Tricyclic compounds degrading new substrates for medical treatment

Abstract

The present invention provides tricyclic compounds that degrade novel substrates for use in the treatment of disorders described herein, including, for example, abnormal cell proliferation, neurodegenerative diseases, and autoimmune diseases.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180079148.7, filed on October 14, 2021, entitled "Tricyclic Compounds for Degrading Novel Substrates for Medical Treatment". CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 091,894, filed on October 14, 2020, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0003] This invention provides tricyclic compounds that degrade cereblon E3 ubiquitin ligases for the treatment of disorders described herein, including, for example, abnormal cell proliferation, inflammatory disorders, neurodegenerative diseases, and autoimmune diseases.

[0004] INCORPORATION BY REFERENCE The contents of the text file named “16010-058WO1_SequenceListing_ST25.txt”, which was created on October 14, 2021 and is 3.94 kilobytes in size, are hereby incorporated in full via inline. Background Technology

[0005] Protein degradation is a highly regulated and critical process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscular degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0006] The protein is labeled for proteasome degradation by covalently linking multiple ubiquitin molecules to terminal lysine residues via E3 ubiquitin ligase. In this process, the protein is digested into small peptides and ultimately broken down into its constituent amino acids, which serve as building blocks for new proteins. Defects in proteasome degradation are associated with a variety of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0007] Thalidomide and its analogues lenalidomide and pomalidomide have attracted interest as immunomodulators and antitumor drugs, particularly in multiple myeloma (see Martininiani, R. et al., “Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma”, Adv Hematol, 2012, 2012:842-945; and Terpos, E. et al., “Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma”, Oncotargets and Therapy, 2013, 6:531). Thalidomide, lenalidomide, pomalidomide, and their analogues contain an imide functional group (C(O)-NH-C(O)). Celegene discloses various imides and their uses, including U.S. Patents 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977; 6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697; 7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531; 8,673,939; 8,735,428; 8,741,929; 8,828,427; Those in 9,056,120; 9,101,621; and 9,101,622.

[0008] The phthalimide moiety of an imide interacts with specific amino acids in the hydroxycerebroside receptor of the ligase-protein complex to "establish" a thermodynamically favorable site known as a "novel substrate." This site is typically not bound to the ligase, but it is established for drug binding to hydroxycerebroside. Current research focuses on identifying novel substrates based on the various chemical structures of the hydroxycerebroside-binding ligand. This opens up a new approach to biological pathways that rely on the interception of novel protein substrates leading to functional disorders, thereby opening new avenues for medical treatment.

[0009] The rapid ubiquitination and proteasome degradation of IKZF1 and IKZF3 by thalidomide, lenalidomide, and pomalidomide has been a subject of extensive research. These drugs recruit IKZF1 / 3 to CRL4 via the Cys2-His2 (C2H2) zinc finger (ZF) domains in IKZF1 and IKZF3. CRBN E3 ubiquitin ligase. Sievers et al., Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN, Science 362, 558 (2018). Sievers et al. tested a large number of proteins with C2H2 zinc finger domains and identified 15 single ZFs and 7 full-length ZF-containing proteins that were degraded by thalidomide derivatives in functional or computational screening. Their work 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 with chemical modifications at the drug-ZF interface were able to convert ZFs with weak affinity for the CRBN-pomalidomide complex into degradation targets. IKZF2 and IKZF4 were not degraded by pomalidomide, lenalidomide, or CC-122, but were efficiently degraded by CC-220, illustrating aspects of protein degradation that are currently unpredictable, and the fact that the novel substrate-binding motif is uniquely based on a combination of hydroxycerebroside and the specific chemical structure of the drug, establishing thermodynamically favorable binding sites for the novel substrate.

[0010] Reports indicate that thalidomide analogues degrade seemingly structurally unrelated proteins, further raising questions about how thalidomide works and how best to use it for therapeutic purposes. For example, in addition to IKZF1 / 3, casein kinase 1α (CK1α) and GSPT1 have been reported to be degraded using this mechanism. (Kronke et al., Lenalidomide induces subiquitination and degradation of CK1α in de(5q) MDS;) Nature , 523, 183-188(2015); Matyskiela et al., A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase, Nature535, 252-257 (2016); Petzold et al., Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase, Nature , 532, 127-130 (2016); Fischer et al., Structure of the DDB1-CRBN E3 ubiquitinligase in complex with thalidomide, Nature , 512, 49-53 (2014).

[0011] Further reports indicate that ARID2 can be degraded via the CRBN proteasome pathway. Yamamoto et al. stated that ARID2 is an apomalidomide-dependent CRL4. CRBN substrate in multiple myeloma cells, Nature Chemical Biology Published online on September 21, 2020. ARID2 is a component of the polybrominated associated BAF (PBAF) chromatin remodeling complex. Yamamoto et al. reported that ARID2 is a component of pomalidomide-induced CRL4. CRBN A novel substrate. BRD7, another subunit of PBAF, is crucial for pomalidomide-induced ARID2 degradation. ARID2 degradation is an example of target protein degradation influenced by cofactors.

[0012] Dana Farber Cancer Institute's WO2020 / 006262 discloses a tricyclic compound containing glutarimide. Kymera's WO2020 / 206424, WO2020 / 010177, and WO2020 / 010227 also disclose tricyclic compounds containing glutarimide.

[0013] PCT / US2019 / 24094 and PCT / US2020 / 02678, filed by C4 Therapeutics, Inc., disclose hydroxycerebroside binders for the degradation of Ikaros (IKZF1 / 3).

[0014] Calico Life Sciences LLC and AbbVie Inc. filed WO 2021 / 127586, which describes PTPN1 and PTPN2 degrading agents that are covalently bound to various hydroxycerebroside ligands.

[0015] Examples of patent applications in the field of zinc finger degradation include WO 2020 / 012334; WO 2020 / 012337; WO2019 / 038717; WO 2020 / 128972; WO 2020 / 006264; WO 2020 / 117759; WO 2021 / 087093; WO2021 / 101919; and WO 2021 / 194914.

[0016] Despite these attempts, there remains a need for new compounds, uses, and methods of preparation for medical treatments (including for treating abnormal cell proliferation, neurodegenerative diseases, and autoimmune diseases), wherein the compound can bind to CRL4. CRBN The E3 ubiquitin ligase's hydroxycerebroside receptor generates new binding sites for novel substrates that act as mediators of human diseases, leading to the degradation of these novel substrate proteins. Summary of the Invention

[0017] Novel tricyclic compounds for treating the diseases described herein, as well as their uses and preparation, are provided. These include diseases characterized by abnormal cell proliferation, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases.

[0018] The tricyclic compound presented in this article can bind to CRL4. CRBN E3 ubiquitin ligases and their cerebroside receptors establish novel binding sites for new protein substrates that act as mediators of human diseases, leading to protein degradation of these new substrates. The tricyclic compounds described herein generate neomorphic durfaces on cerebrosides that can directly interact with the target protein or target protein complex to directly or indirectly reduce protein levels. In various embodiments, the tricyclic compounds described herein can reduce the level of the new substrate target protein through direct ubiquitination of the target protein; or through ubiquitination of the new substrate target protein cofactor or target protein complex, or other proteins responsible for controlling the homeostasis of the target protein. The compounds can lead to degradation of new substrate target proteins that directly bind to ligand-bound cerebrosides; degradation of new substrates as cofactors bound to ligand-bound cerebrosides; degradation of ligand-bound cerebrosides at the complex cofactor-target protein interface; degradation of new substrate target protein complexes bound to ligand-bound CRBNs; or reduction of target protein levels through degradation of proteins that affect the homeostasis of the target protein (but not in the target protein complex) or cofactor.

[0019] In some embodiments, the novel substrate to be degraded is a protein having a glycine-containing β-hairpin turn at a critical position (“g-cyclic protein” or “g-cyclic degrader”), which acts as a “structural degrader” for cerebroside when it is also bound to the tricyclic compound of the present invention, as further described herein. Non-limiting examples of novel substrates include Sal-like protein 4 (SALL4), GSPT1, IKFZ1, IKFZ3, CK1α, ZFP91, ZNF93, protein kinases, C2H2-containing zinc finger proteins, proteins containing RNA-recognition motifs, zinc β-band proteins, β-propeller proteins, P-cyclic NTPase proteins, proteins containing truly interesting new gene (RING) finger domains, proteins containing SRC homology 3 (SH3) domains, proteins containing immunoglobulin E-set domains, proteins containing Tudor domains, FAM38, or ARID. In other embodiments, another disease-mediating protein is degraded by the disclosed tricyclic hydroxycerebroside-binding compound, including any of those described herein or otherwise identified.

[0020] In another implementation, with CRL4 CRBN The tricyclic compound that binds to the E3 ubiquitin ligase's cerebroside receptor can create novel binding sites for more than one novel protein substrate (which is a mediator of human disease), in a manner that leads to the degradation of multiple novel protein substrates. In some embodiments, both IRAK4 and IKZF are degraded. In another embodiment, both SALL4 and IKZF are degraded. In other embodiments, other variants of the various proteins described herein are degraded in a manner that treats the target human disease.

[0021] In the main implementation scheme, a tricyclic compound of selected formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV may be administered in an effective amount to a desired host, such as a human, to treat any of the disorders described herein: (I) (II) (III) (IV) (V) (VI) (VII) (VIII) (IX) (X) (XI) (XII) (XIII) (XIV) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; in: A is selected from , , , , , , , , , , , , , , , and ; B is selected from , , , , and ; n is 0, 1, or 2; X is NR 10 NR 6 ', O or S; X' is NR 10 O, CH2 or S; Q is CR 7 Or N; Q' and Q" are each independently selected from CR 6 and N; Ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein, where valence permits, ring-A is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents of the substituents; Ring -B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein, where valence permits, ring -B is optionally composed of 1, 2, or 3 independently selected from R 2 Substituents of the substituents; In some embodiments, ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-A is optionally composed of one, two, or three independently selected from R 1 Substituents of the substituents; In some embodiments, ring-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-B is optionally composed of one, two, or three independently selected from R 2 Substituents of the substituents; The ring-C is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, and 5- to 6-membered cycloalkenyl, wherein, where valence permits, the ring-C is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents of the substituents; Ring-D is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, and 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-D is optionally composed of 1, 2, or 3 independently selected from R. 2 Substituents of the substituents; R 1 and R 2 Each case is independently selected (a) Hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; (b) , and ;as well as (c) If valence and stability permit, divalent portions such as O, S, or =NR 25 ;and Where appropriate and necessary, R 1 The group may optionally be combined with another R 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-B or ring-C and ring-D; R 3 It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3 and R 6 Combining to form 1 or 2 carbon connections, for example, when R 3 and R 6 When a 1-carbon bond is formed, yes ; Or R 3 and R 4 Combining to form 1, 2, 3, or 4 carbon connections, for example when R 3 and R 4 When a 1-carbon bond is formed, yes ; Or R 3 and R 3 Adjacent R 4 Groups combine to form double bonds; Each R 4 Independently selected from hydrogen, alkyl, halogen, and haloalkyl; R 5 It is hydrogen, alkyl, halogen, or haloalkyl; R 6 and R 7 In each case, it is independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 Where R 6 and R 7 If they are located on the same carbon atom, they can optionally form 3- to 4-membered spirocycles.

[0022] R 6 It is hydrogen, alkyl, or haloalkyl; Or R 3 and R 6 'Combined to form 1 or 2 carbon connections, for example when R 3 and R 6 When a 1-carbon bond is formed, yes ; R 10 and R 11 Each is independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 12 -S(O)R 12 and -SO2R 12 ; Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -NR 13 R 14 and OR 13 ; R 13 and R 14 Each is independently selected from hydrogen, alkyl, and haloalkyl; Each X2 It is the divalent part, selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, alkyl groups, aliphatic groups, heteroaliphatic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 -, -C(S)-, -S(O)-, -S(O)2- and -S-; wherein the heterocyclic, aryl, heteroaryl and bicyclic are each chosen independently by 1, 2, 3 or 4 selected from R 40 Substituents of the substituents; X 3 It is a divalent moiety, selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic compounds, and -NR. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 -, -C(S)-, -S(O)-, -S(O)2-, -S-, arylalkyl, heterocyclic alkyl, or heteroarylalkyl (in any direction); wherein the heterocycle, aryl, heteroaryl, and bicyclic can each be 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 15 R 16 and R 17 Each occurrence is independently selected from the following: bond, alkyl group (which in some embodiments is a carbide ring), -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -、-C(R 40 R 41 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, arylalkyl, heterocyclic alkyl, and heteroarylalkyl (in any direction); wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; R 18 Selected from hydrogen, alkyl, olefin, alkyne, hydroxyl, azide, amino, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11Cyanoyl, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, wherein each of the heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; R 20 R 21 R 22 R 23 and R 24 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -Oxylenes, -C(R) 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefinic, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic, glycolic acid, and carbocyclic; wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; R 25 It is an aliphatic group (including alkyl), aryl, heteroaryl, or hydrogen; R 26 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic groups; R 27 Each time it appears, it is independently selected from 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 Each time it appears, it is independently selected from hydrogen, R 27 Alkyl, olefin, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic group, including alkyl), -N (aliphatic group, including alkyl)2, -NHSO2 (aliphatic group, including alkyl), -N (aliphatic group, including alkyl)SO2alkyl, -NHSO2 (aryl, heteroaryl, or heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl, or heterocyclic), -NHSO2alkenyl, -N (alkyl)SO2alkenyl, -NHSO2ynyl, -N (alkyl)SO2ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl; and R41 It is an aliphatic group (including alkyl), aryl, heteroaryl, or hydrogen.

[0023] In another aspect of the invention, compounds of formula XV, XVI, or XVII are provided: (XV) (XVI) (XVII) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; in AA is selected from , , , , , , , , , , , , , , , , , , and ; Ring-E is selected from (a) , , , , , , and ; (b) A fused ring selected from 5-membered heteroaryl, 5-to-8-membered heterocyclic, 5-to-8-membered cycloalkyl, or 5-to-8-membered cycloalkenyl, optionally composed of one, two, or three independently selected from R, where valence permits. 2 Substituents of the substituents; Ring-F is selected from (a) Selected independently from R by 1, 2 or 3 1 Substituents of phenyl groups; and (b) A fused ring selected from 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, optionally composed of one, two, or three independently selected from R, where valence permits. 1 Substituents of the substituents; R 1 'Selected independently in each case' (a) Alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; (b) , and ;and (c) If valence and stability permit, divalent portions, such as O, S, or =NR. 25 ;and Where R 1 The 'group may optionally be combined with another R' 1 'Group or R 2 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 2 'In each case, it is independently selected from alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyano, nitro, heteroaryl, aryl, and heterocyclic; or alternatively, if valence and stability permit, R 2 'Can be a divalent part, such as O, S, or =NR 25 ; and R 2 The 'group may optionally be combined with another R' 2 'Group or R 1 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 2 "In each case, the components are independently selected from heteroaryl, aryl, and heterocyclic groups, and each heteroaryl, aryl, and heterocyclic group is optionally selected independently from 1, 2, 3, or 4 of R groups." 40 Substituents are substituted, and R is wherein 2 "The group can optionally be combined with R" 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 3a It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3a and R6a Combining to form 1 or 2 carbon connections, for example, when R 3a and R 6a When a 1-carbon bond is formed, yes ; or R 3a and R 4a Combining to form 1, 2, 3, or 4 carbon connections, for example when R 3a and R 4a When a 1-carbon bond is formed, yes ; Or R 3a and R 3a Adjacent R 4a Groups combine to form double bonds; R 4a Selected from hydrogen, alkyl, halogen, and haloalkyl; R 6s and R 7a Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 ; Or R 6a and R 7a Combined to form 3-4 quintic helical rings; Where R 3a R 4a R 6a and R 7a At least one of them is not hydrogen; R 28 Selected from alkyl, olefin, alkyne, hydroxyl, azide, amino, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, arylalkyl, cycloalkyl, and heterocyclic, wherein each heteroaryl, arylalkyl, cycloalkyl, and heterocyclic is optionally selected independently from 1, 2, 3, or 4 of R. 40 Substituents of the substituents; Where R 15 R 16 R 17 and R 20 If at least one of them is not a key, then R 28 It can be hydrogen; and All other variables are as defined in this document.

[0024] In some embodiments, compounds and methods are provided for treating disorders characterized by any abnormal cell proliferation that respond to treatment, including cancer, tumors, or non-cancerous or non-tumor conditions, as described more fully below. In some embodiments, the disorder is, for example, a hematopoietic disorder, such as lymphoid disorders, leukemia, lymphoid leukemia, lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hematologic malignancies, multiple myeloma, myelodysplastic syndromes such as 5q syndrome, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, AML, or chronic lymphocytic leukemia. In another embodiment, selected compounds of the invention are administered to achieve immunomodulation and reduce angiogenesis. In other embodiments, the compounds and methods described herein provide for treating disorders, including but not limited to graft-versus-host rejection, viral infections, bacterial infections, amyloidosis, proteopathies, or fibrotic disorders. Furthermore, other disorders that can be treated with effective amounts of the compounds described herein are described below.

[0025] In some embodiments, any of the compounds described herein has at least one desired atomic isotopic substitution in an amount approximately equal to the natural abundance of the isotope, i.e., enriched. In some embodiments, the compound comprises one or more deuterium atoms.

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

[0027] Therefore, the present invention includes at least the following features: (a) The compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII described herein, or their pharmaceutically acceptable salts, isotope derivatives (including deuterated derivatives) or prodrugs. (b) The compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII described herein, or their pharmaceutically acceptable salts, isotopic derivatives or prodrugs, for use in patients (usually humans) in the treatment of medical disorders in response to the compound, as further described herein; (c) Use of an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XVI or XVII, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, as described herein, in the treatment of a patient (generally a human) suffering from any of the disorders described herein. (d) Use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XVI or XVII, or pharmaceutically acceptable salts, isotopic derivatives or prodrugs thereof, as described herein, in the preparation of a medicament for treating a medical disorder in which the compound is responded, as further described herein; (e) A method of preparing a medicament for treating the 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 preparation. (f) The compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII described herein, or their pharmaceutically acceptable salts, isotope derivatives or prodrugs, are used to treat abnormal cell proliferation or cancer in the host, including any cancer described herein; (g) Use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XVI or XVII, or pharmaceutically acceptable salts, isotopic derivatives or prodrugs thereof, as described herein, in the preparation of medicaments for the treatment of cancer (including any cancers described herein). (h) A method of preparing a medicament for treating abnormal cell proliferation or cancer (including any cancer 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 preparation. (i) The compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII described herein, or their pharmaceutically acceptable salts, isotope derivatives or prodrugs, are used to treat tumors in a host, including any tumors described herein. (j) Use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XVI or XVII, or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof, as described herein, in the preparation of medicaments for the treatment of tumors (including any tumors described herein). (k) A method of preparing a medicament for treating a tumor in a host (including any tumor described herein), 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 preparation. (l) The compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII described herein, or their pharmaceutically acceptable salts, isotope derivatives or prodrugs, are used to treat immune, autoimmune, neurodegenerative, fibrotic or inflammatory disorders in the host. (m) The use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, (n) X, XI, XII, XIII, XIV, XV, XVI or XVII, or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof, in the preparation of medicaments for the treatment of immune, autoimmune, neurodegenerative, fibrotic or inflammatory disorders; (o) A method for preparing a medicament for treating a host’s immune, autoimmune or inflammatory disorders, 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 preparation. (p) The compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII described herein, or their pharmaceutically acceptable salts, isotope derivatives or prodrugs, are used to treat hematologic malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma; (q) Use of compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XVI or XVII, or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof, described herein, in the preparation of medicaments for the treatment of hematologic malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma; (r) A method for preparing a medicament for treating a host hematologic malignancy, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma, characterized in that a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XVI, or XVII is used in the preparation; (s) A pharmaceutical composition comprising an effective host therapeutic amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, and a pharmaceutically acceptable carrier or diluent; (t) The compounds described herein as mixtures of enantiomers or diastereomers (as the case may be), including racemic compounds; (u) The compounds described herein in enantiomeric or diastereomeric (as the case may be) enriched forms, including isolated enantiomers or diastereomeric compounds (i.e., with a purity greater than about 80%, 85%, 90%, 95%, 97%, or 99%); and (v) A method of preparing a therapeutic product comprising 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. Attached Figure Description

[0028] Figure 1 It is shown that it can be used as an intermediate for the addition of a series of R... 1 and / or R 2 Synthetic schemes for non-limiting examples of the synthesis of functional groups.

[0029] Figure 2 It is shown that it can be used as an intermediate 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-5-carboxaldehyde to add a series of R 1 and / or R 2 Synthetic schemes for non-limiting examples of the synthesis of functional groups.

[0030] Figure 3 This is a non-limiting representative formulation of the compound of the present invention. Detailed Implementation

[0031] I. Definition Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. In the specification, the singular form also includes the plural unless the context clearly requires otherwise. Although similar or equivalent methods and materials to those described in this application may be used in practice and testing, suitable methods and materials are described below. All published materials, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not an admission that they are prior art to the claimed application. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and not intended to be restrictive.

[0032] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject belongs.

[0033] In certain embodiments of each compound described herein, the compound may be in the form of a racemic compound, an enantiomer, an enantiomer mixture, a diastereomer, a diastereomer mixture, a tautomer, an N-oxide, or an isomer (e.g., a rotational isomer), as each form is specifically described unless the context explicitly excludes it.

[0034] The terms “an” and “a” do not indicate a limitation of quantity, but rather the presence of at least one referenced item. The term “or” means “and / or”. Unless otherwise indicated, statements herein relating to ranges of values ​​are intended only as a shorthand way of individually referring to each independent value within that range, and each independent value is incorporated into the specification as if it were stated separately herein. The endpoints of all ranges are included within the range and can be combined independently. All methods described herein may be performed in a suitable order unless otherwise indicated herein or otherwise obviously contradicted by the context. The use of examples or exemplary language (e.g., “for example”) is intended only to better illustrate the invention and not to limit the scope of the otherwise claimed invention.

[0035] This invention includes compounds described herein that have at least one desired atomic isotope substitution in an amount higher than the natural abundance of that isotope, i.e., enriched. An isotope is an atom with the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons. If isotope substitution is used, the usual substitution is at least one deuterium replacing hydrogen.

[0036] 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, respectively, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 35 S and 36 Cl. In a non-limiting example, isotope-labeled compounds can be used for metabolic studies (e.g., using...) 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H), detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or for use in patient radiotherapy. Additionally, any hydrogen atoms present in the compounds of this invention can be used... 18 F-atom substitution may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents through the procedures disclosed in the following schemes or examples, and the preparations described below.

[0037] As a general example and not a limitation, isotopes of hydrogen, such as deuterium (… 2 H) and tritium ( 3H) can be used anywhere in the structure to achieve the desired result. Optionally, or additionally, isotopes of carbon, such as 13 C and 14 C.

[0038] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is substituted with deuterium. In some embodiments, the isotope is enriched at any desired location by 90%, 95%, or 99% or higher. In a non-limiting embodiment, deuterium is enriched at the desired location by 90%, 95%, or 99%.

[0039] In a non-limiting embodiment, substitution from hydrogen to deuterium atoms may be provided in any of the compounds described herein. For example, when any group is substituted with or contains, for example, methyl, ethyl, or methoxy groups, the alkyl residue may be deuterated (in non-limiting examples, CDH2, CD2H, CD...). 3、 CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc. In some other embodiments, the unsubstituted carbon may be deuterated when the two substituents combine to form a ring. In some embodiments, at least one deuterium is placed on an atom having a bond that is broken during metabolism within the compound, or on one, two, or three atoms distant from the metabolic bond (e.g., which may be referred to as α, β, or γ, or a primary, secondary, or tertiary isotope effect).

[0040] The compounds of the present invention can form solvates with solvents, including water. Therefore, in a non-limiting embodiment, the present invention includes the solvated form of the compounds. 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 are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvents according to the present invention include those in which the solvent can be isotopically substituted, such as D₂O, d₆-acetone, and d₆-DMSO. Solvates can be in liquid or solid form.

[0041] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -(C=O)NH2 is connected to the carbon atom of a ketone (C=O) group.

[0042] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In some embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein indicate that each member having the described range is an alkyl group of a separate kind. For example, the term C1-C6 alkyl as used herein refers to a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and means that each of these is described as a separate kind. For example, the term C1-C4 alkyl as used herein refers to a straight-chain or branched alkyl group having 1, 2, 3, or 4 carbon atoms, and means that each of these is described as a separate kind. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0043] "Alkenyl" is a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may appear at stable points along the chain. The specified ranges used herein indicate each member having a described range as a separate class of alkenyl, as described above with respect to the alkyl portion. In one non-limiting embodiment, the alkenyl comprises 2 to about 12 carbon atoms, more typically 2 to about 6 or 2 to about 4 carbon atoms. In some embodiments, the alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkenyl include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" is also used with "cis" and "trans" alkenyl geometries, or alternatively, " E "and" Z "Alkenyl geometry is achieved. The term "alkenyl" also includes cycloalkyl or carbocyclic groups having at least one unsaturation point."

[0044] "Alynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can appear at any stable point on the chain. The specified ranges used herein indicate that each member having the described range is an alkynyl group as a separate class, as described above with respect to the alkyl portion. In one non-limiting embodiment, the alkynyl group comprises 2 to about 12 carbon atoms, more typically 2 to about 6 or 2 to about 4 carbon atoms. In some embodiments, the alkynyl group is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkynyl groups 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.

[0045] "Halogen" and "halogen" refer independently to fluorine, chlorine, bromine, or iodine.

[0046] "Haloalkyl" is a branched or straight-chain alkyl group that is substituted with one or more of the aforementioned halogen atoms (up to the maximum permissible 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. "Hyperhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0047] As used herein, “aryl” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., with 6, 10, or 14 π electrons in the ring array) having 6-14 ring atoms and zero heteroatoms in the aromatic ring system (“C”). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring atoms (“C6 aryl”; for example, aryl group). ， Phenyl). In some embodiments, the aryl group has 10 cyclic carbon atoms (“C10”). 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, anthracene. "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or connecting point is on the aryl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4 to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0048] “Arylalkyl” refers to an alkyl group defined herein that is substituted with an aryl group as defined herein, or an aryl group defined herein that is substituted with an alkyl group as defined herein.

[0049] The term "heterocyclic" refers to a saturated or partially saturated heteroatom-containing cyclic group having one, two, three, or four heteroatoms independently selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocyclic groups can include monocyclic 3- to 10-membered rings and 5- to 16-membered bicyclic systems (which can include bridged, fused, and spirofused bicyclic systems). It does not include rings containing -OO-, -OS-, or -SS- motifs. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1-4 nitrogen atoms [e.g., pyrrolyl, imidazolyl, piperidinyl, pyrrololinyl, piperazinel]; saturated 3- to 6-membered heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms [e.g., thiazolyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothiophene, dihydropyrano, dihydrofurano, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolyl, imidazolyl, piperidinyl, pyrrololino, pyrazolyl, piperazinyl, morpholino, tetrahydropyrano, thiazolyl, dihydrothiophene, 2,3-dihydro-benzo[1,4]dioxyl, indololino, isoindolino, dihydrobenzothiophene, dihydrobenzofurano, isochromyl, chromanyl, 1,2-dihydroquinolino, 1,2,3,4-tetrahydro-isoquinolino, 1,2,3,4-tetrahydro-quinolino, 2,3,4,4a,9,9a-hexahydro-l H -3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-] a Isoquinolinyl, 3,4-dihydro-2 H -Benzo[l,4]oxazinyl, benzo[1,4]dioxyl, 2,3-dihydro-1H-1λ'-benzo[ d Isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl.

[0050] "Heterocycle" also includes groups in which a heterocyclic group is fused / condensed with an aryl or carbocyclic group, wherein the linking point is a heterocycle. "Heterocycle" also includes groups in which a heterocyclic group is replaced by an oxo group (i.e., Examples include partially unsaturated fused heterocyclic groups containing 1-5 nitrogen atoms, such as dihydroindole or isodihydroindole; partially unsaturated fused heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms; partially unsaturated fused heterocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms; and saturated fused heterocyclic groups containing 1-2 oxygen or sulfur atoms.

[0051] The term "heterocycle" also includes "bicyclic heterocycle." The term "bicyclic heterocycle" refers to a heterocycle as defined herein, having a bridging, fused, or spirocyclic moiety having one heterocycle. The bridging, fused, or spirocyclic moiety of the heterocycle can be a carbocyclic, heterocyclic, or aryl group, provided that a stable molecule is obtained. Unless the context excludes, the term "heterocycle" includes bicyclic heterocycles. Bicyclic heterocycles include groups in which the fused heterocycle is substituted with an oxo group. Non-limiting examples of bicyclic heterocycles include: , , , , , , , , , and .

[0052] "Heterocyclic alkyl" refers to an alkyl group defined herein that is substituted with a heterocyclic group as defined herein, or a heterocyclic group defined herein that is substituted with an alkyl group as defined herein.

[0053] The term "heteroaryl" refers to a stable aromatic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrroloyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4...]. H -1,2,4-triazolyl, 1 H -1,2,3-triazolyl, 2 H [-1,2,3-triazolyl]; unsaturated 5- to 6-membered heterocyclic groups containing oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc.; unsaturated 5- to 6-membered heterocyclic groups containing sulfur atoms, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5- to 6-membered heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. In some embodiments, the "heteroaryl" is an 8, 9, or 10-membered bicyclic system. Examples of 8, 9, or 10-membered bicyclic heteroaryl groups include benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazoleyl, and benzotriazolyl.

[0054] "Heteroarylalkyl" refers to an alkyl group defined herein that is substituted with a heteroaryl group as defined herein, or a heteroaryl group defined herein that is substituted with an alkyl group as defined herein.

[0055] As used herein, “carbocyclic,” “carbocyclic,” or “cycloalkyl” includes saturated or partially unsaturated (i.e., non-aromatic) groups that, in a non-aromatic ring system, contain all carbon ring atoms and 3–14 ring carbon atoms (“C…”). 3-14 The cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”) and zero heteroatoms. In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3-10 cycloalkyl group”). In some embodiments, the cycloalkyl group has 3 to 9 cyclic carbon atoms (“C10”). 3-9 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C”). 3-7 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms (“C”). 4-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5-6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5-10 cyclic carbon atoms (“C”). 5-10 Cycloalkyl). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example C... 3-8 Cycloalkyl groups include, but are not limited to, the aforementioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. An example C 3-10 Cycloalkyl groups include, but are not limited to, the aforementioned C 3-8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group may be saturated or may contain one or more carbon-carbon double bonds. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring as defined above is fused with a heterocyclic, aryl, or heteroaryl ring, wherein the bonding point is on the cycloalkyl ring, and in these cases, the number of carbons continues to represent the number of carbons in the carbocyclic system. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring as defined above has a spirocyclic heterocyclic, aryl, or heteroaryl ring, wherein the bonding point is on the cycloalkyl ring, and in these cases, the number of carbons continues to represent the number of carbons in the carbocyclic system. The term "cycloalkyl" also includes fused, bridged, or spirocyclic systems of bicyclic or polycyclic rings containing 5-14 carbon atoms and zero heteroatoms in a non-aromatic ring system. Representative examples of "cycloalkyl" include, but are not limited to, those containing, a saturated cycloalkyl ring. , , , , and .

[0056] The term "ring" refers to a ring system in which two rings are fused together, and each ring is independently selected from carbocyclic, heterocyclic, aryl, and heteroaryl rings. Non-limiting examples of bicyclic groups include: , , , , , , and .

[0057] When the term "bicyclic" is used for a divalent residue, the linkage site can be on a separate ring or on the same ring. In some embodiments, the two linkage sites are located on the same ring. In some embodiments, the two linkage sites are located on different rings. Non-limiting examples of divalent bicyclic groups include: , , , , and .

[0058] "Aliphatic group" refers to a saturated or unsaturated, straight-chain, branched, or cyclic hydrocarbon. "Aliphatic group" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and therefore encompasses each of these definitions. In some embodiments, "aliphatic" is used to refer to aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be cis or trans configurations. In some embodiments, the aliphatic group comprises 1 to about 12 carbon atoms, more typically 1 to about 6 or 1 to about 4 carbon atoms. In some embodiments, the aliphatic group comprises 1 to about 8 carbon atoms. In some embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specific scope used herein refers to aliphatic groups having members within the stated scope as a separate class. For example, the term "C1-C6 aliphatic group" as used herein refers to a straight-chain or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to indicate that each of these is described as a separate species. Similarly, the term "C1-C4 aliphatic group" as used herein refers to a straight-chain or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, or 4 carbon atoms, and is intended to indicate that each of these is described as a separate species. In some embodiments, the aliphatic group is substituted with one or more functional groups, resulting in the formation of a stable moiety.

[0059] The term "heteroaliphatic group" refers to an aliphatic moiety containing at least one heteroatom in the chain, such as an amine, carbonyl, carboxyl, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atom replacing a carbon atom. In some embodiments, the only heteroatom is nitrogen. In some embodiments, the only heteroatom is oxygen. In some embodiments, the only heteroatom is sulfur. "Heteroaliphatic group" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloynyl moieties. In some embodiments, "heteroaliphatic group" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-20 carbon atoms. In some embodiments, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of the heteroaliphatic portion are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolic acid, thioether, ether, alkyl-heterocyclic-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0060] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, pellets, creams, ointments, suppositories, inhalable forms, transdermal forms, oral, sublingual, topical, gels, and mucosal dosage forms. "Dosage form" can also include implants, such as ophthalmic implants.

[0061] As used in this article, “endogenous” means any substance that originates from or is produced within an organism, cell, tissue, or system.

[0062] As used herein, the term “exogenous” means any substance introduced from or produced outside of an organism, cell, tissue, or system.

[0063] As used herein, the term "modulation" refers to a detectable increase or decrease in response levels in a subject compared to their response levels in the absence of treatment or the compound and / or to their response levels in other subjects who are otherwise identical but untreated. This term includes disrupting and / or influencing natural signals or responses, thereby mediating a beneficial therapeutic response in the subject, preferably in the individual.

[0064] "Parenteral" administration of compounds includes techniques such as subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection, or infusion.

[0065] As used herein, a “pharmaceutical composition” is a composition comprising at least one active agent (such as the selected active compounds described herein) and at least one other substance (such as a carrier). A “pharmaceutical combination” is a combination of at least two active agents that may be supplied together in a single dosage form or in separate dosage forms, and includes instructions for using the active agents together to treat any of the disorders described herein.

[0066] As used herein, a "pharmaceutically acceptable salt" is a derivative of the disclosed compounds, wherein the parent compound is modified by preparing a biologically acceptable, non-toxic inorganic or organic, acid or base addition salt. Salts of the compounds of the present invention can be synthesized by conventional chemical methods from a parent compound containing a basic or acidic moiety. Typically, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. Typically, where feasible, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical. Salts of the compounds of the present invention further comprise the compound and a solvate of the compound salt.

[0067] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and bases or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, 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, aminosulfonic acid, phosphoric acid, nitric acid, etc.); and from organic acids (such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, ethanesulfonic acid, besylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, HOOC-(CH2)). 1-4 -COOH (where n is 0-4), or salts prepared using different acids that produce the same counterion. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., page 1418 (1985).

[0068] The term "carrier" refers to a diluent, excipient, or medium in which an active agent is used or delivered.

[0069] "Pharmaceutically acceptable excipients" refers to excipients that can be used to prepare pharmaceutical compositions / combinations, are generally safe, and are not biologically or otherwise unsuitable for administration to a host, typically human. In some embodiments, veterinary-acceptable excipients are used.

[0070] "Patient," "host," or "subject" refers to a human or non-human animal that requires treatment for any disorder specifically described herein. Typically, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0071] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention refers to the amount that effectively provides therapeutic benefits, such as improvement of symptoms or reduction or alleviation of the disease itself, when administered to a host.

[0072] In some embodiments, a "prodrug" is a form of the parent molecule that is metabolized or chemically converted into the parent molecule in vivo (e.g., in mammals or humans). Non-limiting examples of prodrugs include esters, amides (e.g., derived from primary or secondary amines), carbonates, carbamates, phosphate esters, ketals, imines, oxazolidinyl ethers, and thiazolidinyl ethers. Prodrugs may be programmed to release the parent molecule upon a change in pH (e.g., in the stomach or intestine) or upon the action of an enzyme (e.g., an esterase or amidase).

[0073] In some embodiments, "stable" means that less than 10%, 5%, 3%, or 1% of the compound degrades under ambient conditions, with a shelf life of at least 3, 4, 5, or 6 months. In some embodiments, the compound stored under ambient conditions is stored at approximately room temperature and exposed to air and relative humidity below approximately 40%, 50%, 60%, or 70%. In some embodiments, the compound stored under ambient conditions is stored under an inert gas (e.g., argon or nitrogen) at approximately room temperature. Generally, the moiety described herein does not have more than one or two heteroatoms directly bonded to each other, unless the moiety is heteroaromatic.

[0074] In this disclosure, various aspects of the invention may be presented in the form of scope. It should be understood that the description in the form of scope is for convenience only and should not be construed as limiting the scope of the invention. The description of scope should be regarded as having explicitly disclosed all possible sub-ranges within that range as well as individual numerical values. For example, the description of a range (e.g., 1 to 6) should be regarded as having specifically disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of how broad the scope may be.

[0075] II. Compounds of the present invention In some embodiments, the compound of formula (I) is selected from formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), and (In): (Ia) (Ib) (Ic) (Id) (Ie) (If) (Ig) (Ih) (Ii) (Ij) (Ik) (Il) (Im) and (In); Or its pharmaceutically acceptable salt.

[0076] In some embodiments, the compound of formula (II) is selected from formulas (IIa), (IIb), (IIc), (IId), (IIe), and (IIIf): (IIa) (IIb) (IIc) (IId) (IIe) and (IIf); Or its pharmaceutically acceptable salt.

[0077] In some embodiments, the compound of formula (III) is selected from formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), (IIIl), (IIIm), and (IIIn): (IIIa) (IIIb) (IIIc) (IIId) (IIIe) (IIIf) (IIIg) (IIIh) (IIIi) (IIIj) (IIIk) (IIIl) (IIIm) and (IIIn), Or its pharmaceutically acceptable salt.

[0078] In some embodiments, the compound of formula (IV) is selected from formulas (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVVi), (IVj), (IVk), (IVl), (IVm), and (IVn): (IVa) (IVb) (IVc) (IVd) (IVe) (IVf) (IVg) (IVh) (IVi) (IVj) (IVk) (IVl) (IVm) and (IVn); Or its pharmaceutically acceptable salt.

[0079] In some embodiments, the compound of formula (V) is selected from formulas (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), and (Vn): (Va) (Vb) (Vc) (Vd) (Ve) (Vf) (Vg) (Vh) (Vi) (Vj) (Vk) (Vl) (Vm) and (Vn); Or its pharmaceutically acceptable salt.

[0080] In some embodiments, the compound of formula (VI) is selected from formulas (VIa), (VIb), (VIc), (VId), (VIIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), and (VIn): (VIa) (VIb) (VIc) (VId) (VIf) (VIg) (VIh) (VIi) (VIj) (VIk) (VIl) (VIm) and (VIn); Or its pharmaceutically acceptable salt.

[0081] In some embodiments, the compound of formula (VII) is selected from formulas (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIg), (VIIh), (VIIi), (VIIj), (VIIk), (VIIl), (VIIm), and (VIIn): (VIIa) (VIIb) (VIIc) (VIId) (VIIe) (VIIf) (VIIg) (VIIh) (VIIi) (VIIj) (VIIk) (VIIl) (VIIm) and (VIIn); Or its pharmaceutically acceptable salt.

[0082] In some embodiments, the compound of formula (VIII) is selected from formulas (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj), (VIIIk), (VIIIl), (VIIIm), and (VIIIn): (VIIIa) (VIIIb) (VIIIc) (VIIId) (VIIIe) (VIIIf) (VIIIg) (VIIIh) (VIIIi) (VIIIj) (VIIIk) (VIIIl) (VIIIm) and (VIIIn); Or its pharmaceutically acceptable salt.

[0083] In some embodiments, the compound of formula (IX) is selected from formulas (IXa), (IXb), (IXc), (IXd), (IXe), (IXf), (IXg), (IXh), (IXi), (IXj), (IXk), (IXl), (IXm), and (IXn): (IXa) (IXb) (IXc) (IXd) (IXe) (IXf) (IXg) (IXh) (IXi) (IXj) (IXk) (IXl) (IXm) and (IXn); Or its pharmaceutically acceptable salt.

[0084] In some embodiments, the compound of formula (X) is selected from formulas (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), (Xg), (Xh), (Xi), (Xj), (Xk), (Xl), (Xm), and (Xn): (Xa) (Xb) (Xc) (Xd) (Xe) (Xf) (Xg) (Xh) (Xi) (Xj) (Xk) (Xl) (Xm) and (Xn); Or its pharmaceutically acceptable salt.

[0085] In some embodiments, the compound of formula (XI) is selected from formulas (XIa), (XIb), (XIc), (XId), (XIe), (XIIf), (XIg), (XIh), (XIi), (XIj), (XIl), (XIm), and (XIin): (XIa) (XIb) (XIc) (XId) (XIe) (XIf) (XIg) (XIh) (XIi) (XIj) (XIl) (XIm) and (XIn); Or its pharmaceutically acceptable salt.

[0086] In some embodiments, the compound of formula (XII) is selected from formulas (XIIa), (XIIb), (XIIc), (XIId), (XIIe), (XIIIf), (XIIg), (XIIh), (XIIi), (XIIj), (XIIk), (XIIl), (XIIm), and (XIIIn): (XIIa) (XIIb) (XIIc) (XIId) (XIIe) (XIIf) (XIIg) (XIIh) (XIIi) (XIIj) (XIIk) (XIIl) (XIIm) and (XIIn); Or its pharmaceutically acceptable salt.

[0087] In some embodiments, the compound of formula (XIII) is selected from formulas (XIIIa), (XIIIb), (XIIIc), (XIIId), (XIIIe), (XIIIf), (XIIIg), (XIIIh), (XIIIi), (XIIIj), (XIIIk), (XIIIl), (XIIIm), and (XIIIn): (XIIIa) (XIIIb) (XIIIc) (XIIId) (XIIIe) (XIIIf) (XIIIg) (XIIIh) (XIIIi) (XIIIj) (XIIIk) (XIIIl) (XIIIm) and (XIIIn); Or its pharmaceutically acceptable salt.

[0088] In some embodiments, the compound of formula (XIV) is selected from formulas (XIVa), (XIVb), (XIVc), (XIVd), (XIVe), (XIVf), (XIVg), (XIVh), (XIVVi), (XIVj), (XIVk), (XIVl), (XIVm), and (XIVn): (XIVa) (XIVb) (XIVc) (XIVd) (XIVe) (XIVf) (XIVg) (XIVh) (XIVi) (XIVj) (XIVk) (XIVl) (XIVm) and (XIVn); Or its pharmaceutically acceptable salt.

[0089] In some embodiments, the compound of formula (XVII) is selected from formulas (XVIIa), (XVIIb), (XVIIc), (XVIId), (XVIIe), (XVIIf), (XVIIg), (XVIIh), (XVIIi), (XVIIj), (XVIIk), (XVIIl), (XVIIm), and (XVIIn): (XVIIa) (XVIIb) (XVIIc) (XVIId) (XVIIe) (XVIIf) (XVIIg) (XVIIh) (XVIIi) (XVIIj) (XVIIk) (XVIIl) (XVIIm) and (XVIIn); Or its pharmaceutically acceptable salt.

[0090] Non-limiting examples of compounds of formula I include: and .

[0091] Non-limiting examples of compounds of formula II include: and .

[0092] Non-limiting examples of compounds of formula III include: and .

[0093] Non-limiting examples of compounds of formula IV include: and .

[0094] Non-limiting examples of compounds of formula V include: and .

[0095] Non-limiting examples of compounds of formula VI include: and .

[0096] Non-limiting examples of compounds of formula VII include: and .

[0097] Non-limiting examples of compounds of formula VIII include: and .

[0098] Non-limiting examples of compounds of formula IX include: and .

[0099] Non-limiting examples of compounds of formula X include: and .

[0100] Non-limiting examples of compounds of formula XI include: and .

[0101] Non-limiting examples of compounds of formula XII include: and .

[0102] Non-limiting examples of compounds of formula XIII include: and .

[0103] Non-limiting examples of compounds of formula XIV include: and .

[0104] Non-limiting examples of compounds of formula XV include: .

[0105] Other non-limiting examples of compounds of formula XV include: .

[0106] Other non-limiting examples of compounds of formula XV include: and .

[0107] Other non-limiting examples of compounds of formula XV include: and .

[0108] Non-limiting examples of compounds of formula XVI include: and .

[0109] Other non-limiting examples of compounds of formula XVI include: Where m is an integer selected from 0, 1, 2, 3, 4 or 5.

[0110] Other non-limiting examples of compounds of formula XVI include: Where m is an integer selected from 0, 1, 2, 3, 4 or 5.

[0111] Other non-limiting examples of compounds of formula XVII include: .

[0112] Non-limiting examples of compounds of formula XVII include: .

[0113] In the structure described herein, hydroxyl groups (e.g., R) 1 or R 2 The group () is located on a heteroaryl ring carbon adjacent to nitrogen. Unless otherwise stated in this specification, only one tautomer is shown as a shorthand for individually referring to each individual tautomer or mixture thereof, and each individual tautomer or mixture thereof is incorporated herein as if it were individually referred to herein. This is demonstrated by the following non-limiting examples: It includes and Both.

[0114] When a bond is depicted in brackets, it indicates that the bond can be located anywhere permitted by valence and stability. As a non-limiting example illustrating the meaning of brackets, the following parenthesized compounds... Independently include and , As if drawn separately.

[0115] Non-limiting examples of compounds of the present invention include: R 1 and R 2 Implementation plan: In some implementations, R 1 It is hydrogen.

[0116] In some implementations, R 1 It is an alkyl group.

[0117] In some implementations, R 1 It is halogen.

[0118] In some implementations, R 1 It is a haloalkyl group.

[0119] In some implementations, R 1 Yes - OR 10 .

[0120] In some implementations, R 1 It is -SR 10 .

[0121] In some implementations, R 1 It is -S(O)R 12 .

[0122] In some implementations, R 1 Yes - SO2R 12 .

[0123] In some implementations, R 1 Yes -NR 10R 11 .

[0124] In some implementations, R 1 It is a cyano group.

[0125] In some implementations, R 1 It is a nitro group.

[0126] In some implementations, R 1 It is a heteroaryl group.

[0127] In some implementations, R 1 It is an aryl group.

[0128] In some implementations, R 1 It is a heterocyclic ring.

[0129] In some implementations, R 2 It is hydrogen.

[0130] In some implementations, R 2 It is an alkyl group.

[0131] In some implementations, R 2 It is halogen.

[0132] In some implementations, R 2 It is a haloalkyl group.

[0133] In some implementations, R 2 Yes - OR 10 .

[0134] In some implementations, R 2 It is -SR 10 .

[0135] In some implementations, R 2 It is -S(O)R 12 .

[0136] In some implementations, R 2 Yes - SO2R 12 .

[0137] In some implementations, R 2 Yes -NR 10 R 11 .

[0138] In some implementations, R 2 It is a cyano group.

[0139] In some implementations, R 2 It is a nitro group.

[0140] In some implementations, R 2It is a heteroaryl group.

[0141] In some implementations, R 2 It is an aryl group.

[0142] In some implementations, R 2 It is a heterocyclic ring.

[0143] R 1 Non-restrictive implementation scheme: In some implementations, R 1 'It is an alkyl group.'

[0144] In some implementations, R 1 It is halogen In some implementations, R 1 'It is a haloalkyl group.

[0145] In some implementations, R 1 'is-OR 10 .

[0146] In some implementations, R 1 'Is -SR 10 .

[0147] In some implementations, R 1 'is-S(O)R 12 .

[0148] In some implementations, R 1 'is-SO2R 12 .

[0149] In some implementations, R 1 'is-NR 10 R 11 .

[0150] In some implementations, R 1 It is a cyano group.

[0151] In some implementations, R 1 It is nitro In some implementations, R 1 It is a heteroaryl group.

[0152] In some implementations, R 1 It is an aryl group.

[0153] In some implementations, R 1 It is a cycloalkyl group.

[0154] In some implementations, R 1 It is a heterocyclic ring.

[0155] R3a Non-restrictive implementation scheme: In some implementations, R 3a It is hydrogen In some implementations, R 3a It is an alkyl group In some implementations, R 3a It's fluorine.

[0156] In some implementations, R 3a It is bromine.

[0157] In some implementations, R 3a It is chlorine.

[0158] In some implementations, R 3a It's iodine.

[0159] In some implementations, R 3a It is a haloalkyl group.

[0160] In some implementations, R 3a It is a fluoroalkyl group.

[0161] In some implementations, R 3a It is a chloroalkyl group.

[0162] In some implementations, R 3a It is a brominated alkyl group.

[0163] In some implementations, R 3a It is an iodoalkyl group.

[0164] R 3 Non-restrictive implementation scheme: In some implementations, R 3 Selected from hydrogen and halogens.

[0165] In some implementations, R 3 Selected from alkyl and haloalkyl groups.

[0166] In some implementations, R 3 It is hydrogen.

[0167] In some implementations, R 3 It is halogen.

[0168] In some implementations, R 3 It is an alkyl group.

[0169] In some implementations, R 3 It is a haloalkyl group.

[0170] In some implementations, R 3 It's fluorine.

[0171] In some implementations, R 3 It is chlorine.

[0172] In some implementations, R 3 It is bromine.

[0173] In some implementations, R 3 It's iodine.

[0174] In some implementations, R 3 It is a methyl group.

[0175] In some implementations, R 3 It is an ethyl group.

[0176] In some implementations, R 3 It is trifluoromethyl.

[0177] In some implementations, R 3 It is pentafluoroethyl.

[0178] In some implementations, R 3 It is difluoromethyl.

[0179] In some implementations, R 3 It is a fluoromethyl group.

[0180] In some implementations, R 3 With R 4 Groups combine to form a 1-carbon link.

[0181] In some implementations, R 3 With R 4 Groups combine to form 2-carbon linkages.

[0182] In some implementations, R 3 With R 4 Groups combine to form 3-carbon linkages.

[0183] In some implementations, R 3 With R 4 Groups combine to form 4-carbon linkages.

[0184] In some implementations, R 3 With R 4 Groups combine to form double bonds.

[0185] R 4 Non-restrictive implementation scheme: In some implementations, R 4 Selected from hydrogen and halogens.

[0186] In some implementations, R 4 Selected from alkyl and haloalkyl groups.

[0187] In some implementations, R 4 It is hydrogen.

[0188] In some implementations, R 4 It is halogen.

[0189] In some implementations, R 4 It is an alkyl group.

[0190] In some implementations, R 4 It is a haloalkyl group.

[0191] In some implementations, R 3 It's fluorine.

[0192] In some implementations, R 3 It is chlorine.

[0193] In some implementations, R 3 It is bromine.

[0194] In some implementations, R 3 It's iodine.

[0195] In some implementations, R 4 It is a methyl group.

[0196] In some implementations, R 4 It is an ethyl group.

[0197] In some implementations, R 4 It is trifluoromethyl.

[0198] In some implementations, R 4 It is pentafluoroethyl.

[0199] In some implementations, R 4 It is difluoromethyl.

[0200] In some implementations, R 4 It is a fluoromethyl group.

[0201] In some implementations, R 4 With R 3 Groups combine to form a 1-carbon link.

[0202] In some implementations, R 4 With R 3 Groups combine to form 2-carbon linkages.

[0203] In some implementations, R 4 With R 3 Groups combine to form 3-carbon linkages.

[0204] In some implementations, R 4 With R 3 Groups combine to form 4-carbon linkages.

[0205] In some implementations, R 4 With R 3 Groups combine to form double bonds.

[0206] R 4a Non-restrictive implementation scheme: In some implementations, R 4a It is hydrogen In some implementations, R 4a It is an alkyl group In some implementations, R 4a It's fluorine.

[0207] In some implementations, R 4a It is bromine.

[0208] In some implementations, R 4a It is chlorine.

[0209] In some implementations, R 4a It's iodine.

[0210] In some implementations, R 4a It is a haloalkyl group.

[0211] In some implementations, R 4a It is a fluoroalkyl group.

[0212] In some implementations, R 4a It is a chloroalkyl group.

[0213] In some implementations, R 4a It is a brominated alkyl group.

[0214] In some implementations, R 4a It is an iodoalkyl group.

[0215] R 5 Non-restrictive implementation scheme: In some implementations, R 5 Selected from hydrogen and halogens.

[0216] In some implementations, R 5 Selected from alkyl and haloalkyl groups.

[0217] In some implementations, R 5 It is hydrogen.

[0218] In some implementations, R 5 It is halogen.

[0219] In some implementations, R 5 It is an alkyl group.

[0220] In some implementations, R 5 It is a haloalkyl group.

[0221] In some implementations, R 3 It's fluorine.

[0222] In some implementations, R 3 It is chlorine.

[0223] In some implementations, R 3 It is bromine.

[0224] In some implementations, R 3 It's iodine.

[0225] In some implementations, R 5 It is a methyl group.

[0226] In some implementations, R 5 It is an ethyl group.

[0227] In some implementations, R 5 It is trifluoromethyl.

[0228] In some implementations, R 5 It is pentafluoroethyl.

[0229] In some implementations, R 5 It is difluoromethyl.

[0230] In some implementations, R 5 It is a fluoromethyl group.

[0231] R 6 and R 7 Non-restrictive implementation scheme: In some implementations, R 6 It is halogen.

[0232] In some implementations, R 6 It is an alkyl group.

[0233] In some implementations, R 6 It is a haloalkyl group.

[0234] In some implementations, R 6 It's fluorine.

[0235] In some implementations, R 6 It is chlorine.

[0236] In some implementations, R 6 It is bromine.

[0237] In some implementations, R 6 It's iodine.

[0238] In some implementations, R 6 It is a methyl group.

[0239] In some implementations, R 6 It is an ethyl group.

[0240] In some implementations, R 6 It is trifluoromethyl.

[0241] In some implementations, R 6 It is pentafluoroethyl.

[0242] In some implementations, R 6 It is difluoromethyl.

[0243] In some implementations, R 6 It is a fluoromethyl group.

[0244] In some implementations, R 6 Yes - OR 10 .

[0245] In some implementations, R 6 It is -SR 10 .

[0246] In some implementations, R 6 It is -S(O)R 12 .

[0247] In some implementations, R 6 Yes - SO2R 12 .

[0248] In some implementations, R 6 Yes -NR 10 R 11 .

[0249] In some implementations, R 6 It is pentafluoroethyl.

[0250] In some implementations, R 6 It is difluoromethyl.

[0251] In some implementations, R 6 It is a fluoromethyl group.

[0252] In some implementations, R 6 With R 7 A 3-membered spiral ring is formed.

[0253] In some implementations, R6 With R 7 A 4-membered spiral ring is formed.

[0254] In some implementations, R 6 With R 3 A 4-membered spiral ring is formed.

[0255] In some implementations, R 6 With R 3 A 5-membered spiral ring is formed.

[0256] In some implementations, R 7 It is halogen.

[0257] In some implementations, R 7 It is an alkyl group.

[0258] In some implementations, R 7 It is a haloalkyl group.

[0259] In some implementations, R 7 It's fluorine.

[0260] In some implementations, R 7 It is chlorine.

[0261] In some implementations, R 7 It is bromine.

[0262] In some implementations, R 7 It's iodine.

[0263] In some implementations, R 7 It is a methyl group.

[0264] In some implementations, R 7 It is an ethyl group.

[0265] In some implementations, R 7 It is trifluoromethyl.

[0266] In some implementations, R 7 It is pentafluoroethyl.

[0267] In some implementations, R 7 It is difluoromethyl.

[0268] In some implementations, R 7 It is a fluoromethyl group.

[0269] In some implementations, R 7 Yes - OR 10 .

[0270] In some implementations, R 7 It is -SR 10.

[0271] In some implementations, R 7 It is -S(O)R 12 .

[0272] In some implementations, R 7 Yes - SO2R 12 .

[0273] In some implementations, R 7 Yes -NR 10 R 11 .

[0274] In some implementations, R 7 It is pentafluoroethyl.

[0275] In some implementations, R 7 It is difluoromethyl.

[0276] In some implementations, R 7 It is a fluoromethyl group.

[0277] In some implementations, R 7 With R 6 A 3-membered spiral ring is formed.

[0278] In some implementations, R 7 With R 6 A 4-membered spiral ring is formed.

[0279] R 6a and R 7a Non-restrictive implementation scheme: In some implementations, R 6a It is halogen.

[0280] In some implementations, R 6a It is an alkyl group.

[0281] In some implementations, R 6a It is a haloalkyl group.

[0282] In some implementations, R 6a It's fluorine.

[0283] In some implementations, R 6a It is chlorine.

[0284] In some implementations, R 6a It is bromine.

[0285] In some implementations, R 6a It's iodine.

[0286] In some implementations, R 6a It is a methyl group.

[0287] In some implementations, R 6a It is an ethyl group.

[0288] In some implementations, R 6a It is trifluoromethyl.

[0289] In some implementations, R 6a It is pentafluoroethyl.

[0290] In some implementations, R 6a It is difluoromethyl.

[0291] In some implementations, R 6a It is a fluoromethyl group.

[0292] In some implementations, R 6a Yes - OR 10 .

[0293] In some implementations, R 6a It is -SR 10 .

[0294] In some implementations, R 6a It is -S(O)R 12 .

[0295] In some implementations, R 6a Yes - SO2R 12 .

[0296] In some implementations, R 6a Yes -NR 10 R 11 .

[0297] In some implementations, R 6a It is pentafluoroethyl.

[0298] In some implementations, R 6a It is difluoromethyl.

[0299] In some implementations, R 6a It is a fluoromethyl group.

[0300] In some implementations, R 6a With R 7a A 3-membered spiral ring is formed.

[0301] In some implementations, R 6a With R 7a A 4-membered spiral ring is formed.

[0302] In some implementations, R 6a With R 7a A 4-membered spiral ring is formed.

[0303] In some implementations, R 6a With R 7a A 5-membered spiral ring is formed.

[0304] In some implementations, R 7a It is halogen.

[0305] In some implementations, R 7a It is an alkyl group.

[0306] In some implementations, R 7a It is a haloalkyl group.

[0307] In some implementations, R 7a It's fluorine.

[0308] In some implementations, R 7a It is chlorine.

[0309] In some implementations, R 7a It is bromine.

[0310] In some implementations, R 7a It's iodine.

[0311] In some implementations, R 7a It is a methyl group.

[0312] In some implementations, R 7a It is an ethyl group.

[0313] In some implementations, R 7a It is trifluoromethyl.

[0314] In some implementations, R 7a It is pentafluoroethyl.

[0315] In some implementations, R 7a It is difluoromethyl.

[0316] In some implementations, R 7a It is a fluoromethyl group.

[0317] In some implementations, R 7a Yes - OR 10 .

[0318] In some implementations, R 7a It is -SR 10 .

[0319] In some implementations, R 7a It is -S(O)R 12 .

[0320] In some implementations, R 7a Yes - SO2R 12 .

[0321] In some implementations, R 7a Yes -NR 10 R 11 .

[0322] In some implementations, R 7a It is pentafluoroethyl.

[0323] In some implementations, R 7a It is difluoromethyl.

[0324] In some implementations, R 7a It is a fluoromethyl group.

[0325] In some implementations, R 7a With R 6a A 3-membered spiral ring is formed.

[0326] In some implementations, R 7a With R 6a A 4-membered spiral ring is formed.

[0327] In some implementations, R 7a With R 6a A 5-membered spiral ring is formed.

[0328] R 10 and R 11 Non-restrictive implementation scheme: In some implementations, R 10 It is hydrogen.

[0329] In some implementations, R 10 It is an alkyl group.

[0330] In some implementations, R 10 It is a heterocyclic ring.

[0331] In some implementations, R 10 It is a haloalkyl group.

[0332] In some implementations, R 10 It is an aryl group.

[0333] In some implementations, R 10 It is a heteroaryl group.

[0334] In some implementations, R 10 It is -C(O)R 12 .

[0335] In some implementations, R 10 It is -S(O)R12 .

[0336] In some implementations, R 10 Yes - SO2R 12 .

[0337] In some implementations, R 11 It is hydrogen.

[0338] In some implementations, R 11 It is an alkyl group.

[0339] In some implementations, R 11 It is a heterocyclic ring.

[0340] In some implementations, R 11 It is a haloalkyl group.

[0341] In some implementations, R 11 It is an aryl group.

[0342] In some implementations, R 11 It is a heteroaryl group.

[0343] In some implementations, R 11 It is -C(O)R 12 .

[0344] In some implementations, R 11 It is -S(O)R 12 .

[0345] In some implementations, R 11 Yes - SO2R 12 .

[0346] R 12 Non-restrictive implementation scheme: In some implementations, R 12 It is hydrogen.

[0347] In some implementations, R 12 It is an alkyl group.

[0348] In some implementations, R 12 It is a heterocyclic ring.

[0349] In some implementations, R 12 It is a haloalkyl group.

[0350] In some implementations, R 12 It is an aryl group.

[0351] In some implementations, R 12 It is a heteroaryl group.

[0352] In some implementations, R 12 Yes -NR 13 R 14 .

[0353] In some implementations, R 12 OR 13 .

[0354] R 13 and R 14 Non-restrictive implementation scheme: In some implementations, R 13 It is hydrogen.

[0355] In some implementations, R 13 It is an alkyl group.

[0356] In some implementations, R 13 It is a fluoroalkyl group.

[0357] In some implementations, R 13 It is a chloroalkyl In some implementations, R 13 It is a brominated alkyl group.

[0358] In some implementations, R 13 It is a haloalkyl group.

[0359] In some implementations, R 13 It is hydrogen and R 14 It is hydrogen.

[0360] In some implementations, R 13 It is hydrogen and R 14 It is an alkyl group.

[0361] In some implementations, R 13 It is hydrogen and R 14 It is a fluoroalkyl group.

[0362] In some implementations, R 13 It is hydrogen and R 14 It is a brominated alkyl group.

[0363] In some implementations, R 13 It is hydrogen and R 14 It is a chloroalkyl group.

[0364] In some implementations, R 13 It is alkyl and R 14 It is hydrogen.

[0365] In some implementations, R 13 It is alkyl and R 14 It is an alkyl group.

[0366] In some implementations, R 13 It is alkyl and R 14 It is a fluoroalkyl group.

[0367] In some implementations, R 13 It is alkyl and R 14 It is a brominated alkyl group.

[0368] In some implementations, R 13 It is alkyl and R 14 It is a chloroalkyl group.

[0369] In some implementations, R 13 It is a haloalkyl and R 14 It is a haloalkyl group.

[0370] In some implementations, R 13 It is alkyl and R 14 It is an alkyl group.

[0371] In some implementations, R 14 It is hydrogen.

[0372] In some implementations, R 14 It is an alkyl group.

[0373] In some implementations, R 14 It is a haloalkyl group.

[0374] In some implementations, R 14 It is a fluoroalkyl group.

[0375] In some implementations, R 14 It is a chloroalkyl group.

[0376] In some implementations, R 14 It is a brominated alkyl group.

[0377] In some implementations, R 14 It is hydrogen and R 13 It is hydrogen.

[0378] In some implementations, R 14 It is hydrogen and R 13 It is an alkyl group.

[0379] In some implementations, R 14 It is hydrogen and R 13 It is a fluoroalkyl group.

[0380] In some implementations, R 14 It is hydrogen and R 13 It is a brominated alkyl group.

[0381] In some implementations, R14 It is hydrogen and R 13 It is a chloroalkyl group.

[0382] In some implementations, R 14 It is alkyl and R 13 It is hydrogen.

[0383] In some implementations, R 14 It is alkyl and R 13 It is an alkyl group.

[0384] In some implementations, R 14 It is alkyl and R 13 It is a fluoroalkyl group.

[0385] In some implementations, R 14 It is alkyl and R 13 It is a brominated alkyl group.

[0386] In some implementations, R 14 It is alkyl and R 13 It is a chloroalkyl group.

[0387] In some implementations, R 14 It is a haloalkyl and R 13 It is a haloalkyl group.

[0388] In some implementations, R 14 It is alkyl and R 13 It is an alkyl group.

[0389] X 2 Non-restrictive implementation scheme: In some implementations, X 2 It is a key.

[0390] In some implementations, X 2 It is a heterocyclic ring.

[0391] In some implementations, X 2 It is a heteroaryl group.

[0392] In some implementations, X 2 It is an aryl group.

[0393] In some implementations, X 2 It is a double ring.

[0394] In some implementations, X 2 It is an alkyl group.

[0395] In some implementations, X 2 It is an aliphatic group.

[0396] In some implementations, X 2It is a heteroaliphatic base.

[0397] In some implementations, X 2 It is NR 27 -

[0398] In some implementations, X 2 It is CR 40 R 41 -

[0399] In some implementations, X 2 It is -C(O)-.

[0400] In some implementations, X 2 It is -C(NR) 27 )-.

[0401] In some implementations, X 2 It is -C(S)-.

[0402] In some implementations, X 2 It is -S(O)-.

[0403] In some implementations, X 2 It is -S(O)2-.

[0404] In some implementations, X 2 Yes -S-.

[0405] In some implementations, X 2 It is a 5-membered aromatic heterocycle with 1,3 orientation at its junction.

[0406] In some implementations, X 2 It is a 5-membered aromatic heterocycle with 1,2 orientation at its junction.

[0407] In some implementations, X 2 It is a 6-membered aromatic heterocycle with 1,2 orientation at its junction.

[0408] In some implementations, X 2 It is a 6-membered aromatic heterocycle with 1,3 orientation at its junction.

[0409] In some implementations, X 2 It is a 6-membered aromatic heterocycle with a 1,4 orientation at its junction.

[0410] In some implementations, X 2 It is a 6-membered aromatic heterocycle with 1,3 orientation at its junction.

[0411] In some implementations, X 2 It is a 5-membered heterocyclic ring with 1,2 orientation at its junctions.

[0412] In some implementations, X 2 It is a 5-membered heterocyclic ring with 1,3 orientation at its junctions.

[0413] In some implementations, X 2 It is a 6-membered heterocyclic ring with 1,2 orientation at its junctions.

[0414] In some implementations, X 2 It is a 6-membered heterocyclic ring with 1,3 orientation at its junctions.

[0415] In some implementations, X 2 It is a 6-membered heterocyclic ring with 1,4 orientation at its junctions.

[0416] In some implementations, X 2 It is a bicyclic heterocycle with one heteroatom.

[0417] In some implementations, X 2 It is a bicyclic heterocycle with two heteroatoms.

[0418] In some implementations, X 2 It is a bicyclic heterocycle with one heteroatom, one linker bonded to nitrogen and the other linker bonded to carbon.

[0419] In some implementations, X 2 It is a bicyclic heterocycle with one heteroatom and both connection points are bonded to carbon.

[0420] In some implementations, X 2 It is a bicyclic heterocycle with two heteroatoms, and both connection points are bonded to nitrogen.

[0421] In some implementations, X 2 It is a bicyclic heterocycle with two heteroatoms.

[0422] In some implementations, X 2 It is a fused bicyclic alkane.

[0423] In some implementations, X 2 It is a spirobicycloalkane.

[0424] X 3 Non-restrictive implementation scheme: In some implementations, X 3 It is a key.

[0425] In some implementations, X 3 It is a heterocyclic ring.

[0426] In some implementations, X 3 It is a heteroaryl group.

[0427] In some implementations, X 3 It is an aryl group.

[0428] In some implementations, X 3 It is a double ring.

[0429] In some implementations, X 3 It is NR 27 -,.

[0430] In some implementations, X 3 It is CR 40 R 41 -

[0431] In some implementations, X 3 It is -C(O)-.

[0432] In some implementations, X 3 It is -C(NR) 27 )-.

[0433] In some implementations, X 3 It is -C(S)-.

[0434] In some implementations, X 3 It is -S(O)-.

[0435] In some implementations, X 3 It is -S(O)2-.

[0436] In some implementations, X 3 Yes -S-.

[0437] In some implementations, X 3 It is a 5-membered aromatic heterocycle with 1,3 orientation at its junction.

[0438] In some implementations, X 3 It is a 5-membered aromatic heterocycle with 1,2 orientation at its junction.

[0439] In some implementations, X 3 It is a 6-membered aromatic heterocycle with 1,2 orientation at its junction.

[0440] In some implementations, X 3 It is a 6-membered aromatic heterocycle with 1,3 orientation at its junction.

[0441] In some implementations, X 3 It is a 6-membered aromatic heterocycle with a 1,4 orientation at its junction.

[0442] In some implementations, X 3It is a 6-membered aromatic heterocycle with 1,3 orientation at its junction.

[0443] In some implementations, X 3 It is a 5-membered heterocyclic ring with 1,2 orientation at its junctions.

[0444] In some implementations, X 3 It is a 5-membered heterocyclic ring with 1,3 orientation at its junctions.

[0445] In some implementations, X 3 It is a 6-membered heterocyclic ring with 1,2 orientation at its junctions.

[0446] In some implementations, X 3 It is a 6-membered heterocyclic ring with 1,3 orientation at its junctions.

[0447] In some implementations, X 3 It is a 6-membered heterocyclic ring with 1,4 orientation at its junctions.

[0448] In some implementations, X 3 It is a bicyclic heterocycle with one heteroatom.

[0449] In some implementations, X 3 It is a bicyclic heterocycle with two heteroatoms.

[0450] In some implementations, X 3 It is a bicyclic heterocycle with one heteroatom, one bonded to nitrogen and one bonded to carbon.

[0451] In some implementations, X 3 It is a bicyclic heterocycle with one heteroatom, and both connection sites are bonded to carbon. In some implementations, X 3 It is a bicyclic heterocycle with two heteroatoms, and both connection points are bonded to nitrogen.

[0452] In some implementations, X 3 It is a bicyclic heterocycle with two heteroatoms.

[0453] In some implementations, X 3 It is a fused bicyclic alkane.

[0454] In some implementations, X 3 It is a spirobicycloalkane.

[0455] In some implementations, X 3 Selected from: R 15 R 16 and R 17 Non-restrictive implementation scheme: In some implementations, R 15 It is a key.

[0456] In some implementations, R 15 It is an alkyl group.

[0457] In some implementations, R 15 It is -C(O)-.

[0458] In some implementations, R 15 It is -C(O)O-.

[0459] In some implementations, R 15 It is -OC(O)-.

[0460] In some implementations, R 15 It is -SO2-.

[0461] In some implementations, R 15 It is -S(O)-.

[0462] In some implementations, R 15 It is -C(S)-.

[0463] In some implementations, R 15 It is C(O)NR 27 -

[0464] In some implementations, R 15 Yes -NR 27 C(O)-.

[0465] In some implementations, R 15 Yes -O-.

[0466] In some implementations, R 15 Yes -S-.

[0467] In some implementations, R 15 Yes -NR 27 -

[0468] In some implementations, R 15 It is C(R) 40 R 41 )-.

[0469] In some implementations, R 15 It is P(O)(OR) 26 )O-.

[0470] In some implementations, R 15 It is -P(O)(OR) 26 )-.

[0471] In some implementations, R 15 It is a double ring.

[0472] In some implementations, R 15 It is an olefin.

[0473] In some implementations, R 15 It is an alkyne.

[0474] In some implementations, R 15 It is a haloalkyl group.

[0475] In some implementations, R 15 It is an alkoxy group.

[0476] In some implementations, R 15 It is an aryl group.

[0477] In some implementations, R 15 It is a heterocyclic ring.

[0478] In some implementations, R 15 It is a heteroaliphatic base.

[0479] In some implementations, R 15 It is a heteroaryl group.

[0480] In some implementations, R 15 It's lactic acid.

[0481] In some implementations, R 15 It is glycolic acid.

[0482] In some implementations, R 15 It is an arylalkyl group.

[0483] In some implementations, R 15 It is a heterocyclic alkyl group.

[0484] In some implementations, R 15 It is a heteroarylalkyl group.

[0485] In some implementations, R 16 It is a key.

[0486] In some implementations, R 16 It is an alkyl group.

[0487] In some implementations, R 16 It is -C(O)-.

[0488] In some implementations, R 16 It is -C(O)O-.

[0489] In some implementations, R 16It is -OC(O)-.

[0490] In some implementations, R 16 It is -SO2-.

[0491] In some implementations, R 16 It is -S(O)-.

[0492] In some implementations, R 16 It is -C(S)-.

[0493] In some implementations, R 16 It is C(O)NR 27 -

[0494] In some implementations, R 16 Yes -NR 27 C(O)-.

[0495] In some implementations, R 16 Yes -O-.

[0496] In some implementations, R 16 Yes -S-.

[0497] In some implementations, R 16 Yes -NR 27 -

[0498] In some implementations, R 16 It is C(R) 40 R 41 )-.

[0499] In some implementations, R 16 It is P(O)(OR) 26 )O-.

[0500] In some implementations, R 16 It is -P(O)(OR) 26 )-.

[0501] In some implementations, R 16 It is a double ring.

[0502] In some implementations, R 16 It is an olefin.

[0503] In some implementations, R 16 It is an alkyne.

[0504] In some implementations, R 16 It is a haloalkyl group.

[0505] In some implementations, R 16 It is an alkoxy group.

[0506] In some implementations, R 16 It is an aryl group.

[0507] In some implementations, R 16 It is a heterocyclic ring.

[0508] In some implementations, R 16 It is a heteroaliphatic base.

[0509] In some implementations, R 16 It is a heteroaryl group.

[0510] In some implementations, R 16 It's lactic acid.

[0511] In some implementations, R 16 It is glycolic acid.

[0512] In some implementations, R 16 It is an arylalkyl group.

[0513] In some implementations, R 16 It is a heterocyclic alkyl group.

[0514] In some implementations, R 16 It is a heteroarylalkyl group.

[0515] In some implementations, R 17 It is a key.

[0516] In some implementations, R 17 It is an alkyl group.

[0517] In some implementations, R 17 It is -C(O)-.

[0518] In some implementations, R 17 It is -C(O)O-.

[0519] In some implementations, R 17 It is -OC(O)-.

[0520] In some implementations, R 17 It is -SO2-.

[0521] In some implementations, R 17 It is -S(O)-.

[0522] In some implementations, R 17 It is -C(S)-.

[0523] In some implementations, R 17 It is C(O)NR 27-

[0524] In some implementations, R 17 Yes -NR 27 C(O)-.

[0525] In some implementations, R 17 Yes -O-.

[0526] In some implementations, R 17 Yes -S-.

[0527] In some implementations, R 17 Yes -NR 27 -

[0528] In some implementations, R 17 It is C(R) 40 R 41 )-.

[0529] In some implementations, R 17 It is P(O)(OR) 26 )O-.

[0530] In some implementations, R 17 It is -P(O)(OR) 26 )-.

[0531] In some implementations, R 17 It is a double ring.

[0532] In some implementations, R 17 It is an olefin.

[0533] In some implementations, R 17 It is an alkyne.

[0534] In some implementations, R 17 It is a haloalkyl group.

[0535] In some implementations, R 17 It is an alkoxy group.

[0536] In some implementations, R 17 It is an aryl group.

[0537] In some implementations, R 17 It is a heterocyclic ring.

[0538] In some implementations, R 17 It is a heteroaliphatic base.

[0539] In some implementations, R 17 It is a heteroaryl group.

[0540] In some implementations, R17 It's lactic acid.

[0541] In some implementations, R 17 It is glycolic acid.

[0542] In some implementations, R 17 It is an arylalkyl group.

[0543] In some implementations, R 17 It is a heterocyclic alkyl group.

[0544] In some implementations, R 17 It is a heteroarylalkyl group.

[0545] R 18 Non-restrictive implementation scheme: In some implementations, R 18 It is hydrogen.

[0546] In some implementations, R 18 It is an alkyl group.

[0547] In some implementations, R 18 It is an olefin.

[0548] In some implementations, R 18 It is an alkyne.

[0549] In some implementations, R 18 It is a hydroxyl group.

[0550] In some implementations, R 18 It is an azide group.

[0551] In some implementations, R 18 It is an amino group.

[0552] In some implementations, R 18 It is halogen.

[0553] In some implementations, R 18 It is a haloalkyl group.

[0554] In some implementations, R 18 Yes - OR 10 .

[0555] In some implementations, R 18 It is -SR 10 .

[0556] In some implementations, R 18 It is -S(O)R 12 .

[0557] In some implementations, R18 Yes - SO2R 12 .

[0558] In some implementations, R 18 Yes -NR 10 R 11 .

[0559] In some implementations, R 18 It is a cyano group.

[0560] In some implementations, R 18 It is a nitro group.

[0561] In some implementations, R 18 It is a heteroaryl group.

[0562] In some implementations, R 18 It is an aryl group.

[0563] In some implementations, R 18 It is an arylalkyl group.

[0564] In some implementations, R 18 It is a cycloalkyl group.

[0565] In some implementations, R 18 It is a heterocyclic ring.

[0566] In some implementations, R 18 It is a key.

[0567] In some implementations, R 18 It is a key.

[0568] In some implementations, R 18 It is a key.

[0569] In some implementations, R 18 It is a key.

[0570] In some implementations, R 18 It is a key.

[0571] In some implementations, R 18 It is a key.

[0572] R 20 R 21 R 22 R 23 and R 24 Non-restrictive implementation scheme: In some implementations, R 20 It is a key.

[0573] In some implementations, R 20 It is an alkyl group.

[0574] In some implementations, R 20 It is -C(O)-.

[0575] In some implementations, R 20 It is -C(O)O-.

[0576] In some implementations, R 20 It is -OC(O)-.

[0577] In some implementations, R 20 It is -SO2-.

[0578] In some implementations, R 20 It is -S(O)-.

[0579] In some implementations, R 20 It is -C(S)-.

[0580] In some implementations, R 20 It is -C(O)NR 27 -

[0581] In some implementations, R 20 Yes -NR 27 C(O)-.

[0582] In some implementations, R 20 Yes -O-.

[0583] In some implementations, R 20 Yes -S-.

[0584] In some implementations, R 20 Yes -NR 27 -

[0585] In some implementations, R 20 It is an olefin oxide.

[0586] In some implementations, R 20 It is -C(R) 40 R 40 )-.

[0587] In some implementations, R 20 It is -P(O)(OR) 26 )O-.

[0588] In some implementations, R 20 It is -P(O)(OR) 26 )-.

[0589] In some implementations, R 20 It is a double ring.

[0590] In some implementations, R 20 It is an olefin.

[0591] In some implementations, R 20 It is an alkyne.

[0592] In some implementations, R 20 It is a haloalkyl group.

[0593] In some implementations, R 20 It is an alkoxy group.

[0594] In some implementations, R 20 It is an aryl group.

[0595] In some implementations, R 20 It is a heterocyclic ring.

[0596] In some implementations, R 20 It is an aliphatic group.

[0597] In some implementations, R 20 It is a heteroaliphatic base.

[0598] In some implementations, R 20 It is a heteroaryl group.

[0599] In some implementations, R 20 It's lactic acid.

[0600] In some implementations, R 20 It is glycolic acid.

[0601] In some implementations, R 20 It is a carbon ring.

[0602] In some implementations, R 21 It is a key.

[0603] In some implementations, R 21 It is an alkyl group.

[0604] In some implementations, R 21 It is -C(O)-.

[0605] In some implementations, R 21 It is -C(O)O-.

[0606] In some implementations, R 21 It is -OC(O)-.

[0607] In some implementations, R 21 It is -SO2-.

[0608] In some implementations, R 21 It is -S(O)-.

[0609] In some implementations, R 21 It is -C(S)-.

[0610] In some implementations, R 21 It is -C(O)NR 27 -

[0611] In some implementations, R 21 Yes -NR 27 C(O)-.

[0612] In some implementations, R 21 Yes -O-.

[0613] In some implementations, R 21 Yes -S-.

[0614] In some implementations, R 21 Yes -NR 27 -

[0615] In some implementations, R 21 It is an olefin oxide.

[0616] In some implementations, R 21 It is -C(R) 40 R 40 )-.

[0617] In some implementations, R 21 It is -P(O)(OR) 26 )O-.

[0618] In some implementations, R 21 It is -P(O)(OR) 26 )-.

[0619] In some implementations, R 21 It is a double ring.

[0620] In some implementations, R 21 It is an olefin.

[0621] In some implementations, R 21 It is an alkyne.

[0622] In some implementations, R 21 It is a haloalkyl group.

[0623] In some implementations, R 21 It is an alkoxy group.

[0624] In some implementations, R21 It is an aryl group.

[0625] In some implementations, R 21 It is a heterocyclic ring.

[0626] In some implementations, R 21 It is an aliphatic group.

[0627] In some implementations, R 21 It is a heteroaliphatic base.

[0628] In some implementations, R 21 It is a heteroaryl group.

[0629] In some implementations, R 21 It's lactic acid.

[0630] In some implementations, R 21 It is glycolic acid.

[0631] In some implementations, R 21 It is a carbon ring.

[0632] In some implementations, R 22 It is a key.

[0633] In some implementations, R 22 It is an alkyl group.

[0634] In some implementations, R 22 It is -C(O)-.

[0635] In some implementations, R 22 It is -C(O)O-.

[0636] In some implementations, R 22 It is -OC(O)-.

[0637] In some implementations, R 22 It is -SO2-.

[0638] In some implementations, R 22 It is -S(O)-.

[0639] In some implementations, R 22 It is -C(S)-.

[0640] In some implementations, R 22 It is -C(O)NR 27 -

[0641] In some implementations, R 22 Yes -NR 27 C(O)-.

[0642] In some implementations, R 22 Yes -O-.

[0643] In some implementations, R 22 Yes -S-.

[0644] In some implementations, R 22 Yes -NR 27 -

[0645] In some implementations, R 22 It is an olefin oxide.

[0646] In some implementations, R 22 It is -C(R) 40 R 40 )-.

[0647] In some implementations, R 22 It is -P(O)(OR) 26 )O-.

[0648] In some implementations, R 22 It is -P(O)(OR) 26 )-.

[0649] In some implementations, R 22 It is a double ring.

[0650] In some implementations, R 22 It is an olefin.

[0651] In some implementations, R 22 It is an alkyne.

[0652] In some implementations, R 22 It is a haloalkyl group.

[0653] In some implementations, R 22 It is an alkoxy group.

[0654] In some implementations, R 22 It is an aryl group.

[0655] In some implementations, R 22 It is a heterocyclic ring.

[0656] In some implementations, R 22 It is an aliphatic group.

[0657] In some implementations, R 22 It is a heteroaliphatic base.

[0658] In some implementations, R 22 It is a heteroaryl group.

[0659] In some implementations, R 22 It's lactic acid.

[0660] In some implementations, R 22 It is glycolic acid.

[0661] In some implementations, R 22 It is a carbon ring.

[0662] In some implementations, R 23 It is a key.

[0663] In some implementations, R 23 It is an alkyl group.

[0664] In some implementations, R 23 It is -C(O)-.

[0665] In some implementations, R 23 It is -C(O)O-.

[0666] In some implementations, R 23 It is -OC(O)-.

[0667] In some implementations, R 23 It is -SO2-.

[0668] In some implementations, R 23 It is -S(O)-.

[0669] In some implementations, R 23 It is -C(S)-.

[0670] In some implementations, R 23 It is -C(O)NR 27 -

[0671] In some implementations, R 23 Yes -NR 27 C(O)-.

[0672] In some implementations, R 23 Yes -O-.

[0673] In some implementations, R 23 Yes -S-.

[0674] In some implementations, R 23 Yes -NR 27 -

[0675] In some implementations, R 23 It is an olefin oxide.

[0676] In some implementations, R 23 It is -C(R) 40 R 40 )-.

[0677] In some implementations, R 23 It is -P(O)(OR) 26 )O-.

[0678] In some implementations, R 23 It is -P(O)(OR) 26 )-.

[0679] In some implementations, R 23 It is a double ring.

[0680] In some implementations, R 23 It is an olefin.

[0681] In some implementations, R 23 It is an alkyne.

[0682] In some implementations, R 23 It is a haloalkyl group.

[0683] In some implementations, R 23 It is an alkoxy group.

[0684] In some implementations, R 23 It is an aryl group.

[0685] In some implementations, R 23 It is a heterocyclic ring.

[0686] In some implementations, R 23 It is an aliphatic group.

[0687] In some implementations, R 23 It is a heteroaliphatic base.

[0688] In some implementations, R 23 It is a heteroaryl group.

[0689] In some implementations, R 23 It's lactic acid.

[0690] In some implementations, R 23 It is glycolic acid.

[0691] In some implementations, R 23 It is a carbon ring.

[0692] In some implementations, R 24 It is a key.

[0693] In some implementations, R24 It is an alkyl group.

[0694] In some implementations, R 24 It is -C(O)-.

[0695] In some implementations, R 24 It is -C(O)O-.

[0696] In some implementations, R 24 It is -OC(O)-.

[0697] In some implementations, R 24 It is -SO2-.

[0698] In some implementations, R 24 It is -S(O)-.

[0699] In some implementations, R 24 It is -C(S)-.

[0700] In some implementations, R 24 It is -C(O)NR 27 -

[0701] In some implementations, R 24 Yes -NR 27 C(O)-.

[0702] In some implementations, R 24 Yes -O-.

[0703] In some implementations, R 24 Yes -S-.

[0704] In some implementations, R 24 Yes -NR 27 -

[0705] In some implementations, R 24 It is an olefin oxide.

[0706] In some implementations, R 24 It is -C(R) 40 R 40 )-.

[0707] In some implementations, R 24 It is -P(O)(OR) 26 )O-.

[0708] In some implementations, R 24 It is -P(O)(OR) 26 )-.

[0709] In some implementations, R24 It is a double ring.

[0710] In some implementations, R 24 It is an olefin.

[0711] In some implementations, R 24 It is an alkyne.

[0712] In some implementations, R 24 It is a haloalkyl group.

[0713] In some implementations, R 24 It is an alkoxy group.

[0714] In some implementations, R 24 It is an aryl group.

[0715] In some implementations, R 24 It is a heterocyclic ring.

[0716] In some implementations, R 24 It is an aliphatic group.

[0717] In some implementations, R 24 It is a heteroaliphatic base.

[0718] In some implementations, R 24 It is a heteroaryl group.

[0719] In some implementations, R 24 It's lactic acid.

[0720] In some implementations, R 24 It is glycolic acid.

[0721] In some implementations, R 24 It is a carbon ring.

[0722] R 25 Non-restrictive implementation scheme: In some implementations, R 25 It is an aliphatic group.

[0723] In some implementations, R 25 It is an aryl group.

[0724] In some implementations, R 25 It is a heteroaryl group.

[0725] In some implementations, R 25 It is hydrogen.

[0726] R 26 Non-restrictive implementation scheme: In some implementations, R 26 It is hydrogen.

[0727] In some implementations, R 26 It is an alkyl group.

[0728] In some implementations, R 26 It is an arylalkyl group.

[0729] In some implementations, R 26 It is a heteroarylalkyl group.

[0730] In some implementations, R 26 It is an olefin.

[0731] In some implementations, R 26 It is an alkyne.

[0732] In some implementations, R 26 It is an aryl group.

[0733] In some implementations, R 26 It is a heteroaryl group.

[0734] In some implementations, R 26 It is a heterocyclic ring.

[0735] In some implementations, R 26 It is an aliphatic group.

[0736] In some implementations, R 26 It is a heteroaliphatic base.

[0737] R 27 Non-restrictive implementation scheme: In some implementations, R 27 It is hydrogen.

[0738] In some implementations, R 27 It is an alkyl group.

[0739] In some implementations, R 27 It is an aliphatic group.

[0740] In some implementations, R 27 It is a heteroaliphatic base.

[0741] In some implementations, R 27 It is a heterocyclic ring.

[0742] In some implementations, R 27 It is an aryl group.

[0743] In some implementations, R 27 It is a heteroaryl group.

[0744] In some implementations, R 27It is -C(O) (aliphatic) In some implementations, R 27 It is -C(O)(aryl) In some implementations, R 27 It is -C(O) (heteroaliphatic group) In some implementations, R 27 It is -C(O)(heteroaryl) In some implementations, R 27 It is an olefin.

[0745] In some implementations, R 27 It is an alkyne.

[0746] R 28 Non-restrictive implementation scheme: In some implementations, R 28 It is an alkyl group.

[0747] In some implementations, R 28 It is an olefin.

[0748] In some implementations, R 28 It is an alkyne.

[0749] In some implementations, R 28 It is a hydroxyl group.

[0750] In some implementations, R 28 It is an azide group In some implementations, R 28 It is an amino group.

[0751] In some implementations, R 28 It is halogen.

[0752] In some implementations, R 28 It is a haloalkyl group.

[0753] In some implementations, R 28 Yes - OR 10 .

[0754] In some implementations, R 28 It is -SR 10 .

[0755] In some implementations, R 28 It is -S(O)R 12 .

[0756] In some implementations, R 28 Yes - SO2R 12 .

[0757] In some implementations, R 28 Yes -NR 10 R 11 .

[0758] In some implementations, R 28 It is a cyano group.

[0759] In some implementations, R 28 It is a nitro group.

[0760] In some implementations, R 28 It is a heteroaryl group.

[0761] In some implementations, R 28 It is an aryl group.

[0762] In some implementations, R 28 It is an arylalkyl group.

[0763] In some implementations, R 28 It is a cycloalkyl group.

[0764] In some implementations, R 28 It is a heterocyclic ring.

[0765] R 40 Non-restrictive implementation scheme: In some implementations, R 40 It is hydrogen.

[0766] In some implementations, R 40 It is R 27 .

[0767] In some implementations, R 40 It is an alkyl group.

[0768] In some implementations, R 40 It is an olefin.

[0769] In some implementations, R 40 It is an alkyne.

[0770] In some implementations, R 40 It's fluorine.

[0771] In some implementations, R 40 It is bromine.

[0772] In some implementations, R 40 It is chlorine.

[0773] In some implementations, R 40 It is a hydroxyl group.

[0774] In some implementations, R 40It is an azide group.

[0775] In some implementations, R 40 It is an amino group.

[0776] In some implementations, R 40 It is a cyano group.

[0777] In some implementations, R 40 It is an alkoxy group.

[0778] In some implementations, R 40 It is -NH (alkyl).

[0779] In some implementations, R 40 It is -NH (aliphatic group).

[0780] In some implementations, R 40 It is -N (aliphatic group)2.

[0781] In some implementations, R 40 It is -N(alkyl)2.

[0782] In some implementations, R 40 It is -NHSO2 (alkyl).

[0783] In some implementations, R 40 It is -NHSO2 (aliphatic group).

[0784] In some implementations, R 40 It is -N(alkyl)SO2alkyl.

[0785] In some implementations, R 40 It is -N (aliphatic)SO2 alkyl.

[0786] In some implementations, R 40 It is -NHSO2 (aryl).

[0787] In some implementations, R 40 It is -NHSO2 (heteroaryl).

[0788] In some implementations, R 40 It is -NHSO2 (heterocyclic ring).

[0789] In some implementations, R 40 It is -N(alkyl)SO2(aryl).

[0790] In some implementations, R 40 It is -N(alkyl)SO2(heteroaryl).

[0791] In some implementations, R40 It is -N(alkyl)SO2 (heterocyclic).

[0792] In some implementations, R 40 It is -NHSO2 alkenyl.

[0793] In some implementations, R 40 It is -N(alkyl)SO2 alkenyl.

[0794] In some implementations, R 40 It is an -NHSO2 acetylinyl group.

[0795] In some implementations, R 40 It is -N(alkyl)SO2 ynyl group.

[0796] In some implementations, R 40 It is a haloalkyl group.

[0797] In some implementations, R 40 It is an aliphatic group.

[0798] In some implementations, R 40 It is a heteroaliphatic base.

[0799] In some implementations, R 40 It is an aryl group.

[0800] In some implementations, R 40 It is a heteroaryl group.

[0801] In some implementations, R 40 It is a heterocyclic ring.

[0802] In some implementations, R 40 It is a cycloalkyl group.

[0803] R 41 Non-restrictive implementation scheme: In some implementations, R 41 It is an aliphatic group.

[0804] In some implementations, R 41 It is an aryl group.

[0805] In some implementations, R 41 It is a heteroaryl group.

[0806] In some implementations, R 41 It is hydrogen.

[0807] Another embodiment of the present invention 1. In some embodiments, compounds selected from the following formula are provided: (I) (II) (III) (IV) (V) (VI) (VII) (VIII) (IX) (X) (XI) (XII) (XIII) (XIV) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; in: A is selected from , , , , , , , , , , , , and ; B is selected from , , , , and ; n is 0, 1, or 2; X is NR 10 NR 6 ', O or S; X' is NR 10 O, CH2 or S; Q is CR 7 Or N; Q' and Q" are each independently selected from CR 6 and N; Ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein, where valence permits, ring-A is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents of the substituents; Ring -B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein, where valence permits, ring -B is optionally composed of 1, 2, or 3 independently selected from R 2 Substituents of the substituents; In some embodiments, ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-A is optionally composed of one, two, or three independently selected from R 1 Substituents of the substituents; In some embodiments, ring-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-B is optionally composed of one, two, or three independently selected from R 2 Substituents of the substituents; The ring-C is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, and 5- to 6-membered cycloalkenyl, wherein, where valence permits, the ring-C is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents of the substituents; Ring-D is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, and 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-D is optionally composed of 1, 2, or 3 independently selected from R. 2 Substituents of the substituents; R 1 and R 2 Each case is independently selected (a) Hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; (b) , and ;and (c) If valence and stability permit, divalent portions, such as O, S, or =NR. 25 ;and Among them, R, if appropriate and necessary 1The group may optionally be combined with another R 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-B or ring-C and ring-D; R 3 It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3 and R 6 Combining to form 1 or 2 carbon connections, for example, when R 3 and R 6 When a 1-carbon bond is formed, yes ; Or R 3 and R 4 Combining to form 1, 2, 3, or 4 carbon connections, for example when R 3 and R 4 When a 1-carbon bond is formed, yes ; Or R 3 and R 3 Adjacent R 4 Groups combine to form double bonds; Each R 4 Independently selected from hydrogen, alkyl, halogen, and haloalkyl; R 5 It is hydrogen, alkyl, halogen, or haloalkyl; R 6 and R 7 In each case, it is independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 Where R 6 and R 7 If they are located on the same carbon atom, they can optionally form 3- to 4-membered spirocycles.

[0808] R 6 It is hydrogen, alkyl, or haloalkyl; or R 3 and R 6 'Combined to form 1 or 2 carbon connections;' R 10 and R 11 Each is independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 12 -S(O)R 12 and -SO2R 12 ; Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -NR 13 R 14 and OR 13 ; R 13 and R 14 Each is independently selected from hydrogen, alkyl, and haloalkyl; Each X 2 It is the divalent part, selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, alkyl groups, aliphatic groups, heteroaliphatic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 -, -C(S)-, -S(O)-, -S(O)2- and -S-; the heterocyclic, aryl, heteroaryl and bicyclic are each optionally selected independently by 1, 2, 3 or 4 from R 40 Substituents of the substituents; X 3 It is a divalent moiety, selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic compounds, and -NR. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 -, -C(S)-, -S(O)-, -S(O)2-, -S-, arylalkyl, heterocyclic alkyl, or heteroarylalkyl (in any direction); the heterocycle, aryl, heteroaryl, and bicyclic can each be 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 15 R 16 and R 17 Each occurrence is independently selected from bonds, alkyl groups (carbocyclic in some embodiments), -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -、-C(R 40 R 41 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, arylalkyl, heterocyclic alkyl, and heteroarylalkyl (in any direction); wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40Substituents of the substituents; R 18 Selected from hydrogen, alkyl, olefin, alkyne, hydroxyl, azide, amino, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is optionally selected independently from 1, 2, 3, or 4 of R. 40 Substituents of the substituents; R 20 R 21 R 22 R 23 and R 24 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -, alkene oxide, -C(R) 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefinic, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic, glycolic acid, and carbocyclic; wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; R 25 It is an aliphatic group (including alkyl), aryl, heteroaryl, or hydrogen; R 26 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic groups; R 27 Each time it appears, it is independently selected from 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 Each time it appears, it is independently selected from hydrogen, R 27Alkyl, olefin, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic group, including alkyl), -N (aliphatic group, including alkyl)2, -NHSO2 (aliphatic group, including alkyl), -N (aliphatic group, including alkyl)SO2alkyl, -NHSO2 (aryl, heteroaryl, or heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl, or heterocyclic), -NHSO2 alkenyl, -N (alkyl)SO2 alkenyl, -NHSO2 ynyl, -N (alkyl)SO2 ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl; and R 41 It is an aliphatic group (including alkyl), aryl, heteroaryl, or hydrogen.

[0809] 2. In some embodiments, compounds selected from the following formula are provided: (XV) (XVI) (XVII) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; in AA is selected from , , , , , , , , , , , , , , , and ; Ring-E is selected from (a) , , , , , , and ;and (b) A fused ring selected from 5-membered heteroaryl, 5-8-membered heterocyclic, 5-8-membered cycloalkyl, or 5-8-membered cycloalkenyl, optionally composed of 1, 2, or 3 selected from R, where valence allows. 2 Substituents of the substituents; Ring-F is selected from (a) Selected by 1, 2 or 3 independent choices from R1 Substituents of phenyl groups; and (b) A fused ring selected from 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, optionally composed of one, two, or three independently selected from R, where valence permits. 1 Substituents of the substituents; R 1’ Selected independently in each case (a) Alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; (b) , and ;and (c) If valence and stability permit, divalent portions, such as O, S, or =NR. 25 ;and Where R 1’ The group may optionally be combined with another R 1’ Group or R 2 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 2 'In each case, it is independently selected from alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyano, nitro, heteroaryl, aryl, and heterocyclic; or alternatively, if valence and stability permit, R 2 'Can be a divalent part, such as O, S, or =NR 25 And R 2’ The group may optionally be combined with another R 2’ Group or R 1 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 2 "In each case, the components are independently selected from heteroaryl, aryl, and heterocyclic groups, and each heteroaryl, aryl, and heterocyclic group is optionally selected independently from 1, 2, 3, or 4 R groups." 40Substituents are substituted, and R is wherein 2 "The group can optionally be combined with R" 1 Group or R 2 Groups are combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 3a It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3a and R 6a Combining to form 1 or 2 carbon connections, for example, when R 3a and R 6a When a 1-carbon bond is formed, yes ; or R 3a and R 4a Combining to form 1, 2, 3, or 4 carbon connections, for example when R 3a and R 4a When a 1-carbon bond is formed, yes ; Or R 3a and R 3a Adjacent R 4a Groups combine to form double bonds; R 4a Selected from hydrogen, alkyl, halogen, and haloalkyl; R 6s Selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 ; Where R 3a R 4a and R 6a At least one of them is not hydrogen; R 28 Selected from alkyl, olefin, alkyne, hydroxyl, azide, amino, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; Where R 15 R 16R 17 and R 20 If at least one of them is not a key, then R 28 It can be hydrogen; and All other variables are as defined in this document.

[0810] 3. The compound of embodiment 2, wherein ring -F is composed of 1, 2, or 3 independently selected from R 1 'The substituent of the phenyl group.

[0811] 4. The compound of embodiment 3, wherein R 1 'Selected from alkyl, halogen and haloalkyl.'

[0812] 5. The compound of embodiment 3, wherein R 1 'Selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 .

[0813] 6. The compound of embodiment 3, wherein R 1 'Selected from alkyl, halogen and haloalkyl.'

[0814] 7. The compound of embodiment 3, wherein R 1 Selected from heteroaryl, aryl, and heterocyclic compounds.

[0815] 8. The compound of embodiment 3, wherein two R 1 Substituents combine to form fused benzene rings.

[0816] 9. The compound of embodiment 3, wherein at least one R 1 'It is an alkyl group.'

[0817] 10. The compound of embodiment 3, wherein at least one R 1 It is a halogen.

[0818] 11. The compound of embodiment 3, wherein one of R 1 'yes .

[0819] 12. The compound of embodiment 3, wherein one of R 1 'yes .

[0820] 13. The compound of embodiment 3, wherein one of R 1 'yes .

[0821] 14. The compound of embodiment 2, wherein ring E is selected from: , , and .

[0822] 15. The compound of embodiment 14, wherein R 2 'Selected from alkyl, halogen and haloalkyl.'

[0823] 16. The compound of embodiment 14, wherein R 2 'Selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 .

[0824] 17. The compound of embodiment 14, wherein R 2 'Selected from alkyl, halogen and haloalkyl.'

[0825] 18. The compound of embodiment 14, wherein R 2 Selected from heteroaryl, aryl, and heterocyclic compounds.

[0826] 19. The compound of embodiment 14, wherein two R... 2 Substituents combine to form fused benzene rings.

[0827] 20. The compound of embodiment 14, wherein at least one R 2 'It is an alkyl group.'

[0828] 21. The compound of embodiment 14, wherein at least one R 2 It is a halogen.

[0829] 22. A compound according to any one of embodiments 11-21, wherein X 3 and X 2 At least one of them is a key.

[0830] 23. A compound according to any one of embodiments 11-21, wherein X 3 and X 2 At least one of them is -O-.

[0831] 24. A compound according to any one of embodiments 11-21, wherein X 3 and X 2 At least one of -S-.

[0832] 25. A compound according to any one of embodiments 11-21, wherein X 3and X 2 At least one of -NR 27 -

[0833] 26. A compound of any one of embodiments 11-25, wherein R 15 and R 24 At least one of them is a key.

[0834] 27. A compound of any one of embodiments 11-26, wherein R 16 and R 23 At least one of them is a key.

[0835] 28. A compound of any one of embodiments 11-27, wherein R 17 and R 22 At least one of them is a key.

[0836] 29. A compound of any one of embodiments 11-25, wherein no more than four are selected from R 15 R 16 R 17 R 19 R 20 R 21 R 22 R 23 and R 24 The substituents are chosen as bonds.

[0837] 30. A compound of any one of embodiments 11-25, wherein no more than three are selected from R 15 R 16 R 17 R 19 R 20 R 21 R 22 R 23 and R 24 The substituents are chosen as bonds.

[0838] 31. A compound of any one of embodiments 11-25, wherein no more than two are selected from R 15 R 16 R 17 R 19 R 20 R 21 R 22 R 23 and R 24 The substituents are chosen as bonds.

[0839] 32. A compound of any one of embodiments 11-25, wherein no more than one is selected from R 15 R 16 R17 R 19 R 20 R 21 R 22 R 23 and R 24 The substituents are chosen as bonds.

[0840] 33. A compound according to any one of embodiments 1-32, wherein ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-A is optionally composed of one, two, or three independently selected from R 1 Substituents are substituted.

[0841] 34. A compound according to any one of embodiments 1-32, wherein ring-A is a fused ring selected from phenyl or a 6-membered heteroaryl group, wherein, where valence permits, ring-A is optionally composed of 1, 2 or 3 independently selected from R 1 Substituents are substituted.

[0842] 35. A compound according to any one of embodiments 1-32, wherein ring -A is optionally selected by one, two or three independently chosen from R, where the valence allows. 1 The phenyl group is substituted with a substituent.

[0843] 36. A compound according to any one of embodiments 1-32, wherein ring -A is optionally selected by one, two or three independently chosen from R, where the valence allows. 1 The substituents are substituted into the 6-membered heteroaryl group.

[0844] 37. A compound according to any one of embodiments 1-36, wherein ring-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-B is optionally composed of one, two, or three independently selected from R 1 Substituents are substituted.

[0845] 38. A compound according to any one of embodiments 1-36, wherein ring-B is a fused ring selected from phenyl or a 6-membered heteroaryl group, wherein, where valence permits, ring-B is optionally composed of one, two, or three independently selected from R 1 Substituents are substituted.

[0846] 39. A compound according to any one of embodiments 1-36, wherein ring B is optionally selected independently from R by one, two or three molecules, subject to the allowable valence. 1 The phenyl group is substituted with a substituent.

[0847] 40. A compound according to any one of embodiments 1-36, wherein ring B is optionally composed of one, two, or three independently selected from R, where the valence allows. 1 The substituents are substituted into the 6-membered heteroaryl group.

[0848] 41. A compound of any one of embodiments 1-40, wherein R 5 It is hydrogen.

[0849] 42. A compound of any one of embodiments 1-40, wherein R 5 It is an alkyl group.

[0850] 43. A compound of any one of embodiments 1-40, wherein R 5 It is halogen.

[0851] 44. A compound of any one of embodiments 1-40, wherein R 5 It is a haloalkyl group.

[0852] 45. A compound of any one of embodiments 1-44, wherein R 7 It is hydrogen.

[0853] 46. ​​A compound according to any one of embodiments 1-44, wherein R 7 It is a halogen, a haloalkyl, or an alkyl group.

[0854] 47. A compound of any one of embodiments 1-44, wherein R 7 Yes - OR 10 -SR 10 or -NR 10 R 11 .

[0855] 48. A compound of any one of embodiments 1-44, wherein R 7 It is -S(O)R 12 or -SO2R 12 .

[0856] 49. A compound of any one of embodiments 1-48, wherein there are 4 Rs. 2 Substituents.

[0857] 50. A compound of any one of embodiments 1-48, wherein three Rs are present. 2 Substituents.

[0858] 51. A compound of any one of embodiments 1-48, wherein there are 2 Rs. 2 Substituents.

[0859] 52. A compound of any one of embodiments 1-48, wherein one R is present. 2Substituents.

[0860] 53. A compound of any one of embodiments 1-52, wherein R 2 Selected from alkyl, halogen and haloalkyl.

[0861] 54. A compound of any one of embodiments 1-52, wherein R 2 Selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 .

[0862] 55. A compound of any one of embodiments 1-52, wherein R 2 Selected from alkyl, halogen and haloalkyl.

[0863] 56. A compound of any one of embodiments 1-52, wherein R 2 Selected from heteroaryl, aryl, and heterocyclic compounds.

[0864] 57. A compound of any one of embodiments 1-51, wherein two R... 2 Substituents combine to form fused benzene rings.

[0865] 58. A compound of any one of embodiments 1-52, wherein at least one R 2 It is an alkyl group.

[0866] 59. A compound of any one of embodiments 1-52, wherein at least one R 2 It is halogen.

[0867] 60. A compound of any one of embodiments 1-52, wherein one of the R... 2 yes .

[0868] 61. A compound of any one of embodiments 1-52, wherein one of the R... 2 yes .

[0869] 62. A compound of any one of embodiments 1-52, wherein one of the R... 2 yes .

[0870] 63. A compound of any one of embodiments 1-62, wherein R 3 It is hydrogen.

[0871] 64. A compound of any one of embodiments 1-62, wherein R 3 It is an alkyl group.

[0872] 65. A compound of any one of embodiments 1-62, wherein R 3 It is a haloalkyl group.

[0873] 66. A compound of any one of embodiments 1-62, wherein R 3 and R 6 Combined to form a one-carbon link.

[0874] 67. A compound of any one of embodiments 1-62, wherein R 3 and R 6 Combined to form a two-carbon bond.

[0875] 68. A compound of any one of embodiments 1-65, wherein R 6 It is hydrogen.

[0876] 69. A compound of any one of embodiments 1-65, wherein R 6 It is an alkyl group.

[0877] 70. A compound of any one of embodiments 1-65, wherein R 6 It is a haloalkyl group.

[0878] 71. A compound of any one of embodiments 1-70, wherein at least one R 4 It is hydrogen.

[0879] 72. A compound of any one of embodiments 1-70, wherein at least one R 4 It is an alkyl group.

[0880] 73. A compound of any one of embodiments 1-70, wherein at least one R 4 It is a haloalkyl group.

[0881] 74. A compound of any one of embodiments 1-70, wherein n is 0.

[0882] 75. A compound of any one of embodiments 1-73, wherein n is 1.

[0883] 76. A compound of any one of embodiments 1-73, wherein n is 2.

[0884] 77. A compound of any one of embodiments 1-76, wherein there are 4 Rs. 1 Substituents.

[0885] 78. A compound of any one of embodiments 1-76, wherein there are 3 Rs. 1 Substituents.

[0886] 79. A compound of any one of embodiments 1-76, wherein there are 2 Rs. 1 Substituents.

[0887] 80. A compound of any one of embodiments 1-76, wherein one R is present. 1 Substituents.

[0888] 81. A compound of any one of embodiments 1-80, wherein R 1 Selected from alkyl, halogen and haloalkyl.

[0889] 82. A compound of any one of embodiments 1-80, wherein R 1 Selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 .

[0890] 83. A compound of any one of embodiments 1-80, wherein R 1 Selected from alkyl, halogen and haloalkyl.

[0891] 84. A compound of any one of embodiments 1-80, wherein R 1 Selected from heteroaryl, aryl, and heterocyclic compounds.

[0892] 85. A compound of any one of embodiments 1-79, wherein two R... 2 Substituents combine to form fused benzene rings.

[0893] 86. A compound of any one of embodiments 1-80, wherein at least one R 2 It is an alkyl group.

[0894] 87. A compound of any one of embodiments 1-80, wherein at least one R 2 It is halogen.

[0895] 88. A compound of any one of embodiments 1-80, wherein one of the R... 2 yes .

[0896] 89. A compound of any one of embodiments 1-80, wherein one of the R... 2 yes .

[0897] 90. A compound of any one of embodiments 1-80, wherein one of the R... 2 yes .

[0898] 91. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (I) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0899] 92. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (II) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0900] 93. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (III) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0901] 94. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (IV) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0902] 95. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (V) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0903] 96. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (VI) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0904] 97. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (VII) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0905] 98. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (VIII) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0906] 99. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (IX) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0907] 100. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (X) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0908] 101. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (XI) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0909] 102. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (XII) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0910] 103. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (XIII) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0911] 104. A compound according to any one of embodiments 1 and 3-90, wherein the compound has the following formula: (XIV) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0912] 105. A compound according to any one of embodiments 2-90, wherein the compound has the following formula: (XV) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0913] 106. A compound according to any one of embodiments 2-90, wherein the compound has the following formula: (XVI) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0914] 107. A compound according to any one of embodiments 2-90, wherein the compound has the following formula: (XVII) Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0915] 108. In some embodiments, a pharmaceutical composition comprising a compound of any one of embodiments 1-107 and a pharmaceutically acceptable excipient is provided.

[0916] 109. In some embodiments, a method of treating a patient’s medical disorder is provided, comprising administering to the patient an effective amount of a compound of any one of embodiments 1-107 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of embodiment 108.

[0917] 110. The method of implementation scheme 109, wherein the obstacle is abnormal cell proliferation.

[0918] 111. The method of implementation scheme 109, wherein the disorder is a neuroregenerative disease.

[0919] 112. The method of implementation scheme 109, wherein the obstacle is an autoimmune disease.

[0920] 113. The method of any one of implementation schemes 109-112, wherein the patient is a person.

[0921] R 1 R 1 '、R 2 and R 2 Non-restrictive implementation scheme: In some implementations, R 1 R 1 '、R 2 and R 2 Each is independently selected from alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 , cyano and nitro.

[0922] In some implementations, R 1 and R 2 Each is independently selected from hydrogen, alkyl, halogen, and haloalkyl.

[0923] In some implementations, R 1 R 1 '、R 2 and R 2 Each is independently selected from halogens, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 , cyano and nitro.

[0924] In some implementations, R 1 R 1 '、R 2 and R 2 Each is independently selected from halogens, -S(O)R 12 -SO2R 12 , cyano and nitro.

[0925] In some implementations, R 1 R 1 '、R 2 and R 2 Each is independently selected from alkyl, haloalkyl, -OR 10 and -SR 10 .

[0926] In some implementations, R 1 R 1 '、R 2 and R 2Each is independently selected from alkyl, haloalkyl, and cyano groups.

[0927] In some implementations, each R 1 and R 2 It is hydrogen.

[0928] In some implementations, R 1 It is hydrogen.

[0929] In some implementations, R 2 It is hydrogen.

[0930] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is an alkyl group.

[0931] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is halogen.

[0932] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is a haloalkyl group.

[0933] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is -OR 10 .

[0934] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is -SR 10 .

[0935] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is -S(O)R 12 .

[0936] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is -SO2R 12 .

[0937] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is -NR 10 R 11 .

[0938] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is cyano.

[0939] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is nitro.

[0940] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is a heteroaryl group.

[0941] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is aryl.

[0942] In some implementations, R 1 R 1 '、R 2 and R 2 One of them is a heterocyclic ring.

[0943] In some implementations, each R 1 R 1 '、R 2 and R 2 'It is an alkyl group.'

[0944] In some implementations, each R 1 R 1 '、R 2 and R 2 It is a halogen.

[0945] In some implementations, each R 1 R 1 '、R 2 and R 2 'It is a haloalkyl group.

[0946] In some implementations, each R 1 R1 '、R 2 and R 2 'is-OR 10 .

[0947] In some implementations, each R 1 R 1 '、R 2 and R 2 'Is -SR 10 .

[0948] In some implementations, each R 1 R 1 '、R 2 and R 2 'is-S(O)R 12 .

[0949] In some implementations, each R 1 R 1 '、R 2 and R 2 'is-SO2R 12 .

[0950] In some implementations, each R 1 R 1 '、R 2 and R 2 'is-NR 10 R 11 .

[0951] In some implementations, each R 1 R 1 '、R 2 and R 2 It is a cyano group.

[0952] In some implementations, each R 1 R 1 '、R 2 and R 2 It is a nitro group.

[0953] In some implementations, each R 1 R 1 '、R 2 and R 2 It is a heteroaryl group.

[0954] In some implementations, each R 1 R 1 '、R 2 and R 2 It is an aryl group.

[0955] In some implementations, each R1 R 1 '、R 2 and R 2 It is a heterocyclic ring.

[0956] In some implementations, only one R exists on ring-A or ring-C. 1 Substituents.

[0957] In some implementations, only two Rs exist on ring-A or ring-C. 1 Substituents.

[0958] In some implementations, three Rs exist on ring-A or ring-C. 1 Substituents.

[0959] In some implementations, only one R exists on ring-A. 1 Substituents, and R 1 The substituent is hydrogen.

[0960] In some implementations, only one R exists on ring-F. 1’ Substituents.

[0961] In some implementations, only two Rs exist on ring-F. 1’ Substituents.

[0962] In some implementations, there are three Rs on ring-F. 1’ Substituents.

[0963] In some implementations, only one R exists on ring-B. 2 Substituents.

[0964] In some implementations, only two Rs exist on ring-B. 2 Substituents.

[0965] In some implementations, there are three Rs on ring-B. 2 Substituents.

[0966] In some implementations, only one R exists on ring-D. 2 Substituents.

[0967] In some implementations, only two Rs exist on ring-D. 2 Substituents.

[0968] In some implementations, there are three Rs on ring-D. 2 Substituents.

[0969] In some implementations, only one R exists on ring-E. 2 Substituents.

[0970] In some implementations, only two Rs exist on ring-E. 2 Substituents.

[0971] In some implementations, there are three Rs on ring-E. 2 Substituents.

[0972] In some implementations, only one R exists on ring-E. 2’ Substituents.

[0973] In some implementations, only two Rs exist on ring-E. 2’ Substituents.

[0974] In some implementations, there are three Rs on ring-E. 2’ Substituents.

[0975] In some implementations, an R 1 The substituent is a halogen.

[0976] In some implementations, two R 1 The substituent is a halogen.

[0977] In some implementations, the three Rs 1 The substituent is a halogen.

[0978] In some implementations, an R 2 The substituent is a halogen.

[0979] In some implementations, two R 2 The substituent is a halogen.

[0980] In some implementations, the three Rs 2 The substituent is a halogen.

[0981] In some implementations, an R 1 The substituent is a haloalkyl group.

[0982] In some implementations, two R 1 The substituent is a haloalkyl group.

[0983] In some implementations, the three Rs 1 The substituent is a haloalkyl group.

[0984] In some implementations, an R 2 The substituent is a haloalkyl group.

[0985] In some implementations, two R 2 The substituent is a haloalkyl group.

[0986] In some implementations, the three Rs 2 The substituent is a haloalkyl group.

[0987] In some implementations, an R 1 The substituent is an alkyl group.

[0988] In some implementations, two R 1 The substituent is an alkyl group.

[0989] In some implementations, the three Rs 1 The substituent is an alkyl group.

[0990] In some implementations, an R 2 The substituent is an alkyl group.

[0991] In some implementations, two R 2 The substituent is an alkyl group.

[0992] In some implementations, the three Rs 2 The substituent is an alkyl group.

[0993] In some implementations, two R 1 The groups combine to form a fused benzene ring.

[0994] In some implementations, two R 1 The groups combine to form a fused 5-membered heteroaryl ring.

[0995] In some implementations, two R 1 The groups combine to form a fused 6-membered heteroaryl ring.

[0996] In some implementations, R 1 Group and R 2 Groups combine to form fused 6-membered heterocycles.

[0997] In some implementations, R 1 Group and R 2 Groups are combined to form fused 5-membered heterocycles.

[0998] In some implementations, two R 2 The groups combine to form a fused benzene ring.

[0999] In some implementations, two R 1 The groups combine to form a fused benzene ring.

[1000] In some implementations, two R 2 The groups form fused 5-membered heteroaryl rings.

[1001] In some implementations, two R 2 The groups form a fused 6-membered heteroaryl ring.

[1002] In some implementations, an R1’ The substituent is a halogen.

[1003] In some implementations, two R 1’ The substituent is a halogen.

[1004] In some implementations, the three Rs 1’ The substituent is a halogen.

[1005] In some implementations, an R 2’ The substituent is a halogen.

[1006] In some implementations, two R 2’ The substituent is a halogen.

[1007] In some implementations, the three Rs 2’ The substituent is a halogen.

[1008] In some implementations, an R 1’ The substituent is a haloalkyl group.

[1009] In some implementations, two R 1’ The substituent is a haloalkyl group.

[1010] In some implementations, the three Rs 1’ The substituent is a haloalkyl group.

[1011] In some implementations, an R 2’ The substituent is a haloalkyl group.

[1012] In some implementations, two R 2’ The substituent is a haloalkyl group.

[1013] In some implementations, the three Rs 2’ The substituent is a haloalkyl group.

[1014] In some implementations, an R 1’ The substituent is an alkyl group.

[1015] In some implementations, two R 1’ The substituent is an alkyl group.

[1016] In some implementations, the three Rs 1’ The substituent is an alkyl group.

[1017] In some implementations, an R 2’ The substituent is an alkyl group.

[1018] In some implementations, two R 2’ The substituent is an alkyl group.

[1019] In some implementations, the three Rs2’ The substituent is an alkyl group.

[1020] In some implementations, two R 1’ The groups combine to form a fused benzene ring.

[1021] In some implementations, two R 1’ The groups combine to form a fused 5-membered heteroaryl ring.

[1022] In some implementations, two R 1’ The groups combine to form a fused 6-membered heteroaryl ring.

[1023] In some implementations, R 1‘ Group and R 2 Groups combine to form fused 6-membered heterocycles.

[1024] In some implementations, R 1’ Group and R 2 Groups are combined to form fused 5-membered heterocycles.

[1025] In some implementations, two R 2’ The groups combine to form a fused benzene ring.

[1026] In some implementations, two R 1‘ The groups combine to form a fused benzene ring.

[1027] In some implementations, two R 2’ The groups combine to form a fused 5-membered heteroaryl ring.

[1028] In some implementations, two R 2‘ The groups combine to form a fused 6-membered heteroaryl ring.

[1029] In some implementations, an R 1 R 2 Or R 1 Selected from: and , Each R' is independently selected from hydrogen, alkyl, haloalkyl, aryl, heterocyclic and heteroaryl.

[1030] In some implementations, R 1 R 2 Or R 1 ' is a heterocyclic group that is optionally substituted with one or two substituents selected from R'.

[1031] In some implementations, R1 R 2 Or R 1 ' is a 6-membered heterocyclic group having one or two nitrogen atoms.

[1032] In some implementations, R 1 R 2 Or R 1 ' is a 6-membered heterocyclic group having one or two oxygen atoms.

[1033] In some implementations, an R 1 R 2 Or R 1 Selected from: and , Each R' is independently selected from hydrogen, alkyl, haloalkyl, aryl, heterocyclic and heteroaryl.

[1034] In some implementations, R 1 It is a heterocyclic group that is optionally substituted with one or two substituents selected from R'.

[1035] In some implementations, R 1 It is a 6-membered heterocyclic group having one or two nitrogen atoms.

[1036] In some implementations, R 1 It is a 6-membered heterocyclic group with one or two oxygen atoms.

[1037] In some implementations, R 2 It is a heterocyclic group that is optionally substituted with one or two substituents selected from R'.

[1038] In some implementations, R 2 It is a 6-membered heterocyclic group having one or two nitrogen atoms.

[1039] In some implementations, R 2 It is a 6-membered heterocyclic group with one or two oxygen atoms.

[1040] In some implementations, R 1 ' is a heterocyclic group that is optionally substituted with one or two substituents selected from R'.

[1041] In some implementations, R 1 ' is a 6-membered heterocyclic group having one or two nitrogen atoms.

[1042] In some implementations, R 1' is a 6-membered heterocyclic group having one or two oxygen atoms.

[1043] In some implementations, an R 1 R 2 or R 1 Selected from: . and .

[1044] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1045] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1046] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1047] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1048] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1049] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1050] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1051] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1052] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1053] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1054] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1055] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1056] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1057] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1058] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1059] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1060] In some implementations, an R 1 R 2 or R1 Selected from: and .

[1061] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1062] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1063] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1064] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1065] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1066] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1067] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1068] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1069] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1070] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1071] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1072] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1073] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1074] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1075] In some implementations, an R 1 R 2 Or R 1 Selected from: and .

[1076] In some implementations, an R 1 R 2 Or R 1 Selected from: and .

[1077] In some implementations, an R 1 R 2 Or R 1 Selected from: and .

[1078] In some implementations, an R 1 R 2 Or R 1 Selected from: and .

[1079] In some implementations, an R 1 R 2 Or R 1 Selected from: and .

[1080] In some implementations, an R 1 R 2 Or R 1 Selected from: and .

[1081] In some implementations, an R 1 R 2 Or R 1 Selected from: and .

[1082] In some implementations, an R 1 R 2 Or R 1Selected from: and .

[1083] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1084] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1085] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1086] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1087] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1088] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1089] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1090] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1091] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1092] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1093] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1094] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1095] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1096] In some implementations, an R1 R 2 or R 1 Selected from: and .

[1097] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1098] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1099] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1100] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1101] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1102] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1103] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1104] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1105] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1106] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1107] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1108] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1109] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1110] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1111] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1112] In some implementations, an R 1 R 2 or R 1 Selected from: and .

[1113] R 3 Non-restrictive implementation scheme: In some implementations, R 3 Selected from hydrogen and halogens.

[1114] In some implementations, R 3 Selected from alkyl and haloalkyl groups.

[1115] In some implementations, R 3 It is hydrogen.

[1116] In some implementations, R 3 It is halogen.

[1117] In some implementations, R 3 It is an alkyl group.

[1118] In some implementations, R 3 It is a haloalkyl group.

[1119] In some implementations, R 3 It's fluorine.

[1120] In some implementations, R 3 It is chlorine.

[1121] In some implementations, R3 It is bromine.

[1122] In some implementations, R 3 It's iodine.

[1123] In some implementations, R 3 It is a methyl group.

[1124] In some implementations, R 3 It is an ethyl group.

[1125] In some implementations, R 3 It is trifluoromethyl.

[1126] In some implementations, R 3 It is pentafluoroethyl.

[1127] In some implementations, R 3 It is difluoromethyl.

[1128] In some implementations, R 3 It is a fluoromethyl group.

[1129] In some implementations, R 3 With R 4 Groups combine to form a 1-carbon link.

[1130] In some implementations, R 3 With R 4 Groups combine to form 2-carbon linkages.

[1131] In some implementations, R 3 With R 4 Groups combine to form 3-carbon linkages.

[1132] In some implementations, R 3 With R 4 Groups combine to form 4-carbon linkages.

[1133] In some implementations, R 3 With R 4 Groups combine to form double bonds.

[1134] R 6 and R 7 Non-restrictive implementation scheme: In some implementations, R 6 and R 7 It is independently selected from hydrogen, alkyl, halogen and haloalkyl.

[1135] In some implementations, R 6 and R 7 Independently selected from -OR 10 -SR10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 .

[1136] In some implementations, R 6 and R 7 Independently selected from alkyl, -OR 10 -SR 10 and -NR 10 R 11 .

[1137] In some implementations, R 6 With R 3 Groups combine to form a 1-carbon link.

[1138] In some implementations, R 6 With R 3 Groups combine to form 2-carbon linkages.

[1139] Implementation schemes for ring-A, ring-B, ring-C, ring-D, ring-E, and ring-F: In some implementations, and selected from the following: and .

[1140] In some implementations, and Selected from the following: and .

[1141] In some implementations, and Selected from: and .

[1142] In some implementations, and Selected from: and .

[1143] In some implementations, and Selected from: and .

[1144] In some implementations, and Selected from: and .

[1145] In some implementations, and Selected from: and .

[1146] In some implementations, and Selected from: and .

[1147] In some implementations, and Selected from: and .

[1148] In some implementations, and Selected from: and .

[1149] In some implementations, , and Selected from: and .

[1150] In some implementations, , and Selected from: and .

[1151] In some implementations, and Selected from: and .

[1152] In some implementations, and Selected from: and .

[1153] In some implementations, and Selected from: and .

[1154] In some implementations, and Selected from: and .

[1155] In some implementations, and Selected from: and .

[1156] In some implementations, and Selected from: and .

[1157] In some implementations, and Selected from: and .

[1158] In some implementations, and Selected from: and .

[1159] In some implementations, Selected from: and .

[1160] In some implementations, and Selected from: and .

[1161] In some implementations, Selected from: and .

[1162] In some implementations, Selected from: and .

[1163] In some implementations, Selected from: and .

[1164] In some implementations, Selected from: and .

[1165] In some implementations, Selected from: and .

[1166] In some implementations, Selected from: and .

[1167] In some implementations, Selected from: and .

[1168] In some implementations, and Selected from: and .

[1169] In some implementations, Selected from: and .

[1170] In some implementations, Selected from: . . and .

[1171] In some implementations, Selected from: . and .

[1172] In some implementations, Selected from: . and .

[1173] In some implementations, Selected from: and .

[1174] In some implementations, Selected from: and .

[1175] In some implementations, Selected from: and .

[1176] In some implementations, Selected from: and .

[1177] In some implementations, Selected from: and .

[1178] In some implementations, Selected from: and .

[1179] In some implementations, Selected from: and .

[1180] In some implementations, Selected from: and .

[1181] In some implementations, Selected from: and .

[1182] In some implementations, Selected from: and .

[1183] In some implementations, Selected from: and .

[1184] In some implementations, Selected from: and .

[1185] In some implementations, Selected from: and .

[1186] In some implementations, Selected from: and .

[1187] In some implementations, Selected from: and .

[1188] In some implementations, Selected from: and .

[1189] In some implementations, Selected from: and .

[1190] In some implementations, Selected from: and .

[1191] In some implementations, Selected from: and .

[1192] In some implementations, Selected from: . . and .

[1193] In some implementations, Selected from: . and .

[1194] In some implementations, Selected from: . and .

[1195] In some implementations, for of Selected from: .

[1196] In some implementations, Inside The selection is from: For example, when yes At that time, yes .

[1197] and .

[1198] In some implementations, for of Selected from: and .

[1199] In the structure of this article, this structure Refers to cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl rings fused with ring-A and ring-B or ring-C and ring-D.

[1200] Implementation scheme of "alkyl" In some implementations, "alkyl" is C1-C 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[1201] In some implementations, "alkyl" has one carbon atom.

[1202] In some implementations, "alkyl" has two carbon atoms.

[1203] In some implementations, "alkyl" has three carbon atoms.

[1204] In some implementations, "alkyl" has four carbon atoms.

[1205] In some implementations, "alkyl" has five carbon atoms.

[1206] In some implementations, "alkyl" has six carbon atoms.

[1207] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[1208] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[1209] Other non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[1210] Other non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[1211] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and reactive pentyl.

[1212] Implementation scheme of "halogenated alkyl" In some implementations, "haloalkyl" is C1-C 10 Halogenated alkyl, C1-C9 halogenated alkyl, C1-C8 halogenated alkyl, C1-C7 halogenated alkyl, C1-C6 halogenated alkyl, C1-C5 halogenated alkyl, C1-C4 halogenated alkyl, C1-C3 halogenated alkyl and C1-C2 halogenated alkyl.

[1213] In some implementations, the "halogenated alkyl" has one carbon atom.

[1214] In some implementations, the "halogenated alkyl" has one carbon atom and one halogen.

[1215] In some implementations, the "halogenated alkyl" has one carbon atom and two halogens.

[1216] In some implementations, the "halogenated alkyl" has one carbon atom and three halogens.

[1217] In some implementations, the "halogenated alkyl" has two carbon atoms.

[1218] In some implementations, the "halogenated alkyl" has three carbons.

[1219] In some implementations, the "halogenated alkyl" has four carbons.

[1220] In some implementations, the "halogenated alkyl" has five carbons.

[1221] In some implementations, the "halogenated alkyl" has six carbons.

[1222] Non-limiting examples of “halogenated alkyl” include: , and .

[1223] Other non-limiting examples of “haloalkyl” include: , , , , , , , , , and .

[1224] Other non-limiting examples of “haloalkyl” include: , and .

[1225] Other non-limiting examples of “haloalkyl” include: , and .

[1226] Implementation plan for "aryl" In some implementations, "aryl" is a 6-carbon aromatic group (phenyl).

[1227] In some implementations, "aryl" is a 10-carbon aromatic group (naphthyl).

[1228] In some embodiments, "aryl" is a 6-carbon aromatic group fused with a heterocycle, wherein the linking point is an aryl ring. Non-limiting examples of "aryl" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linking point of each group is on an aromatic ring.

[1229] For example, It is an "aryl" group.

[1230] but, It is a "heterocyclic" group.

[1231] In some embodiments, "aryl" is a 6-carbon aromatic group fused with a cycloalkyl group, wherein the linking point is an aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is on an aromatic ring.

[1232] For example, It is an "aryl" group.

[1233] but, It is a "cycloalkyl" group.

[1234] Implementation plan of "hybrid aromatics" In some implementations, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3 or 4 nitrogen atoms.

[1235] Non-limiting examples of 5-membered "heteroaryl" compounds include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetraazole, isoxazole, oxazole, oxadiazole, oxtriazole, isothiazole, thiazole, thiazolium, and thiatriazole.

[1236] Other non-limiting examples of 5-membered "hybrid aryl" compounds include: , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[1237] In some embodiments, "heteroaryl" is a 6-membered aromatic group (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl) containing 1, 2, or 3 nitrogen atoms.

[1238] Non-limiting examples of 6-membered "heteroaryl" groups having one or two nitrogen atoms include: , , , , , , , , and .

[1239] In some embodiments, "heteroaryl" is a 9-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen and sulfur.

[1240] Non-limiting examples of bicyclic "heteroaryl" compounds include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazol, benzoxazole, and benzothiazol.

[1241] Other non-limiting examples of bicyclic "heteroaryl" compounds include: , , , , , and .

[1242] Other non-limiting examples of bicyclic "heteroaryl" compounds include: , , , , and .

[1243] Other non-limiting examples of bicyclic "heteroaryl" compounds include: , , , , and .

[1244] In some embodiments, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[1245] Non-limiting examples of bicyclic "heteroaryl" compounds include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cyclophosphine, and naphthidine.

[1246] Other non-limiting examples of bicyclic "heteroaryl" compounds include: , , , , and .

[1247] "Cycloalkyl" implementation scheme In some embodiments, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[1248] In some implementations, "cycloalkyl" has three carbons.

[1249] In some implementations, "cycloalkyl" has four carbons.

[1250] In some implementations, "cycloalkyl" has five carbons.

[1251] In some implementations, "cycloalkyl" has six carbons.

[1252] In some implementations, "cycloalkyl" has seven carbons.

[1253] In some implementations, "cycloalkyl" has eight carbons.

[1254] In some implementations, "cycloalkyl" has nine carbons.

[1255] In some implementations, "cycloalkyl" has ten carbons.

[1256] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[1257] Other non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, wherein the bonding point of each group is on the cycloalkyl ring.

[1258] For example, It is a "cycloalkyl" group.

[1259] but, It is an "aryl" group.

[1260] Other examples of "cycloalkyl" include , and .

[1261] Implementation plan of "heterocyclic" In some implementations, "heterocycle" refers to a cyclic ring having one nitrogen atom and 3, 4, 5, 6, 7 or 8 carbon atoms.

[1262] In some implementations, a "heterocycle" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[1263] In some implementations, "heterocycle" refers to a cyclic ring having two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

[1264] In some implementations, "heterocycle" refers to a cyclic ring having one oxygen atom and 3, 4, 5, 6, 7 or 8 carbon atoms.

[1265] In some implementations, "heterocyclic" refers to a cyclic ring having one sulfur atom and 3, 4, 5, 6, 7 or 8 carbon atoms.

[1266] Non-limiting examples of "heterocycles" include azirropropane, oxacyclopropane, thioheteropropane, azirrobutane, 1,3-diazacyclobutane, oxacyclobutane, and thioheterobutane.

[1267] Other non-limiting examples of "heterocyclic" compounds include pyrrolidine, 3-pyrrolidine, 2-pyrrolidine, pyrazolidine, and imidazoline.

[1268] Other non-limiting examples of "heterocycles" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathionecyclopentane, and 1,3-oxathionecyclopentane.

[1269] Other non-limiting examples of "heterocyclic" compounds include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiaane, 1,4-dithiaane, morpholine, and thiomorpholine.

[1270] Other non-limiting examples of "heterocycles" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the bonding point of each group is on the heterocyclic ring.

[1271] For example, It is a "heterocyclic" group.

[1272] but, It is an "aryl" group.

[1273] Non-limiting examples of "heterocycles" also include: , , , , , , , , and .

[1274] Other non-limiting examples of "heterocycles" include: , , , , , , and .

[1275] Other non-limiting examples of "heterocycles" include: , , , , , , and .

[1276] Non-limiting examples of "heterocycles" also include: , and .

[1277] Non-limiting examples of "heterocycles" also include: , , , , , , and .

[1278] Other non-limiting examples of "heterocycles" include: , , , , and .

[1279] Other non-limiting examples of "heterocycles" include: , , , , and .

[1280] Optional substituents In some embodiments, the portion described herein that can be substituted by 1, 2, 3 or 4 substituents may be substituted by a single substituent.

[1281] In some embodiments, the portion described herein that can be substituted by 1, 2, 3 or 4 substituents is substituted by two substituents.

[1282] In some embodiments, the portion described herein that can be substituted by 1, 2, 3 or 4 substituents is substituted by three substituents.

[1283] In some embodiments, the portion described herein that can be substituted by 1, 2, 3 or 4 substituents is substituted by 4 substituents.

[1284] III. Treatment Methods The tricyclic compound provided by this invention can bind to CRL4. CRBN E3 ubiquitin ligases and their cerebroside receptors generate novel binding sites for new substrates that act as mediators of human diseases, leading to the degradation of these new substrates. These compounds form neodeformed surfaces that can directly interact with the target protein or target protein complex, thereby directly or indirectly reducing protein levels. In various embodiments, the tricyclic compounds described herein can reduce new substrate target protein levels through direct ubiquitination of the target protein; or through ubiquitination of a new substrate target protein cofactor or target protein complex, or other proteins responsible for controlling target protein homeostasis. The compounds can lead to degradation of new substrate target proteins that directly bind to ligands bound to cerebrosides; degradation of new substrates that act as cofactors binding to ligands bound to cerebrosides; degradation at the interface between the cofactor and the target protein at the ligand-bound cerebroside; degradation of new substrate target protein complexes that bind to ligand-bound CRBNs; or reduction in target protein levels through degradation of proteins not in the complex or cofactors of the new substrate protein.

[1285] A. Disease-mediating proteins for degradation by the compounds of the present invention It has been reported that when hydroxycerebroside also binds to novel substrate proteins of thalidomide-like molecules (IMiD), certain proteins with glycine-containing β-hairpin turns at key positions (“g-ring proteins” or “g-ring degradation determinants”) act as “structural degradation determinants” for hydroxycerebroside. Proteins containing a “g-ring degradation determinant” typically consist of small antiparallel β-sheets that form a β-hairpin with an α-turn, a geometric arrangement of three main-chain hydrogen bond acceptors (positions i, i+1, and i+2) at the apex of the turn, and a glycine residue at the critical position (i+3) (see, for example, Matyskiela et al., A novelcereblon modulator recruits GSPT1 to the CRL4-CRBN ubiquitin ligase. Nature 535, 252-257 (2016); Sievers et al., Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, eaat0572 (2018)). These g-ring degradation determinants have been identified in a variety of proteins, including but not limited to Sal-like 4 (SALL4), GSPT1, IKFZ1, IKFZ3, CK1α, ZFP91, and ZNF93.

[1286] In some embodiments, the tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, can be administered to the host in an effective amount to degrade a protein containing a g-ring degradation determinant, wherein the protein is selected from protein kinases, C2H2-containing zinc finger proteins, proteins containing RNA recognition motifs, zinc β-band proteins, β-propeller proteins, P-ring NTPase proteins, proteins containing a very interesting novel gene (RING) finger domain, proteins containing an SRC homolog 3 (SH3) domain, proteins containing an immunoglobulin E group domain, proteins containing a Tudor domain, proteins containing a zinc finger FYVE / PHD type, proteins containing an Ig-like domain, proteins containing a ubiquitin-like domain, proteins containing a concanavalin A-like domain, proteins containing a C1 domain, proteins containing a Pleckstrin homolog (PH) domain, proteins containing an OB fold domain, and proteins containing NADP. Proteins containing Rossman fold domains, proteins containing actin-like ATPase domains, and proteins containing helical-turn-helical (HTH) domains. In some implementations, protein kinases, C2H2 zinc finger proteins, proteins containing RNA recognition motifs, zinc β-band proteins, β-spiral proteins, P-loop NTPase proteins, proteins containing truly interesting new gene (RING) finger domains, proteins containing SRC homolog 3 (SH3) domains, proteins containing immunoglobulin E-group domains, proteins containing Tudor domains, zinc finger FYVE / PHD-type proteins, proteins containing Ig-like domains, proteins containing ubiquitin-like domains, proteins containing concanavalin A-like domains, proteins containing C1 domains, proteins containing Pleckstrin homolog (PH) domains, proteins containing OB fold domains, proteins containing NADP Rossman fold domains, proteins containing actin-like ATPase domains, or proteins containing helical-turn-helical (HTH) domains are overexpressed or contain gain-of-function mutations. In some implementations, the degradation determinant is stabilized by internal hydrogen bonds from the ASX motif and the ST motif.

[1287] In some embodiments, the tricyclic heterobifunctional compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical compositions described herein, can be applied in an effective amount to the host to degrade a protein having a “g-cyclic degradation determinant”, wherein the “g-cyclic degradation determinant” comprises the motif [D / N]XX[S / T]G (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 some embodiments, the protein containing the “g-cyclic degradation determinant” 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 protein containing the “g-cyclic degradation determinant” 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 another embodiment, the protein containing the "g-ring degradation determinant" 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 protein containing the "g-ring degradation determinant" 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 protein containing the "g-ring degradation determinant" comprises the amino acid sequence CXXCG (SEQ ID NO: 6), where C = cysteine, X can be any amino acid residue, and G = glycine. In some embodiments, the protein containing the "g-ring degradation determinant" comprises the amino acid sequence NXXNG (SEQ ID NO: 7), where N = asparagine, X can be any amino acid residue, and G = glycine.

[1288] In some embodiments, the tricyclic heterobifunctional compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical compositions described herein, can be administered to the host in an effective amount to degrade a protein containing a “g-ring degradation determinant” having a C2H2 zinc finger domain. In some embodiments, the zinc finger domain has a consortium sequence CXXCG (SEQ ID NO: 8), wherein C = cysteine, X = any amino acid, and G = glycine. In an alternative embodiment, the protein having the zinc finger domain has a consortium sequence QCXXCG (SEQ ID NO: 9), wherein C = cysteine, X = any amino acid, G = glycine, and Q = glutamine. In yet another embodiment, the zinc finger domain has a consortium sequence QC-X2-CG-X3-F-X5-L-X2-H-X3-H (SEQ ID NO: 10), wherein 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, proteins containing the C2H2 zinc finger domain are overexpressed. In some embodiments, the expression of C2H2 zinc finger proteins is associated with diseases or disorders, including but not limited to cancer.

[1289] For example, the compounds of the present invention or pharmaceutical salts thereof may be administered to the host, optionally in the pharmaceutical compositions described herein, to degrade the zinc finger protein, atypical E3 ubiquitin ligase (ZFP91). The zinc finger protein, atypical E3 ubiquitin ligase, contains a Cys2-His2 zinc finger and protects tumor cell survival and confers chemoresistance through forkhead box A1 (FOXA1) destabilization (see, for example, Tang et al., The ubiquitanse ZFP91 promotes tumor cell survival and conferschemoresistance through FOXA1 destabilization, Carcinogenesis, Col. 41(1), Jan. 2020). Zinc finger proteins, atypical E3 ubiquitin ligases, are thought to function through a non-canonical NF-κB pathway, and their overexpression leads to increased activation of the NF-κB signaling pathway, involved in a variety of cancers, including gastric cancer, breast cancer, colon cancer, kidney cancer, ovarian cancer, pancreatic cancer, gastric cancer, prostate cancer, sarcoma, and melanoma (see, for example, Paschke, ZFP91 zincfinger protein expression pattern in normal tissues and cancers. Oncol Lett. 2019; Mar; 17(3):3599-3606). In some embodiments, the compounds of the present invention or pharmaceutical salts thereof are optionally used in the pharmaceutical compositions described herein to degrade zinc finger proteins. Atypical E3 ubiquitin ligases are used to treat cancers, including but not limited to gastric cancer, breast cancer, colon cancer, lung cancer, kidney cancer, ovarian cancer, pancreatic cancer, gastric cancer, prostate cancer, sarcoma, and melanoma. In some embodiments, the compounds of the present invention or pharmaceutical salts thereof are optionally used in the pharmaceutical compositions described herein to degrade zinc finger proteins, atypical E3 ubiquitin ligases, to treat sarcoma, melanoma, or gastric cancer.

[1290] In another embodiment, the compound of the present invention or a pharmaceutical salt thereof is optionally administered to the host in the pharmaceutical composition described herein to degrade zinc finger protein 276 (ZFP276).

[1291] In another embodiment, the compound of the present invention or a pharmaceutical salt thereof is optionally administered to the host in the pharmaceutical composition described herein to degrade zinc finger protein 653 (ZFP653). Zinc finger protein 653 can be used as a more general transcriptional repressor by competitively binding to SF1 with GRIP1 and other p160 coactivators (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).

[1292] As another example, the compounds of the present invention or pharmaceutical salts thereof are optionally administered to the host in an effective amount in the pharmaceutical compositions described herein to degrade zinc finger protein 692 (ZFP692). Zinc finger protein 692, also known as AICAR response element binding protein (AREBP), contains the Cys2-His2 zinc finger and is considered a key regulator 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. BiochemBiophys Res Commun. 2011 Oct 22;414(2):287-91). Overexpression of zinc finger protein 692 is associated with promoting colon adenocarcinoma and metastasis by activating the PI3K / AKT pathway (see, for example, Xing et al., 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), as well as the development of lung adenocarcinoma and lung cancer metastasis. Short interfering RNA knockdown of zinc finger protein 692 reduces lung cancer cell invasion and increases lung cancer cell apoptosis, and inhibits lung cancer tumor growth in xenograft models (see, 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 some embodiments, the compounds of the present invention or pharmaceutical salts thereof are optionally used in the pharmaceutical compositions described herein to degrade zinc finger protein 692 to treat lung or colon cancer, including lung adenocarcinoma or carcinoma or colon adenocarcinoma.

[1293] The tricyclic compounds of the present invention or pharmaceutically acceptable salts thereof (optionally in the pharmaceutical compositions described herein) can also be administered to the host in an effective amount to degrade zinc finger protein 827 (ZFP827). Zinc finger protein 827 is a zinc finger protein that regulates the telomere elongation replacement (ALT) pathway by binding to nuclear receptors and recruiting nucleosome remodeling and histone deacetylation (NURD) complexes to telomeres to induce homologous recombination (see, e.g., Conomos, D., Reddel, RR, 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-associated promyelocytic leukemia (PML) nucleosomes (APBs) and other telomere abnormalities. Therefore, in some embodiments, the compounds of the present invention or pharmaceutical salts thereof are 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 tumor (NET), neuroendocrine tumor, colorectal cancer, liver cancer, soft tissue cancer (including leiomyosarcoma), malignant fibrous histiocytoma, liposarcoma, gastric / stomach cancer, testicular cancer, and thyroid cancer.

[1294] In other embodiments, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof is optionally administered to the host in an effective amount in the pharmaceutical composition described herein to degrade the E4F transcription factor 1 protein (E4F1). E4F transcription factor 1 is believed to act as a ubiquitin ligase of p53 and is a key post-translational regulator of p53, which plays an important role in p53-controlled cell life-death decisions (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). E4F1 overexpression is 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 some embodiments, the compounds of the present invention or pharmaceutical salts thereof are optionally used in the pharmaceutical compositions described herein to degrade E4F transcription factor 1 for the treatment of myeloid leukemias, including but not limited to acute myeloid leukemia (AML), undifferentiated AML, minimally cellular myeloblastic leukemia, cellularly mature myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, eosinophilic myelomonocytic leukemia, monocytic leukemia, erythroleukemia, megakaryoblastic leukemia, chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, including, for example, polycythemia vera (PV), essential thrombocythemia (ET), myelometaplasia with myelofibrosis (MMM), eosinophilic syndrome (HES), systemic mast cell disease (SMCD), myelofibrosis, and primary myelofibrosis. E4F1 expression is also essential for the survival of 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, P220-233, April 14, 2015).Therefore, in some embodiments, the compounds of the present invention or pharmaceutical salts thereof are optionally used in the pharmaceutical compositions described herein to degrade E4F transcription factor 1 to 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.

[1295] In another aspect, the tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, is optionally administered to the host in an effective amount in the pharmaceutical composition described herein to degrade zinc finger protein 517 (ZFP517). Zinc finger protein 517 has been identified as a carcinogenic driver in adrenocortical carcinoma (ACC) (see, for example, Rahane et al., Establishing a human adrenocortical carcinoma (ACC)-specific gene mutation signature. CancerGenet. 2019; 230:1-12). Therefore, in some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical composition described herein), is used to treat zinc finger protein 517 to treat adrenocortical carcinoma.

[1296] In another aspect, the tricyclic compound of the present invention or its pharmaceutical salt thereof may optionally be applied to the host in an effective amount in the pharmaceutical composition described herein to degrade zinc finger protein 582 (ZFP582). Zinc finger protein 582 is believed to be involved in DNA damage response, proliferation, cell cycle control, and tumor transformation, most notably in cervical, esophageal, and colorectal cancer (see, for example, Huang et al., Methylomic analysis identifies frequent DNA methylation of zinc finger protein 582 (ZNF582) in cervical neoplasms. PLoS One 7: e41060, 2012; Tang et al., Aberrant DNA methylation of PAX1, SOX1 and ZNF582 genes as potential biomarkers for esophageal squamous cell carcinoma. Biomedicine & Pharmacotherapy Volume 120, December 2019, 109488; Harada et al., Analysis of DNA Methylation in Bowel Lavage Fluid for Detection of Colorectal Cancer. CancerPrev Res; 7(10); 1002-10; 2014). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts are optionally used in the pharmaceutical compositions described herein to degrade zinc finger protein 582 for the treatment of cancers, including but not limited to cervical cancer, including cervical adenocarcinoma, esophageal cancer, including squamous cell carcinoma and adenocarcinoma, and colorectal cancer.

[1297] In another embodiment, the tricyclic compound of the present invention or its pharmaceutical salt thereof is optionally administered to the host in an effective amount in the pharmaceutical composition described herein to degrade zinc finger protein 654 (ZFP654).

[1298] Alternatively, the tricyclic compound of the present invention or its pharmaceutical salt may optionally be administered to the host in an effective amount in the pharmaceutical composition described herein to degrade zinc finger protein 787 (ZFP787).

[1299] The tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, can optionally be administered to the host in an effective amount in the pharmaceutical compositions described herein to degrade the cancer hypermethylation 1 (HIC1) protein. The cancer hypermethylation 1 protein comprises an N-terminal BTB / POZ protein-protein interaction domain and five Kruppel-like C2H2 zinc finger motifs in its C-terminal half (see Deltour et al., The carboxy-terminal end of the candidate tumor suppressor gene HIC-1 isphylogenetically conserved. Biochim. Biophys. Acta 1443: 230-232, 1998). Disorders of expression of the cancer hypermethylation 1 protein gene can lead to Miller-Dieker syndrome (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).

[1300] The tricyclic compound of the present invention or its pharmaceutical salt thereof may optionally be administered to the host in an effective amount in the pharmaceutical composition described herein to degrade cancer hypermethylation 2 (HIC2) protein.

[1301] The tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, can optionally be administered to the host in an effective amount in the pharmaceutical compositions 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).

[1302] Alternatively, for example, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical compositions described herein) can be applied to the host in an effective amount to degrade the Odd Skipped Related 1 (OSR1) protein. The Odd Skipped Related 1 protein comprises three C2H2 type zinc fingers, tyrosine phosphorylation sites, and several putative PXXP SH3 binding motifs (see, for example, Katoh, M. Molecular cloning and characterization of OSR1 on humanchromosome 2p24. Int. J. Molec. Med. 10: 221-225, 2002).

[1303] In another aspect, the tricyclic compound of the present invention or its pharmaceutical salt thereof may optionally be administered to the host in an effective amount in the pharmaceutical composition described herein to degrade the Odd Skipped Related 2 (OSR2) protein.

[1304] In another embodiment, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical compositions described herein) may be applied to the host in an effective amount to degrade the SAL-Like 4 (SALL4) protein. The SAL-Like4 protein has three SAL-type C2H2 double zinc finger domains, the second of which has a single C2H2 linked at its C-terminus, and the N-terminal C2HC zinc finger motif typical of vertebrate SAL-Like proteins. Mutations in the SAL-Like 4 protein are associated with the occurrence of Duane-radial ray 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 various cancers, including lung cancer, gastric cancer, liver cancer, kidney cancer, myelodysplastic syndromes, germ cell sex cord-stromal tumors (including dysgerminoma, yolk sac tumor, and choriocarcinoma), and leukemia. Therefore, in some embodiments, the compounds of the present invention or pharmaceutical salts thereof are optionally used in the pharmaceutical compositions described herein to degrade the SAL-Like 4 protein to treat cancers, including but not limited to gastric cancer, liver cancer, kidney cancer, myelodysplastic syndromes, germ cell sex cord-stromal tumors (including dysgerminoma, yolk sac tumor, and choriocarcinoma), and leukemia.

[1305] The tricyclic compounds of the present invention or their pharmaceutically acceptable salts (optionally in the pharmaceutical compositions described herein) can also be applied to the host in an effective amount to degrade the B-cell lymphoma 6 (BCL6) protein. BCL6 comprises an autonomous trans-repressive domain and two non-adjacent regions (including the POZ motif) that mediate maximal trans-repressive activity. BCL6 gene translocations are associated with the development of myeloproliferative disorders such as non-Hodgkin's lymphoma. B-cell lymphoma 6 overexpression prevents the increase of reactive oxygen species and inhibits chemotherapeutic-induced apoptosis in cancer cells (see, for example, Tahara et al., Overexpression of B-cell lymphoma 6 alters gene expression profile in amyeloma cell line and is associated with decreased DNA damage response. Cancer Sci. 2017 Aug;108(8):1556-1564; Cardenas et al., The expanding role of the BCL6 oncoprotein as a cancer therapeutic target. Clin Cancer Res. 2017 Feb15; 23(4): 885-893). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts, optionally in the pharmaceutical compositions described herein, are used to degrade B-cell lymphoma 6 to treat cancer, including but not limited to hematologic 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 lymphomas (DLBCLs) and ABC-DLBCL subtypes, B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer.

[1306] Furthermore, the selected tricyclic compound of the present invention, or its pharmaceutically acceptable salt, is optionally administered to the host in an effective amount in the pharmaceutical composition described herein to degrade the B-cell lymphoma 6B (BCL6B) protein. The B-cell lymphoma 6B protein comprises an N-terminal POZ domain and five C-terminal zinc finger motifs and is considered to function 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 the B-cell lymphoma 6B protein is associated with the development of germ cell tumors (Ishii et al., FGF2 mediates mouse spermatogonial stem cell self-renewal viaupregulation of Etv5 and Bcl6b through MAP2K1 activation. Development 139, 1734-1743 (2012)). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts are optionally used in pharmaceutical compositions as described herein to degrade B-cell lymphoma 6B for the treatment of cancer, including but not limited to germ cell carcinomas, including but not limited to germ cell tumors, including dysgerminomas and seminomas, teratomas, yolk sac tumors and choriocarcinomas.

[1307] Alternatively, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical compositions described herein) can be applied to the host in an effective amount to degrade the Early Growth Response 1 (EGR1) protein. The EGR1 protein directly controls the expression of the transforming growth factor-β1 gene and has been shown to participate in the proliferation and survival of prostate cancer cells and glioma cells by regulating several target genes, including cyclin D2 (CCND2), p19 (Ink4d), and Fas (see, for example, Virolle et al., Erg1 promotes growth and survival of prostate cancer cells: identification of novel Egr1 target genes. J. Biol. Chem. 278: 11802-11810, 2003; Chen et al., Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter. Journal of Experimental & Clinical Cancer Research Volume 36, Article number: 186 (2017)). One mechanism by which Egr1 confers resistance to apoptosis signals is its ability to inhibit Fas expression, thereby leading to insensitivity to FasL. Therefore, in some embodiments, the compounds of the present invention or pharmaceutical salts thereof, optionally in the pharmaceutical compositions described herein, are used to degrade the Early Growth Response 1 protein for the treatment of cancers, including but not limited to prostate cancer or gliomas, including but not limited to pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme.

[1308] On another front, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical compositions described herein) can be applied to the host in an effective amount to degrade the early growth response 4 (EGR4) protein. The EGR4 protein contains three C2 / H2 isoforms of zinc fingers 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 the EGR4 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 some embodiments, the compounds of the present invention or pharmaceutical salts thereof, optionally in the pharmaceutical compositions described herein, are used to degrade the early growth response 4 protein to treat cancer, including but not limited to cholangiocarcinoma.

[1309] In some respects, the tricyclic compounds of the present invention or their pharmaceutical salts (optionally in the pharmaceutical compositions described herein) can be applied to the host in an effective amount to degrade the Sal-like 1 (SALL1) protein.

[1310] In an alternative embodiment, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical compositions described herein) can be applied to the host in an effective amount to degrade the Sal-like 3 (SALL3) protein. The SALL3 protein comprises four double zinc finger (DZF) domains, each containing a sequence identical or closely related to the SAL box, which is a characteristic extension of the second zinc finger motif consisting of eight amino acids.

[1311] In another embodiment, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical compositions described herein) may be applied to the host in an effective amount to degrade the tumor protein p63 (TP63). Overexpression of the tumor protein p63 is associated with the occurrence and poor prognosis of lung cancer, radioresistance in oral and head and neck cancers, and squamous cell carcinoma of the skin (see Massion et al., Significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Res. 2003 Nov 1;63(21):7113-21; 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). Therefore, in some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical compositions described herein, is used to degrade the tumor protein p63 to 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.

[1312] In another embodiment, the selected tricyclic compound of the present invention or its pharmaceutical salt (optionally in the pharmaceutical composition described herein) can be applied to the host in an effective amount to degrade proteins containing wide-spaced zinc fingers (WIZ).

[1313] The tricyclic compound of the present invention or its pharmaceutically acceptable salt (optionally in the pharmaceutical compositions described herein) can also be applied to the host in an effective amount to degrade zinc finger and BTB domain protein 7A (ZBTB7A). Expression of zinc finger and BTB domain protein 7A is associated with a variety of cancers, including prostate cancer, non-small cell lung cancer, bladder cancer, breast cancer, prostate 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; Molloy et al., ZBTB7A governs estrogen receptor alpha expression in breast cancer. Journal of Molecular Cell Biology, Volume 10, Issue 4, August 2018, pp. 273-284). Therefore, in some embodiments, the compounds of the present invention or pharmaceutical salts thereof are optionally used in the pharmaceutical compositions described herein to degrade zinc finger and BTB domain protein 7A 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.

[1314] In other respects, the selected tricyclic compounds of the present invention or pharmaceutically acceptable salts thereof (optionally in the pharmaceutical compositions described herein) can be applied to the host in an effective amount to degrade zinc finger and BTB domain protein 7B (ZBTB7B). Expression of zinc finger and BTB domain protein 7B is associated with breast cancer, prostate cancer, urothelial carcinoma, cervical cancer, and colorectal cancer. Therefore, in some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, optionally in the pharmaceutical compositions described herein, are used to degrade zinc finger and BTB domain protein 7B to treat cancers, including but not limited to breast cancer, prostate cancer, urothelial carcinoma, cervical cancer, and colorectal cancer.

[1315] The selected tricyclic compounds of the present invention, or pharmaceutically acceptable salts thereof (optionally in the pharmaceutical compositions described herein), can be applied to the host in an effective amount to degrade casein kinase I, αI (CK1α or CK1-α). CK1-α 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-α dynamically associates with the CBM complex during T cell receptor engagement to participate in cytokine production and lymphocyte proliferation. However, CK1-α kinase activity has a relative role by subsequently promoting the phosphorylation and inactivation of CARMA1. Thus, CK1-α has a dual “gating” function, first promoting and then terminating receptor-induced NF-κB. ABC DLBCL cells require CK1-α for constitutive NF-κB activity, indicating that CK1-α functions as a conditionally essential malignant gene. CK1-α expression is associated with myelodysplastic diseases with 5q (del(5q) MDS deletion (see, e.g., Kronke et al., Lenalidomide induces ubiquitination and degradation of CK1-alpha indel(5q) MDS. Nature 523: 183-188, 2015), 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. BMCCancer. 2018; 18: 140; Jiang et al., Casein kinase 1α: biological mechanisms and theranostic potential. Cell Commun Signal. 2018; 16: 23).Therefore, in some embodiments, the compounds of the present invention or pharmaceutical salts thereof are optionally used in the pharmaceutical compositions described herein to degrade casein kinase I, αI for the treatment of cancer, including but not limited to colorectal cancer, breast cancer, leukemia, multiple myeloma, lung cancer, diffuse large B-cell lymphoma, non-small cell lung cancer, pancreatic cancer, myelodysplastic syndromes including but not limited to 5q syndrome, refractory cytopenia with monolineage, refractory anemia, refractory neutropenia and refractory thrombocytopenia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia with excessive blasts (REAB) I and II, transformed refractory anemia with excessive blasts (RAEB-T), chronic myelomonocytic leukemia (CMML), unclassified myelodyplasia, and refractory cytopenia in children (childhood dysplasia).

[1316] The tricyclic compounds of the present invention or their pharmaceutical salts (optionally in the pharmaceutical compositions described herein) may also be administered to the host in an effective amount to degrade the sequence-similar family 83, member H (FAM83H). FAM83H is believed to be involved in the progression of human cancers by binding to tumor-associated molecules such as MYC and β-catenin, and its overexpression is 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)). Therefore, in some embodiments, the compounds of the present invention or their pharmaceutical salts are optionally used in the pharmaceutical compositions described herein to degrade FAM83H for the treatment of 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, liver cancer (including but not limited to hepatocellular carcinoma), renal cell carcinoma, osteosarcoma, and gastric cancer.

[1317] Alternatively, the tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical compositions described herein) can be applied to the host in an effective amount to degrade the zinc finger and BTB domain protein 16 (ZBTB16). Overexpression and translocation of ZBTB16 are associated with the development of various hematologic malignancies, including acute promyelocytic leukemia (see, for example, Zhang et al., Genomic sequence, structural organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc finger gene. Proc. Nat. Acad. Sci. 96: 11422-11427, 1999). Therefore, in some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in the pharmaceutical compositions described herein, is used to degrade ZBTB16 to treat cancers, including but not limited to hematologic malignancies, including but not limited to leukemia or lymphoma, including but not limited to acute promyelocytic leukemia, acute lymphoblastic leukemia, adult T-cell lymphoma / ATL, and Birgitt lymphoma.

[1318] In an alternative embodiment, the selected tricyclic compound of the present invention or a pharmaceutically acceptable salt thereof (optionally in the pharmaceutical compositions described herein) may be applied to the host in an effective amount to degrade AT-rich interferon-responsive protein 2 (ARID2). ARID2 is a subunit of the PBAF chromatin remodeling complex, which promotes ligand-dependent transcriptional activation via 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).

[1319] On the other hand, the tricyclic compounds of the present invention or pharmaceutically acceptable salts thereof (optionally in the pharmaceutical compositions described herein) can be applied to the host in an effective amount to degrade polybrominated associated bacillus fibrosis (PBAF). Mutations in PBAF are 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, the compounds of the present invention or pharmaceutically acceptable salts thereof (optionally in the pharmaceutical compositions described herein) are used to degrade PBAF to treat cancers, including but not limited to synovial sarcoma and multiple myeloma.

[1320] In other embodiments, the tricyclic compounds of the present invention, when applied after binding with hydroxycerebrosides and forming a neodeformed surface, are capable of binding a variety of novel substrates, resulting in a "multi-directional pharmacological" form. For example, the tricyclic compounds can bind to and degrade IRAK4, IKZF1, and / or IKZF3, and / or Aiolos. In other embodiments, the tricyclic compounds, upon application, are capable of degrading two or more proteins described above or herein, such as SALL4 and IKZF1 / 3 or IKZF2 / 4.

[1321] 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 that are 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 Georgopoulos, K. et al. Science, 1992, 258:802-812), and in the following two decades, four additional homologs were discovered: Helios (“IKZF2”), Eos (“IKZF3”), Eos (“IKZF4”), and Pegasus (“IKZF5”) (see John, LB and Ward, AC Mol Immunol, 2011, 48:1272-1278). Each homologous gene can produce several protein subtypes through alternative splicing, theoretically allowing for the generation of a large number of protein complexes through different combinations of various homologs.

[1322] The distribution of members of the Icarus protein family varies considerably in vivo. Icarus, Helios, and Eos are primarily found in lymphoid cells and their corresponding progenitor cells. Icarus has also been detected in the brain, and both Icarus and Helios have been detected in erythroid cells. Eos and Pegasus are more widely distributed and are 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).

[1323] In some embodiments, the pharmaceutical salts of the compounds of the present invention, optionally in pharmaceutical compositions as described herein, are used to degrade Icarus or Iorlos as mediators of disorders affecting patients (e.g., humans). The control of protein levels provided by any of the compounds of the present invention provides treatment for a disease state or condition that is regulated by Icarus or Iorlos by reducing the level of that protein in cells (e.g., the patient's cells) or by reducing the level of downstream proteins in the cells.

[1324] In some embodiments, the compounds of the present invention can provide therapeutic effects by directly degrading Icarus or Ioros (which may alter the transcriptional regulation of proteins downstream of Icarus or Ioros).

[1325] Translation termination factor G1-S phase transition protein 1 (GSPT1) is a key terminator of the cell cycle G1-S phase transition 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 nascent proteins from the ribosome (Cheng et al., Genes Dev., 2009, 23, 1106-1118).

[1326] Studies have shown that GSPT1 is involved in processes such as 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 is associated with increased translation efficiency of specific oncogenic transcripts (Malta-Vacas et al. J. Clin. Pathol. 2005, 58, 621).

[1327] In some embodiments, the pharmaceutical salts of the compounds of the present invention, optionally in the pharmaceutical compositions described herein, are used to degrade GSTP1, which is a mediator of a disorder affecting a patient (e.g., a human). The protein level control conferred by any of the compounds of the present invention provides treatment for a disease state or symptom that is regulated by GSTP1 by reducing the level of this protein in cells (e.g., the patient's cells) or by reducing the level of downstream proteins in the cells.

[1328] In some embodiments, the compounds of the present invention can provide therapeutic effects by directly degrading GSTP1, which may alter the transcriptional regulation of downstream proteins of GSTP1.

[1329] In some embodiments, the coronavirus protein is degraded. In some embodiments, the coronavirus protein is a β-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-CoV-2 protein is selected from the spike (S) protein (accession number BCA87361.1), the membrane (M) protein (accession number BCA87364.1), the envelope (E) protein (accession number BCA87363.1), or the nucleocapsid phosphoprotein (N) protein (accession number BCA87368.1), or a structural protein selected from sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, or 98% homologous to it, or its homologs, mutants, conjugates, derivatives, fragments, or orthologs. In some implementations, the SARS-CoV2 protein is a non-structural protein, including nsp1 (leader protein) (accession number YP_009725297.1), nsp2 (accession number YP_009725298.1), nsp3 (papain-like protease) (accession number YP_009725299.1), nsp4 (accession number YP_009725300.1), nsp5 (3C-like protease) (accession number YP_009725301.1), nsp6 (proposed 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), and nsp10. (Accession number YP_009725306.1), nsp11 (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 (endoRNAse) (Accession number YP_009725310.1) or nsp16 (2'-O-ribose-methyltransferase) (accession number YP_009725311.1), or a sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 98% homologous to it, or a homolog, mutant, conjugate, derivative, fragment or ortholog thereof.In some implementations, the SARS-CoV2 protein is selected from the following: ORF3a protein (accession number BCA87362.1), ORF6 protein (accessory protein 6) (accessory number BCA87365.1), ORF7a protein (accessory protein 7a) (accessory number BCA87366.1), ORF7b protein (accessory protein 7b) (accessory number BCB15096.1), ORF8 protein (accessory number QJA17759.1), ORF9b protein (accessory protein 9b) (UniprotKB-P0DTD2), or ORF10 protein (accessory number BCA87369.1), or sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, or 98% homologous to it, or homologs, mutants, conjugates, derivatives, fragments, or orthologs thereof. In some implementations, the SARS-CoV2 protein is the ORF3b protein encoded by nucleotides 25814-25880 of the NCBI reference sequence: NC_045512.2 (see Konno et al., SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant. Cell Reports, Volume 32, Issue 12, 22 September 2020, 108185), or a sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, or 98% homologous to it, or a homolog, mutant, conjugate, derivative, fragment, or ortholog thereof.

[1330] In other embodiments, the protein being degraded is a viral protein of a virus other than a coronavirus, such as a protease, polymerase, exonuclease, helicase, glycosyltransferase, esterase, integrase, reverse transcriptase, kinase, primase, protease, methyltransferase, or nucleotidase.

[1331] Specific examples of novel substrates that can be targeted for degradation by the tricyclic compounds of the present invention using a degradation mechanism include, but are not limited to, the following: • CK1α is a casein kinase that uses acidic proteins (such as casein) as phosphorylation substrates. CK1A is involved in Wnt signaling, and its overexpression is associated with poor cancer survival.

[1332] • GSPT1 (G1 to S phase transition 1) is a translation termination factor. GSPT1 interacts with BIRC2 and is proteolytically processed into IAP-binding proteins. GSPT1 is expressed in cancer tissues, including gastric cancer.

[1333] • 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.

[1334] • SALL4 (Spalt-like transcription factor 4) is a developmental transcription factor associated with developmental syndromes and abnormalities such as Duane-Radial Ray syndrome and Ivic syndrome.

[1335] • PLZF (promyelocytic leukemia zinc finger), also known as ZBTB16 (containing zinc finger and BTB domain 16), is a transcription factor that regulates cell proliferation, differentiation, organ development, cell maintenance, and immune cell development. PLZF acts as a tumor suppressor in some cancers, but in others, such as renal cell carcinoma, glioblastoma, and testicular cancer, PLZF is actually an oncoprotein.

[1336] • p63 (tumor protein p63) is a pleiotropic protein involved in cell proliferation, apoptosis, differentiation, and even aging. There are several subtypes of p63. Some forms of p63 inhibit tumor growth, while other forms and mutants promote cancer metastasis.

[1337] • NRAS is a small GTP-binding protein in which oncogenic activating mutations drive tumorigenesis. For example, NRAS mutations are found in melanoma and thyroid cancer, and sometimes occur at Q61K and Q61R.

[1338] • BRD9 (bromine-containing domain protein 9) is a component of the SWI / SNF (BAF) chromatin remodeling complex. Mutations in BRD9 are associated with several cancers, and even native BRD9 can be oncogenic when overexpressed. Cancers associated with BRD9 include cervical cancer, non-small cell lung cancer, and liver cancer.

[1339] • P13KCA is a kinase that is one of the most frequently mutated oncogenes in various human cancers, including but not limited to breast cancer, endometrial cancer, squamous head and neck cancer, and squamous lung cancer. For example, mutations in H1047R, E545K, and E542K can sometimes lead to aberrant activation of the PI3K-AKT-mTOR pathway.

[1340] • RET (RET proto-oncogene) is a protein that crosses the cell membrane and interacts with the cellular environment. RET binds to growth factors and triggers a complex cascade of chemical reactions within the cell. Non-limiting examples of RET-mediated disorders include non-syndromic paragangliomas, congenital megacolon, various endocrine tumors, lung cancer, and other cancers.

[1341] • 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.

[1342] MCL1 is a member of the BCL2 family and a regulator of apoptosis. Diseases associated with MCL1 include myeloid leukemia and chlamydia.

[1343] • ARID1B is a protein 1 rich in AT-interacting domains. It is a component of the SW1 / SNF complex and binds nonspecifically to DNA. This is highly dependent on ARID1A-mutant cancer cell lines. ARID1A-deficient cancers account for a high proportion of certain tumors, including but not limited to clear cell ovarian carcinoma.

[1344] • P300 (histone acetyltransferase p300 or p300 HAT) is an enzyme that regulates gene transcription via chromatin remodeling by mediating histone wrapping around DNA. Therefore, P300 plays a crucial role in cell growth and division. Mutations in P300 can lead to various types of cancer, including colon cancer, stomach cancer, breast cancer, and pancreatic cancer.

[1345] • ARID2 is a component of the polybrominated associated BAF (PBAF) chromatin remodeling complex.

[1346] • FAM38 (also known as PIEZO1) is a pore-forming subunit of a nonspecific cation channel. As a cation channel subunit, FAM38 participates in the recruitment of R-Ras to the endoplasmic reticulum. Loss of FAM38 has been shown to lead to metathesis in small cell lung cancer cell lines.

[1347] • NSD2, which belongs to the histone methyltransferase (“HMT”) gene class, is overexpressed through oncogenic fusion transcripts in diseases such as multiple myeloma, ALL, CLL, and MCL.

[1348] • CSK is a non-receptor tyrosine-protein kinase involved in regulating cell growth, differentiation, migration, and immune responses.

[1349] • CBLB is an E3 ubiquitin-protein ligase that accepts ubiquitin from an E2 ubiquitin conjugate and then transfers it to a substrate for degradation.

[1350] • 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. In addition, EGFR can be used as a receptor for microbial infection or viral entry (such as HCV).

[1351] • WRN is a RecQ DNA helicase. WRN loss leads to DNA damage in MSI (microsatellite instability) cells but not in MSS (microsatellite stable) cells. This may result in the DSB (double-strand break) response preferentially promoting cell death and cell cycle arrest in MSI cells.

[1352] • NTRK and its gene fusions (including NTRK1, NTRK2, and NTRK3 gene fusions) are oncogenes for several cancers in adults and children. NTRK fusions are a major source of rare cancers such as secretory breast cancer, breast-like secretory carcinoma, and infantile fibrosarcoma. NTRK fusions may also contribute to more common cancers.

[1353] • ADAR is an RNA-specific adenosine deaminase. IFN-stimulated (ISG) signaling-positive cancer cells are sensitive to the loss of ADAR (dsRNA editing enzyme, which is also an ISG). Tumor-derived IFN production leading to chronic signaling induces a cellular state that responds to dsRNA accumulation, thus making ISG-positive tumors susceptible to ADAR loss. The loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by antigen presentation inactivation.

[1354] • SOS1 promotes the generation of the active form of KRAS, so blocking it can resist upstream or mutant activation of KRAS.

[1355] • KRAS is the gene encoding K-Ras, proteins in the RAS / MAPK pathway that transmit extracellular signals to the cell nucleus. These signals lead to proliferation or differentiation. K-Ras signals when it binds to GTP (which acts like a molecular switch). KRAS mutations are frequently observed in cecal cancer. K-Ras is involved in several cancers, including colorectal and lung cancer.

[1356] • WDR5 is a member of the WD repeat protein family. WD repeats are the least conserved region of 40 amino acids, bracketed by gly-his and trp-asp. WDR5 interacts with the host cytokines C1 and MLL and is a key determinant for MYC recruitment. WD5 is involved in mixed lineage leukemia.

[1357] • ALK, including ALK fusions such as EML-ALK and ALK fusion proteins (where the kinase domain of ALK is fused to the N-terminal portion of various proteins), has been described in many cancers, including but not limited to ALCL, IMT, DLBCL, NSCLC, RMC, RCC, breast cancer, colon cancer, serous ovarian cancer (SOC), and esophageal squamous cell carcinoma (ESCC).

[1358] • PTPN2 regulates CD8+ T cell subsets and affects tumor immunity.

[1359] • CTNNB1 (β-catenin) is involved in cell signaling as part of the Wnt signaling pathway. Proteins in this pathway attach to CTNNB1 and trigger protein migration to the nucleus. CTNNB1 is associated with desmoidoma, piloblastoma, nephroblastoma, aldosterone-producing adenoma, ovarian cancer, and other cancers.

[1360] • FGFRs, including FGFR1, FGFR3, or FGFR4 (and fusions), are receptor tyrosine kinases that are amplified in a variety of cancers, including squamous NSCLC, breast cancer, ovarian cancer, bladder cancer, gastric cancer, and endometrial cancer.

[1361] • ROS1 is a proto-oncogene receptor tyrosine kinase that is highly expressed in a variety of tumor cells.

[1362] • MYD88 (Myeloid Differentiation Major Response 88) provides instructions for the formation of proteins involved in signal transduction in immune cells, and mutations of it have been found in cancer cells.

[1363] • HER2 (human epidermal growth factor receptor 2) is a growth-promoting protein located on the outside of breast cells. Even though HER2-negative breast cancer cells possess HER2, those with higher than normal HER2 levels are called HER2-positive. HER2 is a very important gene in breast cancer treatment. Approximately 1 in 5 breast cancer cases has an extra copy of the HER2 gene, which contributes to cancer cell growth.

[1364] • TBXT is a transcription factor overexpressed in a variety of cancers and is associated with tumor grade and invasiveness.

[1365] • PTP4A3 (PRL3) is a protein tyrosine phosphatase IVA3, an isoprenoid phosphatase involved in cell signaling, and its overexpression leads to cell growth.

[1366] • MET (including exon 14 skipping mutations) is a receptor tyrosine kinase; alternatively spliced ​​MET receptors exhibit reduced ubiquitination and delayed downregulation, leading to prolonged activation of MET and MAP kinases, which may be undergoing conversion.

[1367] • USP7 is a deubiquitinating enzyme involved in prostate cancer, lung cancer, brain cancer, colon cancer, breast cancer, and other cancers.

[1368] • NRF2 (NFE2L2) is a basic leucine zipper protein that regulates the expression of cellular protective antioxidant proteins; mutations or activation can promote cancer.

[1369] • SF3B1 is a gene involved in the splicing of RNA units. SF3B1 is involved in RNA splicing, the secondary pathway of mRNA splicing, and stimulation by PKN1 activation of the androgen receptor. Mutations in SF3B1 are associated with various cancers.

[1370] • Any Icarus family protein (IKZF 1, 2, 3, 4, or 5). IKZF 2 (Helios) and IKZF 4 (Eos) are selectively expressed in Treg cells but not in effector or memory cells. FoxP3 / IKZF4 / CtBP1 forms an inhibitory complex that suppresses gene expression (IL-2, IFN-γ) in Tregs and maintains their inhibitory characteristics. Knockdown of IKZF4 in Tregs eliminates the ability of cells to suppress immune responses and enables partial effector functions. IKZF2 regulates Treg differentiation through a different mechanism than IKZF4. Knockout of IKZF2 in FoxP3-expressing Tregs promotes loss of inhibitory properties (with increased IL-2) and expression of T effector cytokines via STAT5 (which regulates FoxP3). Icarus family proteins are upregulated in myeloid leukemia.

[1371] • MEN1 is a putative tumor suppressor associated with a variety of type 1 endocrine neoplasms (MEN-1 syndrome). MEN1 is an autosomal dominant disorder in which affected individuals may develop tumors in the parathyroid gland, anterior pituitary gland, and enteropancreatic endocrine tissues.

[1372] • JCV proteins are encoded by the JC virus genome. In individuals with weakened immune systems, JC virus can cause a severe brain infection called progressive multifocal leukoencephalopathy (PML). PML damages the outer layer of nerve cells. It can lead to permanent disability and may even be fatal. The JC virus genome encodes large and small tumor antigens, agnoprotein, and capsid proteins VP1 through VP3. The capsid proteins play a role in cell entry, and the agnoprotein plays a role in virion maturation.

[1373] • 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 important enzymes in drug metabolism, and others exert their physiological functions by metabolizing endogenous substrates. For example, CYP17A1 is largely associated with endocrine effects and steroid hormone metabolism, and mutations are associated with rare forms of congenital adrenal hyperplasia, particularly 17α-hydroxylase deficiency / 17,20-lyase deficiency and isolated 17,20-lyase deficiency. CYP20A1 is an orphan isoform expressed in the brain and liver of humans.

[1374] • 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 and agnoprotein, as well as capsid proteins VP1 through VP3. Once the virus enters a cell, the agnoprotein helps regulate viral replication and disrupt host cell processes.

[1375] • 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 variety of extracellular signals. Overactivation or mutation in this pathway is associated with many cancers, and inhibition of MEK prevents cell proliferation, leading to apoptosis. For example, β3-αC-loop MEK1 mutants exhibit strong oncogenic potential, but show varying sensitivities to MEK inhibitors in clinical treatment or trials.

[1376] • Ataxin-2 is a member of the Like-Sm (LSm) protein family and is involved in a wide range of functions related to RNA processing and RNA metabolism. Mutations in ATXN2 lead to the neurodegenerative disease spinocerebellar ataxia type 2 (SCA2).

[1377] • JAK2 is a non-receptor tyrosine kinase and a member of the Janus kinase family. It is involved in signal transduction via members of the type II cytokine receptor family, the GM-CSF receptor family, the gp130 receptor family, and single-chain receptors. JAK2 gene fusions with the TEL(ETV6) (TEL-JAK2) and PCM1 genes have been found in patients with leukemia, and mutations in JAK2 are associated with polycythemia vera, essential thrombocythemia, myelofibrosis, and other myeloproliferative disorders.

[1378] • PTPN11 (SHP2) is a non-receptor tyrosine phosphatase that acts as a mediator of RTK signaling. Overexpression has been observed in cancers with recurrent mutations (observed in AML, JMML, and neuroblastoma); loss or inhibition of SHP2 has been shown to suppress the proliferation of AML or other RTK-driven cancers.

[1379] • ERK1 / ERK2 are kinases involved in the regulation of extracellular signals 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 variety of extracellular signals. Overactivation of this pathway is associated with many cancers.

[1380] • BRAF type II mutants are BRAF mutations classified as “constitutive active non-RAS-dependent dimers involving codons beyond 600 with high or moderate BRAF kinase activity, including BRAF fusion mutants.” Patients with type II mutants typically have shorter survival times than those with type I mutants, and their cancer may be more aggressive.

[1381] • ERBB3 is a transmembrane pseudo-RTK and has a strong genetic association with cancer.

[1382] • GRB2 is a scaffold adapter involved in RTK signaling in downstream pathways, including MAPK. GRB2 recruits multiple signaling molecules to receptors to form multi-signaling complexes that lead to cellular responses such as proliferation and invasion, and are therefore associated with cancer and tumorigenesis.

[1383] • CBP is a transcriptional coactivator involved in the transcriptional coactivation of many different transcription factors, and therefore participates in a wide variety of cellular activities, such as DNA repair, cell growth, differentiation, and apoptosis. CBP is also known as CREBBP. It is a CREB-binding protein transcriptional coactivator and is associated with a range of cancers, including leukemia, NSCLC, HCV-related hepatocellular carcinoma, melanoma, lung cancer, lymphoma, and bladder cancer.

[1384] • ATAD2 and ATAD2B are bromine / ATP helicases that can be transcriptional coactivators of the nuclear receptor ESR1 required to induce estradiol target gene subsets and can play a role in triple-negative breast cancer.

[1385] • BAP1 is a deubiquitinating enzyme that functions as a tumor suppressor and metastasis inhibitor in cancer. BAP1's ability to regulate group-environment interactions in tumorigenesis is associated with its dual role in the nucleus and cytoplasm. In the nucleus, BAP1 regulates the transcriptional regulation of several gene programs and promotes DNA repair by facilitating homologous recombination. This is observed in PBRM1-deficient CRC.

[1386] • BRPF1 is a histone reader with a bromine-containing domain associated with Moz and Morf, carrying HAT activity against H3. BRPF1 plays a role in cancers such as hematopoietic cancers, including leukemia.

[1387] • BRD4 is an epigenetic reader and a member of the BET protein family. BRD4 binds to acetylated histones and plays a central role in controlling cellular gene transcription and proliferation, and is therefore important in the development of angiogenesis and inflammation-related diseases, cardiovascular diseases, central nervous system diseases, and cancer.

[1388] • EPAS1 (HIF2a) belongs to a group of transcription factors involved in the physiological response to oxygen concentration and is encoded under hypoxic conditions. It is also important for heart development and for maintaining the catecholamine homeostasis required for cardioprotection. Mutations commonly lead to neuroendocrine tumors, such as paragangliomas, somatostatinomas, and / or pheochromocytomas.

[1389] KMT2D is a histone methyltransferase with a strong genetic link to cancer. This protein co-localizes with lineage-determining transcription factors on transcription enhancers and is crucial for cell differentiation and embryonic development. It also plays an important role in regulating cell fate transitions, metabolism, and tumor suppression.

[1390] • Menin is a bidentate scaffold protein that binds to the N-terminus of the KMT2A (MLL) and MLL fusion protein, enabling it to bind to and localize to chromatin; it is associated with leukemia and other cancers.

[1391] • MLLT1 (ENL) is a protein containing the YEATS domain; it plays a role in transcription initiation / elongation (YEATS domain dependent) and is a key interacting factor with DOT1L.

[1392] • DOT1L is a histone H3K79 methyltransferase that methylates lysine 79 on histone H3, an evolutionarily conserved methylation marker. DOT1L is involved in many key processes ranging from gene expression to DNA damage responses and cell cycle progression. DOT1L is also involved in the development of mixed lineage leukemia (MLL) – a type of leukemia with rearrangements.

[1393] • NSD2 is a histone methyltransferase that is widely expressed in early development and overexpressed in cancer cells including ALL, CLL, and MCL.

[1394] • TAUs are six highly soluble protein isoforms produced by alternative splicing of the gene MAPT (microtubule-associated protein tau). TAU proteins primarily function in maintaining the stability of microtubules in axons and are abundant in neurons of the central nervous system (CNS). Neurological pathologies and dementias (such as Alzheimer's and Parkinson's diseases) are associated with tau proteins, where they become hyperphosphorylated, insoluble aggregates known as neurofibrillary tangles.

[1395] • HTT is the huntingtin protein. HTT is essential for development and is highly expressed in neurons and the testes. Huntington's protein upregulates the expression of brain-derived neurotrophic factor (BDNF) at the transcriptional level, and its mutated form leads to Huntington's disease.

[1396] • NSD3 is a histone methyltransferase and a driver for 8p11-12 amplification found in cancers including squamous cell carcinoma of the lung, breast cancer, and AML.

[1397] • SNCA is a member of the synuclein family and is involved in regulating dopamine release and transport, fibrosis of the microtubule-associated protein tau, and neuroprotective phenotypes in non-dopaminergic neurons. SNCA mutations are associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease (LBD), and muscular atrophy (MSA).

[1398] • SMARCA2 and SMARCA4 are proteins encoded by the SWI / SNF protein family, which have helicase and ATPase activities and regulate gene transcription by altering chromatin structure as ATP-dependent chromatin remodelers.

[1399] • BTK is a tyrosine kinase that plays a crucial role in oncogenic signaling, essential for the proliferation and survival of leukemia cells in many B-cell malignancies. It was initially demonstrated that BTK is mutated in primary immunodeficiency X-linked agammaglobulinemia (XLA) and is required at various stages of B lymphocyte development.

[1400] • TAF1 is a TBP-related factor containing a kinase domain, an acetyltransferase domain, and a bromine domain. TAF1 is a key component of the transcription factor II D complex, playing a crucial role in transcription initiation. Variant versions of the TAF1 gene are associated with neurodevelopmental disorders, including intellectual disability.

[1401] • IRAK4 is a threonine / serine protein kinase involved in the signaling of Toll-like receptors (TLRs) in the innate immune response. Loss of IRAK4 or its intrinsic kinase activity can completely halt signaling via the TLR pathway and is therefore associated with a variety of inflammatory disorders, including rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases.

[1402] • SARM1 is a negative regulator of the transcriptional program activated by Toll-like receptors. Following axonal damage, SARM1 initiates a “self-destruction” mechanism to degrade the metabolite NAD+. This leads to metabolic disturbances in neurons, resulting in axonal degeneration.

[1403] • PPM1D (WIP1) is an oncoprotein and a member of the PP2C family of Ser / Thr protein phosphatases. PPM1D is a negative regulator of cellular stress response pathways and is amplified in various cancers, including breast cancer, esophageal cancer, colon cancer, hematologic malignancies, thyroid cancer, sarcoma, lung cancer, and ovarian cancer.

[1404] Non-limiting examples of diseases that can be treated with tricyclic compounds Any compound described herein may be used in an effective amount to treat a host (including humans) in need, optionally in a pharmaceutically acceptable carrier, to treat any of the disorders described herein. In some embodiments, the method comprises administering an effective amount of the active compound described herein or a salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination with or alternating with other therapeutic agents or pharmaceutical agents.

[1405] In some embodiments, the compound of formula I is used to treat the disorder described herein.

[1406] In some embodiments, the compound of formula II is used to treat the disorder described herein.

[1407] In some embodiments, the compound of formula III is used to treat the disorder described herein.

[1408] In some embodiments, the compound of formula IV is used to treat the disorder described herein.

[1409] In some implementations, the compound of formula V is used to treat the disorder described herein.

[1410] In some embodiments, the compound of formula VI is used to treat the disorder described herein.

[1411] In some embodiments, the compound of formula VII is used to treat the disorder described herein.

[1412] In some embodiments, the compound of formula VIII is used to treat the disorder described herein.

[1413] In some implementations, the compound of formula IX is used to treat the disorder described herein.

[1414] In some embodiments, the compound of formula X is used to treat the disorder described herein.

[1415] In some embodiments, the compound of formula XI is used to treat the disorder described herein.

[1416] In some embodiments, the compound of formula XII is used to treat the disorder described herein.

[1417] In some embodiments, the compound of formula XIII is used to treat the disorder described herein.

[1418] In some embodiments, the compound of formula XIV is used to treat the disorder described herein.

[1419] In some embodiments, the compound of formula XV is used to treat the disorder described herein.

[1420] In some embodiments, the compound of formula XVI is used to treat the disorder described herein.

[1421] In some embodiments, compounds of formula XVII are used to treat the disorders described herein.

[1422] In some embodiments, the disorder treated by the compounds of the present invention is an immune regulatory disorder. In some embodiments, the disorder treated by the compounds of the present invention is mediated by angiogenesis. In some embodiments, the disorder treated with the compounds of the present invention is related to the lymphatic system.

[1423] In some embodiments, the method includes administering an effective amount of the compound described herein, optionally including pharmaceutically acceptable excipients, carriers, adjuvants (i.e., pharmaceutically acceptable compositions), and optionally additional therapeutic agents or combinations of pharmaceutical agents, either in combination or alternating.

[1424] In some embodiments, the compounds of the present invention are used to treat disorders, including but not limited to benign growths, vegetations, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteases, proteases, or fibrotic disorders.

[1425] When used in combination with any compound, the term "disease state" or "symptom" is intended to refer to any disease state or symptom that responds to the compounds of the present invention, such as cell proliferation, and administration of the compounds of the present invention to a patient may provide beneficial treatment or symptom relief to a patient in need of treatment. In some cases, the disease state or symptom may be curable.

[1426] In some embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, suffering from lymphoma or a lymphocyte or myeloid cell proliferation disorder or abnormality. 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 have non-Hodgkin's lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-lytic cell lymphoma); diffuse small cleaved cell 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; transformed lymphoma; treatment-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenström macroglobulinemia.

[1427] In another embodiment, the compound described herein or its corresponding pharmaceutically acceptable salt, isotope derivative, or prodrug may be administered in an effective amount to a host suffering from Hodgkin lymphoma, such as a human, including but not limited to: tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed-cell CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL.

[1428] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, suffering from an immunomodulatory disorder. Non-limiting examples of immunomodulatory disorders include: arthritis, lupus, celiac disease, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, and temporal arteritis.

[1429] In some embodiments, the condition treated with the compounds of the present invention is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly excessive proliferation, can be caused by a variety of factors, including gene mutations, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction.

[1430] Abnormal proliferation of B cells, T cells, and / or NK cells can lead to a variety of diseases, such as cancer, proliferative disorders, and inflammatory / immune diseases. Hosts, such as humans, suffering from any of these disorders can be treated with effective amounts of compounds as described herein to achieve symptom reduction (palliative agents) or reduction of underlying disease (disease modifiers).

[1431] In some embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, suffering from a specific B-cell lymphoma or proliferative disorder, such as, but not limited to: multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphoma; diffuse poorly differentiated lymphocytic lymphoma; mediastinal large B-cell lymphoma; lymph node marginal zone B-cell lymphoma (NMZL); spleen marginal zone lymphoma (SMZL). Intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; splenic lymphoma / leukemia, unclassifiable; diffuse splenic erythromycin small B-cell lymphoma; hairy cell leukemia lesion; lymphoplasmacytic lymphoma; heavy chain disease, such as alpha heavy chain disease, gamma heavy chain disease, μ heavy chain disease; plasmacytic myeloma; solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicular center lymphoma; large B-cell lymphoma rich in T cells / histocytes; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) in the elderly. DLBCL; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma; Kassman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[1432] In some embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, can be used in effective amounts to treat a host with T-cell or NK-cell lymphoma, such as a human, for example, T-cell or NK-cell lymphomas, including, but 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, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermal CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastoblastic NK-cell lymphoma; enteropathy-associated T-cell lymphoma; blood-splenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; treatment-associated T-cell lymphoma; lymphoma following solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; aggressive NK-cell leukemia; childhood systemic EBV+ T-cell lymphoproliferative disorder (associated with chronic active EBV infection); Hydroa vaccinia-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[1433] In some embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, may be used to treat a host, such as a human, suffering from leukemia. For example, the host may have acute or chronic leukemia of lymphocytic or bone marrow origin, such as, but 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); large granular lymphoblastic leukemia; or adult T-cell chronic leukemia. In one implementation, the patient has acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimum cell maturation); myeloblastic leukemia (M2; cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroblastic leukemia (M6); or megakaryoblastic leukemia (M7).

[1434] Many skin diseases are associated with excessive cell proliferation. For example, psoriasis is a benign skin condition typically characterized by plaques covered with thickened scales. This disease is caused by an unexplained increase in the proliferation of epidermal cells. Chronic eczema is also associated with significant excessive proliferation of the epidermis. 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.

[1435] Other proliferative cell disorders include angiogenesis disorders, fibrosis disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[1436] Angiogenic disorders include vascular origin disorders and angiogenesis disorders. In vascular tissue, the proliferation of smooth muscle cells during plaque formation leads to conditions such as restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[1437] Fibrotic disorders are typically caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cell disorder. Cirrhosis is characterized by an increase in extracellular matrix components, leading to liver scarring. Cirrhosis can cause diseases such as liver cirrhosis. The increase in extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Adipocytes appear to play a major role in cirrhosis.

[1438] Glomerular mesangial disorders are caused by the abnormal proliferation of mesangial cells. Disorders involving excessive mesangial cell proliferation include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrocisic nephropathy, thrombotic microangiopathy syndrome, transplant rejection, and glomerular diseases.

[1439] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease, thought to be related to the activity of autoreactive T cells and caused by autoantibodies against collagen and IgE.

[1440] Other disorders that may include abnormal cell proliferation components include Bechet syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, postdialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[1441] The compounds described herein, or their pharmaceutically acceptable salts, isotope analogs, or prodrugs, can be used in effective amounts to treat hosts with proliferative disorders, such as humans, including myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelomecosis with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), eosinophilia (HES), systemic mast cell disease (SMCD), etc. In another embodiment, the compounds provided herein can be used to treat essential myelofibrosis, post-polycythemia vera myelofibrosis, post-esophagectomy myelofibrosis, and secondary acute myeloid leukemia.

[1442] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, isotope analogs, or prodrugs thereof, may be used in effective amounts to treat a host, such as a human, with myelodysplastic syndromes (MDS), including, but not limited to: refractory cytopenia with single lineage dysplasia, refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts-thrombocytosis (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD), including RCMD with multilineage dysplasia and ringed sideroblasts (RCMD-RS), refractory amenorrhea with excessive blast cells I (RAEB-I) and II (RAEB-II), 5q- syndrome, refractory cytopenia in children, etc.

[1443] The terms “tumor formation” or “cancer” are used to refer to the pathological processes that lead to the formation and growth of cancerous or malignant tumors, i.e., abnormal tissue that grows through cell proliferation (usually faster than normal tissue and continues to grow after the stimulus that triggered new growth has ceased). Malignant tumors exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most invade surrounding tissues, metastasize to multiple sites, and are likely to recur after attempted removal, leading to patient death unless adequately treated. As used herein, the term “tumor formation” is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated by the compounds of the present invention, alone or in combination with at least one other anticancer agent, include: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, and lipomas. Liposarcoma, myoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioglioma, ganglioblastoma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma. Other cancers that can be treated with the compounds according to the invention include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[1444] Other cancers that can be treated with the compounds disclosed in this invention include, for example, acute myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, colorectal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double-negative breast cancer (negative of two of estrogen, progesterone, and HER-2), single-negative breast cancer (negative of one of estrogen, progesterone, and HER-2), and estrogen receptor-positive HER2-negative breast cancer. Estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal type A breast cancer, luminal type 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, chondroma, chondrosarcoma, chronic lymphocytic leukemia (CLL), 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 sarcoma, extrahepatic bile duct cancer, ocular cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, stomach Intestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), colorectal cancer, intrahepatic cholangiocarcinoma, invasive / invasive breast cancer, islet cell carcinoma, jawbone cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal... Metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, fungal infections, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumors, primary ovarian peritoneal cancer, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, sinus cancer, parathyroid carcinoma, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancerPheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineal cell carcinoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis carcinoma, rhabdomyosarcoma, salivary gland carcinoma, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cord cancer, spinal cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsillitis Tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-BALL, pre-B lymphoma, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia Chromosomal 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, marginal zone B-cell lymphoma (NMZL); spleen marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary infiltrative lymphoma. Out-of-cell lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, diffuse splenic erythromycin small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease, such as alpha heavy chain disease, gamma heavy chain disease, μ heavy chain disease, plasmacytic myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicular center lymphoma, T-cell / histiocytic rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) in the elderly. DLBCL; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma, Castleman's disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma. In some embodiments, the barrier is adenoid cystic carcinoma. In some embodiments, the barrier is NUT midline carcinoma.

[1445] In another embodiment, the compound described herein, or its pharmaceutically acceptable salt, isotope derivative, or prodrug, may be used in an effective amount to treat a host suffering from an autoimmune disease, such as a human. Examples include, but are not limited to: acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also called Luger's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid syndrome; antisynergistic 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; and so on. Immune peripheral neuropathy; autoimmune ovarian failure; autoimmune polyendocrine syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disease; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; Balo disease / Balo concentric sclerosis; Behçet's disease; Bergey's disease; Bickerstaff encephalitis; Blau syndrome; bullous pemphigoid; cancer; Kassman's disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing multifocal osteomyelitis; Churg-Strauss disease. Syndrome; Cicatricial pemphigoid; Cogan syndrome; Cold agglutinin disease; Supplement 2 deficiency; Contact dermatitis; Cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; Cutaneous leukocytoclastic vasculitis; Dego's disease; Dercum's disease; Herpetic dermatitis; Dermatomyositis; Type 1 diabetes; Diffuse systemic sclerosis of the cutaneous region; Discoid lupus erythematosus; Dereskir syndrome; Drug-induced lupus; Eczema; Endometriosis; Enthes-associated arthritis; Eosinophilic fasciitis; Eosinophilic gastroenteritis; Eosinophilic pneumonia; Epidermolysis bullosa; Erythema nodosum; Erythroblastosis; Basic mixed cryoglobulinemia; Evan's syndrome; External and internal reactivity Airway diseases (asthma); progressive fibrosis; fibrotic alveolitis (or idiopathic pulmonary fibrosis); gastritis; gastrointestinal pemphigoid; glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's thyroiditis; hemolytic anemia; allergic purpura; herpes gestationis (pemphigoid of pregnancy); hidradenitis suppurativa; Hughes-Stoven 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 sclerosis; linear IgA disease (LAD); lupus hepatitis (also known as autoimmune hepatitis); systemic lupus erythematosus; Majid syndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixed connective tissue disease; morphea; Mucha-Habermann disease (also known as acute pityriasis alba lichenoides); multiple sclerosis. Myasthenia gravis; Myositis; Meniere's disease; Narcolepsy; Neuromyelitis optica (also Dweck's disease); Neuromuscular rigidity; Ocular cicatricial pemphigoid; Ocular myoclonus syndrome; Odd's thyroiditis; Palindromic rheumatism; PANDAS (Streptococcus-associated childhood autoimmune neuropsychiatric disorders); Paraneoplastic cerebellar degeneration; Paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; Tonsillitis; Clerk-Turner syndrome; Pemphigus vulgaris; Peripheral encephalomyelitis; Pernicious anemia; PO EMS syndrome; polyarteritis nodosa; polymyalgia rheumatica; polymyositis; primary biliary cirrhosis; primary sclerosing cholangitis; progressive inflammatory neuropathy; psoriasis; psoriatic arthritis; pure red cell aplasia; pyoderma gangrenosa; Rasmussen's encephalitis; Raynaud's phenomenon; Ritter syndrome; relapsing polychondritis; restless legs syndrome; retroperitoneal fibrosis; rheumatic 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); Sussac syndrome; Sweet's syndrome; Sidnam's chorea; sympathetic ophthalmia; systemic lupus erythematosus; Goran's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; indifferentiated spondyloarthritis; urticarial vasculitis; vasculitis and vitiligo.

[1446] In another implementation, treatment addresses viral diseases such as SARS-CoV1, SARS-CoV2, coronaviruses, flaviviruses, dengue virus, West Nile virus, 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 implementations, an autoimmune disease is an allergic condition, including those caused by asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[1447] Skin contact allergies and asthma are just two examples of immune responses that may be associated with a significant incidence rate. Others 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 cause any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[1448] In atopic dermatitis and eczema in general, immune-mediated leukocyte infiltration (particularly monocytes, lymphocytes, neutrophils, and eosinophils) into the skin plays a crucial role in the pathogenesis of these diseases. Chronic eczema is also associated with significant epidermal hyperplasia. Immune-mediated leukocyte infiltration also occurs in sites outside the skin, such as the airways of asthmatic patients and the lacrimal glands of the eyes in patients with keratoconjunctivitis sicca.

[1449] The compounds described herein, or their pharmaceutically acceptable salts, isotopic variants, or prodrugs, can be used in effective amounts to treat hosts with skin diseases such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, and skin allergies (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances (including certain drugs) can cause skin allergies when used topically. In some embodiments, skin diseases are treated by topical application of compounds known in the art in combination with those disclosed herein. In one non-limiting embodiment, the compounds of the present invention are used as topical agents for treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome, including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This new method can also be used to reduce the infiltration of malignant leukocytes into the skin in diseases such as fungal infections.

[1450] Disease states or conditions that can be treated with the compounds according to the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease 1 (PKD1) or 2 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[1451] Other disease states or conditions that can be treated with the compounds of this invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, and vasculitis.

[1452] Other disease states or conditions that can be treated with the compounds of this invention include ceruloplasminemia, type II chondrodysplasia, chondrodysplasia, cranial malformations, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydratase deficiency, adenosine lyase deficiency, adrenocorticotropic syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaline aciduria, Alexander disease, alkaline acidosis, α1-antitrypsin deficiency, α-1 protease inhibitors, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome, Alexander disease, enamel hypoplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemic body angiokeratoma, and retinal angiomatosis (von Willebrand disease). Hippel-Lindau disease, Apert syndrome, slender toe (Marfan syndrome), Stickler syndrome, congenital polyarthropathy (Ehlers-Danlos syndrome # joint laxity type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff's disease, neurofibromatosis type II, Beare-Stevenson gyrate scalp syndrome, familial Mediterranean fever, Benjamin syndrome, β-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombosis, Bloch-Sulzberger syndrome (dyspiky pigmentation), Bloom syndrome, X-linked siderocytic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prions, Birt-Hogg-Dubé syndrome, osteogenesis imperfecta, Rubinstein-Taybi syndrome, bronze diabetes / bronze cirrhosis (hemochromatosis), bulbar spinal muscular atrophy (Kennedy disease), Berg-Grutz syndrome (lipoprotein lipase deficiency), chronic granulomatous disease (CGD), Campomelic dysplasia. Biotinase deficiency, cardiomyopathy (Noonan syndrome), cat-like crying, CAVD (congenital absence of vas deferens), Caylor's cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (chondrodysplasia), auricular hypertrophy and epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal osteodystrophy, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia.Achondroplasia, X-linked sideroblastic anemia, connective tissue disorders, conus medullaris facies syndrome, Cooley's anemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coprophytic porphyria, Cowden syndrome, craniofacial joint disorders (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotrophic lateral dystrophy), Beare-Stevenson gyrate scalp syndrome, primary hyperoxaluria, vertebral metaphyseal dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker types (DBMD), Arthur syndrome, degenerative neurological diseases, including deGrouchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal cord Muscular atrophy, type V, androgen insensitivity syndrome, diffuse spheroid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythroid 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Freund's ataxia-familial paroxysmal polyserositis, delayed-onset cutaneous porphyria, familial barosensitive neuropathy Primary pulmonary hypertension (PPH), pancreatic cystic fibrosis, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthomas elastica), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoretrophoblastic porphyria (HEP), Hippel-Lindau disease (von Willebrand disease) Hippel-Lindau disease, Huntington's disease, Hutchinson-Gilford progeria, hyperandrogenemia, hypochondroitinemia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, kidney disease including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia, Langer-Saldino chondrodysplasia, ataxia-telangiectasia, Lynch syndrome, lysylhydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, and movement disorders.Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, McCune-Albright syndrome, Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, Lesch-Nyhan syndrome, primary pulmonary hypertension, primary Alzheimer's disease, prion diseases, progeria (Hutchinson's disease) Gilford's progeria syndrome, progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthomas elastica), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), relapsing polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia and adrenal gland (SBLA) syndrome, tuberous sclerosis, SDAT, SED congenital (congenital vertebral epiphyseal dysplasia), SED Strudwick (vertebral epiphyseal dysplasia, Strudwick type), SEDc (congenital vertebral epiphyseal dysplasia), SEMD, Strudwick type (vertebral epiphyseal metaphyseal dysplasia, Strudwick type), Shprintzen syndrome, hyperpigmentation, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (porphyria variegata), infantile ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, β-thalassemia, thyroid disease, Tomaculous neuropathy (hereditary neuropathy with susceptibility to pressure paralysis), Treacher Collins syndrome, Triplo X syndrome, Down syndrome (trisomy 21), Trisomy X syndrome, VHL syndrome (Von der Liskov syndrome) Hippel-Lindau disease, visual impairment and blindness (Alström syndrome), Vrolik diseaseWaardenburg syndrome, Warburg-Sjo-Fledelius syndrome, Wolf-Hirschhorn syndrome, Wolff periodicity, Weissenbacher-Zweymüller syndrome, and xeroderma pigmentosum, etc.

[1453] In some embodiments, a method of treating multiple myeloma is provided, comprising administering to a patient 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, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a compound of formula I or II, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, forms a composition for treating multiple myeloma, wherein the method comprises administering the compound to a patient.

[1454] In some embodiments, a method for controlling the progression of multiple myeloma is provided, comprising administering to a patient 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, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a composition is formed in a pharmaceutically acceptable carrier of a compound of formula I, II, III, IV, XV, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, for controlling the progression of multiple myeloma, wherein the method comprises administering the compound to a patient.

[1455] In some implementations, a method is provided for inducing a treatment response in patients with multiple myeloma, the treatment response being assessed using the International Uniform Response Criteria for Multiple Myeloma (IURC) (in Durie BGM et al., "International uniform response criteria for multiple myeloma"). LeukemiaAs described in 2006, 10(10):1-7), comprising administering to a patient 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, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[1456] In some embodiments, a method for treating solid tumors (e.g., non-small cell lung cancer or melanoma) is pro...

Claims

1. A compound with the following formula: (I) (II) (III) (IV) (V) (VI) (VII) (VIII) (IX) (X) (XI) (XII) (XIII) or (XIV) Or its pharmaceutically acceptable salt; in: A is selected from , , , , , , , , , , , , and ; B is selected from , , , , and ; n is 0, 1, or 2; X is NR 10 NR 6' , O or S; X' is NR 10 O, CH2 or S; Q is CR 7 Or N; Q' and Q" are each independently selected from CR 6 and N; Ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein, where valence permits, ring-A is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents of the substituents; Ring -B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein, where valence permits, ring -B is optionally composed of 1, 2, or 3 independently selected from R 2 Substituents of the substituents; The ring-C is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, and 5- to 6-membered cycloalkenyl, wherein, where valence permits, the ring-C is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents of the substituents; Ring-D is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, and 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-D is optionally composed of 1, 2, or 3 independently selected from R. 2 Substituents of the substituents; R 1 and R 2 Each case is independently selected (a) Hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, wherein each of the heteroaryl, aryl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; (b) , and ; as well as (c) If valence and stability permit, divalent portions such as =O, =S, or =NR 25 ;and Where R 1 The group can optionally be combined with another R 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings, which can bridge ring-A and ring-B or ring-C and ring-D; R 3 It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3 and R 6 Combined to form 1 or 2 carbon connections; Or R 3 and R 4 Combining to form 1, 2, 3, or 4 carbon connections; Or R 3 and R 3 Adjacent R 4 Groups combine to form double bonds; Each R 4 Independently selected from hydrogen, alkyl, halogen, and haloalkyl; R 5 It is hydrogen, alkyl, halogen, or haloalkyl; R 6 and R 7 In each case, it is independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 Where R 6 and R 7 On the same carbon atom, they can optionally form 3- to 4-membered spirocycles; R 6 It is hydrogen, alkyl, or haloalkyl; Or R 3 and R 6 'Combined to form 1 or 2 carbon connections;' R 10 and R 11 Each is independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 12 -S(O)R 12 and -SO2R 12 ; Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -NR 13 R 14 and OR 13 ; R 13 and R 14 Each is independently selected from hydrogen, alkyl, and haloalkyl; Each X 2 It is selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, alkyl groups, aliphatic groups, heteroaliphatic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 The divalent moieties of -, -C(S)-, -S(O)-, -S(O)2-, and -S-; the heterocycle, aryl, heteroaryl, and bicyclic are each optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; X 3 It is selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 -, -C(S)-, -S(O)-, -S(O)2-, -S-, arylalkyl, heterocyclic alkyl, or heteroarylalkyl (in any direction) divalent moiety; the heterocycle, aryl, heteroaryl, and bicyclic can each be 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 15 R 16 and R 17 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -、-C(R 40 R 41 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, arylalkyl, heterocyclic alkyl, and heteroarylalkyl (in any direction); each optionally selected by 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 18 Selected from hydrogen, alkyl, olefin, alkyne, hydroxyl, azide, amino, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; R 20 R 21 R 22 R 23 and R 24 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -, alkene oxide, -C(R) 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefinic, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic, glycolic acid, and carbocyclic; each optionally selected by 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 25 It is an aliphatic group, aryl group, heteroaryl group, or hydrogen; R 26 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic groups; R 27 Each time it appears, it is independently selected from 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 Each time it appears, it is independently selected from hydrogen, R 27 Alkyl, olefin, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic), -N (aliphatic)2, -NHSO2 (aliphatic), -N (aliphatic)SO2alkyl, -NHSO2 (aryl, heteroaryl, or heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl, or heterocyclic), -NHSO2alkenyl, -N (alkyl)SO2alkenyl, -NHSO2ynyl, -N (alkyl)SO2ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl; and R 41 It is an aliphatic group, aryl group, heteroaryl group, or hydrogen.

2. A compound with the following formula: (XV) (XVI) or (XVII) Or its pharmaceutically acceptable salt; in AA is selected from , , , , , , , , , , , , , , , and ; n is 0, 1, or 2; X is NR 10 NR 6 ', O or S; Each X 2 It is selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, alkyl groups, aliphatic groups, heteroaliphatic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 The divalent moieties of -, -C(S)-, -S(O)-, -S(O)2-, and -S-; the heterocycle, aryl, heteroaryl, and bicyclic are each optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; X 3 It is selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 -, -C(S)-, -S(O)-, -S(O)2-, -S-, arylalkyl, heterocyclic alkyl, or heteroarylalkyl (in any direction) divalent moiety; the heterocycle, aryl, heteroaryl, and bicyclic can each be 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; Q is CR 7 Or N; Ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein, where valence permits, ring-A is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents of the substituents; Ring -B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, and 5- to 8-membered cycloalkenyl, wherein, where valence permits, ring -B is optionally composed of 1, 2, or 3 independently selected from R 2 Substituents of the substituents; Ring-E is selected from (a) , , , , , , and ;as well as (b) A fused ring selected from 5-membered heteroaryl, 5-to-8-membered heterocyclic, 5-to-8-membered cycloalkyl, or 5-to-8-membered cycloalkenyl, optionally composed of 1, 2, or 3 independently selected from R, where valence permits. 2 Substituents of the substituents; Ring-F is selected from (a) Selected independently from R by 1, 2 or 3 1 'Substituents of phenyl groups; and (b) A fused ring selected from 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, optionally composed of one, two, or three independently selected from R, where valence permits. 1 Substituents of the substituents; R 1 and R 2 Each case is independently selected (a) Hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, wherein each of the heteroaryl, aryl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; (b) , and ;as well as (c) If valence and stability permit, divalent portions such as =O, =S, or =NR 25 ;and Where R 1 The group can optionally be combined with another R 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-B. R 1 'Selected independently in each case' (a) Alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, cycloalkyl, and heterocyclic, wherein each of the heteroaryl, aryl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; (b) , and ;as well as (c) If valence and stability permit, divalent portions such as O, S, or =NR 25 ;and Where R 1 The group can optionally be combined with another R 1 'Group or R 2 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 2 'In each case, it is independently selected from alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyano, nitro, heteroaryl, aryl, and heterocyclic; or, if valence and stability permit, R 2 'Can be a divalent part such as O, S, or =NR 25 ; and R 2 The group can optionally be combined with another R 2 'Group or R 1 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 2 "In each case, the components are independently selected from heteroaryl, aryl, and heterocyclic groups, wherein each of the heteroaryl, aryl, and heterocyclic groups is optionally selected independently from 1, 2, 3, or 4 R groups." 40 Substituents of R, and R 2 "The group can optionally be combined with R" 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings that can bridge ring-A and ring-E; R 3 It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3 and R 6 Combined to form 1 or 2 carbon connections; Or R 3 and R 4 Combining to form 1, 2, 3, or 4 carbon connections; Or R 3 and R 3 Adjacent R 4 Groups combine to form double bonds; Each R 4 Independently selected from hydrogen, alkyl, halogen, and haloalkyl; R 5 It is hydrogen, alkyl, halogen, or haloalkyl; R 6 and R 7 In each case, it is independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 Where R 6 and R 7 On the same carbon atom, they can optionally form 3- to 4-membered spirocycles; R 6 It is hydrogen, alkyl, or haloalkyl; Or R 3 and R 6 'Combined to form 1 or 2 carbon connections;' R 3a It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3a and R 6a Combined to form 1 or 2 carbon connections; Or R 3a and R 4a Combining to form 1, 2, 3, or 4 carbon connections; Or R 3a and R 3a Adjacent R 4a Groups combine to form double bonds; R 4a Selected from hydrogen, alkyl, halogen, and haloalkyl; R 6a Selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 ; Where R 3a R 4a and R 6a At least one of them is not hydrogen; R 10 and R 11 Each is independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 12 -S(O)R 12 and -SO2R 12 ; Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -NR 13 R 14 and OR 13 ; R 13 and R 14 Each is independently selected from hydrogen, alkyl, and haloalkyl; R 28 Selected from alkyl, olefin, alkyne, hydroxyl, azide, amino, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; Where R 15 R 16 R 17 and R 20 If at least one of them is not a key, then R 28 It could be hydrogen; R 15 R 16 and R 17 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -、-C(R 40 R 41 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, arylalkyl, heterocyclic alkyl, and heteroarylalkyl (in any direction); each optionally selected by 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 18 Selected from hydrogen, alkyl, olefin, alkyne, hydroxyl, azide, amino, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyanoyl, nitro, heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic, wherein each heteroaryl, aryl, arylalkyl, cycloalkyl, and heterocyclic is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; R 20 R 21 R 22 R 23 and R 24 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -, alkene oxide, -C(R) 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefinic, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic, glycolic acid, and carbocyclic; each optionally selected by 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 25 It is an aliphatic group, aryl group, heteroaryl group, or hydrogen; R 26 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic groups; R 27 Each time it appears, it is independently selected from 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 Each time it appears, it is independently selected from hydrogen, R 27 Alkyl, olefin, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic), -N (aliphatic)2, -NHSO2 (aliphatic), -N (aliphatic)SO2alkyl, -NHSO2 (aryl, heteroaryl, or heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl, or heterocyclic), -NHSO2alkenyl, -N (alkyl)SO2alkenyl, -NHSO2ynyl, -N (alkyl)SO2ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl; and R 41 It is an aliphatic group, aryl group, heteroaryl group, or hydrogen.

3. The compound according to claim 2, wherein ring -F is composed of 1, 2, or 3 independently selected from R 1 'The substituent of the phenyl group.

4. The compound according to claim 3, wherein R 1 'Selected from alkyl, halogen and haloalkyl.' 5. The compound according to claim 3, wherein R 1 'Selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 .

6. The compound according to claim 3, wherein R 1 Selected from halogens.

7. The compound according to claim 3, wherein R 1 'Selected from heteroaryl, aryl and heterocyclic compounds.' 8. The compound according to claim 3, wherein the two Rs 1 Substituents combine to form fused benzene rings.

9. The compound according to claim 3, wherein at least one R 1 'It is an alkyl group.' 10. The compound according to claim 3, wherein at least one R 1 It is a halogen.

11. The compound according to claim 3, wherein one of R... 1 'yes .

12. The compound according to claim 3, wherein one of R... 1 'yes .

13. The compound according to claim 3, wherein one of R... 1 'for .

14. The compound according to claim 2, wherein the ring-E is selected from: , , and .

15. The compound according to claim 14, wherein R 2 'Selected from alkyl, halogen and haloalkyl.' 16. The compound according to claim 14, wherein R 2 'Selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 .

17. The compound according to claim 14, wherein R 2 Selected from halogens.

18. The compound according to claim 14, wherein R 2 'Selected from heteroaryl, aryl and heterocyclic compounds.' 19. The compound of claim 14, wherein the two Rs 2 Substituents combine to form fused benzene rings.

20. The compound according to claim 14, wherein at least one R 2 'It is an alkyl group.' 21. The compound according to claim 14, wherein at least one R 2 It is a halogen.

22. The compound according to any one of claims 11-21, wherein X 3 and X 2 At least one of them is a key.

23. The compound according to any one of claims 11-21, wherein X 3 and X 2 At least one of them is -O-.

24. The compound according to any one of claims 11-21, wherein X 3 and X 2 At least one of them is -S-.

25. The compound according to any one of claims 11-21, wherein X 3 and X 2 At least one of them is -NR 27 - 26. The compound according to any one of claims 11-25, wherein R 15 and R 24 At least one of them is a key.

27. The compound according to any one of claims 11-26, wherein R 16 and R 23 At least one of them is a key.

28. The compound according to any one of claims 11-27, wherein R 17 and R 22 At least one of them is a key.

29. The compound according to any one of claims 11-25, wherein the compound is selected from R 15 R 16 R 17 R 19 R 20 R 21 R 22 R 23 and R 24 No more than 4 substituents are selected as bonds.

30. The compound according to any one of claims 11-25, wherein the compound is selected from R 15 R 16 R 17 R 19 R 20 R 21 R 22 R 23 and R 24 No more than 3 substituents are selected as bonds.

31. The compound according to any one of claims 11-25, wherein the compound is selected from R 15 R 16 R 17 R 19 R 20 R 21 R 22 R 23 and R 24 No more than two substituents are selected as bonds.

32. The compound according to any one of claims 11-25, wherein the compound is selected from R. 15 R 16 R 17 R 19 R 20 R 21 R 22 R 23 and R 24 No more than one substituent may be selected as a bond.

33. The compound according to any one of claims 1-32, wherein ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, and 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-A is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents are substituted.

34. The compound according to any one of claims 1-32, wherein ring-A is a fused ring selected from phenyl and 6-membered heteroaryl groups, wherein, where valence permits, ring-A is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents are substituted.

35. The compound according to any one of claims 1-32, wherein, where the valence permits, ring -A is optionally composed of 1, 2, or 3 independently selected from R 1 The phenyl group is substituted with a substituent.

36. The compound according to any one of claims 1-32, wherein, where the valence permits, ring -A is optionally composed of 1, 2, or 3 independently selected from R 1 The substituents are substituted into the 6-membered heteroaryl group.

37. The compound according to any one of claims 1-36, wherein ring-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, and 5- to 6-membered cycloalkenyl, wherein, where valence permits, ring-B is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents are substituted.

38. The compound according to any one of claims 1-36, wherein ring-B is a fused ring selected from phenyl or a 6-membered heteroaryl group, wherein, where valence permits, ring-B is optionally composed of 1, 2, or 3 independently selected from R 1 Substituents are substituted.

39. The compound according to any one of claims 1-36, wherein, where the valence permits, ring -B is optionally composed of one, two, or three independently selected from R 1 The phenyl group is substituted with a substituent.

40. The compound according to any one of claims 1-36, wherein, where the valence permits, ring -B is optionally composed of one, two, or three independently selected from R 1 The substituents are substituted into the 6-membered heteroaryl group.

41. The compound according to any one of claims 1-40, wherein R 5 It is hydrogen.

42. The compound according to any one of claims 1-40, wherein R 5 It is an alkyl group.

43. The compound according to any one of claims 1-40, wherein R 5 It is halogen.

44. The compound according to any one of claims 1-40, wherein R 5 It is a haloalkyl group.

45. The compound according to any one of claims 1-44, wherein R 7 It is hydrogen.

46. ​​The compound according to any one of claims 1-44, wherein R 7 It is a halogen, a haloalkyl, or an alkyl group.

47. The compound according to any one of claims 1-44, wherein R 7 Yes - OR 10 -SR 10 or -NR 10 R 11 .

48. The compound according to any one of claims 1-44, wherein R 7 It is -S(O)R 12 or -SO2R 12 .

49. The compound according to any one of claims 1-48, wherein four R's are present. 2 Substituents.

50. The compound according to any one of claims 1-48, wherein three R's are present. 2 Substituents.

51. The compound according to any one of claims 1-48, wherein two R's are present. 2 Substituents.

52. The compound according to any one of claims 1-48, wherein one R is present. 2 Substituents.

53. The compound according to any one of claims 1-52, wherein R 2 Selected from alkyl, halogen and haloalkyl.

54. The compound according to any one of claims 1-52, wherein R 2 Selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 .

55. The compound according to any one of claims 1-52, wherein R 2 Selected from halogens.

56. The compound according to any one of claims 1-52, wherein R 2 Selected from heteroaryl, aryl, and heterocyclic compounds.

57. The compound according to any one of claims 1-51, wherein the two Rs 2 Substituents combine to form fused benzene rings.

58. The compound according to any one of claims 1-52, wherein at least one R 2 It is an alkyl group.

59. The compound according to any one of claims 1-52, wherein at least one R 2 It is halogen.

60. The compound according to any one of claims 1-52, wherein one of R... 2 yes .

61. The compound according to any one of claims 1-52, wherein one of R... 2 yes .

62. The compound according to any one of claims 1-52, wherein one of R... 2 yes .

63. The compound according to any one of claims 1-62, wherein R 3 It is hydrogen.

64. The compound according to any one of claims 1-62, wherein R 3 It is an alkyl group.

65. The compound according to any one of claims 1-62, wherein R 3 It is a haloalkyl group.

66. The compound according to any one of claims 1-62, wherein R 3 and R 6 Combined to form a one-carbon link.

67. The compound according to any one of claims 1-62, wherein R 3 and R 6 Combined to form a two-carbon bond.

68. The compound according to any one of claims 1-65, wherein R 6 It is hydrogen.

69. The compound according to any one of claims 1-65, wherein R 6 It is an alkyl group.

70. The compound according to any one of claims 1-65, wherein R 6 It is a haloalkyl group.

71. The compound according to any one of claims 1-70, wherein at least one R 4 It is hydrogen.

72. The compound according to any one of claims 1-70, wherein at least one R 4 It is an alkyl group.

73. The compound according to any one of claims 1-70, wherein at least one R 4 It is a haloalkyl group.

74. The compound according to any one of claims 1-70, wherein n is 0.

75. The compound according to any one of claims 1-73, wherein n is 1.

76. The compound according to any one of claims 1-73, wherein n is 2.

77. The compound according to any one of claims 1-76, wherein four R's are present. 1 Substituents.

78. The compound according to any one of claims 1-76, wherein three R's are present. 1 Substituents.

79. The compound according to any one of claims 1-76, wherein two R's are present. 1 Substituents.

80. The compound according to any one of claims 1-76, wherein one R is present. 1 Substituents.

81. The compound according to any one of claims 1-80, wherein R 1 Selected from alkyl, halogen and haloalkyl.

82. The compound according to any one of claims 1-80, wherein R 1 Selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 .

83. The compound according to any one of claims 1-80, wherein R 1 Selected from halogens.

84. The compound according to any one of claims 1-80, wherein R 1 Selected from heteroaryl, aryl, and heterocyclic compounds.

85. The compound according to any one of claims 1-79, wherein the two Rs 1 Substituents combine to form fused benzene rings.

86. The compound according to any one of claims 1-80, wherein at least one R 1 It is an alkyl group.

87. The compound according to any one of claims 1-80, wherein at least one R 1 It is halogen.

88. The compound according to any one of claims 1-80, wherein one of R... 1 yes .

89. The compound according to any one of claims 1-80, wherein one of R... 2 yes .

90. The compound according to any one of claims 1-80, wherein one of R... 1 yes .

91. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (I) Or its pharmaceutically acceptable salt.

92. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (II) Or its pharmaceutically acceptable salt.

93. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (III) Or its pharmaceutically acceptable salt.

94. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (IV) Or its pharmaceutically acceptable salt.

95. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (V) Or its pharmaceutically acceptable salt.

96. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (WE) Or its pharmaceutically acceptable salt.

97. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (VII) Or its pharmaceutically acceptable salt.

98. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (VIII) Or its pharmaceutically acceptable salt.

99. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (IX) Or its pharmaceutically acceptable salt.

100. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (X) Or its pharmaceutically acceptable salt.

101. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (XI) Or its pharmaceutically acceptable salt.

102. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (XII) Or its pharmaceutically acceptable salt.

103. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (XIII) Or its pharmaceutically acceptable salt.

104. The compound according to any one of claims 1 and 3-90, wherein the compound has the following formula: (XIV) Or its pharmaceutically acceptable salt.

105. The compound according to any one of claims 2-90, wherein the compound has the following formula: (XV) Or its pharmaceutically acceptable salt.

106. The compound according to any one of claims 2-90, wherein the compound has the following formula: (XVI) Or its pharmaceutically acceptable salt.

107. The compound according to any one of claims 2-90, wherein the compound has the following formula: (XVII) Or its pharmaceutically acceptable salt.

108. A pharmaceutical composition comprising a compound according to any one of claims 1-107 and a pharmaceutically acceptable excipient.

109. A method for treating a medical disorder mediated by hydroxycerebrosides in a patient, comprising administering to the patient an effective amount of the compound according to any one of claims 1-107 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 108.

110. The method of claim 109, wherein the obstacle is abnormal cell proliferation.

111. The method of claim 109, wherein the disorder is a neurodegenerative disease.

112. The method of claim 109, wherein the obstacle is an autoimmune disease.

113. The method according to any one of claims 109-112, wherein the patient is a human being.

114. A compound for preparing a medicament for treating a patient with a disorder mediated by hydroxycerebrosides, wherein the compound is selected from the compounds according to any one of claims 1-107 or pharmaceutically acceptable salts thereof.

115. The compound of claim 114, wherein the barrier is abnormal cell proliferation.

116. The compound of claim 114, wherein the disorder is a neurodegenerative disease.

117. The compound of claim 114, wherein the obstacle is an autoimmune disease.

118. The compound according to any one of claims 114-117, wherein the patient is a human.

119. Use of a compound in the treatment of a patient with a disorder mediated by hydroxycerebrosides, wherein the compound is selected from the compounds according to any one of claims 1-107 or pharmaceutically acceptable salts or compositions thereof.

120. The use according to claim 119, wherein the obstacle is abnormal cell proliferation.

121. The use according to claim 119, wherein the disorder is a neurodegenerative disease.

122. The use according to claim 119, wherein the obstacle is an autoimmune disease.

123. The use according to any one of claims 119-122, wherein the patient is a person.

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