment, R 1 It is cyano.

[0124] In a particular embodiment, R 1 It is nitro.

[0125] In a particular embodiment, R 1 It is a heteroaryl compound.

[0126] In a particular embodiment, R 1 It is Ariel.

[0127] In a particular embodiment, R 1 It is a complex algebra.

[0128] In a particular embodiment, R 2 It is hydrogen.

[0129] In a particular embodiment, R 2 It is alkyl.

[0130] In a particular embodiment, R 2 It is a halogen.

[0131] In a particular embodiment, R 2 It is a haloalkyl.

[0132] In a particular embodiment, R 2 は-OR 10 That is the case.

[0133] In a particular embodiment, R 2 Ha-SR 10 That is the case.

[0134] In a particular embodiment, R 2 -S(O)R 12 That is the case.

[0135] In a particular embodiment, R 2 ha-SO2R12 That is the case.

[0136] In a particular embodiment, R 2 -NR 10 R 11 That is the case.

[0137] In a particular embodiment, R 2 It is cyano.

[0138] In a particular embodiment, R 2 It is nitro.

[0139] In a particular embodiment, R 2 It is a heteroaryl compound.

[0140] In a particular embodiment, R 2 It is Ariel.

[0141] In a particular embodiment, R 2 It is a complex algebra.

[0142] R 1’ Non-limiting embodiments of: In a particular embodiment, R 1’ It is alkyl.

[0143] In a particular embodiment, R 1’ It is a halogen.

[0144] In a particular embodiment, R 1’ It is a haloalkyl.

[0145] In a particular embodiment, R 1’ は-OR 10 That is the case.

[0146] In a particular embodiment, R 1’ Ha-SR 10 That is the case.

[0147] In a particular embodiment, R1’ -S(O)R 12 That is the case.

[0148] In a particular embodiment, R 1’ ha-SO2R 12 That is the case.

[0149] In a particular embodiment, R 1’ -NR 10 R 11 That is the case.

[0150] In a particular embodiment, R 1’ It is cyano.

[0151] In a particular embodiment, R 1’ It is nitro.

[0152] In a particular embodiment, R 1’ It is a heteroaryl compound.

[0153] In a particular embodiment, R 1’ It is Ariel.

[0154] In a particular embodiment, R 1’ It is a cycloalkyl group.

[0155] In a particular embodiment, R 1’ It is a complex algebra.

[0156] R 3a Non-limiting embodiments of: In a particular embodiment, R 3a It is hydrogen.

[0157] In a particular embodiment, R 3a It is alkyl.

[0158] In a particular embodiment, R 3a It is fluorine.

[0159] In a particular embodiment, R 3a It is bromine.

[0160] In a particular embodiment, R 3a It is chlorine.

[0161] In a particular embodiment, R 3a It is iodine.

[0162] In a particular embodiment, R 3a It is a haloalkyl.

[0163] In a particular embodiment, R 3a It is a fluoroalkyl group.

[0164] In a particular embodiment, R 3a It is a chloroalkyl.

[0165] In a particular embodiment, R 3a It is a bromoalkyl.

[0166] In a particular embodiment, R 3a It is an iodoalkyl.

[0167] R 3 Non-limiting embodiments of: In a particular embodiment, R 3 It is selected from hydrogen and halogens.

[0168] In a particular embodiment, R 3 The alkyl group is selected from alkyl and haloalkyl groups.

[0169] In a particular embodiment, R 3 It is hydrogen.

[0170] In a particular embodiment, R 3 It is a halogen.

[0171] In a particular embodiment, R3 It is alkyl.

[0172] In a particular embodiment, R 3 It is a haloalkyl.

[0173] In a particular embodiment, R 3 It is fluorine.

[0174] In a particular embodiment, R 3 It is chlorine.

[0175] In a particular embodiment, R 3 It is bromine.

[0176] In a particular embodiment, R 3 It is iodine.

[0177] In a particular embodiment, R 3 It is methyl.

[0178] In a particular embodiment, R 3 It is ethyl.

[0179] In a particular embodiment, R 3 It is trifluoromethyl.

[0180] In a particular embodiment, R 3 It is pentafluoroethyl.

[0181] In a particular embodiment, R 3 It is difluoromethyl.

[0182] In a particular embodiment, R 3 It is fluoromethyl.

[0183] In a particular embodiment, R 3 is R 4 It combines with the base to form a one-carbon bond.

[0184] In a particular embodiment, R 3 is R 4 Together with the base, it forms a two-carbon bond.

[0185] In a particular embodiment, R 3 is R 4 Together with the base, it forms a 3-carbon bond.

[0186] In a particular embodiment, R 3 is R 4 Together with the base, it forms a 4-carbon bond.

[0187] In a particular embodiment, R 3 is R 4 It combines with the base to form a double bond.

[0188] R 4 Non-limiting embodiments of: In a particular embodiment, R 4 It is selected from hydrogen and halogens.

[0189] In a particular embodiment, R 4 The alkyl group is selected from alkyl and haloalkyl groups.

[0190] In a particular embodiment, R 4 It is hydrogen.

[0191] In a particular embodiment, R 4 It is a halogen.

[0192] In a particular embodiment, R 4 It is alkyl.

[0193] In a particular embodiment, R 4 It is a haloalkyl.

[0194] In a particular embodiment, R 3 It is fluorine.

[0195] In a particular embodiment, R 3 It is chlorine.

[0196] In a particular embodiment, R 3 It is bromine.

[0197] In a particular embodiment, R 3 It is iodine.

[0198] In a particular embodiment, R 4 It is methyl.

[0199] In a particular embodiment, R 4 It is ethyl.

[0200] In a particular embodiment, R 4 It is trifluoromethyl.

[0201] In a particular embodiment, R 4 It is pentafluoroethyl.

[0202] In a particular embodiment, R 4 It is difluoromethyl.

[0203] In a particular embodiment, R 4 It is fluoromethyl.

[0204] In a particular embodiment, R 4 is R 3 It combines with the base to form a one-carbon bond.

[0205] In a particular embodiment, R 4 is R 3 Together with the base, it forms a two-carbon bond.

[0206] In a particular embodiment, R 4 is R 3 Together with the base, it forms a 3-carbon bond.

[0207] In a particular embodiment, R 4 is R 3 Together with the base, it forms a 4-carbon bond.

[0208] In a particular embodiment, R 4 is R 3 It combines with the base to form a double bond.

[0209] R 4a Non-limiting embodiments of: In a particular embodiment, R 4a It is hydrogen.

[0210] In a particular embodiment, R 4a It is alkyl.

[0211] In a particular embodiment, R 4a It is fluorine.

[0212] In a particular embodiment, R 4a It is bromine.

[0213] In a particular embodiment, R 4a It is chlorine.

[0214] In a particular embodiment, R 4a It is iodine.

[0215] In a particular embodiment, R 4a It is a haloalkyl.

[0216] In a particular embodiment, R 4a It is a fluoroalkyl group.

[0217] In a particular embodiment, R 4a It is a chloroalkyl.

[0218] In a particular embodiment, R 4a It is a bromoalkyl.

[0219] In a particular embodiment, R 4a It is an iodoalkyl.

[0220] R 5 Non-limiting embodiments of: In a particular embodiment, R 5 It is selected from hydrogen and halogens.

[0221] In a particular embodiment, R 5 The alkyl group is selected from alkyl and haloalkyl groups.

[0222] In a particular embodiment, R 5 It is hydrogen.

[0223] In a particular embodiment, R 5 It is a halogen.

[0224] In a particular embodiment, R 5 It is alkyl.

[0225] In a particular embodiment, R 5 It is a haloalkyl.

[0226] In a particular embodiment, R 3 It is fluorine.

[0227] In a particular embodiment, R 3 It is chlorine.

[0228] In a particular embodiment, R 3 It is bromine.

[0229] In a particular embodiment, R 3 It is iodine.

[0230] In a particular embodiment, R 5 It is methyl.

[0231] In a particular embodiment, R 5 It is ethyl.

[0232] In a particular embodiment, R 5 It is trifluoromethyl.

[0233] In a particular embodiment, R 5 It is pentafluoroethyl.

[0234] In a particular embodiment, R 5 It is difluoromethyl.

[0235] In a particular embodiment, R 5 It is fluoromethyl.

[0236] R 6 and R 7 A non-limiting embodiment of the same. In a particular embodiment, R 6 It is a halogen.

[0237] In a particular embodiment, R 6 It is alkyl.

[0238] In a particular embodiment, R 6 It is a haloalkyl.

[0239] In a particular embodiment, R 6 It is fluorine.

[0240] In a particular embodiment, R 6 It is chlorine.

[0241] In a particular embodiment, R 6 It is bromine.

[0242] In a particular embodiment, R 6 It is iodine.

[0243] In a particular embodiment, R6 It is methyl.

[0244] In a particular embodiment, R 6 It is ethyl.

[0245] In a particular embodiment, R 6 It is trifluoromethyl.

[0246] In a particular embodiment, R 6 It is pentafluoroethyl.

[0247] In a particular embodiment, R 6 It is difluoromethyl.

[0248] In a particular embodiment, R 6 It is fluoromethyl.

[0249] In a particular embodiment, R 6 は-OR 10 That is the case.

[0250] In a particular embodiment, R 6 Ha-SR 10 That is the case.

[0251] In a particular embodiment, R 6 -S(O)R 12 That is the case.

[0252] In a particular embodiment, R 6 ha-SO2R 12 That is the case.

[0253] In a particular embodiment, R 6 -NR 10 R 11 That is the case.

[0254] In a particular embodiment, R 6 It is pentafluoroethyl.

[0255] In a particular embodiment, R 6 It is difluoromethyl.

[0256] In a particular embodiment, R 6 It is fluoromethyl.

[0257] In a particular embodiment, R 6 is R 7 Together, they form a three-membered spiro ring.

[0258] In a particular embodiment, R 6 is R 7 Together, they form a four-membered spiro ring.

[0259] In a particular embodiment, R 6 is R 3 Together, they form a four-membered spiro ring.

[0260] In a particular embodiment, R 6 is R 3 Together, they form a five-membered spiro ring.

[0261] In a particular embodiment, R 7 It is a halogen.

[0262] In a particular embodiment, R 7 It is alkyl.

[0263] In a particular embodiment, R 7 It is a haloalkyl.

[0264] In a particular embodiment, R 7 It is fluorine.

[0265] In a particular embodiment, R 7 It is chlorine.

[0266] In a particular embodiment, R 7 It is bromine.

[0267] In a particular embodiment, R 7 It is iodine.

[0268] In a particular embodiment, R 7 It is methyl.

[0269] In a particular embodiment, R 7 It is ethyl.

[0270] In a particular embodiment, R 7 It is trifluoromethyl.

[0271] In a particular embodiment, R 7 It is pentafluoroethyl.

[0272] In a particular embodiment, R 7 It is difluoromethyl.

[0273] In a particular embodiment, R 7 It is fluoromethyl.

[0274] In a particular embodiment, R 7 は-OR 10 That is the case.

[0275] In a particular embodiment, R 7 Ha-SR 10 That is the case.

[0276] In a particular embodiment, R 7 -S(O)R 12 That is the case.

[0277] In a particular embodiment, R 7 ha-SO2R 12 That is the case.

[0278] In a particular embodiment, R 7 -NR 10 R 11 That is the case.

[0279] In a particular embodiment, R 7 It is pentafluoroethyl.

[0280] In a particular embodiment, R 7 It is difluoromethyl.

[0281] In a particular embodiment, R 7 It is fluoromethyl.

[0282] In a particular embodiment, R 7 is R 6 Together, they form a three-membered spiro ring.

[0283] In a particular embodiment, R 7 is R 6 Together, they form a four-membered spiro ring.

[0284] R 6a and R 7a A non-limiting embodiment of the same. In a particular embodiment, R 6a It is a halogen.

[0285] In a particular embodiment, R 6a It is alkyl.

[0286] In a particular embodiment, R 6a It is a haloalkyl.

[0287] In a particular embodiment, R 6a It is fluorine.

[0288] In a particular embodiment, R 6a It is chlorine.

[0289] In a particular embodiment, R 6a It is bromine.

[0290] In a particular embodiment, R 6aIt is iodine.

[0291] In a particular embodiment, R 6a It is methyl.

[0292] In a particular embodiment, R 6a It is ethyl.

[0293] In a particular embodiment, R 6a It is trifluoromethyl.

[0294] In a particular embodiment, R 6a It is pentafluoroethyl.

[0295] In a particular embodiment, R 6a It is difluoromethyl.

[0296] In a particular embodiment, R 6a It is fluoromethyl.

[0297] In a particular embodiment, R 6a は-OR 10 That is the case.

[0298] In a particular embodiment, R 6a Ha-SR 10 That is the case.

[0299] In a particular embodiment, R 6a -S(O)R 12 That is the case.

[0300] In a particular embodiment, R 6a ha-SO2R 12 That is the case.

[0301] In a particular embodiment, R 6a -NR 10 R 11 That is the case.

[0302] In a particular embodiment, R6a It is pentafluoroethyl.

[0303] In a particular embodiment, R 6a It is difluoromethyl.

[0304] In a particular embodiment, R 6a It is fluoromethyl.

[0305] In a particular embodiment, R 6a is R 7a Together, they form a three-membered spiro ring.

[0306] In a particular embodiment, R 6a is R 7a Together, they form a four-membered spiro ring.

[0307] In a particular embodiment, R 6a is R 7a Together, they form a four-membered spiro ring.

[0308] In a particular embodiment, R 6a is R 7a Together, they form a five-membered spiro ring.

[0309] In a particular embodiment, R 7a It is a halogen.

[0310] In a particular embodiment, R 7a It is alkyl.

[0311] In a particular embodiment, R 7a It is a haloalkyl.

[0312] In a particular embodiment, R 7a It is fluorine.

[0313] In a particular embodiment, R 7a It is chlorine.

[0314] In a particular embodiment, R 7a It is bromine.

[0315] In a particular embodiment, R 7a It is iodine.

[0316] In a particular embodiment, R 7a It is methyl.

[0317] In a particular embodiment, R 7a It is ethyl.

[0318] In a particular embodiment, R 7a It is trifluoromethyl.

[0319] In a particular embodiment, R 7a It is pentafluoroethyl.

[0320] In a particular embodiment, R 7a It is difluoromethyl.

[0321] In a particular embodiment, R 7a It is fluoromethyl.

[0322] In a particular embodiment, R 7a は-OR 10 That is the case.

[0323] In a particular embodiment, R 7a Ha-SR 10 That is the case.

[0324] In a particular embodiment, R 7a -S(O)R 12 That is the case.

[0325] In a particular embodiment, R 7a ha-SO2R 12 That is the case.

[0326] In a particular embodiment, R7a -NR 10 R 11 That is the case.

[0327] In a particular embodiment, R 7a It is pentafluoroethyl.

[0328] In a particular embodiment, R 7a It is difluoromethyl.

[0329] In a particular embodiment, R 7a It is fluoromethyl.

[0330] In a particular embodiment, R 7a is R 6a Together, they form a three-membered spiro ring.

[0331] In a particular embodiment, R 7a is R 6a Together, they form a four-membered spiro ring.

[0332] In a particular embodiment, R 7a is R 6a Together, they form a five-membered spiro ring.

[0333] R 10 and R 11 A non-limiting embodiment of the same. In a particular embodiment, R 10 It is hydrogen.

[0334] In a particular embodiment, R 10 It is alkyl.

[0335] In a particular embodiment, R 10 It is a complex algebra.

[0336] In a particular embodiment, R 10 It is a haloalkyl.

[0337] In a particular embodiment, R10 It is Ariel.

[0338] In a particular embodiment, R 10 It is a heteroaryl compound.

[0339] In a particular embodiment, R 10 -C(O)R 12 That is the case.

[0340] In a particular embodiment, R 10 -S(O)R 12 That is the case.

[0341] In a particular embodiment, R 10 ha-SO2R 12 That is the case.

[0342] In a particular embodiment, R 11 It is hydrogen.

[0343] In a particular embodiment, R 11 It is alkyl.

[0344] In a particular embodiment, R 11 It is a complex algebra.

[0345] In a particular embodiment, R 11 It is a haloalkyl.

[0346] In a particular embodiment, R 11 It is Ariel.

[0347] In a particular embodiment, R 11 It is a heteroaryl compound.

[0348] In a particular embodiment, R 11 -C(O)R 12 That is the case.

[0349] In a particular embodiment, R 11 -S(O)R12 That is the case.

[0350] In a particular embodiment, R 11 ha-SO2R 12 That is the case.

[0351] R 12 Non-limiting embodiments of: In a particular embodiment, R 12 It is hydrogen.

[0352] In a particular embodiment, R 12 It is alkyl.

[0353] In a particular embodiment, R 12 It is a complex algebra.

[0354] In a particular embodiment, R 12 It is a haloalkyl.

[0355] In a particular embodiment, R 12 It is Ariel.

[0356] In a particular embodiment, R 12 It is a heteroaryl compound.

[0357] In a particular embodiment, R 12 -NR 13 R 14 That is the case.

[0358] In a particular embodiment, R 12 is OR 13 That is the case.

[0359] R 13 and R 14 Non-limiting embodiments of: In a particular embodiment, R 13 It is hydrogen.

[0360] In a particular embodiment, R 13 It is alkyl.

[0361] In a particular embodiment, R 13 It is a fluoroalkyl group.

[0362] In a particular embodiment, R 13 It is a chloroalkyl.

[0363] In a particular embodiment, R 13 It is a bromoalkyl.

[0364] In a particular embodiment, R 13 It is a haloalkyl.

[0365] In a particular embodiment, R 13 is hydrogen, R 14 It is hydrogen.

[0366] In a particular embodiment, R 13 is hydrogen, R 14 It is alkyl.

[0367] In a particular embodiment, R 13 is hydrogen, R 14 It is a fluoroalkyl group.

[0368] In a particular embodiment, R 13 is hydrogen, R 14 It is a bromoalkyl.

[0369] In a particular embodiment, R 13 is hydrogen, R 14 It is a chloroalkyl.

[0370] In a particular embodiment, R 13 is alkyl, R 14 It is hydrogen.

[0371] In a particular embodiment, R 13 is alkyl, R 14It is alkyl.

[0372] In a particular embodiment, R 13 is alkyl, R 14 It is a fluoroalkyl group.

[0373] In a particular embodiment, R 13 is alkyl, R 14 It is a bromoalkyl.

[0374] In a particular embodiment, R 13 is alkyl, R 14 It is a chloroalkyl.

[0375] In a particular embodiment, R 13 is a haloalkyl, and R 14 It is a haloalkyl.

[0376] In a particular embodiment, R 13 is alkyl, R 14 It is alkyl.

[0377] In a particular embodiment, R 14 It is hydrogen.

[0378] In a particular embodiment, R 14 It is alkyl.

[0379] In a particular embodiment, R 14 It is a haloalkyl.

[0380] In a particular embodiment, R 14 It is a fluoroalkyl group.

[0381] In a particular embodiment, R 14 It is a chloroalkyl.

[0382] In a particular embodiment, R 14 It is a bromoalkyl.

[0383] In a particular embodiment, R 14 is hydrogen, R 13 It is hydrogen.

[0384] In a particular embodiment, R 14 is hydrogen, R 13 It is alkyl.

[0385] In a particular embodiment, R 14 is hydrogen, R 13 It is a fluoroalkyl group.

[0386] In a particular embodiment, R 14 is hydrogen, R 13 It is a bromoalkyl.

[0387] In a particular embodiment, R 14 is hydrogen, R 13 It is a chloroalkyl.

[0388] In a particular embodiment, R 14 is alkyl, R 13 It is hydrogen.

[0389] In a particular embodiment, R 14 is alkyl, R 13 It is alkyl.

[0390] In a particular embodiment, R 14 is alkyl, R 13 It is a fluoroalkyl group.

[0391] In a particular embodiment, R 14 is alkyl, R 13 It is a bromoalkyl.

[0392] In a particular embodiment, R 14 is alkyl, R 13 It is a chloroalkyl.

[0393] In a particular embodiment, R 14 is a haloalkyl, and R 13 It is a haloalkyl.

[0394] In a particular embodiment, R 14 is alkyl, R 13 It is alkyl.

[0395] X 2 Non-limiting embodiments of: In a particular embodiment, X 2 It is a combination.

[0396] In a particular embodiment, X 2 It is a complex algebra.

[0397] In a particular embodiment, X 2 It is a heteroaryl compound.

[0398] In a particular embodiment, X 2 It is Ariel.

[0399] In a particular embodiment, X 2 It is a double ring.

[0400] In a particular embodiment, X 2 It is alkyl.

[0401] In a particular embodiment, X 2 It is an aliphatic.

[0402] In a particular embodiment, X 2 It is heterolipid.

[0403] In a particular embodiment, X 2 is NR 27 - is

[0404] In a particular embodiment, X 2 CR 40R 41 - is

[0405] In a particular embodiment, X 2 It is -C(O)-.

[0406] In a particular embodiment, X 2 -C(NR 27 )-is.

[0407] In a particular embodiment, X 2 is -C(S)-.

[0408] In a particular embodiment, X 2 It is -S(O)-.

[0409] In a particular embodiment, X 2 It is -S(O)2-.

[0410] In a particular embodiment, X 2 It is -S-.

[0411] In a particular embodiment, X 2 It is a five-membered aromatic heterocycle with attachment points in 1 and 3 directions.

[0412] In a particular embodiment, X 2 It is a five-membered aromatic heterocycle with attachment points in 1 and 2 directions.

[0413] In a particular embodiment, X 2 It is a six-membered aromatic heterocycle with attachment points in 1 and 2 directions.

[0414] In a particular embodiment, X 2 It is a six-membered aromatic heterocycle with attachment points in 1 and 3 directions.

[0415] In a particular embodiment, X 2 It is a six-membered aromatic heterocycle with attachment points in 1 and 4 directions.

[0416] In a particular embodiment, X 2 It is a six-membered aromatic heterocycle with attachment points in 1 and 3 directions.

[0417] In a particular embodiment, X 2 It is a five-membered complex ring with mounting points in 1 and 2 directions.

[0418] In a particular embodiment, X 2 It is a five-membered complex ring with mounting points in 1 and 3 directions.

[0419] In a particular embodiment, X 2 It is a six-membered complex ring with mounting points in 1 and 2 directions.

[0420] In a particular embodiment, X 2 It is a six-membered complex ring with mounting points in 1 and 3 directions.

[0421] In a particular embodiment, X 2 It is a six-membered complex ring with mounting points in 1 and 4 directions.

[0422] In a particular embodiment, X 2 It is a bicyclic heterocycle having one heteroatom.

[0423] In a particular embodiment, X 2 It is a bicyclic heterocycle having two heteroatoms.

[0424] In a particular embodiment, X 2 It is a bicyclic heterocycle with one heteroatom, where one bond is to nitrogen and the other is to carbon.

[0425] In a particular embodiment, X 2 It is a bicyclic heterocycle with one heteroatom, and both attachment points are bonded to carbon.

[0426] In a particular embodiment, X 2 It is a bicyclic heterocycle with two heteroatoms, both attachment points of which are bonded to nitrogen.

[0427] In a particular embodiment, X 2 It is a bicyclic heterocycle having two heteroatoms.

[0428] In a particular embodiment, X 2 It is a condensed bicyclic alkane.

[0429] In a particular embodiment, X 2 It is a spironic ring alkane.

[0430] X 3 Non-limiting embodiments of: In a particular embodiment, X 3 It is a combination.

[0431] In a particular embodiment, X 3 It is a complex algebra.

[0432] In a particular embodiment, X 3 It is a heteroaryl compound.

[0433] In a particular embodiment, X 3 It is Ariel.

[0434] In a particular embodiment, X 3 It is a double ring.

[0435] In a particular embodiment, X 3 is NR 27 - is

[0436] In a particular embodiment, X 3 CR 40 R 41 - is

[0437] In a particular embodiment, X 3It is -C(O)-.

[0438] In a particular embodiment, X 3 -C(NR 27 )-is.

[0439] In a particular embodiment, X 3 is -C(S)-.

[0440] In a particular embodiment, X 3 It is -S(O)-.

[0441] In a particular embodiment, X 3 It is -S(O)2-.

[0442] In a particular embodiment, X 3 It is -S-.

[0443] In a particular embodiment, X 3 It is a five-membered aromatic heterocycle with attachment points in 1 and 3 directions.

[0444] In a particular embodiment, X 3 It is a five-membered aromatic heterocycle with attachment points in 1 and 2 directions.

[0445] In a particular embodiment, X 3 It is a six-membered aromatic heterocycle with attachment points in 1 and 2 directions.

[0446] In a particular embodiment, X 3 It is a six-membered aromatic heterocycle with attachment points in 1 and 3 directions.

[0447] In a particular embodiment, X 3 It is a six-membered aromatic heterocycle with attachment points in 1 and 4 directions.

[0448] In a particular embodiment, X 3 It is a six-membered aromatic heterocycle with attachment points in 1 and 3 directions.

[0449] In a particular embodiment, X 3 It is a five-membered complex ring with mounting points in 1 and 2 directions.

[0450] In a particular embodiment, X 3 It is a five-membered complex ring with mounting points in 1 and 3 directions.

[0451] In a particular embodiment, X 3 It is a six-membered complex ring with mounting points in 1 and 2 directions.

[0452] In a particular embodiment, X 3 It is a six-membered complex ring with mounting points in 1 and 3 directions.

[0453] In a particular embodiment, X 3 It is a six-membered complex ring with mounting points in 1 and 4 directions.

[0454] In a particular embodiment, X 3 It is a bicyclic heterocycle having one heteroatom.

[0455] In a particular embodiment, X 3 It is a bicyclic heterocycle having two heteroatoms.

[0456] In a particular embodiment, X 3 It is a bicyclic heterocycle with one heteroatom, where one bond is to nitrogen and the other is to carbon.

[0457] In a particular embodiment, X 3 It is a bicyclic heterocycle with one heteroatom, and both attachment points are bonded to carbon.

[0458] In a particular embodiment, X 3 It is a bicyclic heterocycle with two heteroatoms, both attachment points of which are bonded to nitrogen.

[0459] In a particular embodiment, X 3 It is a bicyclic heterocycle having two heteroatoms.

[0460] In a particular embodiment, X 3 It is a condensed bicyclic alkane.

[0461] In a particular embodiment, X 3 It is a spironic ring alkane.

[0462] In a particular embodiment, X 3 The following is selected:

[0463] R 15 , R 16 , and R 17 Non-limiting embodiments of: In a particular embodiment, R 15 It is a combination.

[0464] In a particular embodiment, R 15 It is alkyl.

[0465] In a particular embodiment, R 15 It is -C(O)-.

[0466] In a particular embodiment, R 15 It is -C(O)O-.

[0467] In a particular embodiment, R 15 It is -OC(O)-.

[0468] In a particular embodiment, R 15 It is -SO2-.

[0469] In a particular embodiment, R 15 It is -S(O)-.

[0470] In a particular embodiment, R 15 is -C(S)-.

[0471] In a particular embodiment, R 15 is C(O)NR 27 - is

[0472] In a particular embodiment, R 15 -NR 27 It is C(O)-.

[0473] In a particular embodiment, R 15 It is -O-.

[0474] In a particular embodiment, R 15 It is -S-.

[0475] In a particular embodiment, R 15 -NR 27 - is

[0476] In a particular embodiment, R 15 is C(R 40 R 41 )-is.

[0477] In a particular embodiment, R 15 is P(O)(OR 26 )O-.

[0478] In a particular embodiment, R 15 is -P(O)(OR 26 )-is.

[0479] In a particular embodiment, R 15 It is a double ring.

[0480] In a particular embodiment, R 15 It is an alkene.

[0481] In a particular embodiment, R 15 It is an alkyne.

[0482] In a particular embodiment, R15 It is a haloalkyl.

[0483] In a particular embodiment, R 15 It is an alkoxy.

[0484] In a particular embodiment, R 15 It is Ariel.

[0485] In a particular embodiment, R 15 It is a complex algebra.

[0486] In a particular embodiment, R 15 It is heterolipid.

[0487] In a particular embodiment, R 15 It is a heteroaryl compound.

[0488] In a particular embodiment, R 15 It is lactic acid.

[0489] In a particular embodiment, R 15 It is glycolic acid.

[0490] In a particular embodiment, R 15 It is an arylalkyl.

[0491] In a particular embodiment, R 15 It is a heterocyclic alkyl group.

[0492] In a particular embodiment, R 15 It is a heteroarylalkyl.

[0493] In a particular embodiment, R 16 It is a combination.

[0494] In a particular embodiment, R 16 It is alkyl.

[0495] In a particular embodiment, R 16 It is -C(O)-.

[0496] In a particular embodiment, R 16 It is -C(O)O-.

[0497] In a particular embodiment, R 16 It is -OC(O)-.

[0498] In a particular embodiment, R 16 It is -SO2-.

[0499] In a particular embodiment, R 16 It is -S(O)-.

[0500] In a particular embodiment, R 16 is -C(S)-.

[0501] In a particular embodiment, R 16 is C(O)NR 27 - is

[0502] In a particular embodiment, R 16 -NR 27 It is C(O)-.

[0503] In a particular embodiment, R 16 It is -O-.

[0504] In a particular embodiment, R 16 It is -S-.

[0505] In a particular embodiment, R 16 -NR 27 - is

[0506] In a particular embodiment, R 16 is C(R 40 R 41 )-is.

[0507] In a particular embodiment, R 16 is P(O)(OR 26 )O-.

[0508] In a particular embodiment, R 16 is -P(O)(OR 26 )-is.

[0509] In a particular embodiment, R 16 It is a double ring.

[0510] In a particular embodiment, R 16 It is an alkene.

[0511] In a particular embodiment, R 16 It is an alkyne.

[0512] In a particular embodiment, R 16 It is a haloalkyl.

[0513] In a particular embodiment, R 16 It is an alkoxy.

[0514] In a particular embodiment, R 16 It is Ariel.

[0515] In a particular embodiment, R 16 It is a complex algebra.

[0516] In a particular embodiment, R 16 It is heterolipid.

[0517] In a particular embodiment, R 16 It is a heteroaryl compound.

[0518] In a particular embodiment, R 16 It is lactic acid.

[0519] In a particular embodiment, R 16 It is glycolic acid.

[0520] In a particular embodiment, R 16 It is an arylalkyl.

[0521] In a particular embodiment, R 16 It is a heterocyclic alkyl group.

[0522] In a particular embodiment, R 16 It is a heteroarylalkyl.

[0523] In a particular embodiment, R 17 It is a combination.

[0524] In a particular embodiment, R 17 It is alkyl.

[0525] In a particular embodiment, R 17 It is -C(O)-.

[0526] In a particular embodiment, R 17 It is -C(O)O-.

[0527] In a particular embodiment, R 17 It is -OC(O)-.

[0528] In a particular embodiment, R 17 It is -SO2-.

[0529] In a particular embodiment, R 17 It is -S(O)-.

[0530] In a particular embodiment, R 17 is -C(S)-.

[0531] In a particular embodiment, R 17 is C(O)NR 27 - is

[0532] In a particular embodiment, R 17 -NR 27 It is C(O)-.

[0533] In a particular embodiment, R 17 It is -O-.

[0534] In a particular embodiment, R 17 It is -S-.

[0535] In a particular embodiment, R 17 -NR 27 - is

[0536] In a particular embodiment, R 17 is C(R 40 R 41 )-is.

[0537] In a particular embodiment, R 17 is P(O)(OR 26 )O-.

[0538] In a particular embodiment, R 17 is -P(O)(OR 26 )-is.

[0539] In a particular embodiment, R 17 It is a double ring.

[0540] In a particular embodiment, R 17 It is an alkene.

[0541] In a particular embodiment, R 17 It is an alkyne.

[0542] In a particular embodiment, R 17 It is a haloalkyl.

[0543] In a particular embodiment, R 17 It is an alkoxy.

[0544] In a particular embodiment, R 17 It is Ariel.

[0545] In a particular embodiment, R 17 It is a complex algebra.

[0546] In a particular embodiment, R 17 It is heterolipid.

[0547] In a particular embodiment, R 17 It is a heteroaryl compound.

[0548] In a particular embodiment, R 17 It is lactic acid.

[0549] In a particular embodiment, R 17 It is glycolic acid.

[0550] In a particular embodiment, R 17 It is an arylalkyl.

[0551] In a particular embodiment, R 17 It is a heterocyclic alkyl group.

[0552] In a particular embodiment, R 17 It is a heteroarylalkyl.

[0553] R 18 Non-limiting embodiments of: In a particular embodiment, R 18 It is hydrogen.

[0554] In a particular embodiment, R 18 It is alkyl.

[0555] In a particular embodiment, R 18 It is an alkene.

[0556] In a particular embodiment, R18 It is an alkyne.

[0557] In a particular embodiment, R 18 It is hydroxyl.

[0558] In a particular embodiment, R 18 It is Azid.

[0559] In a particular embodiment, R 18 It is an amino acid.

[0560] In a particular embodiment, R 18 It is a halogen.

[0561] In a particular embodiment, R 18 It is a haloalkyl.

[0562] In a particular embodiment, R 18 は-OR 10 That is the case.

[0563] In a particular embodiment, R 18 Ha-SR 10 That is the case.

[0564] In a particular embodiment, R 18 -S(O)R 12 That is the case.

[0565] In a particular embodiment, R 18 ha-SO2R 12 That is the case.

[0566] In a particular embodiment, R 18 -NR 10 R 11 That is the case.

[0567] In a particular embodiment, R 18 It is cyano.

[0568] In a particular embodiment, R 18It is nitro.

[0569] In a particular embodiment, R 18 It is a heteroaryl compound.

[0570] In a particular embodiment, R 18 It is Ariel.

[0571] In a particular embodiment, R 18 It is an arylalkyl.

[0572] In a particular embodiment, R 18 It is a cycloalkyl group.

[0573] In a particular embodiment, R 18 It is a complex algebra.

[0574] In a particular embodiment, R 18 It is a combination.

[0575] In a particular embodiment, R 18 It is a combination.

[0576] In a particular embodiment, R 18 It is a combination.

[0577] In a particular embodiment, R 18 It is a combination.

[0578] In a particular embodiment, R 18 It is a combination.

[0579] In a particular embodiment, R 18 It is a combination.

[0580] R 20 , R 21 , R 22 , R 23 , and R 24 Non-limiting embodiments of: In a particular embodiment, R20 It is a combination.

[0581] In a particular embodiment, R 20 It is alkyl.

[0582] In a particular embodiment, R 20 It is -C(O)-.

[0583] In a particular embodiment, R 20 It is -C(O)O-.

[0584] In a particular embodiment, R 20 It is -OC(O)-.

[0585] In a particular embodiment, R 20 It is -SO2-.

[0586] In a particular embodiment, R 20 It is -S(O)-.

[0587] In a particular embodiment, R 20 is -C(S)-.

[0588] In a particular embodiment, R 20 -C(O)NR 27 - is

[0589] In a particular embodiment, R 20 -NR 27 It is C(O)-.

[0590] In a particular embodiment, R 20 It is -O-.

[0591] In a particular embodiment, R 20 It is -S-.

[0592] In a particular embodiment, R 20 -NR 27 - is

[0593] In a particular embodiment, R 20 It is an oxyalkylene.

[0594] In a particular embodiment, R 20 is -C(R 40 R 40 )-is.

[0595] In a particular embodiment, R 20 is -P(O)(OR 26 )O-.

[0596] In a particular embodiment, R 20 is -P(O)(OR 26 )-is.

[0597] In a particular embodiment, R 20 It is a double ring.

[0598] In a particular embodiment, R 20 It is an alkene.

[0599] In a particular embodiment, R 20 It is an alkyne.

[0600] In a particular embodiment, R 20 It is a haloalkyl.

[0601] In a particular embodiment, R 20 It is an alkoxy.

[0602] In a particular embodiment, R 20 It is Ariel.

[0603] In a particular embodiment, R 20 It is a complex algebra.

[0604] In a particular embodiment, R 20 It is an aliphatic.

[0605] In certain specific embodiments, R 20 is heteroaliphatic.

[0606] In certain specific embodiments, R 20 is heteroaryl.

[0607] In certain specific embodiments, R<00,00894>is lactic acid.

[0608] In certain specific embodiments, R 20 is glycolic acid.

[0609] In certain specific embodiments, R 20 is a carbocyclic ring.

[0610] In certain specific embodiments, R 21 is a bond.

[0611] In certain specific embodiments, R 21 is alkyl.

[0612] In certain specific embodiments, R 21 is -C(O)-.

[0613] In certain specific embodiments, R 21 is -C(O)O-.

[0614] In certain specific embodiments, R 21 is -OC(O)-

[0615] In certain specific embodiments, R 21 is -SO2-.

[0616] In certain specific embodiments, R 21 is -S(O)-.

[0617] In certain specific embodiments, R 21 is -C(S)-.

[0618] In certain specific embodiments, R 21 is -C(O)NR 27 -.

[0619] In certain specific embodiments, R 21 is -NR 27 C(O)-.

[0620] In certain specific embodiments, R 21 is -O-.

[0621] In certain specific embodiments, R 21 is -S-.

[0622] In certain specific embodiments, R 21 is -NR 27 -.[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0630] In a particular embodiment, R 21 It is a haloalkyl.

[0631] In a particular embodiment, R 21 It is an alkoxy.

[0632] In a particular embodiment, R 21 It is Ariel.

[0633] In a particular embodiment, R 21 It is a complex algebra.

[0634] In a particular embodiment, R 21 It is an aliphatic.

[0635] In a particular embodiment, R 21 It is heterolipid.

[0636] In a particular embodiment, R 21 It is a heteroaryl compound.

[0637] In a particular embodiment, R 21 It is lactic acid.

[0638] In a particular embodiment, R 21 It is glycolic acid.

[0639] In a particular embodiment, R 21 It is a carbon ring.

[0640] In a particular embodiment, R 22 It is a combination.

[0641] In a particular embodiment, R 22 It is alkyl.

[0642] In a particular embodiment, R 22 It is -C(O)-.

[0643] In a particular embodiment, R 22 It is -C(O)O-.

[0644] In a particular embodiment, R 22 It is -OC(O)-.

[0645] In a particular embodiment, R 22 It is -SO2-.

[0646] In a particular embodiment, R 22 It is -S(O)-.

[0647] In a particular embodiment, R 22 is -C(S)-.

[0648] In a particular embodiment, R 22 -C(O)NR 27 - is

[0649] In a particular embodiment, R 22 -NR 27 It is C(O)-.

[0650] In a particular embodiment, R 22 It is -O-.

[0651] In a particular embodiment, R 22 It is -S-.

[0652] In a particular embodiment, R 22 -NR 27 - is

[0653] In a particular embodiment, R 22 It is an oxyalkylene.

[0654] In a particular embodiment, R 22 is -C(R 40 R 40 )-is.

[0655] In a particular embodiment, R 22 is -P(O)(OR 26 )O-.

[0656] In a particular embodiment, R 22 is -P(O)(OR 26 )-is.

[0657] In a particular embodiment, R 22 It is a double ring.

[0658] In a particular embodiment, R 22 It is an alkene.

[0659] In a particular embodiment, R 22 It is an alkyne.

[0660] In a particular embodiment, R 22 It is a haloalkyl.

[0661] In a particular embodiment, R 22 It is an alkoxy.

[0662] In a particular embodiment, R 22 It is Ariel.

[0663] In a particular embodiment, R 22 It is a complex algebra.

[0664] In a particular embodiment, R 22 It is an aliphatic.

[0665] In a particular embodiment, R 22 It is heterolipid.

[0666] In a particular embodiment, R 22 It is a heteroaryl compound.

[0667] In certain embodiments, R 22 is lactic acid.

[0668] In certain embodiments, R 22 is glycolic acid.

[0669] In certain embodiments, R 22 is a carbocyclic ring.

[0670] In certain embodiments, R 23 is a bond.

[0671] In certain embodiments, R 23 is alkyl.

[0672] In certain embodiments, R 23 is -C(O)-.

[0673] In certain embodiments, R 23 is -C(O)O-.

[0674] In certain embodiments, R 23 is -OC(O)-.

[0675] In certain embodiments, R 23 is -SO2-.

[0676] In certain embodiments, R 23 is -S(O)-.

[0677] In certain embodiments, R<x 23 is -C(S)-.

[0678] In certain embodiments, R 23 is -C(O)NR 27 -.

[0679] <x In certain embodiments, R 23 [[ID=x00076]]is -NR 27 C(O)-.

[0680] In a particular embodiment, R 23 It is -O-.

[0681] In a particular embodiment, R 23 It is -S-.

[0682] In a particular embodiment, R 23 -NR 27 - is

[0683] In a particular embodiment, R 23 It is an oxyalkylene.

[0684] In a particular embodiment, R 23 is -C(R 40 R 40 )-is.

[0685] In a particular embodiment, R 23 is -P(O)(OR 26 )O-.

[0686] In a particular embodiment, R 23 is -P(O)(OR 26 )-is.

[0687] In a particular embodiment, R 23 It is a double ring.

[0688] In a particular embodiment, R 23 It is an alkene.

[0689] In a particular embodiment, R 23 It is an alkyne.

[0690] In a particular embodiment, R 23 It is a haloalkyl.

[0691] In a particular embodiment, R 23 It is an alkoxy.

[0692] In a particular embodiment, R 23 It is Ariel.

[0693] In a particular embodiment, R 23 It is a complex algebra.

[0694] In a particular embodiment, R 23 It is an aliphatic.

[0695] In a particular embodiment, R 23 It is heterolipid.

[0696] In a particular embodiment, R 23 It is a heteroaryl compound.

[0697] In a particular embodiment, R 23 It is lactic acid.

[0698] In a particular embodiment, R 23 It is glycolic acid.

[0699] In a particular embodiment, R 23 It is a carbon ring.

[0700] In a particular embodiment, R 24 It is a combination.

[0701] In a particular embodiment, R 24 It is alkyl.

[0702] In a particular embodiment, R 24 It is -C(O)-.

[0703] In a particular embodiment, R 24 It is -C(O)O-.

[0704] In a particular embodiment, R 24 It is -OC(O)-.

[0705] In a particular embodiment, R 24 It is -SO2-.

[0706] In a particular embodiment, R 24 It is -S(O)-.

[0707] In a particular embodiment, R 24 is -C(S)-.

[0708] In a particular embodiment, R 24 -C(O)NR 27 - is

[0709] In a particular embodiment, R 24 -NR 27 It is C(O)-.

[0710] In a particular embodiment, R 24 It is -O-.

[0711] In a particular embodiment, R 24 It is -S-.

[0712] In a particular embodiment, R 24 -NR 27 - is

[0713] In a particular embodiment, R 24 It is an oxyalkylene.

[0714] In a particular embodiment, R 24 is -C(R 40 R 40 )-is.

[0715] In a particular embodiment, R 24 is -P(O)(OR 26 )O-.

[0716] In a particular embodiment, R24 is -P(O)(OR 26 )-is.

[0717] In a particular embodiment, R 24 It is a double ring.

[0718] In a particular embodiment, R 24 It is an alkene.

[0719] In a particular embodiment, R 24 It is an alkyne.

[0720] In a particular embodiment, R 24 It is a haloalkyl.

[0721] In a particular embodiment, R 24 It is an alkoxy.

[0722] In a particular embodiment, R 24 It is Ariel.

[0723] In a particular embodiment, R 24 It is a complex algebra.

[0724] In a particular embodiment, R 24 It is an aliphatic.

[0725] In a particular embodiment, R 24 It is heterolipid.

[0726] In a particular embodiment, R 24 It is a heteroaryl compound.

[0727] In a particular embodiment, R 24 It is lactic acid.

[0728] In a particular embodiment, R 24 It is glycolic acid.

[0729] In a particular embodiment, R 24 It is a carbon ring.

[0730] R 25 Non-limiting embodiments of: In a particular embodiment, R 25 It is an aliphatic.

[0731] In a particular embodiment, R 25 It is Ariel.

[0732] In a particular embodiment, R 25 It is a heteroaryl compound.

[0733] In a particular embodiment, R 25 It is hydrogen.

[0734] R 26 Non-limiting embodiments of: In a particular embodiment, R 26 It is hydrogen.

[0735] In a particular embodiment, R 26 It is alkyl.

[0736] In a particular embodiment, R 26 It is an arylalkyl.

[0737] In a particular embodiment, R 26 It is a heteroarylalkyl.

[0738] In a particular embodiment, R 26 It is an alkene.

[0739] In a particular embodiment, R 26 It is an alkyne.

[0740] In a particular embodiment, R 26 It is Ariel.

[0741] In a particular embodiment, R 26 It is a heteroaryl compound.

[0742] In a particular embodiment, R 26 It is a complex algebra.

[0743] In a particular embodiment, R 26 It is an aliphatic.

[0744] In a particular embodiment, R 26 It is heterolipid.

[0745] R 27 Non-limiting embodiments In a particular embodiment, R 27 It is hydrogen.

[0746] In a particular embodiment, R 27 It is alkyl.

[0747] In a particular embodiment, R 27 It is an aliphatic.

[0748] In a particular embodiment, R 27 It is heterolipid.

[0749] In a particular embodiment, R 27 It is a complex algebra.

[0750] In a particular embodiment, R 27 It is Ariel.

[0751] In a particular embodiment, R 27 It is a heteroaryl compound.

[0752] In a particular embodiment, R 27 It is -C(O) (aliphatic).

[0753] In a particular embodiment, R 27is -C(O)(aryl).

[0754] In a particular embodiment, R 27 It is -C(O) (heteroaliphatic).

[0755] In a particular embodiment, R 27 It is -C(O)(heteroaryl).

[0756] In a particular embodiment, R 27 It is an alkene.

[0757] In a particular embodiment, R 27 It is an alkyne.

[0758] R 28 A non-limiting embodiment of the same. In a particular embodiment, R 28 It is alkyl.

[0759] In a particular embodiment, R 28 It is an alkene.

[0760] In a particular embodiment, R 28 It is an alkyne.

[0761] In a particular embodiment, R 28 It is hydroxyl.

[0762] In a particular embodiment, R 28 It is Azid.

[0763] In a particular embodiment, R 28 It is an amino acid.

[0764] In a particular embodiment, R 28 It is a halogen.

[0765] In a particular embodiment, R 28 It is a haloalkyl.

[0766] In a particular embodiment, R 28 は-OR 10 That is the case.

[0767] In a particular embodiment, R 28 Ha-SR 10 That is the case.

[0768] In a particular embodiment, R 28 -S(O)R 12 That is the case.

[0769] In a particular embodiment, R 28 ha-SO2R 12 That is the case.

[0770] In a particular embodiment, R 28 -NR 10 R 11 That is the case.

[0771] In a particular embodiment, R 28 It is cyano.

[0772] In a particular embodiment, R 28 It is nitro.

[0773] In a particular embodiment, R 28 It is a heteroaryl compound.

[0774] In a particular embodiment, R 28 It is Ariel.

[0775] In a particular embodiment, R 28 It is an arylalkyl.

[0776] In a particular embodiment, R 28 It is a cycloalkyl group.

[0777] In a particular embodiment, R 28 It is a complex algebra.

[0778] R 40 Non-limiting embodiments In a particular embodiment, R 40 It is hydrogen.

[0779] In a particular embodiment, R 40 is R 27 That is the case.

[0780] In a particular embodiment, R 40 It is alkyl.

[0781] In a particular embodiment, R 40 It is an alkene.

[0782] In a particular embodiment, R 40 It is an alkyne.

[0783] In a particular embodiment, R 40 It is fluorine.

[0784] In a particular embodiment, R 40 It is bromine.

[0785] In a particular embodiment, R 40 It is chlorine.

[0786] In a particular embodiment, R 40 It is a hydroxyl group.

[0787] In a particular embodiment, R 40 It is Azid.

[0788] In a particular embodiment, R 40 It is an amino acid.

[0789] In a particular embodiment, R 40 It is cyano.

[0790] In a particular embodiment, R 40It is an alkoxy.

[0791] In a particular embodiment, R 40 It is -NH (alkyl).

[0792] In a particular embodiment, R 40 It is -NH (aliphatic).

[0793] In a particular embodiment, R 40 It is -N(aliphatic)2.

[0794] In a particular embodiment, R 40 It is -N(alkyl)2.

[0795] In a particular embodiment, R 40 It is -NHSO2 (alkyl).

[0796] In a particular embodiment, R 40 It is -NHSO2 (aliphatic).

[0797] In a particular embodiment, R 40 It is -N(alkyl)SO2 alkyl.

[0798] In a particular embodiment, R 40 It is a -N(aliphatic)SO2 alkyl group.

[0799] In a particular embodiment, R 40 It is -NHSO2 (aryl).

[0800] In a particular embodiment, R 40 It is -NHSO2 (heteroaryl).

[0801] In a particular embodiment, R 40 is -NHSO2 (a heterogeneous ring).

[0802] In a particular embodiment, R 40It is -N(alkyl)SO2(aryl).

[0803] In a particular embodiment, R 40 It is -N(alkyl)SO2(heteroaryl).

[0804] In a particular embodiment, R 40 It is a -N(alkyl)SO2 (heterocyclic) ring.

[0805] In a particular embodiment, R 40 It is the -NHSO2 alkenyl.

[0806] In a particular embodiment, R 40 It is an -N(alkyl)SO2 alkenyl.

[0807] In a particular embodiment, R 40 It is -NHSO2 alkynyl.

[0808] In a particular embodiment, R 40 It is -N(alkyl)SO2 alkynyl.

[0809] In a particular embodiment, R 40 It is a haloalkyl.

[0810] In a particular embodiment, R 40 It is an aliphatic.

[0811] In a particular embodiment, R 40 It is heterolipid.

[0812] In a particular embodiment, R 40 It is Ariel.

[0813] In a particular embodiment, R 40 It is a heteroaryl compound.

[0814] In a particular embodiment, R 40It is a complex algebra.

[0815] In a particular embodiment, R 40 It is a cycloalkyl group.

[0816] R 41 Non-limiting embodiments of: In a particular embodiment, R 41 It is an aliphatic.

[0817] In a particular embodiment, R 41 It is Ariel.

[0818] In a particular embodiment, R 41 It is a heteroaryl compound.

[0819] In a particular embodiment, R 41 It is hydrogen.

[0820] Further embodiments of the present invention 1. In a particular embodiment, the following formula is provided: [ka] (In the formula, A is [ka] Selected from, B is [ka] Selected from, n is 0, 1, or 2. X is NR 10 , NR 6’ , O, or S, X' is NR 10 It is O, CH2, or S, Q is CR 7 or N, Q and Q'' are each independently CR 6 Selected from N, Ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, where ring-A is R if permissible by valency. 1 It is optionally substituted with one, two, or three substituents independently selected from the above, Ring-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocycle, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, where ring-B is R if permissible by valency. 2 It is optionally substituted with one, two, or three substituents independently selected from the above, In certain embodiments, ring-A is a fused ring selected from phenyl, a 5- or 6-membered heteroaryl, a 5- or 6-membered heterocycle, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered cycloalkenyl, where ring-A is R if permitted by valency. 1 It is optionally substituted with one, two, or three substituents independently selected from the above, In certain embodiments, ring-B is a fused ring selected from phenyl, a 5- or 6-membered heteroaryl, a 5- or 6-membered heterocycle, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered cycloalkenyl, where ring-B is R if permitted by valency. 2 It is optionally substituted with one, two, or three substituents independently selected from the above, Ring-C is a fused ring selected from phenyl, a 5- or 6-membered heteroaryl, a 5- or 6-membered heterocycle, a 5- or 6-membered cycloalkyl, and a 5- or 6-membered cycloalkenyl, where ring-C is R if permissible by valency. 1 It is optionally substituted with one, two, or three substituents independently selected from the above, Ring-D is a fused ring selected from phenyl, a 5- or 6-membered heteroaryl, a 5- or 6-membered heterocycle, a 5- or 6-membered cycloalkyl, and a 5- or 6-membered cycloalkenyl, where ring-D is R if permitted by valency. 2 It is optionally substituted with one, two, or three substituents independently selected from the above, R 1 and R 2 Each of them operates independently. (a) Hydrogen, alkyl, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 , cyano, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, where each heteroaryl, aryl, cycloalkyl, and heterocyclic is R 40 Optionally substituted with one, two, three, or four substituents independently selected from the above, (b) [ka] ,and, (c) Divalent parts, e.g., O, S, or =NR, where permitted by valency and stability. 25 , Selected from, Here, if appropriate and desired, R 1 The base is, arbitrarily, another R 1 Base or R 2 They may combine with the group to form a fused ring or a diring, which may bridge ring-A and ring-B or ring-C and ring-D. R 3 is hydrogen, alkyl, halogen, or haloalkyl, Or, R 3 and R 6 They come together to form a one-carbon linkage or a two-carbon linkage, for example, R 3 and R 6 When forming a single carbon bond, [ka] teeth, [ka] And, Or, R 3 and R 4These combine to form a 1-carbon linkage, a 2-carbon linkage, a 3-carbon linkage, or a 4-carbon linkage, for example, R 3 and R 4 When forming a single carbon bond, [ka] teeth, [ka] And, Or, R 3 and R 3 Adjacent to R 4 The groups come together to form a double bond, Each R 4 These are independently selected from hydrogen, alkyl, halogen, and haloalkyl, R 5 is hydrogen, alkyl, halogen, or haloalkyl, R 6 and R 7 These are, independently, hydrogen, alkyl, halogen, haloalkyl, and -OR. 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , and -NR 10 R 11 Selected from, here R 6 and R 7 If they are on the same carbon atom, they may optionally form a 3-membered or 4-membered spiro ring. R 6 ' is hydrogen, alkyl, or haloalkyl, Or, R 3 and R 6 'together, they form a 1-carbon linkage or a 2-carbon linkage, Each R 10 and R 11 These are independently hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, and -C(O)R 12 ,-S(O)R 12 , and -SO2R 12 Selected from, Each R 12These are independently hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, and -NR. 13 R 14 , and OR 13 Selected from, R 13 and R 14 Each of these is independently selected from hydrogen, alkyl, and haloalkyl. each X 2 This refers to bonded, heterocyclic, aryl, heteroaryl, bicyclic, alkyl, aliphatic, heteroaliphatic, -NR 27 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27 The divalent moiety is selected from -, -C(S)-, -S(O)-, -S(O)2-, and -S-, and its heterocycle, aryl, heteroaryl, and bicycle are each R 40 It is optionally substituted with one, two, three, or four substituents independently selected from the above, X 3 This refers to bond, heterocycle, aryl, heteroaryl, bicycle, -NR 27 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27 The divalent moiety is selected from -, -C(S)-, -S(O)-, -S(O)2-, -S-, arylalkyl, heterocyclic alkyl, or heteroarylalkyl (in either direction), and the heterocycle, aryl, heteroaryl, and dicyclic rings are each R 40 It may be substituted with one, two, three, or four substituents independently selected from the above. R 15 , R 16 , and R 17 These are, independently, bonds, alkyl (which is a carbon ring in a particular embodiment), -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, and -C(O)NR. 27 -, -NR 27 C(O)-, -O-, -S-, -NR 27 -, -C(R 40 R 41 )-,-P(O)(OR26 )O-, -P(O)(OR 26 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, arylalkyl glycolate, heterocyclic alkyl and heteroarylalkyl (in either direction), each of which is selected from the group consisting of R 40 It is optionally substituted with one, two, three, or four substituents independently selected from the above, R 18 These are hydrogen, alkyl, alkene, alkyne, hydroxy, azide, amino, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 Selected from cyano, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, where each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is R 40 It is optionally substituted with one, two, three, or four substituents independently selected from the above, R 20 , R 21 , R 22 , R 23 , and R 24 These are, independently, bonded, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 27 -, -NR 27 C(O)-, -O-, -S-, -NR 27 -, oxyalkylene, -C(R 40 R 40 )-,-P(O)(OR 26 )O-, -P(O)(OR 26 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocyclic are selected from the group, each of which is R 40 It is optionally substituted with one, two, three, or four substituents independently selected from the above, R25 These are aliphatic (including alkyl), aryl, heteroaryl, or hydrogen. R 26 Each of these is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic elements. R 27 Each is independently selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkenes, and alkynes. R 40 These are, independently, hydrogen and R 27 Selected from the group consisting of alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH (alliphatic containing alkyl), -N (alliphatic containing alkyl)2, -NHSO2 (alliphatic containing alkyl), -N (alliphatic containing alkyl)SO2 alkyl, -NHSO2 (aryl, heteroaryl or heterocyclic), -N(alkyl)SO2 (aryl, heteroaryl or heterocyclic), -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl. R 41 A compound selected from aliphatic (including alkyl), aryl, heteroaryl, or hydrogen compounds, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug, is provided in a pharmaceutically acceptable carrier for optionally forming a composition.

[0821] 2. In a particular embodiment, the following formula: [ka] (In the formula, AA is, [ka] Selected from, Ring E is, (a) [ka] ,and, (b) If permitted by valence, R 2 A fused ring selected from a 5-membered heteroaryl, a 5- to 8-membered heterocycle, a 5- to 8-membered cycloalkyl, or a 5- to 8-membered cycloalkenyl, optionally substituted with one, two, or three substituents independently selected from the above. Selected from, Ring F is, (a)R 1 Phenyl substituted with one, two, or three substituents independently selected from ', (b) If permitted by valence, R 1 A fused ring selected from a 5-membered or 6-membered heteroaryl, a 5- to 8-membered heterocycle, a 5- to 8-membered cycloalkyl, or a 5- to 8-membered cycloalkenyl, optionally substituted with one, two, or three substituents independently selected from the above. Selected from, R 1 'Each of them is independent, (a) alkyl, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 , cyano, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, where each heteroaryl, aryl, and heterocyclic is R 40 Substituting with one, two, three, or four substituents independently selected from the original, (b) [ka] ,and, (c) Divalent parts, e.g., O, S, or =NR, where permitted by valency and stability.25 , Selected from, Here, R 1’ The base is, arbitrarily, another R 1’ Base or R 2 They may combine with the base to form a fused ring or a biring, which may bridge ring-A and ring-E. R 2 ' are, independently, alkyl, halogen, haloalkyl, and -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 R is selected from cyano, nitro, heteroaryl, aryl, and heterocyclic compounds, or alternatively, if acceptable by valency and stability. 2’ This is the divalent part, for example, O, S, or =NR 25 It may also be the case that R 2’ The base is, arbitrarily, another R 2’ Base or R 1 They may combine with the base to form a fused ring or a biring, which may bridge ring-A and ring-E. R 2 Each of the elements is independently selected from heteroaryl, aryl, and heterocycles, and each heteroaryl, aryl, and heterocycle is optionally R 40 It is substituted with one, two, three, or four substituents independently selected from R, where R 2’’ The base is arbitrarily R 1 Base or R 2 They may combine with the base to form a fused ring or a biring, which may bridge ring-A and ring-E. R 3a is hydrogen, alkyl, halogen, or haloalkyl, Or, R 3a and R 6a They come together to form a one-carbon linkage or a two-carbon linkage, for example, R 3a and R 6a When forming a single carbon bond, [ka] teeth, [ka] And, Or, R 3a and R 4a These combine to form a 1-carbon linkage, a 2-carbon linkage, a 3-carbon linkage, or a 4-carbon linkage, for example, R 3a and R 4a When forming a single carbon bond, [ka] teeth, [ka] And, Or, R 3a and R 3a Adjacent to R 4a The groups come together to form a double bond, R 4a It is selected from hydrogen, alkyl, halogen, and haloalkyl, R 6s These are hydrogen, alkyl, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , and -NR 10 R 11 Selected from, Here R 3a , R 4a and R 6a At least one of them is not hydrogen, R 28 Alkyl, alkene, alkyne, hydroxy, azide, amino, halogen, haloalkyl, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 Selected from cyano, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, where each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is optionally R40 Substituted with one, two, three, or four substituents independently selected from, Here R 15 , R 16 , R 17 , and R 20 If at least one of them is not a bond, R 28 It may be hydrogen, A compound selected from (where all other variable parts are as defined herein) or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof is provided in a pharmaceutically acceptable carrier for forming a composition.

[0822] 3. Ring F is R 1 The compound of Embodiment 2 is a phenyl compound substituted with one, two, or three substituents independently selected from '.

[0823] 4.R 1’ The compound of Embodiment 3 is selected from alkyl, halogen, and haloalkyl.

[0824] 5.R 1’ は-OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , and -NR 10 R 11 A compound of Embodiment 3, selected from the above.

[0825] 6.R 1’ The compound of Embodiment 3 is selected from alkyl, halogen, and haloalkyl.

[0826] 7.R 1’ The compound of Embodiment 3 is selected from heteroaryl, aryl, and heterocyclic compounds.

[0827] 8.2 R 1’ The compound of Embodiment 3, in which the substituents combine to form a condensed phenyl ring.

[0828] 9. At least one R1’ The compound of Embodiment 3, wherein is alkyl.

[0829] 10. At least one R 1’ The compound of Embodiment 3, wherein is a halogen.

[0830] 11. One R 1 'teeth, [ka] The compound of Embodiment 3.

[0831] 12. One R 1 'teeth, [ka] The compound of Embodiment 3.

[0832] 13. One R 1 'teeth, [ka] The compound of Embodiment 3.

[0833] 14. Ring E is, [ka] A compound of Embodiment 2, selected from the above.

[0834] 15.R 2’ The compound of Embodiment 14 is selected from alkyl, halogen, and haloalkyl compounds.

[0835] 16.R 2’ は-OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 A compound of Embodiment 14, selected from the above.

[0836] 17.R2’ The compound of Embodiment 14 is selected from alkyl, halogen, and haloalkyl compounds.

[0837] 18.R 2’ The compound of Embodiment 14 is selected from heteroaryl, aryl, and heterocyclic compounds.

[0838] 19.2 R 2’ The compound of Embodiment 14, in which the substituents combine to form a condensed phenyl ring.

[0839] 20. At least one R 2’ The compound of Embodiment 14, wherein is alkyl.

[0840] 21. At least one R 2’ The compound of Embodiment 14, wherein is a halogen.

[0841] 22.X 3 and X 2 A compound from any one of embodiments 11 to 21, wherein at least one of the compounds is a bond.

[0842] 23.X 3 and X 2 A compound from any one of embodiments 11 to 21, wherein at least one of the elements is -O-.

[0843] 24.X 3 and X 2 A compound from any one of embodiments 11 to 21, wherein at least one of the elements is -S-.

[0844] 25.X 3 and X 2 At least one of them is -NR 27 -A compound from any one of embodiments 11 to 21.

[0845] 26.R 15 and R 24 A compound from any one of embodiments 11 to 25, wherein at least one of the compounds is a bond.

[0846] 27.R 16 and R 23 A compound from any one of embodiments 11 to 26, wherein at least one of the compounds is a bond.

[0847] 28.R 17 and R 22 A compound from any one of embodiments 11 to 27, wherein at least one of the compounds is a bond.

[0848] 29.R 15 , R 16 , R 17 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 Four or fewer substituents selected from are chosen to bond to any one of the compounds of Embodiments 11 to 25.

[0849] 30.R 15 , R 16 , R 17 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 Three or fewer substituents selected from are chosen to bond to any one of the compounds of Embodiments 11 to 25.

[0850] 31.R 15 , R 16 , R 17 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 Two or fewer substituents selected from are chosen to bond to any one of the compounds of Embodiments 11 to 25.

[0851] 32.R 15 , R 16 , R 17 , R 19 , R 20 , R 21 , R22 , R 23 , and R 24 One or fewer substituents selected from are chosen to bond to any one of the compounds from Embodiments 11 to 25.

[0852] 33. Ring-A is a fused ring selected from phenyl, a 5- or 6-membered heteroaryl, a 5- or 6-membered heterocycle, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered cycloalkenyl, where ring-A is R if permitted by valency. 1 Any one of the compounds from Embodiments 1 to 32, which is optionally substituted with one, two, or three substituents independently selected from the above.

[0853] 34. Ring-A is a fused ring selected from phenyl or a 6-membered heteroaryl, where ring-A is R if permitted by valency. 1 Any one of the compounds from Embodiments 1 to 32, which is optionally substituted with one, two, or three substituents independently selected from the above.

[0854] 35. Ring-A is R if permitted by valency. 1 A compound from any one of Embodiments 1 to 32, which is a phenyl compound optionally substituted with one, two, or three substituents independently selected from the above.

[0855] 36. Ring-A is R if permitted by valency. 1 A compound from any one of Embodiments 1 to 32, which is a 6-membered heteroaryl that is optionally substituted with one, two, or three substituents independently selected from the above.

[0856] 37. Ring-B is a fused ring selected from phenyl, a 5- or 6-membered heteroaryl, a 5- or 6-membered heterocycle, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered cycloalkenyl, where ring-B is R if permitted by valency. 1 Any one of the compounds from Embodiments 1 to 36, which is optionally substituted with one, two, or three substituents independently selected from the above.

[0857] 38. Ring-B is a fused ring selected from phenyl or a 6-membered heteroaryl, where ring-B is R if permitted by valency. 1 Any one of the compounds from Embodiments 1 to 36, which is optionally substituted with one, two, or three substituents independently selected from the above.

[0858] 39. Ring-B is R if permitted by valency. 1 A compound from any one of Embodiments 1 to 36, which is a phenyl compound optionally substituted with one, two, or three substituents independently selected from the above.

[0859] 40. Ring-B is R if permitted by valency. 1 A compound from any one of Embodiments 1 to 36, which is a six-membered heteroaryl that is optionally substituted with one, two, or three substituents independently selected from the above.

[0860] 41.R 5 The compound is hydrogen, one of any one of embodiments 1 to 40.

[0861] 42.R 5 is an alkyl compound, one of any one of embodiments 1 to 40.

[0862] 43.R 5 is a halogen, which is one of the compounds from Embodiments 1 to 40.

[0863] 44.R 5 is a haloalkyl compound, one of any one of Embodiments 1 to 40.

[0864] 45.R 7 The compound is hydrogen, one of any one of embodiments 1 to 44.

[0865] 46.R 7 is a compound from any one of Embodiments 1 to 44, which is a halogen, a haloalkyl, or an alkyl.

[0866] 47.R 7 is -OR 10 , -SR 10 , or -NR 10 R 11 The compound is one of any four embodiments 1 to 44.

[0867] 48.R 7 is -S(O)R 12 or -SO2R 12 The compound is one of any four embodiments 1 to 44.

[0868] 49.4 R 2 A compound from any one of embodiments 1 to 48, wherein a substituent is present.

[0869] 50.3 R 2 A compound from any one of embodiments 1 to 48, wherein a substituent is present.

[0870] 51.2 R 2 A compound from any one of embodiments 1 to 48, wherein a substituent is present.

[0871] 52.1 R 2 A compound from any one of embodiments 1 to 48, wherein a substituent is present.

[0872] 53.R 2 is one of any two compounds from Embodiments 1 to 52, selected from alkyl, halogen, and haloalkyl compounds.

[0873] 54.R 2 is -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 A compound selected from any one of Embodiments 1 to 52.

[0874] 55.R 2 is one of any two compounds from Embodiments 1 to 52, selected from alkyl, halogen, and haloalkyl compounds.

[0875] 56.R 2 This is one of any two compounds from Embodiments 1 to 52, selected from heteroaryl, aryl, and heterocyclic compounds.

[0876] 57.2 R 2 A compound from any one of Embodiments 1 to 51, wherein the substituents combine to form a condensed phenyl ring.

[0877] 58. At least one R 2 is an alkyl compound, one of any one of embodiments 1 to 52.

[0878] 59. At least one R 2 is a halogen, which is one of the compounds from Embodiments 1 to 52.

[0879] 60. One R 2 teeth, [ka] The compound is one of any two embodiments 1 to 52.

[0880] 61. One R 2 teeth, [ka] The compound is one of any two embodiments 1 to 52.

[0881] 62. One R 2 teeth, [ka] The compound is one of any two embodiments 1 to 52.

[0882] 63.R 3 The compound is hydrogen, one of any one of embodiments 1 to 62.

[0883] 64.R 3is an alkyl compound, one of any one of embodiments 1 to 62.

[0884] 65.R 3 is a compound from any one of Embodiments 1 to 62, which is a haloalkyl compound.

[0885] 66.R 3 and R 6 A compound from any one of embodiments 1 to 62, which together forms a one-carbon bond.

[0886] 67.R 3 and R 6 A compound from any one of embodiments 1 to 62, which together forms a two-carbon bond.

[0887] 68.R 6 The compound is hydrogen, one of any one of embodiments 1 to 65.

[0888] 69.R 6 The compound is an alkyl compound, one of any one of embodiments 1 to 65.

[0889] 70.R 6 is a compound from any one of Embodiments 1 to 65, which is a haloalkyl compound.

[0890] 71. At least one R 4 The compound is hydrogen, one of any one of embodiments 1 to 70.

[0891] 72. At least one R 4 is an alkyl compound, one of any one of embodiments 1 to 70.

[0892] 73. At least one R 4 is a compound from any one of Embodiments 1 to 70, which is a haloalkyl compound.

[0893] 74.n is 0, which is any one of the compounds from Embodiments 1 to 70.

[0894] 75.n is one of any one of the compounds from Embodiments 1 to 73.

[0895] 76.n is one of the compounds from Embodiments 1 to 73, which is 2.

[0896] 77.4 R 1 A compound having a substituent, one of any one of embodiments 1 to 76.

[0897] 78.3 R 1 A compound having a substituent, one of any one of embodiments 1 to 76.

[0898] 79.2 R 1 A compound having a substituent, one of any one of embodiments 1 to 76.

[0899] 80.1 R 1 A compound having a substituent, one of any one of embodiments 1 to 76.

[0900] 81.R 1 is one of any two compounds from Embodiments 1 to 80, selected from alkyl, halogen, and haloalkyl compounds.

[0901] 82.R 1 は-OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 A compound selected from any one of embodiments 1 to 80.

[0902] 83.R 1 is one of any two compounds from Embodiments 1 to 80, selected from alkyl, halogen, and haloalkyl compounds.

[0903] 84.R 1 is one of the compounds from Embodiments 1 to 80, selected from heteroaryl, aryl, and heterocyclic compounds.

[0904] 85.2 R 2A compound from any one of Embodiments 1 to 79, wherein the substituents combine to form a condensed phenyl ring.

[0905] 86. At least one R 2 The compound is alkyl, one of any one of embodiments 1 to 80.

[0906] 87. At least one R 2 A compound from any one of embodiments 1 to 80, wherein is a halogen.

[0907] 88. One R 2 teeth, [ka] The compound is one of any one of embodiments 1 to 80.

[0908] 89. One R 2 teeth, [ka] The compound is one of any one of embodiments 1 to 80.

[0909] 90. One R 2 teeth, [ka] The compound is one of any one of embodiments 1 to 80.

[0910] 91. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0911] 92. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0912] 93. Any one compound from Embodiments 1 and 3 to 90, located in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0913] 94. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0914] 95. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0915] 96. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0916] 97. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0917] 98. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0918] 99. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0919] 100. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0920] 101. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0921] 102. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0922] 103. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0923] 104. Any one of the compounds from Embodiments 1 and 3 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0924] 105. Any one of the compounds from Embodiments 2 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0925] 106. Any one of the compounds from Embodiments 2 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0926] 107. Any one of the compounds of Embodiments 2 to 90, which is contained in a pharmaceutically acceptable carrier for forming a composition, wherein the compound has the formula: [ka] A compound that is a compound of, or a pharmaceutically acceptable salt thereof, N-oxide, isotopic derivative, or prodrug.

[0927] 108. In a particular embodiment, a pharmaceutical composition is provided comprising one compound from any one of embodiments 1 to 107 and a pharmaceutically acceptable additive.

[0928] 109. In a particular embodiment, a method is provided for treating a medical disorder in a patient, comprising administering to the patient an effective amount of any one compound from Embodiments 1 to 107 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 108.

[0929] 110. The method of Embodiment 109, wherein the disorder is abnormal cell proliferation.

[0930] 111. The method of Embodiment 109, wherein the disorder is a neurodegenerative disease.

[0931] 112. The method of Embodiment 109, wherein the disorder is an autoimmune disease.

[0932] 113. The patient is human, one of the embodiments 109 to 112.

[0933] R 1 , R 1’ , R 2 , and R 2’ Non-limiting embodiments In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ These are independently alkyl, halogen, haloalkyl, and -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 Selected from cyano and nitro.

[0934] In a particular embodiment, each R 1 and R 2 These are independently selected from hydrogen, alkyl, halogen, and haloalkyl.

[0935] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ These are, independently, halogen, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , -NR 10 R 11 Selected from cyano and nitro.

[0936] In a particular embodiment, each R 1 , R 1’ , R2 , and R 2’ These are, independently, halogen, -S(O)R 12 , -SO2R 12 Selected from cyano and nitro.

[0937] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ These are independently alkyl, haloalkyl, and -OR 10 , and -SR 10 Selected from.

[0938] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ These are independently selected from alkyl, haloalkyl, and cyano.

[0939] In a particular embodiment, each R 1 and R 2 It is hydrogen.

[0940] In a particular embodiment, R 1 It is hydrogen.

[0941] In a particular embodiment, R 2 It is hydrogen.

[0942] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is alkyl.

[0943] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is halogen.

[0944] In a particular embodiment, R 1, R 1’ , R 2 , and R 2’ One of them is a haloalkyl.

[0945] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is -OR 10 That is the case.

[0946] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is -SR 10 That is the case.

[0947] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is -S(O)R 12 That is the case.

[0948] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is -SO2R 12 That is the case.

[0949] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is -NR 10 R 11 That is the case.

[0950] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is cyano.

[0951] In a particular embodiment, R 1 , R1’ , R 2 , and R 2’ One of them is nitro.

[0952] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is a heteroaryl.

[0953] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of them is Ariel.

[0954] In a particular embodiment, R 1 , R 1’ , R 2 , and R 2’ One of these is a complex algebra.

[0955] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ It is an alkyl group.

[0956] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ It is a halogen.

[0957] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ It is a haloalkyl compound.

[0958] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ is -OR 10 That is the case.

[0959] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ -SR 10 That is the case.

[0960] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ is -S(O)R 12 That is the case.

[0961] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ is -SO2R 12 That is the case.

[0962] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ -NR 10 R 11 That is the case.

[0963] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ It is cyano.

[0964] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ It is nitro.

[0965] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ It is a heteroaryl compound.

[0966] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ That is Ariel.

[0967] In a particular embodiment, each R 1 , R 1’ , R 2 , and R 2’ This is a complex algebra.

[0968] In a particular embodiment, there is only one R on ring-A or ring-C. 1 A substituent is present.

[0969] In a particular embodiment, there are only two R on ring-A or ring-C. 1 A substituent is present.

[0970] In a particular embodiment, there are three R's on ring-A or ring-C. 1 A substituent is present.

[0971] In a particular embodiment, there is only one R on ring-A. 1 It has substituents, R 1 The substituent is hydrogen.

[0972] In a particular embodiment, there is only one R on ring-F. 1’ A substituent is present.

[0973] In a particular embodiment, there are only two R on ring-F. 1’ A substituent is present.

[0974] In a particular embodiment, there are three R's on ring-F. 1’ A substituent is present.

[0975] In a particular embodiment, there is only one R on ring-B. 2 A substituent is present.

[0976] In a particular embodiment, there are only two R on ring-B. 2 A substituent is present.

[0977] In a particular embodiment, there are three R's on ring-B. 2 A substituent is present.

[0978] In a particular embodiment, there is only one R on ring-D. 2 A substituent is present.

[0979] In a particular embodiment, there are only two R on ring-D. 2 A substituent is present.

[0980] In a particular embodiment, there are three R's on ring-D. 2 A substituent is present.

[0981] In a particular embodiment, there is only one R on ring-E. 2 A substituent is present.

[0982] In a particular embodiment, there are only two R on ring-E. 2 A substituent is present.

[0983] In a particular embodiment, there are three R's on ring-E. 2 A substituent is present.

[0984] In a particular embodiment, there is only one R on ring-E. 2’ A substituent is present.

[0985] In a particular embodiment, there are only two R on ring-E. 2’ A substituent is present.

[0986] In a particular embodiment, there are three R's on ring-E. 2’ A substituent is present.

[0987] In a particular embodiment, one R 1The substituent is a halogen.

[0988] In a particular embodiment, two R 1 The substituent is a halogen.

[0989] In a particular embodiment, three R 1 The substituent is a halogen.

[0990] In a particular embodiment, one R 2 The substituent is a halogen.

[0991] In a particular embodiment, two R 2 The substituent is a halogen.

[0992] In a particular embodiment, three R 2 The substituent is a halogen.

[0993] In a particular embodiment, one R 1 The substituent is a haloalkyl group.

[0994] In a particular embodiment, two R 1 The substituent is a haloalkyl group.

[0995] In a particular embodiment, three R 1 The substituent is a haloalkyl group.

[0996] In a particular embodiment, one R 2 The substituent is a haloalkyl group.

[0997] In a particular embodiment, two R 2 The substituent is a haloalkyl group.

[0998] In a particular embodiment, three R 2 The substituent is a haloalkyl group.

[0999] In a particular embodiment, one R1 The substituent is alkyl.

[1000] In a particular embodiment, two R 1 The substituent is alkyl.

[1001] In a particular embodiment, three R 1 The substituent is alkyl.

[1002] In a particular embodiment, one R 2 The substituent is alkyl.

[1003] In a particular embodiment, two R 2 The substituent is alkyl.

[1004] In a particular embodiment, three R 2 The substituent is alkyl.

[1005] In a particular embodiment, two R 1 The groups combine to form a condensed phenyl ring.

[1006] In a particular embodiment, two R 1 The groups combine to form a condensed five-membered heteroaryl ring.

[1007] In a particular embodiment, two R 1 The groups combine to form a condensed six-membered heteroaryl ring.

[1008] In a particular embodiment, R 1 The base is R 2 Together with the base, it forms a condensed six-membered heterocycle.

[1009] In a particular embodiment, R 1 The base is R 2 Together with the base, it forms a condensed five-membered heterocycle.

[1010] In a particular embodiment, two R2 The groups combine to form a condensed phenyl ring.

[1011] In a particular embodiment, two R 1 The groups combine to form a condensed phenyl ring.

[1012] In a particular embodiment, two R 2 The groups combine to form a condensed five-membered heteroaryl ring.

[1013] In a particular embodiment, two R 2 The groups combine to form a condensed six-membered heteroaryl ring.

[1014] In a particular embodiment, one R 1’ The substituent is a halogen.

[1015] In a particular embodiment, two R 1’ The substituent is a halogen.

[1016] In a particular embodiment, three R 1’ The substituent is a halogen.

[1017] In a particular embodiment, one R 2’ The substituent is a halogen.

[1018] In a particular embodiment, two R 2’ The substituent is a halogen.

[1019] In a particular embodiment, three R 2’ The substituent is a halogen.

[1020] In a particular embodiment, one R 1’ The substituent is a haloalkyl group.

[1021] In a particular embodiment, two R 1’ The substituent is a haloalkyl group.

[1022] In a particular embodiment, three R 1’ The substituent is a haloalkyl group.

[1023] In a particular embodiment, one R 2’ The substituent is a haloalkyl group.

[1024] In a particular embodiment, two R 2’ The substituent is a haloalkyl group.

[1025] In a particular embodiment, three R 2’ The substituent is a haloalkyl group.

[1026] In a particular embodiment, one R 1’ The substituent is alkyl.

[1027] In a particular embodiment, two R 1’ The substituent is alkyl.

[1028] In a particular embodiment, three R 1’ The substituent is alkyl.

[1029] In a particular embodiment, one R 2’ The substituent is alkyl.

[1030] In a particular embodiment, two R 2’ The substituent is alkyl.

[1031] In a particular embodiment, three R 2’ The substituent is alkyl.

[1032] In a particular embodiment, two R 1’ The groups combine to form a condensed phenyl ring.

[1033] In a particular embodiment, two R 1’The groups combine to form a condensed five-membered heteroaryl ring.

[1034] In a particular embodiment, two R 1’ The groups combine to form a condensed six-membered heteroaryl ring.

[1035] In a particular embodiment, R 1’ The base is R 2 Together with the base, it forms a condensed six-membered heterocycle.

[1036] In a particular embodiment, R 1’ The base is R 2 Together with the base, it forms a condensed five-membered heterocycle.

[1037] In a particular embodiment, two R 2’ The groups combine to form a condensed phenyl ring.

[1038] In a particular embodiment, two R 1’ The groups combine to form a condensed phenyl ring.

[1039] In a particular embodiment, two R 2’ The groups combine to form a condensed five-membered heteroaryl ring.

[1040] In a particular embodiment, two R 2’ The groups combine to form a condensed six-membered heteroaryl ring.

[1041] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] (wherein each R' is independently selected from hydrogen, alkyl, haloalkyl, aryl, heterocyclic, and heteroaryl.)

[1042] In a particular embodiment, R1 , R 2 , or R 1’ R ’ It is a heterocyclic group that is optionally substituted with one or two substituents selected from the following.

[1043] In a particular embodiment, R 1 , R 2 , or R 1’ It is a six-membered heterocyclic group containing one or two nitrogen atoms.

[1044] In a particular embodiment, R 1 , R 2 , or R 1’ It is a six-membered heterocyclic group containing one or two oxygen atoms.

[1045] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] (wherein each R' is independently selected from hydrogen, alkyl, haloalkyl, aryl, heterocyclic, and heteroaryl.)

[1046] In a particular embodiment, R 1 R ’ It is a heterocyclic group that is optionally substituted with one or two substituents selected from the following.

[1047] In a particular embodiment, R 1 It is a six-membered heterocyclic group containing one or two nitrogen atoms.

[1048] In a particular embodiment, R 1 It is a six-membered heterocyclic group containing one or two oxygen atoms.

[1049] In a particular embodiment, R 2 R ’ It is a heterocyclic group that is optionally substituted with one or two substituents selected from the following.

[1050] In a particular embodiment, R 2 It is a six-membered heterocyclic group containing one or two nitrogen atoms.

[1051] In a particular embodiment, R 2 It is a six-membered heterocyclic group containing one or two oxygen atoms.

[1052] In a particular embodiment, R 1’ R ’ It is a heterocyclic group that is optionally substituted with one or two substituents selected from the following.

[1053] In a particular embodiment, R 1’ It is a six-membered heterocyclic group containing one or two nitrogen atoms.

[1054] In a particular embodiment, R 1’ It is a six-membered heterocyclic group containing one or two oxygen atoms.

[1055] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1056] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1057] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1058] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1059] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1060] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from TIFF0007863101000156.tif160170.

[1061] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from TIFF0007863101000158.tif228170 and TIFF0007863101000159.tif161170.

[1062] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1063] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1064] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1065] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1066] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1067] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1068] In a particular embodiment, one R 1 , R2 , or R 1’ teeth, [ka] Selected from.

[1069] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1070] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1071] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1072] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1073] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1074] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1075] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1076] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1077] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1078] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from TIFF0007863101000177.tif103170.

[1079] In a particular embodiment, one R1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1080] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1081] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1082] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1083] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1084] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1085] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1086] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1087] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1088] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1089] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1090] In a particular embodiment, one R 1 , R2 , or R 1’ teeth, [ka] Selected from.

[1091] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1092] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1093] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1094] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1095] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1096] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1097] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1098] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1099] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1100] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1101] In a particular embodiment, one R 1 , R 2 , or R1’ teeth, [ka] Selected from.

[1102] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1103] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1104] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1105] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1106] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1107] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from TIFF0007863101000207.tif180170.

[1108] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1109] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1110] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1111] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1112] In a particular embodiment, one R 1 , R 2, or R 1’ teeth, [ka] Selected from.

[1113] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1114] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1115] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1116] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1117] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1118] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1119] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from TIFF0007863101000220.tif229170.

[1120] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1121] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1122] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1123] In a particular embodiment, one R 1 , R2 , or R 1’ teeth, [ka] Selected from.

[1124] In a particular embodiment, one R 1 , R 2 , or R 1’ teeth, [ka] Selected from.

[1125] R 3 Non-limiting embodiments In a particular embodiment, R 3 The element is selected from hydrogen and halogens.

[1126] In a particular embodiment, R 3 The alkyl and haloalkyl elements are selected from alkyl and haloalkyl groups.

[1127] In a particular embodiment, R 3 It is hydrogen.

[1128] In a particular embodiment, R 3 It is a halogen.

[1129] In a particular embodiment, R 3 It is an alkyl group.

[1130] In a particular embodiment, R 3 It is a haloalkyl compound.

[1131] In a particular embodiment, R 3 It is fluoro.

[1132] In a particular embodiment, R 3 That is Chlorophyll.

[1133] In a particular embodiment, R 3 It is Bromo.

[1134] In a particular embodiment, R 3 It is iodine.

[1135] In a particular embodiment, R 3 It is methyl.

[1136] In a particular embodiment, R 3 It is ethyl.

[1137] In a particular embodiment, R 3 It is trifluoromethyl.

[1138] In a particular embodiment, R 3 It is pentafluoroethyl.

[1139] In a particular embodiment, R 3 It is difluoromethyl.

[1140] In a particular embodiment, R 3 It is fluoromethyl.

[1141] In a particular embodiment, R 3 is R 4 It combines with the base to form a one-carbon bond.

[1142] In a particular embodiment, R 3 is R 4 Together with the base, it forms a two-carbon bond.

[1143] In a particular embodiment, R 3 is R 4 Together with the base, it forms a 3-carbon bond.

[1144] In a particular embodiment, R 3 is R 4Together with the base, it forms a 4-carbon bond.

[1145] In a particular embodiment, R 3 is R 4 It combines with the base to form a double bond.

[1146] R 6 and R 7 Non-limiting embodiments In a particular embodiment, R 6 and R 7 These are independently selected from hydrogen, alkyl, halogen, and haloalkyl.

[1147] In a particular embodiment, R 6 and R 7 These are, independently, -OR 10 , -SR 10 ,-S(O)R 12 , -SO2R 12 , and -NR 10 R 11 Selected from.

[1148] In a particular embodiment, R 6 and R 7 These are independently alkyl, -OR 10 , -SR 10 , and -NR 10 R 11 Selected from.

[1149] In a particular embodiment, R 6 is R 3 It combines with the base to form a one-carbon bond.

[1150] In a particular embodiment, R 6 is R 3 Together with the base, it forms a two-carbon bond.

[1151] Embodiments of ring-A, ring-B, ring-C, ring-D, ring-E, and ring-F In a particular embodiment, [ka] The following: [ka] Selected from.

[1152] In a particular embodiment, [ka] The following: [ka] Selected from.

[1153] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1154] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1155] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1156] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1157] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1158] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1159] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1160] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1161] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1162] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1163] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1164] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1165] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1166] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1167] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1168] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1169] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1170] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1171] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1172] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1173] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1174] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1175] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1176] In a particular embodiment, [ka] is selected from

Chemical formula

[1177] In a certain specific embodiment,

Chemical formula

Chemical formula

[1178] In a certain specific embodiment,

Chemical formula

Chemical formula

[1179] In a certain specific embodiment,

Chemical formula

Chemical formula

[1180] In a certain specific embodiment, [[ID=6b]]

Chemical formula

Chemical formula

[1181] In a certain specific embodiment,

Chemical formula

[1182] In a particular embodiment, [ka] teeth, [ka] Selected from TIFF0007863101000290.tif57170.

[1183] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1184] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1185] In a particular embodiment, [ka] The following: [ka] Selected from.

[1186] In a particular embodiment, [ka] The following: [ka] Selected from.

[1187] In a particular embodiment, [ka] The following: [ka] Selected from TIFF0007863101000301.tif94170.

[1188] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1189] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1190] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1191] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1192] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1193] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1194] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1195] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1196] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1197] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1198] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1199] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1200] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1201] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1202] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1203] In a particular embodiment, [ka] teeth, [ka] Selected from TIFF0007863101000334.tif31170.

[1204] In a particular embodiment, [ka] teeth, [ka] Selected from TIFF0007863101000337.tif137170.

[1205] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1206] In a particular embodiment, [ka] teeth, [ka] Selected from.

[1207] In a particular embodiment, [ka] About [ka] teeth, [ka] Selected from.

[1208] In a particular embodiment, [ka] inside [ka] teeth, [ka] Selected from, for example, [ka] but, [ka] In that case, [ka] teeth, [ka] That is the case. [ka]

[1209] In a particular embodiment, [ka] About [ka] teeth, [ka] Selected from.

[1210] In the structure described herein, structure: [ka] This refers to a cycloalkyl ring, cycloalkene ring, heterocyclic ring, aryl ring, or heteroaryl ring condensed on either ring-A and ring-B or ring-C and ring-D.

[1211] "alkyl" embodiment In a particular embodiment, "alkyl" is C1-C 10 It is alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1 or C2 alkyl.

[1212] In a particular embodiment, the "alkyl" contains one carbon atom.

[1213] In a particular embodiment, the "alkyl" contains two carbon atoms.

[1214] In a particular embodiment, the "alkyl" contains three carbon atoms.

[1215] In a particular embodiment, the "alkyl" contains four carbon atoms.

[1216] In a particular embodiment, the "alkyl" contains five carbon atoms.

[1217] In a particular embodiment, the "alkyl" contains six carbon atoms.

[1218] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[1219] Additional, non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[1220] Additional, non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[1221] Additional, non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[1222] Additional, non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[1223] "Haloalkyl" embodiment In a particular embodiment, "haloalkyl" is C1-C 10 These include haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, and C1 or C2 haloalkyl.

[1224] In a particular embodiment, the "haloalkyl" has one carbon atom.

[1225] In a particular embodiment, the "haloalkyl" has one carbon atom and one halogen atom.

[1226] In a particular embodiment, the "haloalkyl" has one carbon atom and two halogen atoms.

[1227] In a particular embodiment, the "haloalkyl" has one carbon atom and three halogen atoms.

[1228] In a particular embodiment, the "haloalkyl" has two carbon atoms.

[1229] In a particular embodiment, the "haloalkyl" has three carbon atoms.

[1230] In a particular embodiment, the "haloalkyl" has four carbon atoms.

[1231] In a particular embodiment, the "haloalkyl" has five carbon atoms.

[1232] In a particular embodiment, the "haloalkyl" has six carbon atoms.

[1233] Non-specific examples of "haloalkyl" include: [ka] These are some examples.

[1234] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[1235] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[1236] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[1237] "Aryl" embodiment In a particular embodiment, "aryl" is a six-carbon aromatic group (phenyl).

[1238] In a particular embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[1239] In certain embodiments, "aryl" is a six-carbon aromatic group fused to a heterocycle, with an aryl ring as its attachment point. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the attachment point of each group is on an aromatic ring.

[1240] for example, [ka] This is an "aryl" group.

[1241] however, [ka] This is a "heterocyclic" group.

[1242] In certain embodiments, "aryl" is a six-carbon aromatic group condensed with a cycloalkyl group, with an aryl ring as the attachment point. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, where the attachment point of each group is on an aromatic ring.

[1243] for example, [ka] This is an "aryl" group.

[1244] however, [ka] This is a "cycloalkyl" group.

[1245] "Heteroaryl" Embodiment In a particular embodiment, the "heteroaryl" is a five-membered aromatic group containing one, two, three, or four nitrogen atoms.

[1246] Non-exclusive examples of five-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[1247] Additional non-limiting examples of five-membered "heteroaryl" groups include: [ka] These are some examples.

[1248] In certain embodiments, the "heteroaryl" is a six-membered aromatic group containing one, two, or three nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[1249] Non-limiting examples of six-membered "heteroaryl" groups having one or two nitrogen atoms include: [ka] These are some examples.

[1250] In a particular embodiment, "heteroaryl" is a nine-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[1251] Non-exclusive examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzoxazole, and benzothiazole.

[1252] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[1253] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[1254] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[1255] In a particular embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[1256] Non-exclusive examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[1257] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[1258] "Cycloalkyl" Embodiment In a particular embodiment, "cycloalkyl" is a C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[1259] In a particular embodiment, the "cycloalkyl" has three carbon atoms.

[1260] In a particular embodiment, the "cycloalkyl" has four carbon atoms.

[1261] In a particular embodiment, the "cycloalkyl" has five carbon atoms.

[1262] In a particular embodiment, the "cycloalkyl" has six carbon atoms.

[1263] In a particular embodiment, the "cycloalkyl" has seven carbon atoms.

[1264] In a particular embodiment, the "cycloalkyl" has eight carbon atoms.

[1265] In a particular embodiment, the "cycloalkyl" has nine carbon atoms.

[1266] In a particular embodiment, the "cycloalkyl" has 10 carbon atoms.

[1267] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[1268] Additional, non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, where the attachment points of each group are located on the cycloalkyl ring.

[1269] for example, [ka] This is a "cycloalkyl" group.

[1270] however, [ka] This is an "aryl" group.

[1271] Additional examples of the "cycloalkyl" group include: [ka] These are some examples.

[1272] "Hybrid Algebra" Embodiment In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen atom and three, four, five, six, seven, or eight carbon atoms.

[1273] In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and three, four, five, six, seven, or eight carbon atoms.

[1274] In certain embodiments, “heterocycle” refers to a cyclic ring having two nitrogen atoms and three, four, five, six, seven, or eight carbon atoms.

[1275] In certain embodiments, "heterocycle" refers to a cyclic ring having one oxygen atom and three, four, five, six, seven, or eight carbon atoms.

[1276] In certain embodiments, “heterocycle” refers to a cyclic ring having one sulfur atom and three, four, five, six, seven, or eight carbon atoms.

[1277] Non-restrictive examples of "heterocyclic compounds" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thiethane.

[1278] Additional, non-restrictive examples of "heterocyclic compounds" include pyrrolidines, 3-pyrroline, 2-pyrroline, pyrazolidines, and imidazolidines.

[1279] Additional, non-restrictive examples of "heterocyclic" compounds include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[1280] Additional, non-restrictive examples of "heterocyclic compounds" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[1281] Additional, non-restrictive examples of "heterocyclic" structures include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the attachment points of each group lie on the heterocyclic ring.

[1282] for example, [ka] This is a "heterocyclic" group.

[1283] however, [ka] This is an "aryl" group.

[1284] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[1285] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[1286] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[1287] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[1288] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[1289] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[1290] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[1291] Any substituent In certain embodiments, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with one substituent.

[1292] In a particular embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with two substituents.

[1293] In a particular embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with three substituents.

[1294] In a particular embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with four substituents.

[1295] III. Treatment method The tricyclic compounds provided herein induce proteolytic degradation of the neosubstrate CRL4 CRBN These compounds can bind to the cereblon receptor of E3 ubiquitin ligases, generating novel binding sites for neosubstrates, which are mediators of human diseases. These compounds generate novel surface configurations that can directly interact with target proteins or target protein complexes to directly or indirectly reduce protein levels. In various embodiments, the tricyclic compounds described herein can cause a reduction in neosubstrate target protein levels through direct ubiquitination of the target protein, or through ubiquitination of neosubstrate target protein cofactors, target protein complexes, or other proteins involved in regulating target protein homeostasis. The compounds can cause a reduction in target protein levels by degradation of neosubstrate target proteins directly bound to ligand-bound cereblon, degradation of neosubstrates that are cofactors bound to ligand-bound cereblon, degradation of the binding site between the complex cofactor and target protein interface to ligand-bound cereblon, degradation of neosubstrate target protein complexes bound to ligand-bound CRBN, or degradation of proteins not present in the neosubstrate protein complex or cofactor.

[1296] A. Disease-mediated proteins for degradation by the compound of the present invention Certain proteins that have a β-hairpin turn containing glycine at a major position ("g-loop proteins" or "g-loop degrons") have been reported to act as "structural degrons" for cereblon when cereblon is also bound to thalidomide-like molecule (IMiD) neosubstrate proteins. Proteins containing such "g-loop degrons" generally include small antiparallel β-sheets that form a β-hairpin with an α-turn, have a geometric arrangement of three skeletal hydrogen bond acceptors (positions i, i+1, and i+2) at the apex of the turn, and have a glycine residue at the major position (i+3) (see, for example, Non-Patent Documents 5 and 3). These g-loop degrons have been identified in many proteins, including, but are not limited to, Sal-like 4 (SALL4), GSPT1, IKFZ1, IKFZ3, and CK1α, ZFP91, ZNF93, etc.

[1297] In some embodiments, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade a protein containing g-loop degron, where the protein is a protein kinase, a C2H2-containing zinc finger protein, an RNA recognition motif-containing protein, a zinc β-ribbon-containing protein, a β-propeller-containing protein, a P-loop NTPase-containing protein, and a really interesting new gene. The proteins are selected from the following: gene)(RING) finger domain-containing proteins, SRC homology 3 (SH3) domain-containing proteins, immunoglobulin E-set domain-containing proteins, Tudor domain-containing proteins, zinc finger FYVE / PHD type-containing proteins, Ig-like domain-containing proteins, ubiquitin-like domain-containing proteins, concanavalin-like domain-containing proteins, C1 domain-containing proteins, plextrin homology (PH) domain-containing proteins, OB-fold domain-containing proteins, NADP-Rossmann-fold domain-containing proteins, actin-like ATPase domain-containing proteins, and helix-turn-helix (HTH) domain-containing proteins.In some embodiments, protein kinases, C2H2-containing zinc finger proteins, RNA recognition motif-containing proteins, zinc β-ribbon-containing proteins, β-propeller-containing proteins, P-loop NTPase-containing proteins, Really Interesting New Gene (RING) finger domain-containing proteins, SRC homology 3 (SH3) domain-containing proteins, immunoglobulin E-set domain-containing proteins, Tudor domain-containing proteins, zinc finger FYVE / PHD type-containing proteins, Ig-like domain-containing proteins, ubiquitin-like domain-containing proteins, concanavalin-like domain-containing proteins, C1 domain-containing proteins, plextrin homology (PH) domain-containing proteins, OB-fold domain-containing proteins, NADP-Rossmann-fold domain-containing proteins, actin-like ATPase domain-containing proteins, or helix-turn-helix (HTH) domain-containing proteins are overexpressed or contain gain-of-function mutations. In some embodiments, deglon is stabilized by internal hydrogen bonding from ASX and ST motifs.

[1298] In some embodiments, a tricyclic heterobifunctional compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade a protein having "g-loop degron," where "g-loop degron" comprises a [D / N]XX[S / T]G motif (SEQ ID NO: 1), where D = aspartic acid, N = asparagine, X can be any amino acid residue, S = serine, T = threonine, and G = glycine. In a particular embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence DXXSG (SEQ ID NO: 2), where D = aspartic acid, X can be any amino acid residue, S = serine, and G = glycine. In another embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence NXXSG (SEQ ID NO: 3), where N = asparagine, X can be any amino acid residue, S = serine, and G = glycine. In yet another embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence DXXTG (SEQ ID NO: 4), where D = aspartic acid, X can be any amino acid residue, T = threonine, and G = glycine. In yet another embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence NXXTG (SEQ ID NO: 5), where N = asparagine, X can be any amino acid residue, T = threonine, and G = glycine. In some embodiments, the "g-loop degron"-containing protein comprises the amino acid sequence CXXCG (SEQ ID NO: 6), where C = cysteine, X can be any amino acid residue, and G = glycine. In a particular embodiment, the "g-loop degron"-containing protein comprises the amino acid sequence NXXNG (SEQ ID NO: 7), where N = asparagine, X can be any amino acid residue, and G = glycine.

[1299] In some embodiments, the tricyclic heterobifunctional compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade a protein having a C2H2 zinc finger domain containing "g-loop degron". In some embodiments, the zinc finger domain has a consensus sequence CXXCG (SEQ ID NO: 8), where C = cysteine, X = any amino acid, and G = glycine. In alternative embodiments, the protein having the zinc finger domain has a consensus sequence QCXXCG (SEQ ID NO: 9), where C = cysteine, X = any amino acid, G = glycine, and Q = glutamine. In further embodiments, the zinc finger domain has the consensus sequence QC-X2-CG-X3-F-X5-L-X2-H-X3-H (SEQ ID NO: 10), where C=cysteine, X=any amino acid, G=glycine, Q=glutamine, F=phenylalanine, L=leucine, and H=histidine. In some embodiments, the C2H2 zinc finger domain comprises X2-C-X2-CG-X2-C-X5 (SEQ ID NO: 11), where C=cysteine, X=any amino acid, and G=glycine. In some embodiments, the C2H2 zinc finger domain-containing protein is overexpressed. In some embodiments, the expression of the C2H2 zinc finger-containing protein is associated with diseases or disorders, including but not limited to cancer.

[1300] For example, the compounds of the present invention or their pharmaceutically acceptable salts are administered to a host in a pharmaceutical composition as described herein to degrade atypical E3 ubiquitin ligase (ZFP91), a zinc finger protein. Atypical E3 ubiquitin ligase, a zinc finger protein, contains Cys2-His2 zinc fingers and protects tumor cell survival and confers chemoresistance through the destabilization of forkhead box A1 (FOXA1) (see, for example, Tang, et al., "The ubiquitanse ZFP91 promotes tumor cell survival and confers chemoresistance through FOXA1 destabilization," Carcinogenesis, Col. 41(1), Jan. 2020). The atypical E3 ubiquitin ligase, a zinc finger protein, is thought to act through the regulation of the non-classical NF-κB pathway. Its overexpression leads to increased activation of the NF-κB signaling pathway and is associated with many cancers, including gastric, breast, colon, kidney, ovarian, pancreatic, prostate, sarcoma, and melanoma (see, for example, Paschke, "ZFP91 zinc finger protein expression pattern in normal tissues and cancers," Oncol Lett. 2019; Mar; 17(3):3599-3606). In certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade atypical E3 ubiquitin ligase, which is a zinc finger protein, and to treat cancers including, but not limited to, gastric cancer, breast cancer, colon cancer, lung cancer, kidney cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and melanoma.In certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade atypical E3 ubiquitin ligase, which is a zinc finger protein, in order to treat sarcoma, melanoma, or gastric cancer.

[1301] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in a pharmaceutical composition as described herein to degrade zinc finger protein 276 (ZFP276).

[1302] In yet another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host, optionally in a pharmaceutical composition as described herein, to degrade zinc finger protein 653 (ZFP653). Zinc finger protein 653 may act as a more general transcriptional repressor by competing with GRIP1 and other p160 coactivators for binding to SF1 (see, for example, Borud et al., "Cloning and characterization of a novel zinc finger protein that modulates the transcriptional activity of nuclear receptors," Molec. Endocr. 17: 2303-2319, 2003).

[1303] Another example involves administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein, to degrade zinc finger protein 692 (ZFP692). Zinc finger protein 692, also known as AICAR response element-binding protein (AREBP), contains Cys2-His2 zinc fingers and is considered a major modulator of hepatic glucose production regulated by AMPK in vivo (see Shirai et al., "AICAR response element binding protein (AREBP), a key modulator of hepatic glucose production regulated by AMPK in vivo." Biochem Biophys Res Commun. 2011 Oct 22;414(2):287-91). Overexpression and its overexpression are associated with the promotion of colon adenocarcinoma and metastasis by activating the PI3K / AKT pathway (see, for example, "Zinc finger protein 692 promotes colon adenocarcinoma cell growth and metastasis by activating the PI3K / AKT pathway." Int J Oncol. 2019 May; 54(5): 1691-1703) and the development of metastasis in lung adenocarcinoma and lung cancer.Knockdown of zinc finger protein 692 expression via short interfering RNA reduced cell invasion, increased apoptosis in lung cancer cells, and suppressed lung cancer tumor growth in xenograft models (see, for example, Zhang et al., "ZNF692 promotes proliferation and cell mobility in lung adenocarcinoma," Biochem Biophys Res Commun. 2017 Sep 2;490(4):1189-1196). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically active salts may be used optionally in the pharmaceutical compositions described herein to degrade zinc finger protein 692 and treat lung cancer or colon cancer, including lung adenocarcinoma or carcinoma or colon adenocarcinoma.

[1304] The tricyclic compound of the present invention or its pharmaceutically acceptable salt can also be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade zinc finger protein 827 (ZFP827). Zinc finger protein 827 is a zinc finger protein that binds to a nuclear receptor and regulates the alternative telomere elongation (ALT) pathway by recruiting the nucleosome remodeling and histone deacetylation (NURD) complex to telomeres to induce homologous recombination (see, for example, Conomos, D., Reddel, RR, and Pickett, HA, "NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination," Nature Struct. Molec. Biol. 21: 760-770, 2014). Zinc finger protein 827 is associated with ALT-related promyelocytic leukemia (PML), nucleolus (APB), and other telomere abnormalities. Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically active salts may be optionally used in the pharmaceutical compositions described herein to degrade ZNF827 in ALT-related disorders, including, but not limited to, ALT-positive promyelocytic leukemia, osteosarcoma, adrenal / PNS neuroblastoma, breast cancer, glioblastoma, colorectal cancer, pancreatic neuroendocrine tumors (NETs), neuroendocrine tumors, colorectal cancer, liver cancer, soft tissue cancers including leiomyosarcoma, malignant fibrous histiocytoma, liposarcoma, gastric cancer / gastric cancer, testicular cancer, and thyroid cancer.

[1305] In other embodiments, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade the E4F transcription factor 1 protein (E4F1). E4F transcription factor 1 is thought to function as a ubiquitin ligase for p53 and is a major posttranslational regulator of p53, playing a crucial role in determining the survival or death of p53-regulated cells (see, for example, Le Cam et al., "The E4F protein is required for mitotic progression during embryonic cell cycles," Molec. Cell. Biol. 24: 6467-6475, 2004). Overexpression of E4F1 has been associated with the development of myeloid leukemia cells (see, for example, Hatachi et al., "E4F1 deficiency results in oxidative stress-mediated cell death of leukemic cells," J Exp Med. 2011 Jul 4; 208(7): 1403-1417). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade E4F transcription factor 1, and not limited to, acute myeloid leukemia (AML), undifferentiated AML, myeloblastic leukemia with minimal cell maturation, myeloblastic leukemia with cell maturation, promyelocytic leukemia, myelomonocytic leukemia, myelomonocytic leukemia with eosinophilia, monocytic leukemia To treat diseases, myeloid leukemias including erythroleukemia, megakaryoblastic leukemia, chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, such as polycythemia (PV), essential thrombocythemia (ET), myelodysplasia with myelofibrosis (MMM), eosinophilic syndrome (HES), systemic mast cell disease (SMCD), myelofibrosis, and primary myelofibrosis.E4F1 expression is also essential for survival in p53-deficient cancer cells (see, for example, Rodier et al., "The Transcription Factor E4F1 Coordinates CHK1-Dependent Checkpoint and Mitochondrial Functions," Cell Reports Volume 11, ISSUE 2, pp. 220-233, April 14, 2015). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade E4F transcription factor 1 and treat p53 deficiency-related disorders, including, but not limited to, ovarian cancer, small cell lung cancer, pancreatic cancer, head and neck squamous cell carcinoma, and triple-negative breast cancer.

[1306] In another embodiment, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade zinc finger protein 517 (ZFP517). Zinc finger protein 517 has been identified as an oncogenic driver in adrenocortical carcinoma (ACC) (see, for example, Rahane et al., “Establishing a human adrenocortical carcinoma (ACC)-specific gene mutation signature,” Cancer Genet. 2019; 230:1-12). Therefore, in certain embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is used in conjunction with zinc finger protein 517, optionally in a pharmaceutical composition described herein, to treat adrenocortical carcinoma.

[1307] In yet another embodiment, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade zinc finger protein 582 (ZFP582). Zinc finger protein 582 is thought to be involved in DNA damage response, proliferation, cell cycle regulation, and neoplastic transformation, most notably in cervical cancer, esophageal cancer, and colorectal cancer (e.g., "Methylomic analysis identifies frequent DNA methylation of zinc finger protein 582 (ZNF582) in cervical neoplasms." by Huang et al., PLoS One 7: e41060, 2012; and "Aberrant DNA methylation of PAX1, SOX1 and ZNF582 genes as potential biomarkers for esophageal squamous cell carcinoma." by Tang et al., Biomedicine & Pharmacotherapy Volume 120). See "Analysis of DNA Methylation in Bowel Lavage Fluid for Detection of Colorectal Cancer" by Harada et al., December 2019, 109488, Cancer Prev Res; 7(10); 1002-10; 2014. Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade zinc finger protein 582 and treat cancers, including but not limited to cervical cancer including cervical adenocarcinoma, esophageal cancer including squamous cell carcinoma and squamous cell adenocarcinoma, and colorectal cancer.

[1308] In another embodiment, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade zinc finger protein 654 (ZFP654).

[1309] Alternatively, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof may be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade zinc finger protein 787 (ZFP787).

[1310] The tricyclic compound of the present invention or its pharmaceutically acceptable salt can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade the hypermethylated in cancer 1 (HIC1) protein in cancer. The hypermethylated in cancer 1 protein contains an N-terminal BTB / POZ protein-protein interaction domain and five Kruppel-like C2H2 zinc finger motifs in its C-terminal half (see, for example, Deltour et al., "The carboxy-terminal end of the candidate tumor suppressor gene HIC-1 is phylogenetically conserved," Biochim. Biophys. Acta 1443: 230-232, 1998). Miller-Dieker syndrome is characterized by impaired expression of hypermethylated protein 1 genes in cancer (see, for example, Grimm et al., "Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome." Hum. Molec. Genet. 8: 697-710, 1999).

[1311] The tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade hypermethylated in cancer 2 (HIC2) protein in cancer.

[1312] The tricyclic compound of the present invention or its pharmaceutically acceptable salt can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade GDNF-inducible zinc finger protein 1 (GZF1). GDNF-inducible zinc finger protein 1 is a transcriptional regulator that binds to the 12 bp GZF1 response element (GRE) and represses gene transcription (see, for example, Morinaga et al., "GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region," Nucleic Acids Res. 33: 4191-4201, 2005).

[1313] Alternatively, the Odd-Skipped Related 1 (OSR1) protein can be degraded by administering, for example, an effective amount of the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. The Odd-Skipped Related 1 protein contains three C2H2 type zinc fingers, a tyrosine phosphorylation site, and several putative PXXP SH3 binding motifs (see, for example, Katoh, M., "Molecular cloning and characterization of OSR1 on human chromosome 2p24," Int. J. Molec. Med. 10: 221-225, 2002).

[1314] In another embodiment, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade the odd-skipped related 2 (OSR2) protein.

[1315] In yet another embodiment, the SAL-like 4 (SALL4) protein can be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. The SAL-like 4 protein has three SAL-type C2H2 double zinc finger domains, the second of which has a single C2H2 zinc finger attached to its C-terminus and an N-terminal C2HC zinc finger motif typical of vertebrate SAL-like proteins. Mutations in the SAL-like 4 protein are associated with the development of Duane-radial row syndrome (see, for example, Borozdin et al., "SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism," J. Med. Genet. 41: e113, 2004). Overexpression of the SAL-like 4 protein is associated with the promotion, growth, and metastasis of many cancers, including lung cancer, gastric cancer, liver cancer, kidney cancer, myelodysplastic syndromes, germ cell and sex cord-stromal tumors including anaplastic germ cell tumors, yolk sac tumors, and choriocarcinoma, as well as leukemia. Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade SAL-like 4 protein and to treat cancers including, but not limited to, gastric cancer, liver cancer, kidney cancer, myelodysplastic syndrome, undifferentiated germ cell tumors, yolk sac tumors, and germ cell-sex cord-stromal tumors including choriocarcinoma, as well as leukemia.

[1316] The B-cell lymphoma 6 (BCL6) protein can also be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. B-cell lymphoma 6 contains an autonomous transrepressor domain, and two discontinuous regions containing a POZ motif mediate the maximum trans-repressive activity. Translocation of the B-cell lymphoma 6 gene is associated with the development of myeloproliferative disorders such as non-Hodgkin lymphoma. Overexpression of B-cell lymphoma 6 prevents the increase of reactive oxygen species and inhibits chemotherapy-induced apoptosis in cancer cells (see, for example, Tahara et al., "Overexpression of B-cell lymphoma 6 alters gene expression profile in a myeloma cell line and is associated with decreased DNA damage response," Cancer Sci. 2017 Aug;108(8):1556-1564, and Cardenas et al., "The expanding role of the BCL6 oncoprotein as a cancer therapeutic target," Clin Cancer Res. 2017 Feb 15; 23(4): 885-893). Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade B-cell lymphoma 6 and to treat, but not limited to, hematological malignancies or solid tumors, such as, but not limited to, B-cell leukemia or lymphoma, such as, but not limited to, diffuse large B-cell lymphoma (DLBCL) and ABC-DLBCL subtypes, B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer.

[1317] Furthermore, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is optionally administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade the B-cell lymphoma 6B (BCL6B) protein. The B-cell lymphoma 6B protein contains an N-terminal POZ domain and five C-terminal zinc finger motifs and is thought to act as a transcriptional repressor (see, for example, Okabe et al., "BAZF, a novel Bcl6 homolog, functions as a transcriptional repressor," Molec. Cell. Biol. 18: 4235-4244, 1998). Overexpression of B-cell lymphoma 6B protein has been associated with the development of germ cell tumors (Ishii et al., "FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation," Development 139, 1734-1743 (2012)). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade B-cell lymphoma 6B and treat cancers including, but not limited to, undifferentiated germ cell tumors and seminomas, and, but not limited to, germ cell tumors, teratomas, yolk sac tumors, and germ cell carcinomas, including choriocarcinoma.

[1318] Alternatively, the early growth response 1 (EGR1) protein can be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. Early growth response 1 protein has been shown to be involved in the proliferation and survival of not only prostate cancer cells but also glioma cells by directly regulating the expression of the transforming growth factor-beta-1 gene and modulating several target genes, including cyclin D2 (CCND2), p19 (Ink4d), and Fas (e.g., "Erg1 promotes growth and survival of prostate cancer cells: identification of novel Egr1 target genes." by Virolle et al., J. Biol. Chem. 278: 11802-11810, 2003; "Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter." by Chen et al., Journal of Experimental & Clinical Cancer Research Volume 36, Article number: 186). (See 2017). One mechanism used by Egr1 to confer resistance to apoptotic signaling is Egr1's ability to inhibit Fas expression, which leads to insensitivity to FasL. Therefore, in certain embodiments, compounds of the present invention or pharmaceutically active salts thereof may be used optionally in pharmaceutical compositions described herein to degrade early growth response 1 protein and treat cancers including, but not limited to, prostate cancer or, but not limited to, gliomas including pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme.

[1319] In yet another embodiment, the early growth response 4 (EGR4) protein can be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. The early growth response 4 protein contains three zinc fingers of the C2 / H2 subtype near its carboxyl terminus (see, for example, Crosby et al., “Neural-specific expression, genomic structure, and chromosomal localization of the gene encoding the zinc-finger transcription factor NGFI-C.” Proc. Nat. Acad. Sci. 89: 4739-4743, 1992). Overexpression of early growth response 4 protein is associated with the development of cholangiocarcinoma (see, for example, Gong et al., "Gramicidin inhibits cholangiocarcinoma cell growth by suppressing EGR4," Artificial Cells, Nanomedicine, and Biotechnology, 48:1, 53-59 (2019)). Therefore, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used, optionally in pharmaceutical compositions described herein, to degrade early growth response 4 protein and treat cancer, including but not limited to cholangiocarcinoma.

[1320] In certain embodiments, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade Sal-like 1 (SALL1) protein.

[1321] In alternative embodiments, the Sal-like 3 (SALL3) protein can be degraded by administering an effective amount of a selected tricyclic compound or a pharmaceutically acceptable salt thereof to a host, optionally in a pharmaceutical composition as described herein. The SALL3 protein comprises four double zinc finger (DZF) domains, each containing a sequence identical to or closely related to the SAL box, which is a characteristic 8-amino acid stretch within a second zinc finger motif.

[1322] In yet another embodiment, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade the tumor protein p63 (TP63). Overexpression of the tumor protein p63 is associated with poor development and prognosis of lung cancer, radiation resistance in oral and head and neck cancers, and squamous cell carcinoma of the skin (see, for example, Massion et al., "Significance of p63 amplification and overexpression in lung cancer development and prognosis," Cancer Res. 2003 Nov 1;63(21):7113-21, and Moergel et al., "Overexpression of p63 is associated with radiation resistance and prognosis in oral squamous cell carcinoma," Oral Oncol. 2010 Sep;46(9):667-71). Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used in any pharmaceutical composition described herein to degrade tumor protein p63 and treat cancers, including, but not limited to, non-small cell lung cancer, small cell lung cancer, head and neck cancer, and squamous cell carcinoma of the skin.

[1323] In yet another embodiment, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade widely-interspaced zinc finger (WIZ) proteins.

[1324] The selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof may also be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade Zinc Finger and BTB Domain Containing Protein 7A (ZBTB7A). The expression of zinc finger and BTB domain-containing protein 7A is associated with many cancers, including prostate cancer, non-small cell lung cancer, bladder cancer, breast cancer, ovarian cancer, oral squamous cell carcinoma, and hepatocellular carcinoma (see, for example, Han et al., "ZBTB7A Mediates the Transcriptional Repression Activity of the Androgen Receptor in Prostate Cancer," Cancer Res 2019;79:5260-71, and Molloy et al., "ZBTB7A governs estrogen receptor alpha expression in breast cancer," Journal of Molecular Cell Biology, Volume 10, Issue 4, August 2018, Pages 273-284). Accordingly, in certain embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to degrade zinc finger and BTB domain-containing protein 7A and to treat cancers, including, but not limited to, prostate cancer, non-small cell lung cancer, breast cancer, oral squamous cell carcinoma, prostate cancer, ovarian cancer, glioma, bladder cancer, and hepatocellular carcinoma.

[1325] In other embodiments, selected tricyclic compounds of the present invention or pharmaceutically active salts thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade zinc finger and BTB domain-containing protein 7B (ZBTB7B). Expression of zinc finger and BTB domain-containing protein 7B is associated with breast cancer, prostate cancer, urothelial carcinoma, cervical cancer, and colorectal cancer. Therefore, in certain embodiments, compounds of the present invention or pharmaceutically active salts thereof can be used, optionally in a pharmaceutical composition as described herein, to degrade zinc finger and BTB domain-containing protein 7B and treat cancers, including, but not limited to, breast cancer, prostate cancer, urothelial carcinoma, cervical cancer, and colorectal cancer.

[1326] A selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition as described herein, to degrade casein kinase I alpha I (CK1α or CK1 alpha). CK1 alpha is a bifunctional regulator of NF-κB (see, for example, Bidere et al., "Casein kinase 1-alpha governs antigen-receptor-induced NF-kappa-B activation and human lymphoma cell survival," Nature 458: 92-96, 2009). CK1 alpha dynamically associates with the CBM complex upon T cell receptor binding and is involved in cytokine production and lymphocyte proliferation. However, CK1 alpha kinase activity plays a contrasting role in subsequently promoting CARMA1 phosphorylation and inactivation. Therefore, CK1 alpha has a dual "gating" function that first promotes receptor-induced NF-κB and then terminates it. ABC DLBCL cells require CK1 alpha for constitutive NF-κB activity, indicating that CK1 alpha functions as a conditionally essential malignant gene.CK1 alpha expression has been associated with myelodysplastic disorders with 5q (del(5q)MDS) depletion (see, e.g., Non-Patent Literature 4), colorectal cancer, breast cancer, leukemia, multiple myeloma, lung cancer, diffuse large B-cell lymphoma, non-small cell lung cancer, and pancreatic cancer (see, e.g., Richter et al., "CK1α overexpression correlates with poor survival in colorectal cancer," BMC Cancer. 2018; 18: 140; and Jiang et al., "Casein kinase 1α: biological mechanisms and theranostic potential," Cell Commun Signal. 2018; 16: 23). Accordingly, in some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in the pharmaceutical compositions described herein to degrade casein kinase I alpha-I and treat cancers including, but not limited to, colorectal cancer, breast cancer, leukemia, multiple myeloma, lung cancer, diffuse large B-cell lymphoma, non-small cell lung cancer, and pancreatic cancer; myelodysplastic syndromes including, but not limited to, 5q syndrome, refractory cytopenia with monocytic lineage dysplasia, refractory anemia, refractory neutropenia, and refractory thrombocytopenia; refractory anemia with ring sideroblasts, refractory cytopenia with polycytic lineage dysplasia (RCMD), refractory anemia with supervast blasts (REAB) I and II, refractory anemia with blast plasia in the transitional phase (RAEB-T), chronic myelomonocytic leukemia (CMML), unclassifiable myelodysplasia, and refractory cytopenia in childhood (childhood dysplasia).

[1327] The selected tricyclic compounds of the present invention or their pharmaceutically acceptable salts can optionally be administered to a host in an effective amount in a pharmaceutical composition as described herein to degrade Family with Sequence Similarity 83 member H (FAM83H). FAM83H is thought to be involved in the progression of human cancers along with tumor-associated molecules such as MYC and β-catenin, and its overexpression has been associated with lung cancer, breast cancer, colon cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, glioma, hepatocellular carcinoma, thyroid cancer, renal cell carcinoma, osteosarcoma, and gastric cancer (see, for example, Kim et al., "FAM83H is involved in stabilization of β-catenin and progression of osteosarcomas," Journal of Experimental & Clinical Cancer Research volume 38, Article number: 267 (2019)). Accordingly, in some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in pharmaceutical compositions described herein to decompose FAM83H and treat cancers including, but not limited to, lung cancer, breast cancer, colon cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, glioma, thyroid cancer, and, but not limited to, liver cancer including hepatocellular carcinoma, renal cell carcinoma, osteosarcoma, and gastric cancer.

[1328] Alternatively, the zinc finger and BTB domain-containing protein 16 (ZBTB16) can be degraded by administering an effective amount of a selected tricyclic compound or pharmaceutically active salt thereof to a host, optionally in a pharmaceutical composition as described herein. Overexpression and translocation of ZBTB16 have been associated with the development of various hematological cancers, including acute promyelocytic leukemia (see, for example, Zhang et al., "Genomic sequence, structure organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc finger gene." Proc. Nat. Acad. Sci. 96: 11422-11427, 1999). Accordingly, in some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts may be used optionally in the pharmaceutical compositions described herein to degrade ZBTB16 and treat cancers, including but not limited to acute promyelocytic leukemia, acute lymphoblastic leukemia, adult T-cell lymphoma / ATL, and Burkitt lymphoma, including but not limited to leukemia or lymphoma, and including but not limited to hematological cancers.

[1329] In alternative embodiments, AT-rich interaction domain-containing protein 2 (ARID2) can be degraded by administering an effective amount of a selected tricyclic compound or pharmaceutically salt thereof to a host, optionally in a pharmaceutical composition as described herein. ARID2 is a subunit of the PBAF chromatin-remodeling complex, which promotes ligand-dependent transcriptional activation by nuclear receptors (see, for example, Yan et al., "PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes," Genes Dev. 19: 1662-1667, 2005).

[1330] In another embodiment, a selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof can be administered to a host in an effective amount, optionally in a pharmaceutical composition described herein, to degrade polybromo-associated BAF (PBAF). Mutations in PBAF have been associated with the development of synovial sarcoma and multiple myeloma (see, for example, Alfert et al., “The BAF complex in development and disease,” Epigenetics & Chromatin volume 12, Article number: 19 (2019)). Therefore, in some embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof can be used, optionally in a pharmaceutical composition described herein, to degrade PBAF and treat cancers, including, but not limited to, synovial sarcoma and multiple myeloma.

[1331] In other embodiments, selected tricyclic compounds of the present invention, upon administration after binding to cereblon to form a new phenotype surface, can bind to numerous neosubstrates, thus resulting in a “multiple pharmacological” form. For example, the tricyclic compounds can bind to and degrade IRAK4, IKZF1 and / or IKZF3 and / or Aiolos. In other examples, upon administration, the tricyclic compounds can degrade two or more of the proteins named above or herein, for example, SALL4 and IKZF1 / 3 or IKZF2 / 4.

[1332] In certain specific embodiments, the compounds of the present invention degrade IKZF proteins. The Ikaros("IKZF") family is a series of zinc finger protein transcription factors important for certain physiological processes, particularly lymphocyte development (see Fan, Y. and Lu, D. Acta Pharmaceutica Sinica B, 2016, 6:513-521). Ikaros ("IKZF1") was first discovered in 1992 (see Geoglopoulos, K. et al. Science, 1992, 258:802-812), and over the following 20 years, four further homologs, Helios ("IKZF2"), Aiolos ("IKZF3"), Eos ("IKZF4"), and Pegasus ("IKZF5"), have been identified (see John, LB, and Ward, AC Mol Immunol, 2011, 48:1272-1278). Each homolog gene can produce several protein isoforms through alternative splicing, theoretically enabling the generation of numerous protein complexes through diverse combinations of homologs.

[1333] The distribution of the diverse members of the Ikaros protein family in the body is quite varied. Ikaros, Helios, and Aiolos are primarily found in lymphocytes and their corresponding progenitor cells, with Ikaros also detected in the brain, and both Ikaros and Helios detected in erythrocytes. Eos and Pegasus are more widely distributed and found in skeletal muscle, liver, brain, and heart (see Perdomo, J. et al. J Biol Chem, 2000, 275:38347-38354, Schmitt, C. et al. Apoptosis, 2002, 7:277-284, Yoshida, T. and Georgopoulos, K. Int J Hematol, 2014, 100:220-229).

[1334] In certain embodiments, the compounds of the present invention, or their pharmaceutically acceptable salts, are used in a pharmaceutical composition, as optionally described herein, to degrade Ikaros or Aiolos, which are mediators of disorders affecting a patient, e.g., a human. The control of protein levels provided by any of the compounds of the present invention provides treatment for a disease state or condition, which is regulated through Ikaros or Aiolos by reducing the level of this protein in cells, e.g., patient cells, or by reducing the level of downstream proteins in cells.

[1335] In certain embodiments, the compounds of the present invention can provide therapeutic effects by directly degrading Ikaros or Aiolos, which can alter the transcriptional regulation of downstream proteins of Ikaros or Aiolos.

[1336] Translation termination factor G1-to-S phase transition protein 1 (GSPT1) is an essential termination factor for the transition from the G1 to the S phase of the cell cycle and is known to function as polypeptide chain release factor 3 (eRF3) (Kikuchi et al., 1988). GSPT1 interacts with eRF1 to mediate stop codon recognition and the release of newly synthesized proteins from ribosomes (Cheng et al. Genes Dev., 2009, 23, 1106-1118).

[1337] Studies have shown that GSPT1 is involved in processes such as the cell cycle, apoptosis, and transcription (Hegde et al. J. Biol. Chem. 2003, Park et al. Oncogene, 2008, 27, 1297), and therefore, GSPT1 may play a role in abnormal cell proliferation. For example, overexpression of eRF3 / GSTP1 in certain intestinal gastric tumors was associated with increased translation efficiency of specific oncogenic transcripts (Malta-Vacas et al. J. Clin. Pathol. 2005, 58, 621).

[1338] In certain embodiments, the compounds of the present invention, or their pharmaceutically acceptable salts, are used, optionally in pharmaceutical compositions as described herein, to degrade GSTP1, a mediator of disorders affecting a patient, e.g., a human. The control of protein levels provided by any of the compounds of the present invention provides treatment for a disease state or condition, which is regulated through GSTP1 by reducing the level of this protein in cells, e.g., patient cells, or by reducing the level of downstream proteins in cells.

[1339] In certain embodiments, the compounds of the present invention can provide therapeutic effects by directly degrading GSTP1, which can alter the transcriptional regulation of proteins downstream of GSTP1.

[1340] In some embodiments, the coronavirus protein is degraded. In some embodiments, the coronavirus protein is the beta-coronavirus protein. In some embodiments, the coronavirus protein is the severe acute respiratory syndrome (SARS)-CoV protein, the Middle East respiratory syndrome (MERS)-CoV protein, or the SARS-CoV-2 protein. In some embodiments, the target protein is the SARS-CoV-2 protein. In some embodiments, the SARS-CoV2 protein is selected from the spike (S) protein (accession no. BCA87361.1), the membrane (M) protein (accession no. BCA87364.1), the envelope (E) protein (accession no. BCA87363.1), or the nucleocapsidrin protein (N) protein (accession no. BCA87368.1), or structural proteins selected from sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, or 98% homologous thereto, or homologs, mutants, conjugates, derivatives, fragments, or orthologues thereof.In some embodiments, the SARS-CoV2 protein is composed of nsp1 (leader protein) (accession number YP_009725297.1), nsp2 (accession number YP_009725298.1), nsp3 (papain-like proteinase) (accession number YP_009725299.1), nsp4 (accession number YP_009725300.1), nsp5 (3C-like proteinase) ( Session number YP_009725301.1), nsp6 (presumed transmembrane domain) (accession number YP_009725302.1), nsp7 (accession number YP_009725303.1), nsp8 (primase) (accession number YP_009725304.1), nsp9 (accession number YP_009725305.1), nsp10 (accession number YP_009725306.1), n sp11 (accession number YP_009725312.1), nsp12 (RNA-dependent RNA polymerase) (accession number YP_009725307.1), nsp13 (helicase) (accession number YP_009725308.1), nsp14 (3'-5' exonuclease, guanine N7-methyltransferase) (accession number YP_009725309.1), nsp15 (endo-RN The non-structural protein includes nsp16 (2'-O-ribose-methyltransferase) (accession number YP_009725310.1), or nsp16 (2'-O-ribose-methyltransferase) (accession number YP_009725311.1), or sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, or 98% homologous thereto, or homologs, mutants, conjugates, derivatives, fragments, or orthologues thereof.In some embodiments, the SARS-CoV2 protein is selected from ORF3a protein (accession number BCA87362.1), ORF6 protein (accessory protein 6) (accession number BCA87365.1), ORF7a protein (accessory protein 7a) (accession number BCA87366.1), ORF7b protein (accessory protein 7b) (accession number BCB15096.1), ORF8 protein (accession number QJA17759.1), ORF9b protein (accessory protein 9b) (UniprotKB-P0DTD2), or ORF10 protein (accession number BCA87369.1), or sequences homologous to them by at least 70%, 75%, 80%, 85%, 90%, 95%, or 98%, or homologs, mutants, conjugates, derivatives, fragments, or orthologues thereof. In some embodiments, the SARS-CoV-2 protein is the ORF3b protein encoded by nucleotides 25814-25880 of the NCBI reference sequence: NC_045512.2 (see "SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant." by Konno et al., Cell Reports, Volume 32, Issue 12, 22 September 2020, 108185), or sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, or 98% homologous thereto, or homologs, mutants, conjugates, derivatives, fragments, or orthologues thereof.

[1341] In other embodiments, the protein to be degraded is a viral protein of a virus other than coronavirus, such as a protease, polymerase, exonuclease, helicase, glycosyltransferase, esterase, integrase, reverse transcriptase, kinase, primase, proteinase, methyltransferase, or nucleotidase.

[1342] Specific examples of neosubstrates that can be targeted for degradation by the tricyclic compounds of the present invention, along with the principles of degradation, which are not limited to the present invention, include the following:

[1343] CK1α is a casein kinase that utilizes acidic proteins such as casein as phosphorylation substrates. CK1α is involved in Wnt signaling, and its overexpression is correlated with poor survival rates in cancer.

[1344] GSPT1 (G1 to S phase transition 1) is a translation termination factor. GSPT1 interacts with BIRC2 and is proteolytically processed to become an IAP-binding protein. GSPT1 is expressed in cancer tissue, including gastric cancer.

[1345] STAT proteins are cytoplasmic transcription factors that can be activated by various extracellular signaling proteins. Stat proteins have been shown to upregulate various genes involved in uncontrolled cell proliferation, anti-apoptotic responses, and / or angiogenesis.

[1346] SALL4 (Spalt-like transcription factor 4) is a developmental transcription factor associated with developmental syndromes and developmental abnormalities such as Duane-radial row syndrome and Ivic syndrome.

[1347] PLZF (promyelocytic leukemia zinc finger), also known as ZBTB16 (zinc finger and BTB domain-containing 16), is a transcription factor that regulates cell proliferation, differentiation, organ development, cell maintenance, and immune cell development. While PLZF acts as a tumor suppressor in some cancers, it is actually an oncoprotein in certain cancers such as renal cell carcinoma, glioblastoma, and testicular cancer.

[1348] p63 (oncoprotein p63) is a multifaceted protein involved in cell proliferation, apoptosis, differentiation, and even aging. Several isoforms of p63 exist. Some forms of p63 suppress tumors, while other forms and mutants promote cancer metastasis.

[1349] NRAS is a small GTP-binding protein, and its oncogenic activating mutations induce tumorigenesis. NRAS mutations are found, for example, in melanoma and thyroid cancer, and can occur in Q61K and Q61R.

[1350] BRD9 (bromodomain-containing protein 9) is a component of the SWI / SNF (BAF) chromatin remodeling complex. Mutations in BRD9 have been associated with several cancers, and even native BRD9 can become oncogenic when overexpressed. Cancers associated with BRD9 include cervical cancer, non-small cell lung cancer, and liver cancer.

[1351] P13KCA is a kinase that is one of the most commonly mutated oncogenes across a wide range of human cancers, including, but not limited to, breast cancer, endometrial cancer, head and neck squamous cell carcinoma, and lung squamous cell carcinoma. Mutations, such as H1047R, E545K, and E542K, can lead to abnormal activation of the PI3K-AKT-mTOR pathway.

[1352] RET (proto-RET oncogene) is a protein that spans the cell membrane and interacts with the cellular environment. RET binds to growth factors and triggers complex cascades of chemical reactions within the cell. Non-limited examples of RET-mediated disorders include asymptomatic paraganglioma, Hirschsprung's disease, multiple endocrine neoplasia, lung cancer, and other cancers.

[1353] RIT1 is a small GTP-binding protein that is an activating mutation in cancers, such as Noonan syndrome (RAS opathy), lung cancer, and heme malignancies.

[1354] MCL1 is a member of the BCL2 family and is a regulator of apoptosis. Diseases associated with MCL1 include myeloid leukemia and chlamydia.

[1355] ARID1B is an AT-rich interaction domain-containing protein 1. ARID1B is a component of the SW1 / SNF complex and binds nonspecifically to DNA. This is a specific superior dependency on ARID1A-mutant cancer cell lines. ARID1A-deficient cancers include, but are not limited to, certain tumors, including ovarian clear cell carcinoma, at a high percentage.

[1356] P300 (histone acetyltransferase p300 or p300 HAT) is an enzyme that regulates gene transcription through chromatin remodeling by mediating histone wrapping around DNA. As a result, P300 plays a crucial role in cell growth and cell division. Mutations in P300 can cause various types of cancer, including colon cancer, gastric cancer, breast cancer, and pancreatic cancer.

[1357] ARID2 is a component of the polybromo-associated BAF (PBAF) chromatin remodeling complex.

[1358] FAM38 (also known as PIEZO1) is a nonspecific cation channel pore-forming subunit. As a cation channel subunit, FAM38 is involved in the recruitment of R-Ras to the endoplasmic reticulum. Loss of FAM38 has been shown to cause metathesis in small cell lung cancer lines.

[1359] NSD2, which belongs to the histone methyltransferase ("HMT") gene class, is overexpressed, for example, in oncogenic fusion transcripts of multiple myeloma, ALL, CLL, and MCL.

[1360] CSK is a non-receptor tyrosine protein kinase involved in regulating cell growth, differentiation, migration, and immune responses.

[1361] CBLB is an E3 ubiquitin-protein ligase that receives ubiquitin from an E2 ubiquitin conjugate enzyme, transfers it to a substrate, and then degrades it.

[1362] EGFR (epidermal growth factor receptor) is a tyrosine kinase receptor. EGFR is associated with the progression of several epithelial malignancies, including colorectal cancer, adenocarcinoma (including lung adenocarcinoma), glioblastoma, and epithelial tumors of the head and neck. Furthermore, EGFR can be used as a receptor for microbial infections or viral invasions such as HCV.

[1363] WRN is a RecQ DNA helicase. WRN loss leads to DNA damage in MSI (microsatellite instability) cells but not in MSS (microsatellite stability) cells. This may lead to a DSB (double-strand break) response that preferentially promotes cell death and cell cycle arrest in MSI cells.

[1364] NTRK and its gene fusions (including NTRK1, NTRK2, and NTRK3 gene fusions) are oncogenes for several adult and childhood cancers. NTRK fusions are the primary cause of rare cancers such as secretory breast cancer, mammary gland-like secretory carcinoma, and infantile fibrosarcoma. NTRK fusions may also cause more common cancers.

[1365] ADAR is an RNA-specific adenosine deaminase. Cancer cells positive for IFN-induced (ISG) signatures are susceptible to loss of ADAR, a dsRNA editing enzyme that is also an ISG. Tumor-derived IFN, which leads to chronic signaling, induces a primed cellular state in response to dsRNA accumulation, making ISG-positive tumors susceptible to ADAR loss. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation.

[1366] Since SOS1 promotes the production of the active form of KRAS, blocking it can negate the activation of KRAS upstream or mutants.

[1367] KRAS is a gene that encodes K-Ras, a protein in the RAS / MAPK pathway that relays extracellular signals to the cell nucleus. These signals lead to either proliferation or differentiation. K-Ras sends signals when it binds to GTP, which acts like an on / off switch for molecules. KRAS mutations are frequently observed in cecal cancer. K-Ras is involved in several cancers, including colorectal cancer and lung cancer.

[1368] WDR5 is a member of the WD repeat protein family. The WD repeat is a minimally conserved 40-amino acid region surrounded by gly-his and trp-asp. WDR5 interacts with host cell factor C1, MLL, and is a key determinant of MYC recruitment. WD5 is involved in mixed-phenotype leukemia.

[1369] ALK fusions, including EML-ALK and ALK fusion proteins in which the kinase domain of ALK is fused to the amino-terminus of various proteins, have been reported in many cancers, including, but are not limited to, ALCL, IMT, DLBCL, NSCLC, RMC, RCC, breast cancer, colon cancer, serous ovarian cancer (SOC), and esophageal squamous cell carcinoma (ESCC).

[1370] PTPN2 is CD8 + It regulates T cell subpopulations and influences tumor immunity.

[1371] CTNNB1 (β-catenin) is involved in cellular signaling as a component of the Wnt signaling pathway. Proteins in this pathway attach to CTNNB1, triggering protein translocation to the nucleus. CTNNB1 is associated with desmoid tumors, pilomatoma, Wilms' tumor, aldosterone-producing adenoma, ovarian cancer, and other cancers.

[1372] FGFRs, including FGFR1, FGFR3, or FGFR4 (and fusions), are receptor tyrosine kinases that are amplified in numerous cancers, including squamous cell carcinoma (NSCLC), breast cancer, ovarian cancer, bladder cancer, gastric cancer, and endometrial cancer.

[1373] ROS1 is a proto-oncogene receptor tyrosine kinase that is highly expressed in a wide range of tumor cells.

[1374] MYD88 (Myelo-first differentiation response 88) is a protein that signals the production of proteins involved in signal transduction in immune cells, and mutations in this protein are observed in cancer cells.

[1375] HER2 (human epidermal growth factor receptor 2) is a growth-promoting protein found on the outer layer of mammary cells. While HER2-negative breast cancer cells also possess HER2, those with HER2 levels exceeding normal levels are called HER2-positive. HER2 is a crucial gene in the treatment of breast cancer. Approximately one in five breast cancers has an extra copy of the HER2 gene, which contributes to cancer cell growth.

[1376] TBXT is a transcription factor that is overexpressed in many cancers and is correlated with tumor malignancy and aggressiveness.

[1377] PTP4A3 (PRL3) is a protein tyrosine phosphatase IVA3, a prenylated phosphatase involved in cell signaling, whose overexpression induces cell growth.

[1378] MET (including exon 14 skipping mutations) is a receptor tyrosine kinase, and alternatively spliced ​​MET receptors exhibit reduced ubiquitination and delayed downregulation, potentially leading to prolonged activation and transformation of MET and MAP kinases.

[1379] USP7 is a deubiquitinating enzyme involved in prostate cancer, lung cancer, brain cancer, colon cancer, breast cancer, and other cancers.

[1380] NRF2 (NFE2L2) is a fundamental leucine zipper protein that regulates the expression of cytoprotective antioxidant proteins, and mutations or activation of this protein may promote cancer.

[1381] SF3B1 is a gene involved in RNA unit splicing. SF3B1 is involved in RNA splicing, the mRNA splicing minor pathway, and the PKN1 activation stimulation of the androgen receptor. Mutations in SF3B1 are associated with various cancers.

[1382] One of the Ikaros family proteins (IKZF1, IKZF2, IKZF3, IKZF4, or IKZF5). IKZF2 (Helios) and IKZF4 (Eos) are selectively expressed in Treg cells but not in effector or memory cells. FoxP3 / IKZF4 / CtBP1 forms an inhibitory complex that represses gene expression (IL-2, IFN-γ) in Tregs and maintains its repressive signature. Knockdown of IKZF4 in Tregs disables the cell's ability to suppress the immune response and enables partial effector function. IKZF2 regulates Treg differentiation through a different mechanism than IKZF4. Knockout of IKZF2 in FoxP3-expressing Tregs results in loss of inhibitory properties (with increased IL-2) and promotion of T effector cytokine expression via STAT5 (which modulates FoxP3). Ikaros family proteins are upregulated in myeloid leukemia.

[1383] MEN1 is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 (MEN-1 syndrome). MEN1 is an autosomal dominant inherited disorder in which affected individuals develop various tumors in the parathyroid glands, anterior pituitary gland, and enteropancreatic endocrine tissues.

[1384] The JC virus protein is encoded by the JC virus genome. In individuals with weakened immune systems, the JC virus can cause a serious brain infection called progressive multiple leukoencephalopathy (PML). PML damages the outer membrane of nerve cells, which can cause permanent damage and even be fatal. The JC virus genome encodes large and small tumor antigens, agunoproteins, and capsid proteins VP1-VP3. Capsid proteins are involved in cell entry, and agunoproteins are involved in virion maturation.

[1385] CYP17A1 and CYP20A1 are heme proteins and members of the cytochrome P450 family. Cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipids. Many P450s are enzymes crucial for drug metabolism, while others play physiological roles by metabolizing endogenous substrates. For example, CYP17A1 is primarily associated with endocrine activity and steroid hormone metabolism, and mutations are associated with rare forms of congenital adrenal hyperplasia, specifically 17α-hydroxylase deficiency / 17,20-lyase deficiency and isolated 17,20-lyase deficiency. CYP20A1 is a human orphan isoform expressed in the brain and liver.

[1386] BKV proteins are encoded by the BK virus genome. Human polyomavirus BK (BKV) infects humans worldwide and establishes persistent infection in the kidneys. The BK virus genome encodes three regulatory proteins, large and small tumor antigens, agunoproteins, and capsid proteins VP1-VP3. Agnoproteins regulate viral replication and help disrupt host cell processes once the virus enters a cell.

[1387] MEK1 / 2 are extracellular signal-regulated kinases involved in the Ras / Raf / MEK / ERK pathway, a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a wide range of extracellular signals. Overactivation or mutations in this pathway are associated with many cancers, and inhibition of MEK leads to apoptosis by blocking cell proliferation. For example, β3-αC loop MEK1 mutants exhibit strong oncogenic potential but show different sensitivities to MEK inhibitors in clinical therapy or clinical trials.

[1388] Ataxin 2 is a member of the Like-Sm (LSm) protein family and is involved in numerous functions related to RNA processing and RNA metabolism. Mutations in ATXN2 cause the neurodegenerative disease spinocerebellar ataxia type 2 (SCA2).

[1389] JAK2 is a non-receptor tyrosine kinase and a member of the Janus kinase family. JAK2 is involved in signal transduction by members of the type II cytokine receptor family, GM-CSF receptor family, gp130 receptor family, and single-chain receptors. Fusion products of the JAK2 gene with the TEL (ETV6) gene and with the PCM1 gene have been found in patients with leukemia, and mutations in JAK2 are involved in polycythemia vera, essential thrombocythemia, and myelofibrosis, as well as other myeloproliferative disorders.

[1390] PTPN11 (SHP2) is a non-receptor tyrosine phosphatase that functions as a mediator of RTK signal transduction. Overexpression has been observed in cancers with recurrent mutations found in AML, JMML, and neuroblastoma, and loss or inhibition of SHP2 has been shown to suppress the growth of AML or other RTK-induced cancers.

[1391] ERK1 / ERK2 is an extracellular signal-regulated kinase that is involved in the Ras / Raf / MEK / ERK pathway, a signal transduction cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a diverse range of extracellular signals. Hyperactivation of this pathway has been associated with many cancers.

[1392] Type II mutants of BRAF are BRAF mutations that are classified as "constitutively active RAS-independent dimers with high or moderate BRAF kinase activity, including codons other than 600 that include BRAF fusion mutants". Patients with type II mutants typically have a shorter survival period than patients with type I mutants, and the cancer may be more aggressive.

[1393] ERBB3 is a transmembrane pseudo-RTK with a strong genetic link to cancer.

[1394] GRB2 is a scaffold adapter involved in RTK signaling to downstream pathways, including MAPK. GRB2 is associated with cancer and tumorigenesis because it recruits a wide range of signaling molecules to its receptor to form a multimeric signaling complex that leads to cellular responses such as proliferation and invasion.

[1395] CBP is a transcriptional coactivator involved in the transcriptional coactivation of many different transcription factors, and is therefore involved in a wide range of cellular activities, including DNA repair, cell growth, differentiation, and apoptosis. CBP is also known as CREBBP. CBP is a CREB-binding protein transcriptional coactivator and is associated with various cancers, including leukemia, NSCLC, HCV-associated hepatocellular carcinoma, melanoma, lung cancer, lymphoma, and bladder cancer.

[1396] ATAD2 and ATAD2B are bromo / ATP helicases that may be involved in triple-negative breast cancer by acting as transcriptional coactivators of the nuclear receptor ESR1, which is required to induce a subset of estradiol target genes.

[1397] BAP1 is a deubiquitinating enzyme that can function as a tumor suppressor and metastasis inhibitor in cancer. BAP1's ability to regulate gene-environment interactions in oncogenesis is linked to its dual role in the nucleus and cytoplasm. In the nucleus, BAP1 regulates transcriptional regulation of several gene programs and promotes DNA repair by facilitating homologous recombination. BAP1 is found in PBRM1-deficient CRCs.

[1398] BRPF1 is a bromodomain-containing histone reader associated with Moz and Morf, possessing HAT activity against H3. BRPF1 is involved in cancers such as hematopoietic malignancies, including leukemia.

[1399] BRD4 is an epigenetic leader and a member of the BET protein family. BRD4 binds to acetylated histones and plays a central role in regulating cellular gene transcription and cell proliferation, making it important for the development of angiogenesis and inflammation-related diseases, cardiovascular diseases, central nervous system disorders, and cancer.

[1400] EPAS1(HIF2a) belongs to a group of transcription factors involved in the physiological response to oxygen concentration and is encoded under hypoxic conditions. EPAS1(HIF2a) is also important in cardiac development and plays a crucial role in maintaining the balance of catecholamines necessary for cardiac protection. Mutations often cause neuroendocrine tumors such as paragangliomas, somatostatinomas, and / or pheochromocytomas.

[1401] KMT2D is a histone methyltransferase with a strong genetic link to cancer. This protein co-localizes with phylogenetic transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development. KMT2D also plays a crucial role in regulating cell fate transitions, metabolism, and tumor suppression.

[1402] Menin is a scaffold protein that binds bidentally to the N-terminus of KMT2A(MLL) and MLL fusion proteins, enabling its binding and localization to chromatin, and is associated with leukemia and other cancers.

[1403] MLLT1(ENL) is a YEATS domain-containing protein that is involved in transcription initiation / elongation (YEATS domain-dependent) and plays an important role as an interacting factor with DOT1L.

[1404] DOT1L is a histone H3K79 methyltransferase that methylates lysine 79 of histone H3, an evolutionarily conserved methylation mark. DOT1L is involved in many major processes, from gene expression to DNA damage response and cell cycle progression. DOT1L is also involved in the development of mixed-phenotype leukemia (MLL) rearrangement leukemia.

[1405] NSD2 is a histone methyltransferase that is ubiquitously expressed during early development and is overexpressed in cancer cells, including ALL, CLL, and MCL.

[1406] TAU consists of six highly soluble protein isoforms produced by alternative splicing from the MAPT (microtubule-associated protein tau) gene. TAU proteins primarily play a role in maintaining microtubule stability in axons and are abundant in neurons of the central nervous system (CNS). Neurological disorders such as Alzheimer's disease and Parkinson's disease, as well as dementia, are associated with tau proteins that have become hyperphosphorylated, insoluble aggregates called neurofibrillary tangles.

[1407] HTT is a Huntington's protein. HTT is essential for development and is highly expressed in neurons and testes. Huntington's protein upregulates the expression of brain-derived neurotrophic factor (BDNF) at the transcriptional level, and mutations in HTT cause Huntington's disease.

[1408] NSD3 is a histone methyltransferase and a driver of 8p11-12 amplification found in cancers including squamous cell lung cancer, breast cancer, and AML.

[1409] SNCAs are members of the synuclein family and are involved in the regulation of dopamine release and transport, microtubule-associated protein tau fibrillation, and neuroprotective phenotypes in non-dopaminergic neurons. Mutations in SNCAs are associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease (AD), Lewy body disease (LBD), and muscular atrophy (MSA).

[1410] SMARCA2 and SMARCA4 are proteins encoded by the SWI / SNF family of proteins, possessing helicase and ATPase activity, and regulating gene transcription by altering chromatin structure as ATP-dependent chromatin remodelers.

[1411] BTK is a tyrosine kinase that plays an important role in oncogenic signal transduction, which is crucial for the proliferation and survival of leukemia cells in many B-cell malignancies. BTK was initially found to be mutated in patients with primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential at various stages of B-lymphocyte development.

[1412] TAF1 is a TBP-related factor that has a kinase domain, an acetyltransferase, and a bromodomain. TAF1 is an important component of the transcription factor II D complex, which plays a crucial role during transcription initiation. Variants of the TAF1 gene are associated with neurodevelopmental disorders including intellectual disability.

[1413] IRAK4 is a threonine / serine protein kinase that is involved in the signal transduction of the innate immune response from Toll-like receptors (TLRs). Loss of IRAK4 or its intrinsic kinase activity may completely halt signal transduction via the TLR pathway, and thus is associated with various inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases.

[1414] SARM1 is a negative regulator of the Toll-like receptor activation transcription program. After axonal injury, SARM1 initiates a "self-destruction" mechanism to degrade the metabolite NAD + This causes metabolic failure in neurons and leads to axonal degeneration.

[1415] PPM1D (WIP1) is a cancer protein and a member of the PP2C family of Ser / Thr protein phosphatases. PPM1D is a negative regulator of the cellular stress response pathway and is amplified in various cancers including breast cancer, esophageal cancer, colon cancer, blood cancer, thyroid cancer, sarcoma, lung cancer, and ovarian cancer.

[1416] Non-limiting examples of diseases that can be treated with tricyclic compounds Any of the compounds described herein may be used in an effective amount for the treatment of a host, including a human, in need, in an optionally pharmaceutically acceptable carrier, to treat any of the disorders described herein. In certain embodiments, the method involves administering an effective amount of the active compound described herein or a salt thereof, in an optionally pharmaceutically acceptable additive, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), in combination with or alternately with optionally additional therapeutic agents or combinations of therapeutic agents.

[1417] In a particular embodiment, a compound of formula I is used to treat the disorders described herein.

[1418] In a particular embodiment, a compound of formula II is used to treat the disorders described herein.

[1419] In a particular embodiment, a compound of formula III is used to treat the disorders described herein.

[1420] In a particular embodiment, a compound of formula IV is used to treat the disorders described herein.

[1421] In a particular embodiment, a compound of formula V is used to treat the disorders described herein.

[1422] In a particular embodiment, a compound of formula VI is used to treat the disorders described herein.

[1423] In a particular embodiment, a compound of formula VII is used to treat the disorders described herein.

[1424] In a particular embodiment, a compound of formula VIII is used to treat the disorders described herein.

[1425] In a particular embodiment, a compound of formula IX is used to treat the disorders described herein.

[1426] In a particular embodiment, a compound of formula X is used to treat the disorders described herein.

[1427] In a particular embodiment, a compound of formula XI is used to treat the disorders described herein.

[1428] In a particular embodiment, a compound of formula XII is used to treat the disorders described herein.

[1429] In a particular embodiment, a compound of formula XIII is used to treat the disorders described herein.

[1430] In a particular embodiment, a compound of formula XIV is used to treat the disorders described herein.

[1431] In a particular embodiment, a compound of formula XV is used to treat the disorders described herein.

[1432] In a particular embodiment, a compound of formula XVI is used to treat the disorders described herein.

[1433] In a particular embodiment, a compound of formula XVII is used to treat the disorders described herein.

[1434] In certain embodiments, the disorder treated by the compounds of the present invention is an immunomodulatory disorder. In certain embodiments, the disorder treated by the compounds of the present invention is mediated by angiogenesis. In certain embodiments, the disorder treated by the compounds of the present invention is related to the lymphatic system.

[1435] In certain embodiments, the method comprises administering an effective amount of the compound described herein, optionally comprising pharmaceutically acceptable additives, carriers, and adjuvants (i.e., a pharmaceutically acceptable composition), in combination with or alternately with an optional additional therapeutic agent or combination of therapeutic agents.

[1436] In certain embodiments, the compounds of the present invention may be used to treat disorders including, but are not limited to, benign tumors, neoplasms, tumors, cancer, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid protein disorders, protein disorders, or fibrous disorders.

[1437] The terms “disease state” or “pathological condition,” when used in connection with any of the compounds, mean any disease state or pathological condition that is responsive to the compounds of the present invention, such as cell proliferation, and in which administration of the compounds of the present invention to a patient may provide a beneficial therapy or symptom relief to the patient in need. In certain specific cases, the disease state or pathological condition may be curable.

[1438] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, with lymphoma or lymphocytic or myeloid proliferative disorders or abnormalities. For example, the compounds described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may include, but is not limited to, AIDS-associated lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-incisional nuclear cell lymphoma); small incisional nuclear cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy type T-cell lymphoma; follicular lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transforming lymphoma; treatment-related T-cell lymphoma; and non-Hodgkin lymphoma such as Langerhans cell histiocytosis or Waldenström macroglobulinemia.

[1439] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, having Hodgkin lymphoma, including but not limited to tuberous sclerosis classical Hodgkin lymphoma (CHL), mixed cell type CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-dominant Hodgkin lymphoma, or nodular lymphocyte-dominant HL.

[1440] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host having an immunomodulatory condition, such as a human. Non-limiting examples of immunomodulatory conditions include arthritis, lupus, celiac disease, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes mellitus, alopecia areata, vasculitis, and temporal arteritis.

[1441] In certain embodiments, the conditions treated with the compounds of the present invention are disorders associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can result from a wide range of factors, including gene mutations, infections, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[1442] Abnormal proliferation of B cells, T cells, and / or NK cells can lead to a wide range of diseases, including cancer, proliferative disorders, and inflammatory / immune diseases. A host suffering from any of these disorders, such as a human, can be treated with an effective amount of one of the compounds described herein to achieve a reduction in symptoms (palliative agent) or a reduction in the underlying disease (disease modifying agent).

[1443] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, are not limited to, multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphocytic lymphoma; diffuse poorly differentiated lymphocytic lymphoma; mediastinal large B-cell lymphoma B-cell lymphoma; nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; hairy cell leukemia; unclassifiable splenic lymphoma / leukemia; diffuse red pulp small B-cell lymphoma; hairy cell leukemia - subtype; lymphoplasmacytic lymphoma; heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; form It can be used in effective doses to treat specific B-cell lymphomas or proliferative disorders in hosts, such as humans, including: plasmacytomyeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL lower extremity type; ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma occurring in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate features between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; or unclassifiable B-cell lymphoma with intermediate features between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[1444] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, are not limited to, anaplastic lymphoma kinase (ALK)-positive, ALK-negative, anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphomas, e.g., mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous progressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium cell CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); bud It can be used in effective doses to treat hosts, such as humans, who have T-cell or NK-cell lymphomas, including: cytoplasmic NK-cell lymphoma; enteropathy-type T-cell lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; treatment-associated T-cell lymphoma; lymphoma occurring after, for example, solid organ or bone marrow transplantation; pre-T-cell lymphocytic leukemia; T-cell macrogranular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; rapidly progressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disorder in children (associated with chronic active EBV infection); vaccinia-like varicella-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[1445] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used to treat a host having leukemia, such as a human. For example, the host may have, but is not limited to, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); macrogranular lymphocytic leukemia; or acute or chronic leukemia of lymphocyte or myeloid origin, such as adult T-cell chronic leukemia. In certain embodiments, the patient suffers from acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or subtype M3 (M3V)); myelomonocytic leukemia (M4 or subtype M4 with eosinophilia (M4E)); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[1446] Numerous skin disorders are associated with cell overgrowth. For example, psoriasis is a benign disease of human skin generally characterized by plaques covered with thickened scales. This disease is caused by an increase in the proliferation of epidermal cells of unknown origin. Chronic eczema is also associated with marked epidermal overgrowth. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[1447] Other hyperproliferative cell disorders include vascular disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

[1448] Vascular proliferative disorders include neovascularization and vascular disorders. The proliferation of smooth muscle cells during plaque formation in vascular tissue leads to conditions such as restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[1449] Fibrotic disorders are often caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cytotoxicity. Cirrhosis is characterized by an increase in extracellular matrix components that lead to the formation of liver scars. Cirrhosis can lead to diseases such as liver cirrhosis. The increase in extracellular matrix that leads to liver scars may also be due to viral infections such as hepatitis. Lipid cells appear to play an important role in liver cirrhosis.

[1450] Mesangial disorders are caused by the abnormal proliferation of mesangial cells. Mesangial hyperproliferative cytotoxicity includes various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, and glomerulopathy.

[1451] Another disease caused by proliferative components is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[1452] Other disorders that may contain abnormal cell proliferation components include Behçet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[1453] The compounds described herein, or their pharmaceutically acceptable salts, isotope analogs, or prodrugs, can be used in effective amounts to treat hosts, such as humans, that have proliferative conditions including myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelometaplastic myelopathy with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), eosinophilic syndrome (HES), and systemic mastocytosis (SMCD). In another embodiment, the compounds provided herein are useful for the treatment of primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myeloid leukemia.

[1454] In certain embodiments, the compounds described herein, or their pharmaceutically acceptable salts, isotopic analogs, or prodrugs, can be used in effective amounts to treat hosts, such as humans, who have myelodysplastic syndromes (MDS), including but not limited to refractory cytopenia with monocytic lineage dysplasia, refractory anemia with ring sideroblasts (RARS), refractory anemia-thrombocytosis with ring sideroblasts (RARS-t), refractory cytopenia with polycytic lineage dysplasia (RCMD), including RCMD-RS, refractory anemia I (RAEB-I) and II (RAEB-II), 5q syndrome, and childhood refractory cytopenia.

[1455] The terms “neoplasia” or “cancer” are used to refer to the pathological process that results in the formation and growth of malignant or cancerous neoplasms, which are abnormal tissues that grow more rapidly than normal through cell proliferation and continue to grow even after the stimulus that initiated the new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most invade surrounding tissues, metastasize to several sites, and may recur even after attempts to remove them, leading to patient death if not properly treated. As used herein, the term neoplasia is used to describe all cancerous disease conditions and includes or encompasses pathological processes associated with malignant hematological malignancies, ascites tumors, and solid tumors. Exemplary cancers that can be treated with this compound alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's positivity. Sarcomas including sarcomas, liposarcomas, myosarcomas, peripheral neuroepitheliomas, synovial sarcomas, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and Schwann cell tumors; intestinal cancers, breast cancers, prostate cancers, cervical cancers, uterine cancers, lung cancers, ovarian cancers, testicular cancers, thyroid cancers, astrocytomas, esophageal cancers, pancreatic cancers, gastric cancers, liver cancers, colon cancers, melanomas; carcinosarcomas, Hodgkin's disease, Wilms' tumors, and teratomas. Additional cancers that can be treated with the compounds according to the present invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[1456] Additional cancers that can be treated with the compounds disclosed according to the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (estrogen, progesterone, and HER-2) (negative for both progesterone and HER-2), single-negative (negative for one of estrogen, progesterone, and HER-2), estrogen receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CL) L), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, ocular cancer, fallopian tubes Cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasion Lobular carcinoma (ILC), inflammatory breast cancer (IBC), colon cancer, intrahepatic cholangiocarcinoma, invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leukemia, lip cancer, liposarcoma, liver cancer, non-invasive lobular carcinoma, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, mouth cancerCancer), mucinous carcinoma, mucosal melanoma, multiple bone marrow abscess, fungal polyposis, osteomyelopathy syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-homologous lymphadenopathy, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, intraocular melanoma, follicular colloid tumor, oral cancer, oral cavity cancer, oral and pharyngeal cancer, osteosarcoma, osteosarcoma, ovarian carcinoma, epithelial ovarian carcinoma, ovarian germ cell tumor, ovarian Primary peritoneal carcinoma, ovarian cord-stromal tumor, pethopathy, lipoma, papillary carcinoma, paranasal cavity carcinoma, parathyroid carcinoma, pelvic carcinoma, penile cancer, peripheral nerve carcinoma, peritoneal carcinoma, pharyngeal carcinoma, brown cell tumor, trichomeal stellate tumor, pineal gland tumor, pineal bud, pituitary carcinoma, primary central nervous system (CNS) lipoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma. Sarcoma, sarcoma, paranasal cavity cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal cord cancer, spinal marrow cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell leukemia, seminal vesicle cancer, pharyngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, cancer of unknown diagnosis, ureteral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute leukemia (T-ALL), T-cell leukemia (T-LL), peripheral T-cell leukemia, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (a subtype of AML), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma; Mucosa-associated lymphoid tissue lymphoma (MALT), Small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, Nodal marginal zone B-cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary exudative lymphoma; or Lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; Unclassifiable splenic lymphoma / leukemia, Diffuse red pulp small B-cell lymphoma; Lymphoid Plasma cell lymphoma; heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; plasma cell myeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL lower extremity type; ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. In certain embodiments, the lesion is adenoid cystic carcinoma. In certain embodiments, the lesion is NUT midline carcinoma.

[1457] In another embodiment, the compounds described herein, or their pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host with an autoimmune disorder, such as a human. Examples include acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as Lou Gehrig's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid antibody syndrome; antisynthetic enzyme syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune enteropathy; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian failure; polyglandular autoimmune syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disorder; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; and Barlow's disease. (disease) / Barrow concentric sclerosis; Behçet's disease; Berger's disease; Bickerstaff's encephalitis; Blau syndrome; bullous pemphigoid; cancer; Castleman disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing polymyelitis; Churg-Strauss syndrome; scarring pemphigoid; Cogan syndrome; cold agglutinin disease; complement component 2 deficiency; contact dermatitis; cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; cutaneous leukocytoclastic vasculitis; Degos disease; Darkham's disease; herpetiform dermatitis; dermatomyositis; type 1 diabetes; diffuse dermatitis Systemic sclerosis of the skin; discoid lupus erythematosus; Dressler syndrome; drug-induced lupus; eczema; endometriosis; enthesitis-associated arthritis; eosinophilic fasciitis; eosinophilic gastroenteritis; eosinophilic pneumonia; acquired epidermolysis bullosa; erythema nodosum; erythroblastosis fetus; essential mixed cryoglobulinemia; Evans syndrome; exogenous and endogenous reactive airway disease (asthma); fibrodysplasia ossificans progressive; fibrous alveolitis (or idiopathic pulmonary fibrosis); gastritis; pemphigoid gastroenteritis; glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's disease; hemolytic anemia; Henoch-Schönlein purpura;Herpes zoster of pregnancy (bullous pemphigoid of pregnancy); hidradenitis suppurativa; Hughes-Stovin syndrome; hypogammaglobulinemia; idiopathic inflammatory demyelinating disease; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; IgA nephropathy; immune glomerulonephritis; immune nephritis; immune pneumonia; inclusion body myositis; inflammatory bowel disease; interstitial cystitis; juvenile idiopathic arthritis, also known as juvenile rheumatoid arthritis; Kawasaki disease; Lambert-Eaton myasthenic syndrome; leukocytoclastic vasculitis; lichen planus; lichen sclerosing; linear IgA disease (LAD) ); Lupoid hepatitis, also known as autoimmune hepatitis; lupus erythematosus; Magid's syndrome; microscopic polyangiitis; Miller-Fischer syndrome; mixed connective tissue disease; focal scleroderma; Mucher-Habermann disease, also known as acute pityriasis lichenoides; multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also known as Devic's disease); neuromyotonia; ocular pemphigoid; opsoclonus myoclonus syndrome; Ord's thyroiditis Thyroiditis; Recurrent rheumatoid arthritis; PANDAS (Pediatric autoimmune streptococcal neuropsychiatric disorder); Paraneoplastic cerebellar degeneration; Paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; Slamic mange; Personage-Turner syndrome; Pemphigus vulgaris; Perivenous encephalomyelitis; Pernicious anemia; POEMS syndrome; Polyarteritis nodosa; Polymyalgia rheumatica; Polymyositis; Primary biliary cirrhosis; Primary sclerosing cholangitis; Progressive inflammatory neuropathy; Psoriasis; Psoriatic arthritis; Pure red cell aplasia; Pyoderma gangrenosum; Rasmussen's encephalitis; Raynaud's phenomenon; Reiter's syndrome; Relapsing polychondritis; Restless legs syndrome; Retroperitoneal fibrosis; Rh Machia fever; rheumatoid arthritis; sarcoidosis; schizophrenia; Schmidt syndrome; Schnitzler syndrome; scleritis; scleroderma; sclerosing cholangitis; serum sickness; Sjögren's syndrome; spondyloarthritis; stiff person syndrome; Still's disease; subacute bacterial endocarditis (SBE); Suzak syndrome; Sweet's syndrome; Sydenham's chorea; sympathetic ophthalmitis; systemic lupus erythematosus; Takayasu's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; undifferentiated spondyloarthritis; urticarial vasculitis; vasculitis; and vitiligo are among the conditions that may be present, but are not limited to these.

[1458] In another embodiment, the treatment includes viral diseases such as SARS-CoV-1, SARS-CoV-2, coronaviruses, flaviviridae, dengue fever, West Nile fever, RSV, Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus (VZV), and human papillomavirus (HPV), or Wegener's granulomatosis. In some embodiments, autoimmune diseases are allergic conditions, including asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[1459] Skin contact hypersensitivity and asthma are just two examples of immune responses that may have a significant prevalence. Other examples include atopic dermatitis, eczema, Sjögren's syndrome including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may present with one or more of the following symptoms or signs: itching, swelling, redness, blistering, crusting, ulceration, pain, desquamation, cracking, hair loss, scarring, or exudation of fluid from the skin, eyes, or mucous membranes.

[1460] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly mononuclear cells, lymphocytes, neutrophils, and eosinophils) generally plays a significant role in the development of these diseases. Chronic eczema is also associated with marked epidermal hyperplasia. Immune-mediated leukocyte infiltration can occur in areas other than the skin, such as the airways in asthma and the tear-producing glands in keratoconjunctivitis sicca.

[1461] The compounds described herein, or their pharmaceutically acceptable salts, isotopic variants...

Claims

1. formula: (In the formula, AA is, Selected from, n is 1, X is NR １０ , NR ６’ , O, or S, Ring-A is a fused ring selected from phenyl, a 5- or 6-membered heteroaryl, a 5- to 8-membered heterocycle, a 5- to 8-membered cycloalkyl, and a 5- to 8-membered cycloalkenyl, where ring-A is R if permissible by valency. １ It is optionally substituted with one, two, or three substituents that are selected more independently. Ring-B is a fused ring selected from phenyl, a 5- or 6-membered heteroaryl, a 5- to 8-membered heterocycle, a 5- to 8-membered cycloalkyl, and a 5- to 8-membered cycloalkenyl, where ring-B is R if permissible by valency. ２ It is optionally substituted with one, two, or three substituents independently selected from the above, Ring E is, (b) If permitted by valence, R ２ A fused ring selected from a 5-membered to 8-membered cycloalkenyl, 5-membered to 8-membered cycloalkyl, 5-membered to 8-membered heterocycle, or 5-membered heteroaryl ring, which is optionally substituted with one, two, or three substituents independently selected from the above. Selected from, Ring F is, (a) R １’ Phenyls substituted with one, two, or three substituents independently selected from, and (b) If permitted by valence, R １ A fused ring selected from a 5-membered to 8-membered cycloalkenyl, 5-membered to 8-membered cycloalkyl, 5-membered to 8-membered heterocycle, or 5-membered or 6-membered heteroaryl, which is optionally substituted with one, two, or three substituents independently selected from the above. Selected from, R １ and R ２ are each independently (a) Hydrogen, alkyl, halogen, haloalkyl, -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , -NR １０ R １１ , cyano, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, where each heteroaryl, aryl, cycloalkyl, and heterocyclic is R ４０ Optionally substituted with one, two, three, or four substituents independently selected from the above, (b) (c) When permitted by valency, the divalent part = O, Selected from, Here R １ The base is, arbitrarily, another R １ Base or R ２ It may be combined with a group to form a fused ring or a biring, which may bridge ring-A and ring-B. R １’ Each of them operates independently. (a) alkyl, halogen, haloalkyl, -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , -NR １０ R １１ , cyano, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, where each heteroaryl, aryl, and heterocyclic is R ４０ Optionally substituted with one, two, three, or four substituents independently selected from the above, (b) (c) When permitted by valency, the divalent part = O, Selected from, and, Here R １’ The base is, arbitrarily, another R １’ Base or R ２ It may be combined with a group to form a fused ring or a biring, which may bridge ring-A and ring-E. R ２’ These are, independently, alkyl, halogen, haloalkyl, and -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , -NR １０ R １１ R is selected from cyano, nitro, heteroaryl, aryl, and heterocyclic compounds, or alternatively, if permitted by valency, ２’ The divalent part may be O, and Here R ２’ The base is, arbitrarily, another R ２’ Base or R １ It may be combined with a group to form a fused ring or a biring, which may bridge ring-A and ring-E. R ３ is hydrogen, alkyl, halogen, or haloalkyl, Or, R ３ and R ６ These combine to form one or two carbon deposits. Or, R ３ and R ４ These combine to form one, two, three, or four carbon deposits. Or, R ３ and R ３ Adjacent to R ４ The groups combine to form a double bond, Each R ４ These are independently selected from hydrogen, alkyl, halogen, and haloalkyl, R ５ is hydrogen, alkyl, halogen, or haloalkyl, R ６ and R ７ These are, independently, hydrogen, alkyl, halogen, haloalkyl, and -OR. １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , and -NR １０ R １１ Selected from, here R ６ and R ７ If they are on the same carbon atom, they may optionally form a three-membered or four-membered spiro ring. R ６ ' is hydrogen, alkyl, or haloalkyl, Or, R ３ and R ６ These combine to form one or two carbon deposits. R ３ａ is hydrogen, alkyl, halogen, or haloalkyl, Or, R ３ａ and R ６ａ These combine to form one or two carbon deposits. Or, R ３ａ and R ４ａ These combine to form one, two, three, or four carbon deposits. Or, R ３ａ and R ３ａ Adjacent to R ４ａ The groups combine to form a double bond, R ４ａ It is selected from hydrogen, alkyl, halogen, and haloalkyl, R ６ａ is hydrogen, alkyl, halogen, haloalkyl, -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , and -NR １０ R １１ Selected from, here R ３ａ , R ４ａ , and R ６ａ At least one of them is not hydrogen, Each R １０ and R １１ are each independently hydrogen, alkyl, haloalkyl, heterocycle, aryl, heteroaryl, -C(O)R １２ , -S(O)R １２ , and -SO ２ R １２ selected from, Each R １２ is independently selected from hydrogen, alkyl, haloalkyl, heterocycle, aryl, heteroaryl, -NR １３ R １４ , and OR １３ and is selected from R １３ and R １４ Each of these is independently selected from hydrogen, alkyl, and haloalkyl. Each X ２ is bonded, heterocyclic, aryl, heteroaryl, bicyclic, alkyl, -NR ２７ -, -CR ４０ R ４１ -, -O-, -C(O)-, -C(NR ２７ )-, -C(S)-, -S(O)-, -S(O) ２ The divalent moiety is selected from - and -S-, and its heterocycle, aryl, heteroaryl, and bicycle are each R ４０ It is optionally substituted with one, two, three, or four substituents independently selected from the above, X ３ is bond, heterocycle, aryl, heteroaryl, bicycle, -NR ２７ -, -CR ４０ R ４１ -, -O-, -C(O)-, -C(NR ２７ )-, -C(S)-, -S(O)-, -S(O) ２ The divalent moiety is selected from -, -S-, arylalkyl, heterocyclic alkyl, or heteroarylalkyl (in either direction), and the heterocycle, aryl, heteroaryl, and dicyclic rings are each R ４０ It may be substituted with one, two, three, or four substituents independently selected from the above. R １５ , R １６ , and R １７ These are, independently, bonded, alkyl, -C(O)-, -C(O)O-, -OC(O)-, and -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２７ -, -NR ２７ C(O)-, -O-, -S-, -NR ２７ -, -C(R ４０ R ４１ ) - Selected from the group consisting of bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, heteroaryl, arylalkyl, heterocycloalkyl and heteroarylalkyl (in either direction), each of which is R ４０ It is optionally substituted with one, two, three, or four substituents independently selected from the above, R １８ This includes hydrogen, alkyl, alkene, alkyne, hydroxy, azide, amino, halogen, haloalkyl, -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , -NR １０ R １１ Selected from cyano, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is R ４０ It is optionally substituted with one, two, three, or four substituents independently selected from the above, R ２０ , R ２１ , R ２２ , R ２３ , and R ２４ These are, independently, bonded, alkyl, -C(O)-, -C(O)O-, -OC(O)-, and -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２７ -, -NR ２７ C(O)-, -O-, -S-, -NR ２７ -, oxyalkylene, -C(R ４０ R ４０ ) - Selected from the group consisting of bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, heteroaryl, and carbocyclic, each of which is R ４０ It is optionally substituted with one, two, three, or four substituents independently selected from the above, R ２７ Each of these is independently selected from the group consisting of hydrogen, alkyl, heterocyclic, aryl, heteroaryl, -C(O)(alkyl, aryl, or heteroaryl), -C(O)O(alkyl, aryl, or heteroaryl), alkenes, and alkynes. R ２８ Alkyl, alkene, alkyne, hydroxy, azide, amino, halogen, haloalkyl, -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , -NR １０ R １１ Selected from cyano, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is R ４０ It is optionally substituted with one, two, three, or four substituents independently selected from R, where R １５ , R １６ , R １７ , and R ２０ If at least one of them is not a bond, R ２８ It may also be hydrogen. R ４０ These are, independently, hydrogen and R ２７ Alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl) ２ Selected from the group consisting of haloalkyl, aryl, heteroaryl, heterocyclic, and cycloalkyl, R ４１ A compound of (which is alkyl, aryl, heteroaryl, or hydrogen), or a pharmaceutically acceptable salt thereof.

2. Formula: A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Formula: A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. Formula: A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. Ring F is R １ The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is a phenyl substituted with one or two substituents independently selected from '.

6. Ring E is, A compound according to claim 3 or a pharmaceutically acceptable salt thereof, selected from the above.

7. X ３ and X ２ At least one of them is bonded, -O-, -S-, or -NR ２７ - The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

8. R １５ , R １６ , R １７ , R ２２ , R ２３ and R ２４ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein at least one of the compounds is a bond.

9. Ring-A is a fused ring selected from phenyl and a 6-membered heteroaryl, where ring-A is R if permitted by valency. １ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the compound.

10. Ring-B is a fused ring selected from phenyl or a 6-membered heteroaryl, where ring-B is R if permitted by valency. ２ The compound according to claim 2 or 4, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the compound.

11. One R ２ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein a substituent is present.

12. One R １ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, having a substituent.

13. R １ , R ２ , and R ２’ Alkyl, halogen, haloalkyl, heteroaryl, aryl, heterocyclic, -OR １０ , -SR １０ , -S(O)R １２ , -SO ２ R １２ , and -NR １０ R １１ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, independently selected from the above.

14. R １ , R １’ , and R ２ One of them is, The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

15. R １ , R １’ , and R ２ One of them is, The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

16. R １ , R １’ , and R ２ One of them is, The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

17. .

18. A pharmaceutical composition for treating cereblon-mediated cancer or tumor in a human patient, comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

19. The pharmaceutical composition according to claim 18, wherein the cancer or tumor is a hematological malignant tumor.

20. The pharmaceutical composition according to claim 19, wherein the hematological malignancy is leukemia.

21. The pharmaceutical composition according to claim 19, wherein the hematological malignant tumor is multiple myeloma.

22. The pharmaceutical composition according to claim 19, wherein the hematological malignancy is non-Hodgkin lymphoma.

23. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating cancer or tumor mediated by cereblon in human patients.

24. The use according to claim 23, wherein the cancer or tumor is a hematological malignant tumor.

25. The use according to claim 24, wherein the hematological malignancy is leukemia.

26. The use according to claim 24, wherein the hematological malignancy is multiple myeloma.

27. ​​The use according to claim 24, wherein the hematological malignancy is a non-Hodgkin lymphoma.

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