Ikaros and Aiolos tricyclic decomposition inducers

Abstract

To provide: new compounds that cause the degradation of Ikaros or Aiolos for medical therapy, including the treatment of hematopoietic disorders that involve abnormal cellular proliferation, including tumors and cancers; and treatment methods.SOLUTION: As a tricyclic cereblon binder, a compound of formula I or II is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 833,107, filed on 12 April 2019. This application in its entirety constitutes a part of this specification by reference for all purposes.

[0002] The present invention provides cereblon conjugates for the degradation of Ikaros (IKZF1) or Aiolos (IKZF3) via the ubiquitin-proteasome pathway for therapeutic applications as further described herein. [Background technology]

[0003] Proteolysis is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved by the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of virtually all cellular processes, including antigen processing, apoptosis, organelle biosynthesis, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neurodegeneration and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biosynthesis, and viral infection.

[0004] The covalent bonding of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases labels proteins for proteasomal degradation, where the protein is digested into small peptides and ultimately into its constituent amino acids, which become the building blocks of new proteins. Defects in proteasomal degradation have been associated with a variety of clinical disorders, particularly Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0005] The Ikaros ("IKZF") family consists of a series of zinc finger protein transcription factors crucial for certain physiological processes, particularly lymphocyte development (see Non-Patent Literature 1). Ikaros ("IKZF1") was first discovered in 1992 (see Non-Patent Literature 2), and over the following 20 years, four additional homologs—Helios ("IKZF2"), Aiolos ("IKZF3"), Eos ("IKZF4"), and Pegasus ("IKZF5")—have been identified (see Non-Patent Literature 3). Each homolog gene can produce several protein isoforms through alternative splicing, and theoretically, a large number of protein complexes can be generated by various combinations of homologs. A set of two C-terminal Cys2His2 zinc finger motifs that mediate protein interactions between various members of this protein family is highly conserved among the members of this family. Up to four zinc finger motifs are present at the N-terminus for DNA sequence recognition, and the number of these N-terminal zinc fingers is altered by alternative splicing. Isoforms lacking these N-terminal zinc fingers exhibit a dominant-negative effect on transcriptional activation (see Non-Patent Document 4).

[0006] The distribution of various members of the Ikaros protein family within the body varies considerably. Ikaros, Helios, and Aiolos are primarily found in lymphoid cells and their corresponding progenitor cells, with Ikaros also being detected in the brain, and both Ikaros and Helios being detected in erythroid cells. Eos and Pegasus are more widely distributed and found in skeletal muscle, liver, brain, and heart (see Non-Patent Documents 5, 6, and 7).

[0007] Ikaros is crucial for proper lymphocyte development. Deletion of the exons encoding the first three N-terminal zinc fingers results in mice lacking T cells, B cells, natural killer (NK) cells, and their precursor cells. Genetic alterations in Ikaros are associated with poor outcomes in the treatment of acute lymphoblastic leukemia (ALL). Ikaros and Aiolos are involved in the proliferation of multiple myeloma cells, suggesting a potential role in malignant tumors.

[0008] The drug thalidomide, and its analogs lenalidomide and pomalidomide, have attracted particular interest as immunomodulators and antineoplastic agents, especially in the treatment of multiple myeloma (see Non-Patent Documents 8 and 9). Although the exact mechanisms of therapeutic action of thalidomide, lenalidomide, and pomalidomide are unknown, these compounds are used to treat several cancers, including multiple myeloma. Clinical and preclinical studies are also being conducted on their use in the treatment of renal cell carcinoma, glioblastoma, prostate cancer, melanoma, colorectal cancer, Crohn's disease, rheumatoid arthritis, Behçet's syndrome, breast cancer, head and neck cancer, ovarian cancer, chronic heart failure, graft-versus-host disease, and tuberculous meningitis.

[0009] Thalidomide and its analogs have been found to bind to the ubiquitin ligase cereblon, altering the direction of its ubiquitination activity (see Non-Patent Literature 10). Cereblon is part of the E3 ubiquitin ligase complex, and interacts with damaged DNA-binding protein 1 to form the E3 ubiquitin ligase complex with karin 4 and the E2-binding protein ROC1 (known as RBX1), functioning as a substrate receptor that selects proteins for ubiquitination.

[0010] The binding of lenalidomide to cereblon promotes the subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and degradation by the proteasome (see Non-Patent Documents 11 and 12).

[0011] The disclosure that thalidomide binds to cereblon E3 ubiquitin ligase has led to research investigating the incorporation of thalidomide and certain derivatives into compounds for targeted protein disruption. Celgene, Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4. The invention discloses IMDs for similar uses, including those described in Patent Documents 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24.

[0012] Patent document 25, filed by the Dana Farber Cancer Institute, discloses a cereblon regulator.

[0013] Patent document 26, filed by C4 Therapeutics, Inc., describes the decomposition of Ikaros. The document discloses a cereblon binder. [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] U.S. Patent No. 6,045,501 [Patent Document 2] U.S. Patent No. 6,315,720 [Patent Document 3] U.S. Patent No. 6,395,754 [Patent Document 4] U.S. Patent No. 6,561,976 [Patent Document 5] U.S. Patent No. 6,561,977 [Patent Document 6] U.S. Patent No. 6,755,784 [Patent Document 7] U.S. Patent No. 6,869,399 [Patent Document 8] U.S. Patent No. 6,908,432 [Patent Document 9] U.S. Patent No. 7,141,018 [Patent Document 10] U.S. Patent No. 7,230,012 [Patent Document 11] U.S. Patent No. 7,820,697 [Patent Document 12] U.S. Patent No. 7,874,984 [Patent Document 13] U.S. Patent No. 7,959,566 [Patent Document 14] U.S. Patent No. 8,204,763 [Patent Document 15] U.S. Patent No. 8,315,886 [Patent Document 16] U.S. Patent No. 8,589,188 [Patent Document 17] U.S. Patent No. 8,626,531 [Patent Document 18] U.S. Patent No. 8,673,939 [Patent Document 19] U.S. Patent No. 8,735,428 [Patent Document 20] U.S. Patent No. 8,741,929 [Patent Document 21] U.S. Patent No. 8,828,427 [Patent Document 22] U.S. Patent No. 9,056,120 [Patent Document 23] U.S. Patent No. 9,101,621 [Patent Document 24] U.S. Patent No. 9,101,622 [Patent Document 25] International Publication No. 2020 / 006262 [Patent Document 26] International application PCT / US19 / 24094 [Non-patent literature]

[0015] [Non-Patent Document 1] Fan, Y. and Lu, D. "The Ikaros family of zinc-finger proteins" Acta Pharmaceutica Sinica B, 2016, 6:513-521

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[0016] The object of the present invention is to provide novel compounds, uses, and manufacturing processes that induce the degradation of Ikaros or Aiolos for medical therapies, including the treatment of hematopoietic disorders accompanied by abnormal cell proliferation, including tumors and cancer. [Means for solving the problem]

[0017] This paper provides novel compounds that bind to cereblon, along with their uses and manufacturing processes. It is believed that the binding of the disclosed compounds to cereblon increases the interaction between cereblon and Ikaros (IKZF1) or Aiolos (IKZF3), leading to their subsequent ubiquitination and proteasomal degradation. A decrease in Ikaros or Aiolos levels results in altered transcriptional regulation of their downstream proteins. The selected compounds are found to be not only potent binding agents for cereblon but also to exhibit potent inhibition of multiple myeloma cell proliferation compared to pomalidomide.

[0018] The selected compounds, pharmaceutically acceptable salts thereof or pharmaceutically acceptable compositions disclosed herein can be used for the treatment of disorders mediated by Ikaros or Aiolos, such as hematopoietic malignancies such as multiple myeloma, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, etc., or other target indications. Accordingly, in one embodiment, there is provided a method of treating a host (usually a human) having a disorder mediated by Ikaros or Aiolos, which comprises administering to the host an effective amount of the disclosed compound described herein or a pharmaceutically acceptable salt thereof, optionally as a pharmaceutically acceptable composition.

[0019] In one aspect, in a pharmaceutically acceptable carrier optionally for forming a composition, of formula I:

Chemical formula

[0020] In one embodiment, the compound of formula I is formulas Ia, Ib, and Ic: [ka] (All variable parts in the formula are as defined herein) are selected from:

[0021] In another embodiment, compounds of formula I are formulas Id, Ie, If, and Ig: [ka] (All variable parts in the formula are as defined herein) are selected from:

[0022] In another embodiment, a compound of formula I has the formula Ih: [ka] (All variable parts in the formula are as defined herein) are selected from:

[0023] In one embodiment, a compound of formula (II) in a pharmaceutically acceptable carrier for optionally forming a composition: [ka] (In the ceremony X 3 is a combination, NR 2 , C(R 3 R 3’ ), selected from O, C(O), C(S), S, S(O), and S(O)2, R 20 , R 21 , R 22 , R 23 and R 24 In each case, the bonds are independent: alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -P(O)(R 28 Selected from the group consisting of )-, -P(O)-, alkenes, alkynes, haloalkyls, aryls, heterocyclics, heteroaryls, bicyclics, and carbocyclics, each of which is R 40Optionally substituted with one, two, three, or four substituents independently selected from R 20 , R 21 , R 22 , R 23 and R 24 teeth, i. -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -P(O)(R 28 The )-, -P(O)-, and -C(S)- parts are adjacent to each other, or ii. -O-, -S-, or -NR 2 - The parts are adjacent to each other, or iii. Otherwise, unstable molecules will be produced (partial R 20 , R 21 , R 22 , R 23 and R 24 The selection of parts cannot be performed in such an order that the parts are selected, which is defined as producing molecules with a shelf life of less than approximately 4 months (or alternatively, less than approximately 6 months or 5 months) at room temperature due to degradation caused by the selection and order of the parts. R 25 Hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -OR 2 , -NR 2 R 2’ , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 , selected from haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic and cycloalkyl, and its R 25 Each of the elements is R 12 It is optionally replaced by one, two, three, or four elements independently selected from the above, R 28 In either case, hydrogen and -NR are produced independently. 2 R 2’ , -OR 2 , -SR 2 Selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, R 40In each case, these are independently hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, and -NR. 2 R 2’ , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 Selected from the group consisting of haloalkyl, aryl, heteroaryl, heterocyclic, and cycloalkyl, and its R 40 Each of the elements is R 12 It can be arbitrarily replaced by one, two, three, or four elements selected independently from it, or two R 40 They combine to form an oxo group, A formula is provided in which all other variable parts are as defined herein) or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof.

[0024] In one embodiment, the compounds described herein bind to cereblon, increasing the interaction between cereblon and Ikaros (IKZF1) or Aiolos (IKZF3), leading to subsequent ubiquitination and protein degradation in the proteasome.

[0025] In one embodiment, the compound of the present invention selectively decomposes IKZF1 and / or IKZF3 with respect to one or more IKZF2 and / or IKZF4 and / or IKZF5.

[0026] Accordingly, in several embodiments, based on this discovery, compounds and methods are provided for the treatment of patients having disorders mediated by Ikaros(IKZF1) or Aiolos(IKZF3). Ikaros(IKZF1) or Aiolos(IKZF3) are targeted for selective degradation by a method comprising administering, either alone or in combination with another activator, an effective amount of the selected compound described herein in a pharmaceutically acceptable carrier for optionally forming a composition to a patient (usually a human) in need. In one embodiment, the disorder is a lymphatic disorder. In another embodiment, the disorder is leukemia. In one embodiment, the disorder is lymphocytic leukemia. In one embodiment, the disorder is lymphoblastic leukemia. In several embodiments, the disorder is a hematological malignancy, such as multiple myeloma, myelodysplastic syndromes such as 5q- syndrome, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia. In another embodiment, the selected compound of the present invention is administered to achieve immunomodulation and reduce angiogenesis.

[0027] In other embodiments, but not limited to, benign tumors, neoplasms, tumors, cancer, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteinopathy, proteinopathy, or fibrosis. Compounds and methods for the treatment of disorders, including sexual disorders, are presented. Furthermore, other disorders that can be treated with an effective amount of the compounds described herein are listed below.

[0028] In certain embodiments, any compound described herein has isotopic substitution of at least one desired atom in amounts approximately equal to the natural abundance of the isotope, i.e., an enriched amount. In one embodiment, the compound comprises one or more deuterium atoms.

[0029] Other features and advantages of the present invention will become apparent from the following detailed description and claims.

[0030] Therefore, the present invention includes at least the following features: (a) Compounds of formula I or formula II as described herein, or pharmaceutically acceptable salts, isotopic derivatives (including deuterated derivatives) or prodrugs thereof, (b) Compounds of formula I or formula II described herein, or pharmaceutically acceptable salts, isotopic derivatives or prodrugs thereof, for the treatment of disorders mediated by Ikaros or Aiolos. (c) Patients having any one of the disorders described herein, including disorders mediated by Ikaros or Aiolos, typically, the use of an effective amount of a compound of formula I or formula II described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, (d) Use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the manufacture of a drug for the treatment of a medical disorder to which the person is sensitive as further described herein. (e) A method for producing a drug for the treatment of a disorder described herein in a host, characterized by using a compound of formula I or formula II in the production. (f) For the treatment of cancer in a host including any cancer described herein, a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt thereof, isotope derivative or prodrug thereof (g) Use of compounds of formula I or formula II as described herein, or pharmaceutically acceptable salts, isotopic derivatives or prodrugs thereof, in the manufacture of agents for the treatment of cancer, including any cancer described herein. (h) A method for producing a drug for the treatment of cancer in a host, including any cancer described herein, characterized by using a compound of formula I or formula II in the production process. (i) For the treatment of tumors in a host containing any tumor described herein, a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, (j) Use of a compound of formula I or formula II as described herein, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the manufacture of a drug for the treatment of any tumor described herein, including any tumor described herein. (k) The invention described herein, characterized in that a compound of formula I or formula II is used in the production. A method for producing a drug for the treatment of tumors in a host containing any tumor, (l) Compounds of formula I or formula II as described herein, or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof, for the treatment of immune disorders, autoimmune disorders or inflammatory disorders in a host. (m) Use of compounds of formula I or formula II described herein, or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof, in the manufacture of agents for the treatment of immunodeficiency, autoimmune disorder or inflammatory disorder. (n) A method for producing a drug for the treatment of an immune disorder, autoimmune disorder, or inflammatory disorder in a host, characterized by using a compound of formula I or formula II in the production process. (o) Compounds of formula I or formula II as described herein, or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof, for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma. (p) Use of compounds of formula I or formula II described herein, or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof, in the manufacture of agents for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma. (q) A method for producing a drug for the treatment of hematological malignancies in a host, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma, characterized by using a compound of formula I or formula II in the production process. (r) A pharmaceutical composition comprising an effective host therapeutic dose of a compound of formula I or formula II described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent. (s) Compounds described herein as a mixture of enantiomers or diastereomers (where appropriate), including a racemate. (t) Compounds described herein in concentrated forms (where appropriate) as enantiomers or diastereomers, including isolated enantiomers or diastereomers (i.e., 85%, 90%, 95%, 97%, or 99% ultrapure), and (u) A process for preparing a therapeutic product containing an effective amount of a compound of formula I or formula II described herein. [Modes for carrying out the invention]

[0031] I. Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this application pertains. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Methods and materials similar to or equivalent to those described herein may be used in the implementation and testing of this application, but preferred methods and materials are described below. All publications, patent applications, patents and other references referenced herein constitute part of this specification by reference. References cited herein are not considered prior art to this application. In case of conflict, this specification, including definitions, shall prevail. In addition, materials, methods and examples are illustrative and not intended to be limiting.

[0032] Compounds are described using their formal names. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains.

[0033] In one embodiment of each compound described herein, unless explicitly excluded by context, the compound is a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, or N-oxygen compound, as specifically described. It may be in the form of a dolome, or an isomer such as a rotational isomer.

[0034] The terms "a" and "an" do not indicate a limit on quantity, but rather indicate the presence of at least one of the items mentioned. The term "or" means "and / or". Unless otherwise specified herein, the enumeration of value ranges is intended to serve merely as a simple way to refer individually to each distinct value contained within that range, and each distinct value constitutes part of this specification by reference as if they were individually enumerated herein. The endpoints of all ranges are contained within that range and can be combined independently. All methods described herein can be performed in a preferred order unless otherwise specified herein or clearly contradicted by the context. The use of example or illustrative words (e.g., "such as") is merely intended to better illustrate the invention. This does not indicate a limitation of the scope of the present invention unless otherwise stated.

[0035] The present invention includes compounds described herein that have isotopic substitution of at least one desired atom in an amount exceeding the natural abundance of the isotope, i.e., enriched. Isotopes are atoms that have the same atomic number but different mass numbers, i.e., the same number of protons but different number of neutrons. When isotopic substitution is used, substitution of hydrogen with at least one deuterium is common.

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

[0037] As a general example, though not limited to them, hydrogen isotopes, for example, deuterium ( 2 H) and tritium ( 3 H) can be used in any part of the described structure in which the desired result is achieved. Alternatively or additionally, carbon isotopes, for example 13 C and 14 You can use C.

[0038] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is replaced by deuterium. In certain embodiments, isotopes are enriched to 90%, 95%, 99%, or more at any position of interest. In one non-limiting embodiment, deuterium is enriched to 90%, 95%, or 99% at a desired position.

[0039] In one non-limiting embodiment, the substitution of a hydrogen atom with a deuterium atom can occur in any of the compounds described herein. For example, if any of the groups are methyl, ethyl, or methoxy, or contain these by substitution, for example, an alkyl residue may be deuterated (e.g., CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 in a non-limiting embodiment). In a certain other embodiment, if two substituents combine to form a ring, an unsubstituted carbon may be deuterated. One Embodiment In this compound, at least one deuterium atom is located on an atom having a bond that is degraded during the metabolism of the compound in vivo, or is located one, two, or three atoms away from the bond that is metabolized (for example, this may be referred to as α, β, or γ or primary, secondary, or tertiary isotope effects).

[0040] The compounds of the present invention can form solvates with a solvent (including water). Therefore, in one non-limiting embodiment, the present invention includes compounds in the solvated forms described herein. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent may be isotope-substituted, such as D2O, d6-acetone, and d6-DMSO. Solvates may be in liquid or solid form.

[0041] A dash ("-") without a space between two letters or symbols is used to indicate the attachment point of a substituent. For example, -(C=O)NH2 is attached via the carbon of the keto (C=O) group.

[0042] "Alkyl" refers to a branched or linear saturated aliphatic hydrocarbon group. In one non-limiting embodiment, an alkyl group contains 1 to about 12 carbon atoms, more commonly 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In one non-limiting embodiment, an alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The designations used herein refer to alkyl groups having members in each range that are described as independent species. For example, the term C1-C6 alkyl as used herein refers to linear or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to mean that these are each described as independent species. For example, the term C1-C4 alkyl as used herein refers to linear or branched alkyl groups having 1, 2, 3, or 4 carbon atoms, and is intended to mean that these are each described as independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0043] An "alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable points along the chain. The designated ranges used herein refer to alkenyl groups having each member in the range described above as a separate species for the alkyl moiety. In one non-limiting embodiment, an alkenyl contains 2 to about 12 carbon atoms, more generally 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkenyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one unsaturated point.

[0044] "Alkynyl" is a branched or linear aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. The designations used herein refer to alkynyl groups having each member in the range described above as an independent species for the alkyl moiety. In one non-limiting embodiment, the alkynyl has 2 to about 12 It contains carbon atoms, more generally 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, the alkynyl is C2, C2-C3, C2-C4, C2-C5, or C2-C6. Examples of alkynyls include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0045] "Halo" and "halogen" are independently fluorine, chlorine, bromine, or iodine.

[0046] A "haloalkyl" is a branched or linear alkyl group substituted with one or more of the above halo atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A "perhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0047] As used herein, "aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms within the aromatic ring system (e.g., 6, 10, or 14 π electrons shared in a cyclic configuration). 6~14 This refers to "aryl". In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl" (for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl," for example, anthracyl. "Aryl" This includes ring systems in which the above-specified aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the radical or bond site is on the aryl ring, in which case the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4- to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0048] The term "heterocyclic" refers to saturated and partially saturated heteroatom-containing ring radicals that contain one, two, three, or four heteroatoms independently selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocyclic rings may include monocyclic rings with 3 to 10 members, and bicyclic ring systems with 5 to 16 members (which may include bridged fusion and spirofused bicyclic ring systems). Heterocyclic rings do not include rings containing -OO-, -OS-, or -SS- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl), saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclic radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanil, chromanil, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl Examples include, but are not limited to, lyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0049] "Heterocyclic" also includes groups in which a heterocyclic radical fuses / condenses with an aryl or carbocyclic radical, and the attachment site is a heterocyclic system. "Heterocyclic" also includes groups in which a heterocyclic radical is an oxo group (i.e., [ka] This also includes groups substituted with ), for example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline or isoindoline; partially unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0050] The term “heterocycle” also includes “bicyclic heterocycle.” The term “bicyclic heterocycle” refers to a heterocycle as defined herein that has one bridging, fusion, or spirocyclic portion of the heterocycle. The bridging, fusion, or spirocyclic portion of the heterocycle can be a carbocyclic, heterocycle, or aryl group, insofar as a stable molecule is formed. Unless otherwise excluded by context, the term “heterocycle” includes bicyclic heterocycles. A bicyclic heterocycle includes a group in which the fusion heterocycle is substituted with an oxo group. Non-restrictive examples of bicyclic heterocycles include: [ka] These are some examples.

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

[0052] As used herein, "carbocyclic," "carbocyclic," or "cycloalkyl" means that the non-aromatic ring system contains all carbocyclic atoms and 3 to 14 ring carbon atoms ("C"). 3~14The cycloalkyl group comprises a saturated or partially unsaturated (i.e., non-aromatic) group having 3 to 10 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C"). 3~10 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 9 ring carbon atoms ("C"). 3~9 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3~8 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 7 ring carbon atoms ("C"). 3~7 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C"). 4~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has five or six ring carbon atoms ("C"). 5~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C"). 5~10 Cycloalkyl). Exemplary C 3~6 Examples of cycloalkyl groups, though not limited to them, include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8 The cycloalkyl group is not limited to the above C 3~6 Examples include cycloalkyl groups, and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Exemplary C 3~10 The cycloalkyl group is not limited to the above C 3~8 Cycloalkyl groups, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9)10 ), cyclodecenyl (C 10 Examples include the following. As shown in the above examples, in certain embodiments, the cycloalkyl group may be saturated or contain one or more intercarbon double bonds. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring defined above is fused with one heterocycle, aryl, or heteroaryl ring, and the attachment site is on the cycloalkyl ring, in which case the carbon number continues to represent the carbon number in the carbocyclic system. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring defined above has a spirocyclic heterocycle, aryl, or heteroaryl ring, and the attachment site is on the cycloalkyl ring, in which case the carbon number continues to represent the carbon number in the carbocyclic system. The term "cycloalkyl" also includes bicyclic or polycyclic fusions, bridges, or spirocyclic systems containing 5 to 14 carbon atoms and 0 heteroatoms in the non-aromatic ring system. Typical examples of "cycloalkyl" include: [ka] These include, but are not limited to, the following:

[0053] The term "biring" refers to a combination of two rings that are fused together, with each ring independently being a carbon ring, heteroring, or aryl ring. This refers to ring systems selected from and heteroaryl groups. Non-restrictive examples of bicyclic groups include: [ka] These are some examples.

[0054] The term "double ring" is R 20 , R 21 , R 22 , R 23 or R 24 When used in relation to divalent residues such as, the attachment sites may be on separate rings or on the same ring. In certain embodiments, both attachment sites are on the same ring. In certain embodiments, both attachment sites are on different rings. Non-limiting examples of divalent bicyclic groups include, [ka] These are some examples.

[0055] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, oral forms, sublingual forms, topical forms, gels, and mucosal forms. "Dosage form" may also include implants, such as optical implants.

[0056] As used herein, “endogenous” means any substance that originates from or is produced within an organism, cell, tissue, or system.

[0057] As used herein, the term “exogenous” refers to any substance introduced from or produced outside of an organism, cell, tissue, or system.

[0058] As used herein, the term "modulate" means mediating a detectable increase or decrease in the level of response in a subject compared to the level of response in the subject in the absence of the treatment or compound, and / or otherwise identical, compared to the level of response in an untreated subject. This term encompasses mediating a beneficial therapeutic response in a subject, preferably a human, by disrupting and / or affecting an inherent signal or response.

[0059] Parenteral administration of compounds includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection, or infusion methods.

[0060] As used herein, “pharmaceutical composition” is a composition comprising at least one activator, such as a selective active compound described herein, and at least one other substance, such as a carrier. “Pharmaceutical combinations” are combinations of substances into a single dosage form. or a combination of at least two activators that can be administered together in separate drug formulations. Furthermore, it is indicated that an activator may be used in combination to treat any of the disorders described herein.

[0061] As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound obtained by modifying the parent compound to produce its inorganic and organic salts, acid addition salts, or base addition salts, with the loss of bioacidic toxicity. Salts of the compound can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid form with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K) or by reacting these compounds in their free base form with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical when practical. Salts of the compound further include solvates of the compound and salts of the compound.

[0062] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, ecylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nExamples of salts prepared from organic acids such as -COOH (where n is 0-4) or using different acids that produce the same counterion. A further list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418. This can be seen in (1985).

[0063] The term "carrier" means a diluent, excipient, or vehicle in which the activator is used or delivered.

[0064] "Pharmacologically acceptable excipients" means excipients that are generally safe and not inappropriate for administration to a host (usually a human) biologically or otherwise, and that are useful in the preparation of a pharmaceutical composition / combination. In one embodiment, excipients acceptable for veterinary use are used.

[0065] "Patient," "host," or "subject" is a human or non-human animal requiring treatment for any of the disorders specifically described herein. Typically, the host is human. "Host" may also alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0066] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention means an amount that is effective in producing a therapeutic effect such as improvement of symptoms or reduction or mitigation of the disease itself when administered to a host.

[0067] Throughout this disclosure, various aspects of the present invention may be presented in range form. It should be understood that the use of range form is for convenience only and should not be interpreted as a limitation of the scope of the invention. The range description should be considered to specifically disclose all conceivable subranges and the individual numbers within those ranges. For example, a range description such as 1-6 discloses subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and the individual numbers within those ranges, for example, 1. Sections 2, 2.7, 3, 4, 5, 5.3, and 6 should be considered as specifically disclosed. This applies regardless of the scope.

[0068] II. Compounds of the present invention "alkyl" embodiment In one embodiment, "alkyl" is C1-C 10 It is alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1 or C2 alkyl.

[0069] In one embodiment, the "alkyl" contains one carbon atom.

[0070] In one embodiment, the "alkyl" contains two carbon atoms.

[0071] In one embodiment, the "alkyl" contains three carbon atoms.

[0072] In one embodiment, the "alkyl" contains four carbon atoms.

[0073] In one embodiment, the "alkyl" contains five carbon atoms.

[0074] In one embodiment, the "alkyl" contains six carbon atoms.

[0075] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0076] Additional, non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0077] Additional, non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0078] Additional, non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0079] Additional, non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0080] "Haloalkyl" embodiment In one embodiment, "haloalkyl" is C1-C 10 These include haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, and C1 or C2 haloalkyl.

[0081] In one embodiment, the "haloalkyl" has one carbon atom.

[0082] In one embodiment, the "haloalkyl" has one carbon atom and one halogen atom.

[0083] In one embodiment, the "haloalkyl" has one carbon atom and two halogen atoms.

[0084] In one embodiment, the "haloalkyl" has one carbon and three halogens.

[0085] In one embodiment, the "haloalkyl" has two carbon atoms.

[0086] In one embodiment, the "haloalkyl" has three carbon atoms.

[0087] In one embodiment, the "haloalkyl" has four carbon atoms.

[0088] In one embodiment, the "haloalkyl" has five carbon atoms.

[0089] In one embodiment, the "haloalkyl" has six carbon atoms.

[0090] Non-specific examples of "haloalkyl" include: [ka] These are some examples.

[0091] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0092] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0093] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0094] "Aryl" embodiment In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0095] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0096] In one embodiment, "aryl" is a six-carbon aromatic group fused to a heterocycle, with an aryl ring as the bonding site. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where, The bonding points of each group are located on the aromatic ring.

[0097] for example, [ka] This is an "aryl" group.

[0098] however, [ka] This is a "heterocyclic" group.

[0099] In one embodiment, "aryl" is a six-carbon aromatic group condensed with a cycloalkyl group, with the bonding site being an aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, where the bonding site of each group is on an aromatic ring.

[0100] for example, [ka] This is an "aryl" group.

[0101] however, [ka] This is a "cycloalkyl" group.

[0102] "Heteroaryl" Embodiment In one embodiment, the "heteroaryl" is a five-membered aromatic group containing one, two, three, or four nitrogen atoms.

[0103] Non-exclusive examples of a five-membered "heteroaryl" group include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0104] Additional non-limiting examples of five-membered "heteroaryl" groups include: [ka] These are some examples.

[0105] In one embodiment, the "heteroaryl" is a six-membered aromatic group containing one, two, or three nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0106] Non-limiting examples of six-membered "heteroaryl" groups having one or two nitrogen atoms include: [ka] These are some examples.

[0107] In one embodiment, the "heteroaryl" is a nine-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0108] Non-exclusive examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzoxazole, and benzothiazole.

[0109] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0110] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0111] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0112] In one embodiment, the "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0113] Non-exclusive examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0114] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0115] "Cycloalkyl" Embodiment In one embodiment, "cycloalkyl" is a C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0116] In one embodiment, the "cycloalkyl" has three carbon atoms.

[0117] In one embodiment, the "cycloalkyl" has four carbon atoms.

[0118] In one embodiment, the "cycloalkyl" has five carbon atoms.

[0119] In one embodiment, the "cycloalkyl" has six carbon atoms.

[0120] In one embodiment, the "cycloalkyl" has seven carbon atoms.

[0121] In one embodiment, the "cycloalkyl" has eight carbon atoms.

[0122] In one embodiment, the "cycloalkyl" has nine carbon atoms.

[0123] In one embodiment, the "cycloalkyl" has 10 carbon atoms.

[0124] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0125] Additional, non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, where the bonding sites of each group are located on the cycloalkyl ring.

[0126] for example, [ka] This is a "cycloalkyl" group.

[0127] however, [ka] This is an "aryl" group.

[0128] Additional examples of the "cycloalkyl" group include: [ka] These are some examples.

[0129] "Hybrid Algebra" Embodiment In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen atom and three, four, five, six, seven, or eight carbon atoms.

[0130] In one embodiment, "heterocyclic ring" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and three, four, five, six, seven, or eight carbon atoms.

[0131] In one embodiment, "heterocyclic ring" refers to a cyclic ring having two nitrogen atoms and three, four, five, six, seven, or eight carbon atoms.

[0132] In one embodiment, "heterocyclic ring" refers to a cyclic ring having one oxygen atom and three, four, five, six, seven, or eight carbon atoms.

[0133] In one embodiment, "heterocyclic ring" refers to a cyclic ring having one sulfur atom and three, four, five, six, seven, or eight carbon atoms.

[0134] Non-restrictive examples of "heterocyclic compounds" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thiethane.

[0135] Additional, non-restrictive examples of "heterocyclic compounds" include pyrrolidines, 3-pyrroline, 2-pyrroline, pyrazolidines, and imidazolidines.

[0136] Additional, non-restrictive examples of "heterocyclic" compounds include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0137] Additional, non-restrictive examples of "heterocyclic compounds" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0138] Additional, non-restrictive examples of "heterocyclic" structures include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the bonding sites of each group lie on the heterocyclic ring.

[0139] for example, [ka] This is a "heterocyclic" group.

[0140] however, [ka] This is an "aryl" group.

[0141] A non-restrictive example of a "complex algebra" is: [ka] This can also be mentioned.

[0142] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0143] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0144] A non-restrictive example of a "complex algebra" is: [ka] This can also be mentioned.

[0145] A non-restrictive example of a "complex algebra" is: [ka] This can also be mentioned.

[0146] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0147] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0148] Any substituent In one embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with one substituent.

[0149] In one embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with two substituents.

[0150] In one embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with three substituents.

[0151] In one embodiment, a portion described herein that may be substituted with one, two, three, or four substituents is substituted with four substituents.

[0152] Non-limiting embodiments of a triring core The tricyclic core section has one, two, or three nitrogen atoms.

[0153] In one embodiment, the compound of formula I is [ka] Selected from.

[0154] Non-limiting embodiments of formula I: In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0155] In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0156] In a particular embodiment, the compound of the present invention is of formula: [ka] and Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0157] In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0158] In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0159] In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0160] In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0161] In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0162] In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0163] In a particular embodiment, the compound of the present invention is of formula: [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0164] In a particular embodiment, the compound of the present invention is [ka] Select from TIFF0007898577000049.tif215170, TIFF0007898577000050, TIFF195170, TIFF0007898577000051, TIFF196170, and TIFF0007898577000052.tif75170.

[0165] In one embodiment, the compound of formula I is [ka] Selected from.

[0166] In one embodiment, the compound of formula I is [ka] Selected from.

[0167] In one embodiment, the compound of formula I is [ka] Selected from.

[0168] In one embodiment, the compound of formula I is [ka] Selected from.

[0169] In one embodiment, the compound of formula I is [ka] and Selected from.

[0170] In one embodiment, the compound of formula I is [ka] Selected from.

[0171] In one embodiment, the compound of formula I is [ka] Selected from.

[0172] In one embodiment, the compound of formula I is [ka] Selected from.

[0173] In one embodiment, the compound of formula I is [ka] Selected from.

[0174] In one embodiment, the compound of formula I is [ka] Selected from.

[0175] In one embodiment, the compound of formula I is [ka] Selected from.

[0176] In one embodiment, the compound of formula I is [ka] Selected from.

[0177] In one embodiment, the compound of formula I is [ka] Selected from.

[0178] In one embodiment, the compound of formula I is [ka] Selected from.

[0179] In one embodiment, the compound of formula I is [ka] Selected from.

[0180] In one embodiment, the compound of formula I is [ka] Selected from.

[0181] In one embodiment, the compound of formula I is [ka] Selected from.

[0182] R 1 Non-limiting embodiments In one embodiment of formula I, R 1 is -NH(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 is -NH(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -NH(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -NH(R 6 Selected from heteroaryls substituted with R. In one embodiment of formula I, R 1 is -N(CH3)(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 is -N(CH3)(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -N(CH3)(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -N(CH3)(R 6 Selected from heteroaryls (substituted with ).

[0183] In one embodiment of formula I, R 1 is -O(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 is -O(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -O(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -O(R 6 Selected from heteroaryls (substituted with ).

[0184] In one embodiment of formula I, R 1 -S(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 -S(R 6Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 -S(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 -S(R 6 Selected from heteroaryls (substituted with ).

[0185] In one embodiment of formula I, R 1 R is selected from -NH-C(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -NH-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 R is selected from -NH-C(O)- (heterocyclic ring). In one embodiment of formula I, R 1 R is selected from -NH-C(O)-(aryl). In one embodiment of formula I, R 1 R is selected from -NH-C(O)-(heteroaryl). In one embodiment of formula I, R 1 The group is selected from -N(CH3)-C(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -N(CH3)-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 R is selected from -N(CH3)-C(O)-(heterocyclic ring). In one embodiment of formula I, R 1 R is selected from -N(CH3)-C(O)-(aryl). In one embodiment of formula I, R 1 The group is selected from -N(CH3)-C(O)-(heteroaryl).

[0186] In one embodiment of formula I, R 1 is selected from -OC(O)-(alkyl). In one embodiment of formula I, R 1 is selected from -OC(O)-(cycloalkyl). In one embodiment of formula I, R 1 is selected from -OC(O)- (heterogeneic ring). In one embodiment of equation I, R 1 R is selected from -OC(O)-(aryl). In one embodiment of formula I, R1 The group is selected from -OC(O)- (heteroaryl).

[0187] In one embodiment of formula I, R 1 R is selected from -SC(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -SC(O)-(cycloalkyl). In one embodiment of formula I, R 1 is selected from -SC(O)- (heterogenetic ring). In one embodiment of formula I, R 1 R is selected from -SC(O)-(aryl). In one embodiment of formula I, R 1 The element is selected from -SC(O)-(heteroaryl).

[0188] In one embodiment of formula I, R 1 -CH2(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 -CH2(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 -CH2(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 -CH2(R 6 Selected from heteroaryls substituted with R. In one embodiment of formula I, R 1 -CF2(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 -CF2(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 -CF2(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 -CF2(R 6 Selected from heteroaryls substituted with R. In one embodiment of formula I, R 1 is -CH(OH)(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R1 is -CH(OH)(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -CH(OH)(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -CH(OH)(R 6 Selected from heteroaryls (substituted with ).

[0189] In one embodiment of formula I, R 1 R is selected from -CH2-C(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -CH2-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 R is selected from -CH2-C(O)-(heterocyclic ring). In one embodiment of formula I, R 1 R is selected from -CH2-C(O)-(aryl). In one embodiment of formula I, R 1 R is selected from -CH2-C(O)-(heteroaryl). In one embodiment of formula I, R 1 R is selected from -CF2-C(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -CF2-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 R is selected from -CF2-C(O)-(heterocyclic ring). In one embodiment of formula I, R 1 R is selected from -CF2-C(O)-(aryl). In one embodiment of formula I, R 1 R is selected from -CF2-C(O)-(heteroaryl). In one embodiment of formula I, R 1 R is selected from -CH(OH)-C(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -CH(OH)-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 R is selected from -CH(OH)-C(O)- (heterocyclic). In one embodiment of formula I, R 1 R is selected from -CH(OH)-C(O)-(aryl). In one embodiment of formula I, R1 The group is selected from -CH(OH)-C(O)-(heteroaryl).

[0190] In one embodiment of formula I, R 1 is -CH2-NH(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 is -CH2-NH(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -CH2-NH(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -CH2-NH(R 6 Selected from heteroaryls substituted with R. In one embodiment of formula I, R 1 is -CH2-N(CH3)(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 is -CH2-N(CH3)(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -CH2-N(CH3)(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -CH2-N(CH3)(R 6 Selected from heteroaryls (substituted with ).

[0191] In one embodiment of formula I, R 1 is -CH2-O(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 is -CH2-O(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -CH2-O(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -CH2-O(R 6 Selected from heteroaryls (substituted with ).

[0192] In one embodiment of formula I, R 1 R is selected from -CH2-NH-C(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -CH2-NH-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 R is selected from -CH2-NH-C(O)-(heterocyclic ring). In one embodiment of formula I, R 1 R is selected from -CH2-NH-C(O)-(aryl). In one embodiment of formula I, R 1 R is selected from -CH2-NH-C(O)-(heteroaryl). In one embodiment of formula I, R 1 R is selected from -CH2-N(CH3)-C(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -CH2-N(CH3)-C(O)-(cycloalkyl). In one embodiment of formula I, R 1 R is selected from -CH2-N(CH3)-C(O)-(heterocyclic ring). In one embodiment of formula I, R 1 R is selected from -CH2-N(CH3)-C(O)-(aryl). In one embodiment of formula I, R 1 The group is selected from -CH2-N(CH3)-C(O)-(heteroaryl).

[0193] In one embodiment of formula I, R 1 R is selected from -CH2-OC(O)-(alkyl). In one embodiment of formula I, R 1 R is selected from -CH2-OC(O)-(cycloalkyl). In one embodiment of formula I, R 1 R is selected from -CH2-OC(O)-(heterocyclic ring). In one embodiment of formula I, R 1 R is selected from -CH2-OC(O)-(aryl). In one embodiment of formula I, R 1 The group is selected from -CH2-OC(O)-(heteroaryl).

[0194] In one embodiment of formula I, R 1 is -C(O)-(R 6Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 is -C(O)-(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -C(O)-(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -C(O)-(R 6 Selected from heteroaryls (substituted with ).

[0195] In one embodiment of formula I, R 1 is -S(O)-(R 6 Selected from cycloalkyls substituted with R. In one embodiment of formula I, R 1 is -S(O)-(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -S(O)-(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -S(O)-(R 6 Selected from heteroaryls (substituted with ).

[0196] In one embodiment of formula I, R 1 is -S(O)2-(R 6 cycloalkyl substituted with ) is selected from. In one embodiment of formula I, R 1 is -S(O)2-(R 6 Selected from a complex ring substituted with R. In one embodiment of formula I, R 1 is -S(O)2-(R 6 Selected from the aryl(s) substituted by. In one embodiment of formula I, R 1 is -S(O)2-(R 6 Selected from heteroaryls (substituted with ).

[0197] In one embodiment of formula I, R 1 teeth, [ka] Selected from.

[0198] In a particular embodiment, R 1 R is selected from halogen, hydrogen, amino, or cyano. In one embodiment, R 1 It is bromine.

[0199] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 This is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0200] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is a complex algebra. A non-limiting example of this embodiment is: [ka] These are some examples.

[0201] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is R 11 A complex ring arbitrarily substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0202] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is a cycloalkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0203] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is R 11A cycloalkyl group optionally substituted with R 11 is cyano. A non-limiting example of this embodiment is, [ka] These are some examples.

[0204] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0205] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 is a haloalkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0206] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is R 11 It is an alkyl group that is arbitrarily substituted with R 11 This is selected from hydrogen, hydroxyl, and cyano. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0207] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is a haloalkyl. This embodiment is not limited to Typical examples include, [ka] These are some examples.

[0208] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, here, R 10 is R 11 It is an alkyl group that is arbitrarily substituted with R 11 is OR 8 A non-limiting example of this embodiment is: [ka] These are some examples.

[0209] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 It is a complex ring arbitrarily substituted with R. In a further embodiment, R 9 -C(O)R 10 And here, R 10 is R 11 A heteroaryl or aryl which is arbitrarily substituted with R 11 This is selected from hydrogen and alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0210] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 It is a complex ring arbitrarily substituted with R. In a further embodiment, R 9 -C(O)NR 2 R 10 or -C(O)OR 10 And here, R10 is alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0211] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -CH2R 10 Selected from, here, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0212] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -CH2R 10 Selected from, here, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 This is selected from haloalkyl or cyano. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0213] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -CH2R 10 Selected from, here, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 is OR 8 A non-limiting example of this embodiment is: [ka] These are some examples.

[0214] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -CH2R 10 Selected from, here, R 10 is R 11 It is an alkyl group that is arbitrarily substituted with R 11 is hydrogen, cyano and OR 8 Selected from: A non-limiting example of this embodiment is: [ka] These are some examples.

[0215] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 It is a complex ring arbitrarily substituted with R. In a further embodiment, R 9 is R 10 And R 10 is a cycloalkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0216] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 7 Replaced with R 6 A heteroaryl substituted with, where R 6 is R 9 A heterocycle optionally substituted with one or two groups selected from. In further embodiments, R 9 is alkyl and -C(O)R 10 Selected from, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0217] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is a cycloalkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0218] In a particular embodiment, R 1 -C(O)R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is a complex ring. In a further embodiment, R 6 is R 9 It is arbitrarily replaced with R 9 is -C(O)OR 10 And here, R 10 is Al It is a kill. A non-limiting example of this embodiment is: [ka] These are some examples.

[0219] In a particular embodiment, R 1 -CH(CH3)R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is a complex ring. In a further embodiment, R 6 is R 9 It is arbitrarily replaced with R 9 is -C(O)OR 10 or -C(O)R 10 And here, R 10 is R 11 It is an alkyl or cycloalkyl which is optionally substituted with R 11 This is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0220] In a particular embodiment, R 1 -CH(NH2)R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is a complex ring. In a further embodiment, R6 is R 9 It is arbitrarily replaced with R 9 is -C(O)OR 10 or -C(O)R 10 And here, R 10 is R 11 It is an alkyl or cycloalkyl which is optionally substituted with R 11 This is selected from alkyl and hydrogen. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0221] In a particular embodiment, R 1 Ha-SR 4 ,-S(O)R 4 Or -S(O)2R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 It is a complex ring arbitrarily substituted with R. In a further embodiment, R 9 -C(O)R 10 And here, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0222] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 It is a cycloalkyl which is optionally substituted with R. In a further embodiment, R 9 は-OR 10 Selected from, here, R 10 is R 11It is an alkyl group that is arbitrarily substituted with R 11 is an aryl. A non-limiting example of this embodiment is: [ka] These are some examples.

[0223] In a particular embodiment, R 1 Ha-(CR 3 R 3’ )-R 4 And here, R 3 and R 3’ They form a three-membered cycloalkyl ring together with the carbon to which they are attached, R 4 is R 6 A heteroaryl is arbitrarily substituted with, where R 6 is R 9 It is a complex ring arbitrarily substituted with R. In a further embodiment, R 9 -C(O)R 10 or -CH2R 10 And here, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 is alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0224] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 It is an aryl substituted with R 6 is R 9 It is an alkyl group optionally substituted with R. In a further embodiment, R 9 is R 10 And R 10 is R 11 It is a complex ring arbitrarily substituted with, where R 11 is -C(O)OR 8 , -C(O)R 8 or -SO2R8 And R 8 is alkyl, cycloalkyl, haloalkyl, or aryl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0225] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 It is an aryl substituted with R 6 is R 9 It is an alkyl group optionally substituted with R. In a further embodiment, R 9 is R 10 And R 10 is a heterocycle or heteroaryl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0226] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 It is an aryl substituted with R 6 is R 9 It is an alkyl group optionally substituted with R. In a further embodiment, R 9 is R 10 And R 10 is R 11 A heterocycle or heteroaryl in which R is arbitrarily substituted, where R 11 R is selected from hydrogen, alkyl, or haloalkyl. In one embodiment, two R on the same carbon 11 The groups combine to form an oxo group. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0227] In a particular embodiment, R 1 -CH2-R 4 And here, R 4 is R 6 It is an aryl that has been arbitrarily substituted with R 6 is R 9 It is an alkyl group optionally substituted with R. In a further embodiment, R 9 is R 10 And here, R 10 is R 11 A complex ring arbitrarily substituted with R 11 is a -CH2 aryl atom optionally substituted with a halogen. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0228] In a particular embodiment, R 1 -CH2-R 4 And here, R 4 is R 6 It is an aryl that has been arbitrarily substituted with R 6 is R 9 It is an alkyl group optionally substituted with R. In a further embodiment, R 9 is R 10 And here, R 10 is R 11 A complex ring arbitrarily substituted with R 11 is an aryl atom optionally substituted with a halogen. A non-limiting example of this embodiment is: [ka] These are some examples.

[0229] In a particular embodiment, R 1 -CH2-R 4 And here, R 4 is R 6 It is an aryl that has been arbitrarily substituted with R 6 is R 9It is a complex ring arbitrarily substituted with R. In a further embodiment, R 9 -CH2R 10 or -C(O)R 10 And here, R 10 is R 11 A cycloalkyl group optionally substituted with R 11 is hydrogen or alkyl. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0230] In a particular embodiment, R 1 ha-(CH2)-R 4 And here, R 4 is R 6 A heteroaryl compound arbitrarily substituted with R 6 is R 9 It is a complex ring arbitrarily substituted with R. In a further embodiment, R 9 is R 10 Selected from, here, R 10 R is selected from halogens and hydrogen. 11 It is a heteroaryl compound optionally substituted with a base. Non-limiting examples of this embodiment include: [ka] These are some examples.

[0231] In a particular embodiment, R 1 teeth, [ka] Selected from.

[0232] R 4 Non-limiting embodiments In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0233] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0234] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0235] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0236] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0237] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0238] In one embodiment of formula I, R 4 teeth, [ka] and Selected from.

[0239] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0240] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0241] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0242] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0243] In one embodiment of formula I, R 4 teeth, [ka] Selected from.

[0244] In a particular embodiment, R 4 teeth, [ka] Selected from.

[0245] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000118.tif220170, TIFF0007898577000119.tif207170, and TIFF0007898577000120.tif33170.

[0246] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000122.tif207170 and TIFF0007898577000123.tif161170.

[0247] In one embodiment, the compound of formula I is [ka] Selected from.

[0248] In one embodiment, the compound of formula I is [ka] Selected from.

[0249] In one embodiment, the compound of formula I is [ka] Selected from.

[0250] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000128.tif203170 and TIFF0007898577000129.tif159170.

[0251] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000131.tif218170, TIFF0007898577000132.tif206170, and TIFF0007898577000133.tif65170.

[0252] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000135.tif210170 and TIFF0007898577000136.tif181170.

[0253] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000138.tif217170, TIFF0007898577000139.tif206170, and TIFF0007898577000140.tif65170.

[0254] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000142.tif211170 and TIFF0007898577000143.tif184170.

[0255] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000145.tif219170, TIFF0007898577000146.tif204170, and TIFF0007898577000147.tif63170.

[0256] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000149.tif210170 and TIFF0007898577000150.tif183170.

[0257] In one embodiment, the compound of formula I is [ka] Selected from TIFF0007898577000152.tif179170 and TIFF0007898577000153.tif136170.

[0258] In one embodiment, the compound of formula I is [ka] Select from TIFF0007898577000155.tif180170, TIFF0007898577000156.tif180170, and TIFF0007898577000157.tif90170.

[0259] In one embodiment, the compound of formula I is [ka] Selected from.

[0260] In one embodiment, the compound of formula I is [ka] Selected from.

[0261] In one embodiment, the compound of formula I is [ka] Selected from.

[0262] In one embodiment, the compound of formula I is [ka] Selected from.

[0263] R 6 Non-limiting embodiments In one embodiment of formula I, R 6 teeth, [ka] Selected from.

[0264] In one embodiment of formula I, R 6 teeth, [ka] Selected from.

[0265] In one embodiment of formula I, R 6 teeth, [ka] Selected from.

[0266] In one embodiment of formula I, R 6 teeth, [ka] Selected from.

[0267] In one embodiment of formula I, R 6 teeth, [ka] Selected from.

[0268] In one embodiment of formula I, R 6 teeth, [ka] Selected from.

[0269] In a particular embodiment, R 6teeth, [ka] Selected from.

[0270] R 9 Non-limiting embodiments In one embodiment, R 9 teeth, [ka] Selected from.

[0271] In one embodiment, R 9 teeth, [ka] Selected from.

[0272] In one embodiment, R 9 teeth, [ka] Selected from.

[0273] In one embodiment, R 9 teeth, [ka] Selected from.

[0274] In one embodiment, R 9 teeth, [ka] That is the case.

[0275] In one embodiment, R 9 teeth, [ka] Selected from.

[0276] In one embodiment, R 9 teeth, [ka] Selected from.

[0277] In one embodiment, R 9 teeth, [ka] Selected from.

[0278] In one embodiment, R 9 teeth, [ka] Selected from.

[0279] In one embodiment, R 9 teeth, [ka] Selected from.

[0280] In one embodiment, R 9 teeth, [ka] Selected from.

[0281] In one embodiment, R 9 teeth, [ka] Selected from.

[0282] In one embodiment, R 9 teeth, [ka] Selected from.

[0283] In one embodiment, R9 teeth, [ka] Selected from.

[0284] In one embodiment, R 9 teeth, [ka] Selected from.

[0285] In one embodiment, R 9 teeth, [ka] and Selected from.

[0286] In one embodiment, R 9 teeth, [ka] Selected from.

[0287] In one embodiment, R 9 teeth, [ka] That is the case.

[0288] In one embodiment, R 9 teeth, [ka] That is the case.

[0289] In one embodiment, R 9 teeth, [ka] Selected from.

[0290] In one embodiment, R9 teeth, [ka] That is the case.

[0291] In one embodiment, R 9 teeth, [ka] Selected from.

[0292] In one embodiment, R 9 teeth, [ka] Selected from.

[0293] In one embodiment, R 9 teeth, [ka] That is the case.

[0294] In one embodiment, R 9 teeth, [ka] That is the case.

[0295] In one embodiment, R 9 teeth, [ka] That is the case.

[0296] In one embodiment, R 9 teeth, [ka] That is the case.

[0297] In one embodiment, R 9 teeth, [ka] That is the case.

[0298] In one embodiment, R 9 teeth, [ka] That is the case.

[0299] In one embodiment, R 9 teeth, [ka] Selected from.

[0300] In one embodiment, R 9 teeth, [ka] Selected from.

[0301] In one embodiment, R 9 teeth, [ka] That is the case.

[0302] In one embodiment, R 9 teeth, [ka] Selected from.

[0303] In one embodiment, R 9 teeth, [ka] Selected from.

[0304] In one embodiment, R 9 teeth, [ka] That is the case.

[0305] In one embodiment, R 9 teeth, [ka] Selected from.

[0306] In one embodiment, R 9 teeth, [ka] Selected from.

[0307] In one embodiment, R 9 teeth, [ka] That is the case.

[0308] In one embodiment, R 9 teeth, [ka] Selected from.

[0309] In one embodiment, R 9 teeth, [ka] Selected from.

[0310] In one embodiment, R 9 teeth, [ka] Selected from.

[0311] In one embodiment, R 9 teeth, [ka] Selected from.

[0312] In one embodiment, R 9 teeth, [ka] That is the case.

[0313] In one embodiment, R 9 teeth, [ka] That is the case.

[0314] In one embodiment, R 9 teeth, [ka] Selected from.

[0315] In one embodiment, R 9 teeth, [ka] Selected from.

[0316] In one embodiment, R 9 teeth, [ka] Selected from.

[0317] In one embodiment, R 9 teeth, [ka] Selected from.

[0318] In one embodiment, R 9 teeth, [ka] Selected from.

[0319] In one embodiment, R 9 teeth, [ka] Selected from.

[0320] In one embodiment, R 9 teeth, [ka] That is the case.

[0321] In one embodiment, R 9 teeth, [ka] That is the case.

[0322] In one embodiment, R 9 teeth, [ka] Selected from.

[0323] In one embodiment, R 9 teeth, [ka] Selected from.

[0324] In one embodiment, R 9 teeth, [ka] That is the case.

[0325] In one embodiment, R 9 teeth, [ka] Selected from.

[0326] In one embodiment, R 9 teeth, [ka] Selected from.

[0327] In one embodiment, R 9 teeth, [ka] Selected from.

[0328] In one embodiment, R 9 teeth, [ka] Selected from.

[0329] In one embodiment, R 9 teeth, [ka] Selected from.

[0330] In one embodiment, R 9 teeth, [ka] Selected from.

[0331] In one embodiment, R 9 teeth, [ka] That is the case.

[0332] In one embodiment, R 9 teeth, [ka] That is the case.

[0333] In one embodiment, R9 is selected from [Chemical formula] In one embodiment, R

[0334] is 9 In one embodiment, R [Chemical formula] is

[0335] In one embodiment, R 9 is selected from [Chemical formula] In one embodiment, R

[0336] is selected from 9 In one embodiment, R [Chemical formula] In one embodiment, R

[0337] is selected from 9 In one embodiment, R [Chemical formula] In one embodiment, R

[0338] is 9 In one embodiment, R [Chemical formula] is

[0339] [[ID=`]] In one embodiment, R 9 is selected from [Chemical formula] In one embodiment, R

[0340] is 9 is [Chemical formula] selected from the following.

[0341] In one embodiment, R 9 is [Chemical formula] as follows.

[0342] In one embodiment, R 9 is [Chemical formula] selected from the following.

[0343] In one embodiment, R 9 is [Chemical formula] selected from the following.

[0344] In one embodiment, R 9 is [Chemical formula] selected from the following.

[0345] In one embodiment, R 9 is [Chemical formula] selected from the following.

[0346] In one embodiment, R 9 is [Chemical formula] selected from the following.

[0347] In one embodiment, R 9 is [ka] Selected from.

[0348] R 10 Non-limiting embodiments -C(O)R 10 A non-restrictive example of this is: [ka] These are some examples.

[0349] -CH2R 10 A non-restrictive example of this is: [ka] These are some examples.

[0350] R 10 A non-restrictive example of this is: [ka] These are some examples.

[0351] Non-limiting examples of compounds of formula I or formula II: Typical examples of compounds of formula I or formula II include: [ka] These are some examples.

[0352] Additional representative examples of compounds of formula I or formula II include: [ka] Examples include TIFF0007898577000252.tif183170, TIFF0007898577000253.tif206170, TIFF0007898577000254.tif201170, and TIFF0007898577000255.tif35170.

[0353] Additional representative examples of compounds of formula I or formula II include: [ka] Examples include TIFF0007898577000257.tif204170, TIFF0007898577000258.tif193170, and TIFF0007898577000259.tif131170.

[0354] In a particular embodiment, the compound of the present invention is [ka] Select from TIFF0007898577000261.tif191170, TIFF0007898577000262.tif194170, and TIFF0007898577000263.tif123170.

[0355] In one embodiment, the compound of the present invention is [ka] or a pharmaceutically acceptable salt thereof.

[0356] Non-restrictive isotope embodiments In one embodiment, the compound is isotope-labeled. In one embodiment, R 1 , R 2 , R 3 , R 3’ , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 28 or R40 At least one R group, independently selected from the others, isotoped with one, two, or more isotopes, to the extent permitted by the valence. In one embodiment, the isotope label is deuterium. In one embodiment, at least one deuterium is located on an atom having a bond that is degraded during the metabolism of the compound in vivo, or is one, two, or three atoms away from the bond that is metabolized (e.g., α, β, or γ, or may be referred to as a primary, secondary, or tertiary isotope effect). In another embodiment, the isotope label is 13 It is C. In another embodiment, the isotope label is 18 It is F.

[0357] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0358] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0359] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0360] In a particular embodiment, the compound of the present invention is of formula: [ka] Selected from TIFF0007898577000269.tif113170 or a pharmaceutically acceptable salt thereof.

[0361] In a particular embodiment, the compound of the present invention is of formula: [ka] Selected from TIFF0007898577000271.tif189170, TIFF0007898577000272.tif138170, TIFF0007898577000273.tif170170, or a pharmaceutically acceptable salt thereof.

[0362] In a particular embodiment, the compound of the present invention is of formula: [ka] Selected from TIFF0007898577000275.tif114170 or a pharmaceutically acceptable salt thereof.

[0363] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0364] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0365] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0366] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0367] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0368] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0369] In a particular embodiment, the compound of the present invention is [ka] Selected from TIFF0007898577000283.tif178170TIFF0007898577000284.tif187170TIFF0007898577000285.tif183170TIFF0007898577000286.tif183170TIFF0007898577000287.tif178170TIFF0007898577000288.tif183170TIFF0007898577000289.tif90170 or a pharmaceutically acceptable salt thereof.

[0370] In a particular embodiment, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0371] In any of the above structures where two deuterium atoms are present on the methylene group, the same molecule with one deuterium atom at that position can be assumed. In any of the above structures where three deuterium atoms are present on the methyl group, the same molecule with one or two deuterium atoms at that position can be assumed.

[0372] Additional Embodiments 1. In a particular embodiment, formula I or formula II:

Chemical formula

[0373] 2.Formula: [ka] A compound of the compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, N-oxide, isotope derivative, or prodrug.

[0374] 3.R 6 R is selected from alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, and each R 6 R 9 It is optionally replaced by one, two, three, or four elements independently selected from the above, R 11 is optionally substituted with hydrogen; halogen; hydroxyl; cyano; nitro; alkyl; haloalkyl; aryl or heteroaryl group; alkenyl; optionally substituted with aryl or heteroaryl group; cycloalkyl; heterocyclic; one, two, three or four halogen, alkyl or -OR 8 Aryls optionally substituted with a group; one, two, three or four halogens, alkyls or -OR groups. 8Heteroaryl groups optionally substituted with a group; one, two, three, or four halogens, alkyls, or -OR groups. 8 -CH2 aryl groups optionally substituted with a group; one, two, three, or four halogens, alkyls, or -OR groups. 8 -CH2 heteroaryl compounds optionally substituted with the base; -OR 8 ;-NR 8 R 8’ ;-C(O)R 8 ;-C(O)OR 8 ;-C(O)-NR 8 R 8’ ;-C (O)CH2R 8 ;-C(O)CH2OR 8 ;-C(O)CH2-NR 8 R 8’ ;-OC(O)R 8 ;-NR 2 -C(O)R 8 ;-CH2-OC(O)R 8 ;-CH2-NR 2 -C(O)R 8 ;-S(O)R 8 ;-SO2R 8 ;-SO2-OR 8 ; and -SO2-NR 8 R 8’ Select from, or two R on the same carbon 11 The compound of Embodiment 2, in which the groups may form an oxo group together.

[0375] 4.R 12 A compound of Embodiment 1 or Embodiment 2, wherein is selected from halogens, alkyls, and haloalkyls.

[0376] 5.R 12 A compound of Embodiment 1 or 2, wherein is selected from hydroxyl, cyano, nitro, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0377] 6.R 12 -CH2 aryl, -CH2 heteroaryl, -OR 8 , -NR8 R 8’ , -C(O)R 8 , -C(O)OR 8 -C(O)-NR 8 R 8’ -C(O)CH2R 8 -C(O)CH2OR 8 -C(O)CH2-NR 8 R 8’ ,-OC(O)R 8 , -NR 2 -C(O)R 8 -CH2-OC(O)R 8 -CH2-NR 2 -C(O)R 8 ,-S(O)R 8 , -SO2R 8 , -SO2-OR 8 , oxo and -SO2-NR 8 R 8’ A compound of Embodiment 1 or 2, selected from the above.

[0378] 7. One R 12 A compound of Embodiment 1 or 2, wherein the substituent is a halogen.

[0379] 8. Two Rs 12 A compound of Embodiment 1 or 2, wherein the substituent is a halogen.

[0380] 9. One R 12 A compound of Embodiment 1 or 2, wherein the substituent is alkyl.

[0381] 10. Two Rs 12 A compound of Embodiment 1 or 2, wherein the substituent is alkyl.

[0382] 11. One R 12 A compound of Embodiment 1 or 2, wherein the substituent is a haloalkyl group.

[0383] 12. One R 12 A compound of Embodiment 1 or 2, wherein the substituent is a cycloalkyl group.

[0384] 13.R 11 However, R12 A compound from any one of Embodiments 4 to 12, which is an alkyl group optionally substituted with one, two, three, or four substituents selected from the above.

[0385] 14.R 11 However, R 12 A compound from any one of Embodiments 4 to 12, which is a cycloalkyl compound optionally substituted with one, two, three, or four substituents selected from the above.

[0386] 15.R 11 However, R 12 A compound from any one of Embodiments 4 to 12, which is a heterocycle optionally substituted with one, two, three, or four substituents selected from the above.

[0387] 16.R 11 However, R 12 A compound from any one of Embodiments 4 to 12, which is an aryl optionally substituted with one, two, three, or four substituents selected from the above.

[0388] 17.R 11 However, R 12 A compound from any one of Embodiments 4 to 12, which is a heteroaryl compound optionally substituted with one, two, three, or four substituents selected from the above.

[0389] 18.R 11 A compound from any one of embodiments 1 to 12, wherein the parent element is alkyl.

[0390] 19.R 11 A compound from any one of embodiments 1 to 12, wherein the compound is cyano.

[0391] 20.R 11 A compound from any one of Embodiments 1 to 12, wherein the compound is a haloalkyl group.

[0392] 21.R 11 A compound from any one of Embodiments 1 to 12, wherein the compound is hydrogen.

[0393] 22.R 11A compound from any one of Embodiments 1 to 12, wherein the compound is a hydroxyl group.

[0394] 23.R 11 is OR 8 A compound which is any one of embodiments 1 to 12.

[0395] 24.R 11 A compound from any one of embodiments 1 to 12, wherein the compound is aryl.

[0396] 25.R 11 A compound from any one of Embodiments 1 to 12, wherein is a heteroaryl compound.

[0397] 26.R 11 ga-C(O)OR 8 , -C(O)R 8 or -SO2R 8 A compound which is any one of embodiments 1 to 12.

[0398] 27.R 11 A compound from any one of Embodiments 1 to 12, wherein is -CH2aryl.

[0399] 28.R 1 ga-NR 2 R 4 The compound is one of any two of the embodiments 1 to 27.

[0400] 29.R 1 ga-OR 4 The compound is one of any two of the embodiments 1 to 27.

[0401] 30.R 1 -C(O)R 4 The compound is one of any two of the embodiments 1 to 27.

[0402] 31.R 1 ga-SR 4 The compound is one of any two of the embodiments 1 to 27.

[0403] 32.R 1 ga-S(O)R4 The compound is one of any two of the embodiments 1 to 27.

[0404] 33.R 1 -S(O)2R 4 The compound is one of any two of the embodiments 1 to 27.

[0405] 34.Formula: [ka] A compound of any one of the compounds in Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof.

[0406] 35.Formula: [ka] A compound of any one of the compounds in Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof.

[0407] 36.Formula: [ka] or A compound of any one of the compounds in Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof.

[0408] 37.Formula: [ka] A compound of any one of the compounds in Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof.

[0409] 38.R 1 ga-(CR 3 R 3’ )-R 5 The compound is one of any two of the embodiments 1 to 27.

[0410] 39.R 3 A compound of embodiment 37 or 38, wherein the compound is hydrogen.

[0411] 40.R 3 ga-NR 8 R 8’ The compound of embodiment 37 or 38.

[0412] 41.R 3 A compound of embodiment 37 or 38, wherein the parent is alkyl.

[0413] 42.R 3’ A compound from any one of embodiments 37 to 41, wherein the compound is hydrogen.

[0414] 43.R 1 ga-NR 2 R 5 The compound is one of any two of the embodiments 1 to 27.

[0415] 44.R 1 ga-OR 5 The compound is one of any two of the embodiments 1 to 27.

[0416] 45.R 5 However, R 9 Any one of the compounds from Embodiments 38 to 44, which is a -C(O)alkyl group optionally substituted with one, two, three, or four groups independently selected from the above.

[0417] 46.R 5 However, R 9 Any one of the compounds from Embodiments 38 to 44, which is a -C(O) heterocycle optionally substituted with one, two, three, or four groups independently selected from the above.

[0418] 47.R 5 However, R 9 Any one of the compounds from Embodiments 38 to 44, which is a -C(O)aryl optionally substituted with one, two, three, or four groups independently selected from the above.

[0419] 48.R 5 However, R 9Any one of the compounds from Embodiments 38 to 44, which is a -C(O) heteroaryl optionally substituted with one, two, three, or four groups independently selected from the above.

[0420] 49.Formula: [ka] A compound of any one of the compounds from Embodiments 1 to 48, or a pharmaceutically acceptable salt thereof.

[0421] 50.Formula: [ka] A compound of any one of the compounds from Embodiments 1 to 48, or a pharmaceutically acceptable salt thereof.

[0422] 51.Formula: [ka] A compound of any one of the compounds from Embodiments 1 to 48, or a pharmaceutically acceptable salt thereof.

[0423] 52.R 4 However, R 6 Substituted with one group selected from R 7 Any one of the compounds from Embodiments 49 to 51, which is a cycloalkyl group optionally substituted with one, two, three, or four groups independently selected from the above.

[0424] 53.R 4 However, R 6 Substituted with one group selected from R 7 A compound from any one of embodiments 49 to 51, which is a heterocycle optionally substituted with one, two, three, or four groups independently selected from the above.

[0425] 54.R 4 However, R 6 Substituted with one group selected from R 7Any one of the compounds from Embodiments 49 to 51, which is an aryl compound optionally substituted with one, two, three, or four groups independently selected from the above.

[0426] 55.R 4 However, R 6 Substituted with one group selected from R 7 A compound from any one of embodiments 49 to 51, which is a heteroaryl compound optionally substituted with one, two, three, or four groups independently selected from the above.

[0427] 56.R 4 but, [ka] The compound is one of any of embodiments 49 to 51.

[0428] 57.R 4 but, [ka] The compound is one of any of embodiments 49 to 51.

[0429] 58.R 4 but, [ka] The compound is one of any of embodiments 49 to 51.

[0430] 59.R 4 but, [ka] The compound is one of any of embodiments 49 to 51.

[0431] 60.R 4 but, [ka] The compound is one of any of embodiments 49 to 51.

[0432] 61.R 7 hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, - Ure 8 and -NR 8 R 8’ A compound selected from any one of embodiments 1 to 60.

[0433] 62.R 7 Hydrogen, halogen, alkyl, haloalkyl, -C(O)R 8 , -C(O)OR 8 -C(O)-NR 8 R 8’ ,-OC(O)R 8 , -NR 2 -C(O)R 8 ,-S(O)R 8 , -SO2R 8 , -SO2-OR 8 , and -SO2-NR 8 R 8’ A compound selected from any one of embodiments 1 to 60.

[0434] 63. One R 7 A compound from any one of embodiments 1 to 60, wherein the compound is hydrogen.

[0435] 64. Two R's 7 A compound from any one of embodiments 1 to 60, wherein the compound is hydrogen.

[0436] 65. The three R's 7 A compound from any one of embodiments 1 to 60, wherein the compound is hydrogen.

[0437] 66. One R 7 A compound from any one of embodiments 1 to 65, wherein is a halogen.

[0438] 67. Two R's 7 A compound from any one of embodiments 1 to 64, wherein the compound is a halogen.

[0439] 68. One R 7 A compound from any one of embodiments 1 to 65, wherein the parent compound is alkyl.

[0440] 69. Two R's 7 A compound from any one of embodiments 1 to 64, wherein the parent compound is alkyl.

[0441] 70. One R 7 A compound from any one of embodiments 1 to 65, wherein the compound is a haloalkyl group.

[0442] 71. Two R's 7 A compound from any one of Embodiments 1 to 64, wherein the compound is a haloalkyl group.

[0443] 72.R 6 but, [ka] A compound selected from any one of embodiments 1 to 71.

[0444] 73.R 6 but, [ka] A compound selected from any one of embodiments 1 to 71.

[0445] 74.R 6 but, [ka] A compound selected from any one of embodiments 1 to 71.

[0446] 75.R 6 However, R 9 A compound from any one of Embodiments 1 to 71, which is an alkyl group optionally substituted with one, two, three, or four groups independently selected from the above.

[0447] 76.R 6 However, R 9Any one of the compounds from Embodiments 1 to 71, which is a cycloalkyl group optionally substituted with one, two, three, or four groups independently selected from the above.

[0448] 77.R 6 However, R 9 A compound from any one of Embodiments 1 to 71, which is a heterocycle optionally substituted with one, two, three, or four groups independently selected from the above.

[0449] 78.R 6 However, R 9 A compound from any one of Embodiments 1 to 71, which is an aryl optionally substituted with one, two, three, or four groups independently selected from the above.

[0450] 79.R 6 However, R 9 A compound from any one of Embodiments 1 to 71, which is a heteroaryl compound optionally substituted with one, two, three, or four groups independently selected from the above.

[0451] 80.R 6 A compound from any one of embodiments 75 to 79 in which the compound is not substituted.

[0452] 81.R 6 R 9 A compound from any one of embodiments 75 to 79, which is substituted with one group selected from the following.

[0453] 82.R 6 R 9 A compound from any one of embodiments 75 to 79, which is substituted with two groups independently selected from the above.

[0454] 83.R 6 R 9 A compound from any one of embodiments 75 to 79, which is substituted with three groups independently selected from the above.

[0455] 84.R 6 R 9A compound from any one of embodiments 75 to 79, which is substituted with four groups independently selected from the above.

[0456] 85.R 9 A compound from any one of Embodiments 1 to 84, wherein is selected from hydrogen, halogen, alkyl, haloalkyl, cyano, and nitro.

[0457] 86.R 9 R 10 A compound selected from any one of embodiments 1 to 84.

[0458] 87.R 9 ga-CH2R 10 , -OR 10 , -NR 2 R 10 , -C(O)R 10 -C(O)CH2R 10 -C(O)CH2OR 10 -C(O)CH2NR 2 R 10 ,-OC(O)R 10 , -NR 2 -C(O)R 10 , -C(O)OR 10 -C(O)NR 2 R 10 ,-S(O)R 10 , -SO2R 10 SO2CH2R 10 , -SO2CH2OR 10 -SO2CH2NR 2 R 10 , -NR 2 SO2R 10 , -SO2-OR 10 and -SO2-NR 2 R 10 A compound selected from any one of embodiments 1 to 84.

[0459] 88.R 10 However, R 11 The compound of Embodiment 86 or 87, which is an alkyl group optionally substituted with one, two, three, or four groups independently selected from the above.

[0460] 89.R 10 However, R 11 The compound of Embodiment 86 or 87 is a haloalkyl which is optionally substituted with one, two, three, or four groups independently selected from the above.

[0461] 90.R 10 However, R 11 The compound of Embodiment 86 or 87, which is an alkenyl optionally substituted with one, two, three, or four groups independently selected from the above.

[0462] 91.R 10 However, R 11 The compound of Embodiment 86 or 87, which is an alkynyl optionally substituted with one, two, three, or four groups independently selected from the above.

[0463] 92.R 10 However, R 11 The compound of Embodiment 86 or 87 is a cycloalkyl compound optionally substituted with one, two, three, or four groups independently selected from the above.

[0464] 93.R 10 However, R 11 The compound of Embodiment 86 or 87 is a heterocycle optionally substituted with one, two, three, or four groups independently selected from the above.

[0465] 94.R 10 However, R 11 The compound of Embodiment 86 or 87, which is an aryl optionally substituted with one, two, three, or four groups independently selected from the above.

[0466] 95.R 10 However, R 11 The compound of Embodiment 86 or 87 is a heteroaryl compound optionally substituted with one, two, three, or four groups independently selected from the above.

[0467] 96.R 10 A compound from any one of embodiments 88 to 95 in which the compound is not substituted.

[0468] 97.R 10 R 11 Any one of the compounds from embodiments 88 to 95, which is substituted with one group selected from the following.

[0469] 98.R 10 R 11 A compound from any one of embodiments 88 to 95, which is substituted with two groups independently selected from the above.

[0470] 99.R 10 R 11 A compound from any one of embodiments 88 to 95, which is substituted with three groups independently selected from the above.

[0471] 100.R 10 R 11 A compound from any one of embodiments 88 to 95, which is substituted with four groups independently selected from the above.

[0472] 101.R 2 , R 8 and R 8’ A compound from any one of Embodiments 1 to 100, wherein the compound is hydrogen.

[0473] 102.R 2 , R 8 and R 8’ A compound from any one of Embodiments 1 to 100, wherein the parent compound is alkyl.

[0474] 103.R 6 but, [ka] A compound selected from any one of embodiments 1 to 71.

[0475] 104.R 6 but, [ka] A compound selected from any one of embodiments 1 to 71.

[0476] 105.R 6 but, [ka] A compound selected from any one of embodiments 1 to 71.

[0477] 106.Formula: [ka] A compound of the compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, N-oxide, isotope derivative, or prodrug.

[0478] 107.Formula: [ka] A compound of the compound of Embodiment 106 or a pharmaceutically acceptable salt thereof, N-oxide, isotope derivative, or prodrug.

[0479] 108.Formula: [ka] A compound of the compound of Embodiment 106 or a pharmaceutically acceptable salt thereof, N-oxide, isotope derivative, or prodrug.

[0480] 109.Formula: [ka] A compound of the compound of Embodiment 106 or a pharmaceutically acceptable salt thereof, N-oxide, isotope derivative, or prodrug.

[0481] 110.X 3 A compound from any one of embodiments 106 to 109, wherein the bond is a compound.

[0482] 111.X 3 is C(R 3 R 3’) one of the compounds from Embodiments 106 to 109.

[0483] 112.X 3 A compound from any one of embodiments 106 to 109, wherein C(O).

[0484] 113.X 3 A compound from any one of embodiments 106 to 109, wherein C(S) is present.

[0485] 114.X 3 A compound from any one of embodiments 106 to 109, wherein the element is S(O).

[0486] 115.X 3 A compound from any one of embodiments 106 to 109, wherein the parent compound is S(O)2.

[0487] 116.X 3 NR 2 The compound is one of any two compounds from embodiments 106 to 109.

[0488] 117.X 3 A compound from any one of embodiments 106 to 109, wherein the compound is O.

[0489] 118.X 3 NR 2 The compound is one of any two compounds from embodiments 106 to 109.

[0490] 119.X 3 A compound from any one of embodiments 106 to 109, wherein the compound is O.

[0491] 120.X 3 A compound from any one of embodiments 106 to 109, wherein S is present.

[0492] 121.R 20 A compound from any one of embodiments 106 to 120, wherein the bond is a compound.

[0493] 122.R 20 However, R 40Any one of the compounds from Embodiments 106 to 120, which is an alkyl group optionally substituted with one, two, three, or four substituents independently selected from the above.

[0494] 123.R 20 However, R 40 Any one of the compounds from Embodiments 106 to 120 is an alkene or alkyne optionally substituted with one, two, three, or four substituents independently selected from the above.

[0495] 124.R 20 However, R 40 Any one of the compounds from Embodiments 106 to 120 is a haloalkyl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0496] 125.R 20 However, R 40 Any one of the compounds from Embodiments 106 to 120 is an aryl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0497] 126.R 20 However, R 40 Any one of the compounds from Embodiments 106 to 120 is a heteroaryl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0498] 127.R 20 However, R 40 Any one of the compounds from Embodiments 106 to 120 is a heterocycle optionally substituted with one, two, three, or four substituents independently selected from the above.

[0499] 128.R 20 However, R 40 Any one of the compounds from Embodiments 106 to 120, which is a biring compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0500] 129.R 20A compound from any one of embodiments 106 to 115, wherein the compound is -O-.

[0501] 130.R 20 A compound from any one of embodiments 106 to 115, wherein the compound is -S-.

[0502] 131.R 20 ga-NR 2 -A compound from any one of embodiments 106 to 115.

[0503] 132.R 20 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -, -P(O)(R 28 A compound from any one of embodiments 106 to 111, which is -P(O)- or -P(O)-.

[0504] 133.R 21 A compound from any one of embodiments 106 to 132, wherein the bond is a compound.

[0505] 134.R 21 However, R 40 Any one of the compounds from Embodiments 106 to 132, which is an alkyl group optionally substituted with one, two, three, or four substituents independently selected from the above.

[0506] 135.R 21 However, R 40 Any one compound from Embodiments 106 to 132, which is an alkene or alkyne optionally substituted with one, two, three, or four substituents independently selected from the above.

[0507] 136.R 21 However, R 40 Any one of the compounds from Embodiments 106 to 132, which is a haloalkyl compound optionally substituted with one, two, three, or four substituents independently selected from the above. thing.

[0508] 137.R 21 However, R 40Any one of the compounds from Embodiments 106 to 132, which is an aryl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0509] 138.R 21 However, R 40 Any one of the compounds from Embodiments 106 to 132 is a heteroaryl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0510] 139.R 21 However, R 40 A compound from any one of embodiments 106 to 132, which is a heterocycle optionally substituted with one, two, three, or four substituents independently selected from the above.

[0511] 140.R 21 However, R 40 Any one of the compounds from Embodiments 106 to 132, which is a biring compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0512] 141.R 21 A compound from any one of embodiments 106 to 128, wherein the compound is -O-.

[0513] 142.R 21 A compound from any one of embodiments 106 to 128, wherein the compound is -S-.

[0514] 143.R 21 ga-NR 2 -A compound from any one of embodiments 106 to 128.

[0515] 144.R 21 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -, -P(O)(R 28 A compound from any one of embodiments 106 to 131, which is -P(O)- or -P(O)-.

[0516] 145.R 22A compound from any one of embodiments 106 to 144, wherein the bond is a compound.

[0517] 146.R 22 However, R 40 Any one of the compounds from Embodiments 106 to 144, which is an alkyl group optionally substituted with one, two, three, or four substituents independently selected from the above.

[0518] 147.R 22 However, R 40 Any one compound from Embodiments 106 to 144, which is an alkene or alkyne optionally substituted with one, two, three, or four substituents independently selected from the above.

[0519] 148.R 22 However, R 40 Any one compound from Embodiments 106 to 144, which is a haloalkyl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0520] 149.R 22 However, R 40 Any one of the compounds from Embodiments 106 to 144, which is an aryl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0521] 150.R 22 However, R 40 Any one of the compounds from Embodiments 106 to 144, which is a heteroaryl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0522] 151.R 22 However, R 40 Any one of the compounds from Embodiments 106 to 144, which is a heterocycle optionally substituted with one, two, three, or four substituents independently selected from the above.

[0523] 152.R 22 However, R 40 One, two, three, or four substituents independently selected from A compound from any one of embodiments 106 to 144, which is a biring ring optionally substituted with .

[0524] 153.R 22 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -, -P(O)(R 28 A compound from any one of embodiments 106 to 143, which is -P(O)- or -P(O)-.

[0525] 154.R 22 A compound from any one of embodiments 106 to 140, wherein the compound is -O-.

[0526] 155.R 22 A compound from any one of embodiments 106 to 140, wherein the compound is -S-.

[0527] 156.R 22 ga-NR 2 -A compound from any one of embodiments 106 to 140.

[0528] 157.R 23 or R 24 A compound from any one of embodiments 106 to 156, wherein the bond is a compound.

[0529] 158.R 23 or R 24 However, R 40 Any one of the compounds from Embodiments 106 to 156, which is an alkyl group optionally substituted with one, two, three, or four substituents independently selected from the above.

[0530] 159.R 23 or R 24 However, R 40 Any one compound from Embodiments 106 to 156, which is an alkene or alkyne optionally substituted with one, two, three, or four substituents independently selected from the above.

[0531] 160.R 23 or R 24 However, R40 Any one of the compounds from Embodiments 106 to 156, which is a haloalkyl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0532] 161.R 23 or R 24 However, R 40 Any one of the compounds from Embodiments 106 to 156, which is an aryl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0533] 162.R 23 or R 24 However, R 40 Any one of the compounds from Embodiments 106 to 156 is a heteroaryl compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0534] 163.R 23 or R 24 However, R 40 A compound from any one of Embodiments 106 to 156, which is a heterocycle optionally substituted with one, two, three, or four substituents independently selected from the above.

[0535] 164.R 23 or R 24 However, R 40 Any one of the compounds from Embodiments 106 to 156, which is a biring compound optionally substituted with one, two, three, or four substituents independently selected from the above.

[0536] 165.R 23 or R 24 is -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -, -P(O)(R 28 A compound from any one of embodiments 106 to 156, which is -P(O)- or -P(O)-.

[0537] 166.R 23 or R 24A compound from any one of embodiments 106 to 156, wherein the compound is -O-.

[0538] 167.R 23 or R 24 A compound from any one of embodiments 106 to 156, wherein the compound is -S-.

[0539] 168.R 23 or R 24 ga-NR 2 -A compound from any one of embodiments 106 to 156.

[0540] 169.R 25 A compound from any one of embodiments 106 to 168, wherein the compound is hydrogen.

[0541] 170.R 25 A compound from any one of embodiments 106 to 168, wherein is a halogen.

[0542] 171.R 25 However, R 12 Any one compound from Embodiments 106 to 168, which is an alkyl group optionally substituted with one, two, three, or four groups independently selected from the above.

[0543] 172.R 25 Alkenes, alkynes, hydroxyls, alkoxyls, azides, aminos, cyanos, -OR 2 , -NR 2 R 2’ , -NR 2 SO2R 28 , -OSO2R 28 , -SO2R 28 , selected from haloalkyl, aryl, heteroaryl, heterocyclic, bicyclic and cycloalkyl, and its R 25 Each of the elements is R 12 Any one of the compounds from Embodiments 106 to 168, which is optionally substituted with one, two, three, or four groups independently selected from the above.

[0544] 173.R 40The R is selected from alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclic, oxo, and cycloalkyl, and its R 40 Each of the elements is R 12 Any one of the compounds from Embodiments 106 to 172, which is optionally substituted with one, two, three, or four groups independently selected from the above.

[0545] 174.R 40 The compound of Embodiment 173, in which the compound is not substituted.

[0546] 175. [ka] A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, selected from TIFF0007898577000316.tif205170 and TIFF0007898577000317.tif175170.

[0547] 176. A compound of Embodiment 1, selected from Table 2 or a pharmaceutically acceptable salt thereof.

[0548] 177. Structure: [ka] A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0549] 178. Structure: [ka] A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0550] 179. Structure: [ka] A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0551] 180. Structure: [ka] A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0552] 181. Structure: [ka] A compound of Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0553] 182. In a particular embodiment, a pharmaceutical composition is provided comprising one compound or a pharmaceutical salt thereof from any one of Embodiments 1 to 181 and a pharmaceutically acceptable excipient.

[0554] 183. In a particular embodiment, a method is provided for treating a cereblon-mediated disorder in a human, comprising administering an effective dose of any one compound from Embodiments 1 to 181 or a pharmaceutically acceptable salt or composition thereof to a human in need.

[0555] 184. The method of Embodiment 183, wherein the fault is mediated by Ikaros or Aiolos.

[0556] 185. The method of Embodiment 183 or 184, wherein the disorder is cancer.

[0557] 186. The method of Embodiment 183 or 184, wherein the disorder is a tumor.

[0558] 187. The method of Embodiment 183 or 184, wherein the disorder is an immune disorder, an autoimmune disorder, or an inflammatory disorder.

[0559] 188. The method of Embodiment 183 or 184, wherein the disorder is a hematological malignancy.

[0560] 189. The method of Embodiment 183 or 184, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

[0561] 190. In a particular embodiment, a compound is provided for use in the manufacture of a drug for the treatment of cereblon-mediated disorders in humans, selected from any one of the compounds in Embodiments 1 to 181 or a pharmaceutically acceptable salt or composition thereof.

[0562] 191. Compounds for use in Embodiment 190, wherein the impairment is mediated by Ikaros or Aiolos.

[0563] 192. Compounds for use in Embodiment 190 or 191, wherein the disorder is cancer.

[0564] 193. Compounds for use in Embodiment 190 or 191, wherein the disorder is a tumor.

[0565] 194. Compounds for use in Embodiment 190 or 191, wherein the disorder is an immune disorder, an autoimmune disorder, or an inflammatory disorder.

[0566] 195. Compounds for use in Embodiment 190 or 191, wherein the disorder is a hematological malignancy.

[0567] 196. Compounds for use in Embodiment 190 or 191, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

[0568] 197. In a particular embodiment, a use of the compound is provided for the treatment of cereblon-mediated disorders in humans, wherein the compound is selected from any one of the compounds in Embodiments 1 to 181 or a pharmaceutically acceptable salt or composition thereof.

[0569] 198. Use of Embodiment 197, wherein the fault is mediated by Ikaros or Aiolos.

[0570] 199. Use of Embodiment 197 or 198, wherein the disorder is cancer.

[0571] 200. Use of Embodiment 197 or 198, wherein the disorder is a tumor.

[0572] 201. Use of Embodiment 197 or 198, wherein the disorder is an immune disorder, autoimmune disorder, or inflammatory disorder.

[0573] 202. Use of Embodiment 197 or 198, wherein the disorder is a hematological malignancy.

[0574] 203. Use of Embodiment 197 or 198, wherein the disorder is multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

[0575] III. Treatment method Any of the compounds described herein may be used in an effective amount for the treatment of a host, including a human, in need, in an optionally pharmaceutically acceptable carrier, to treat any of the disorders described herein. In certain embodiments, the method comprises administering an effective amount of the active compound described herein or a salt thereof, in an optionally pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), in combination with or alternately with optionally additional therapeutic activators or combinations of therapeutic activators.

[0576] In one embodiment, the compound of the present invention selectively decomposes IKZF1 and / or IKZF3 with respect to one or more IKZF2 and / or IKZF4 and / or IKZF5.

[0577] In one embodiment, a compound of formula I is used to treat the disorders described herein.

[0578] In one embodiment, the compound of formula II is used to treat the disorders described herein.

[0579] In one embodiment, a compound of formula Ia is used to treat the disorders described herein.

[0580] In one embodiment, a compound of formula Ib is used to treat the disorder described herein.

[0581] In one embodiment, a compound of formula Ic is used to treat the disorders described herein.

[0582] In one embodiment, a compound of formula Id is used to treat the disorder described herein.

[0583] In one embodiment, a compound of formula Ie is used to treat the disorders described herein.

[0584] In one embodiment, a compound of formula If is used to treat the disorders described herein.

[0585] In one embodiment, a compound of formula Ig is used to treat the disorders described herein.

[0586] In one embodiment, the disorder treated by the compound of the present invention is an immunomodulatory disorder. The disorder is mediated by angiogenesis. In one embodiment, the disorder treated by the compound of the present invention is related to the lymphatic system.

[0587] In one embodiment, a compound of the present invention or a pharmaceutical salt thereof in an optional pharmaceutical composition described herein is used to degrade Ikaros or Aiolos, which are mediators of disorders affecting a patient such as a human. The control of protein levels obtained by any of the compounds of the present invention results in the treatment of a disease state or pathology modulated by Ikaros or Aiolos by reducing the level of that protein in cells, for example, in a patient's cells, or by reducing the level of downstream proteins within the cell. In certain embodiments, the method includes administering an effective amount of a compound described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), in combination with or alternately with an optional additional therapeutic agent or combination of therapeutic agents.

[0588] In one embodiment, the compounds of the present invention are used to treat disorders including, but are not limited to, benign tumors, neoplasms, tumors, cancer, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid protein disorders, protein disorders, or fibrous disorders.

[0589] The terms “disease state” or “pathological condition,” when used in relation to any compound, are intended to refer to any disease state or pathological condition mediated by Ikaros or Aiolos, such as cell proliferation, or any disease state or pathological condition mediated by downstream proteins of Ikaros or Aiolos, the degradation of such proteins in a patient may provide beneficial therapy or symptom relief to the patient in need. In some cases, the disease state or pathological condition may be cured.

[0590] In one 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, with lymphoma or lymphocytic or myeloid proliferative disorders or abnormalities. For example, the compounds described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may include, but is not limited to, AIDS-associated lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-incisional nuclear cell lymphoma); small incisional nuclear cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy type T-cell lymphoma; follicular lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transforming lymphoma; treatment-related T-cell lymphoma; and non-Hodgkin lymphoma such as Langerhans cell histiocytosis or Waldenström macroglobulinemia.

[0591] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host, such as a human, having Hodgkin lymphoma, including but not limited to tuberous sclerosis classical Hodgkin lymphoma (CHL), mixed cell type CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-dominant Hodgkin lymphoma, or nodular lymphocyte-dominant HL.

[0592] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host having an immunomodulatory condition, such as a human. Non-limiting examples of immunomodulatory conditions include arthritis, lupus, celiac disease, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes mellitus, alopecia areata, vasculitis, and temporal arteritis.

[0593] In certain embodiments, the conditions treated with the compounds of the present invention are disorders associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can result from a wide range of factors, including gene mutations, infections, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[0594] Abnormal proliferation of B cells, T cells, and / or NK cells can lead to a wide range of diseases, including cancer, proliferative disorders, and inflammatory / immune diseases. Treating a host suffering from any of these disorders, such as a human, with an effective amount of the compounds described herein can reduce (palliative) the symptoms. Achieve a reduction in underlying disease (disease-modifying agent) It is possible.

[0595] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, are not limited to, multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosal-associated lymphoid lymphoma. MALT); Small cell lymphocytic lymphoma; Diffuse poorly differentiated lymphocytic lymphoma; Mediastinal large B-cell lymphoma; Nodal marginal zone B-cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; Hairy cell leukemia; Unclassifiable splenic lymphoma / leukemia; Diffuse red pulp small B-cell lymphoma; Hairy cell leukemia - subtype; Lymphoplasmacytic lymphoma; Heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone; Extraskeletal plasmacytoma; Primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma It can be used in effective doses to treat specific B-cell lymphomas or proliferative disorders in hosts, such as humans, including pediatric cystoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL of the lower extremities; ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma occurring in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma; or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0596] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, are not limited to, anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, e.g., mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous progressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium cell CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastic It can be used in effective doses to treat hosts, such as humans, who have T-cell or NK-cell lymphomas, including NK-cell lymphoma; enteropathy-type T-cell lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; treatment-associated T-cell lymphoma; lymphoma occurring after, for example, solid organ or bone marrow transplantation; pre-T-cell lymphocytic leukemia; T-cell macrogranular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; rapidly progressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disorder in children (associated with chronic active EBV infection); vaccinia-like varicella-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0597] In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used to treat a host having leukemia, for example, a human. For example, the host may have, but is not limited to, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); macrogranular lymphocytic leukemia; or acute or chronic leukemia of lymphocyte or myeloid origin, such as adult T-cell chronic leukemia. In one embodiment, the patient suffers from acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or M3 subtype (M3V)); myelomonocytic leukemia (M4 or M4 subtype with eosinophilia (M4E)); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[0598] Numerous skin disorders are associated with cell overgrowth. For example, psoriasis is a benign disease of human skin generally characterized by plaques covered with thickened scales. This disease is caused by an increase in the proliferation of epidermal cells of unknown origin. Chronic eczema is also associated with marked epidermal overgrowth. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, and verruca vulgaris. Examples include pemphigus genitalia, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0599] Other hyperproliferative cell disorders include vascular disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

[0600] Vascular proliferative disorders include neovascularization and vascular disorders. The proliferation of smooth muscle cells during plaque formation in vascular tissue leads to conditions such as restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0601] Fibrotic disorders are often caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cytotoxicity. Cirrhosis is characterized by an increase in extracellular matrix components that lead to the formation of liver scars. Cirrhosis can lead to diseases such as liver cirrhosis. The increase in extracellular matrix that leads to liver scars may also be due to viral infections such as hepatitis. Lipid cells appear to play an important role in liver cirrhosis.

[0602] Mesangial disorders are caused by the abnormal proliferation of mesangial cells. Mesangial hyperproliferative cytotoxicity includes various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, and glomerulopathy.

[0603] Another disease caused by proliferative components is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[0604] Other disorders that may contain abnormal cell proliferation components include Behçet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0605] The compounds described herein, or their pharmaceutically acceptable salts, isotope analogs, or prodrugs, can be used in effective amounts to treat hosts, such as humans, that have proliferative conditions including myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelometaplastic myelopathy with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), eosinophilic syndrome (HES), and systemic mastocytosis (SMCD). In another embodiment, the compounds provided herein are useful for the treatment of primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myeloid leukemia.

[0606] In one embodiment, the compounds described herein, or their pharmaceutically acceptable salts, isotope analogs, or prodrugs, can be used in effective amounts to treat hosts, such as humans, who have myelodysplastic syndromes (MDS) including, but not limited to, refractory cytopenia with monocytic lineage dysplasia, refractory anemia with ring sideroblasts (RARS), refractory anemia-thrombocytosis with ring sideroblasts (RARS-t), refractory cytopenia with polycytic lineage dysplasia (RCMD), including RCMD-RS, refractory anemia I and II with blast cell proliferation (RAEB-I and RAEB-II), 5q syndrome, and childhood refractory cytopenia.

[0607] In one embodiment, the compounds of the present invention can induce therapeutic effects by directly degrading Ikaros or Aiolos, which can alter the transcriptional regulation of downstream proteins of Ikaros or Aiolos.

[0608] The terms "neoplasia" or "cancer" refer to cancerous or malignant neoplasms, i.e., In many cases, cells grow more rapidly than normal through proliferation, and the stimulus that initiates new growth is The term is used to refer to the pathological processes that result in the formation and growth of abnormal tissues that continue to grow after cessation. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most invade surrounding tissues, metastasize to several sites, and can recur even after attempted removal, leading to patient death if not properly treated. As used herein, the term neoplasia is used to describe all cancerous disease conditions and includes or encompasses pathological processes associated with malignant hematological malignancies, ascites tumors, and solid tumors. Exemplary cancers that can be treated with this compound alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's positivity. Sarcomas including sarcomas, liposarcomas, myosarcomas, peripheral neuroepitheliomas, synovial sarcomas, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and Schwann cell tumors; intestinal cancers, breast cancers, prostate cancers, cervical cancers, uterine cancers, lung cancers, ovarian cancers, testicular cancers, thyroid cancers, astrocytomas, esophageal cancers, pancreatic cancers, gastric cancers, liver cancers, colon cancers, melanomas; carcinosarcomas, Hodgkin's disease, Wilms' tumors, and teratomas. Additional cancers that can be treated with the compounds according to the present invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0609] Additional cancers that can be treated with the compounds disclosed according to the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (estrogen, progesterone, and HER-2) (negative for both progesterone and HER-2), single-negative (negative for one of estrogen, progesterone, and HER-2), estrogen receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CL) L), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, ocular cancer, fallopian tubes Cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasion Lobular carcinoma (ILC), inflammatory breast cancer (IBC), colon cancer, intrahepatic cholangiocarcinoma, invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leukemia, lip cancer, liposarcoma, liver cancer, non-invasive lobular carcinoma, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, mouth cancer, mucinous carcinoma Mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), ophthalmic cancer, intraocular melanoma, oligodendroglioma, oral cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, primary peritoneal cancer of the ovary, ovarian cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, genital cancer Stem cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal gland tumor, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, paranasal sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, diagnosis unconfirmed certain cancers, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (a subtype of AML), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma; Mucosa-associated lymphoid tissue lymphoma (MALT), Small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, Nodal marginal zone B-cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary exudative lymphoma; or Lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; Unclassifiable splenic lymphoma / leukemia, Diffuse red pulp small B-cell lymphoma; Lymphoid Plasma cell lymphoma; heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; plasma cell myeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL lower extremity type; ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. In one embodiment, the lesion is adenoid cystic carcinoma. In another embodiment, the lesion is midline NUT carcinoma.

[0610] In another embodiment, the compounds described herein, or their pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be used in effective amounts to treat a host with an autoimmune disorder, such as a human. Examples include acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as Lou Gehrig's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid antibody syndrome; antisynthetic enzyme syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune enteropathy; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian failure; polyglandular autoimmune syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disorder; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; and Barlow's disease. (disease) / Barrow concentric sclerosis; Behçet's disease; Berger's disease; Bickerstaff's encephalitis; Blau syndrome; bullous pemphigoid; cancer; Castleman disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing polymyelitis; Churg-Strauss syndrome; scarring pemphigoid; Cogan syndrome; cold agglutinin disease; complement component 2 deficiency; contact dermatitis; cranial arteritis; CREST syndrome; Crohn's disease; Cushions Ng's syndrome; cutaneous leukocytosis; Degos disease; Darkham's disease; herpetiform dermatitis; dermatomyositis; type 1 diabetes; diffuse systemic cutaneous sclerosis; discoid lupus erythematosus; Dressler syndrome; drug-induced lupus; eczema; endometriosis; enthesitis-associated arthritis; eosinophilic fasciitis; eosinophilic gastroenteritis; eosinophilic pneumonia; acquired epidermolysis bullosa; erythema nodosum; erythroblastosis fetus; essential mixed cryoglobulinemia; Evans syndrome; exogenous and endogenous reactive airway disease (asthma); progressive ossifying fibrous dysplasia Plastic diseases; fibrotic alveolitis (or idiopathic pulmonary fibrosis); gastritis; pemphigoid gastroenteritis; glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's disease; hemolytic anemia; Henoch-Schönlein purpura; herpes zoster of pregnancy (pemphigoid of pregnancy); hidradenitis suppurativa; Hughes-Stowin 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; leukocytosis; lichen planus; lichen sclerosing; linear IgA disease (LAD); lupoid hepatitis, also known as autoimmune hepatitis; lupus erythematosus; Magid's syndrome; microscopic polyangiitis; Miller-Fischer syndrome; mixed connective tissue disease; focal scleroderma; Mucher-Habermann disease, also known as acute pityriasis lichenoides; multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also known as Devic's disease); neuromyotonia; ocular pemphigoid; opsoclonus myoclonus syndrome; Ord's thyroiditis; recurrent li Rheumatism; PANDAS (Pediatric Autoimmune Streptococcal Neuropsychiatric Disorder); Paraneoplastic Cerebellar Degeneration; Paroxysmal Nocturnal Hemoglobinuria (PNH); Parry-Romberg Syndrome; Slamic Cholesterol; Personage-Turner Syndrome; Pemphigus Vulgaris; Perivenous Encephalomyelitis; Pernicious Anemia; POEMS Syndrome; Polyarteritis Nodosa; Polymyalgia Rheumatica; Polymyositis; Primary Biliary Cirrhosis; Primary Sclerosing Cholangitis; Progressive Inflammatory Neuropathy; Psoriasis; Psoriatic Arthritis; Pure Red Cell Aplasia; Pyoderma Gangrenous; Rasmussen Encephalitis; Raynaud's Phenomenon; Reiter's Syndrome; Relapsing Polychondritis; Restless Legs Syndrome; Retroperitoneal Fibrosis; Rheumatic Fever; Rheumatoid Arthritis; Sarcoid Syndrome This includes, but is not limited to, cerebrospinal fluid disorders; schizophrenia; Schmidt syndrome; Schnitzler syndrome; scleritis; scleroderma; sclerosing cholangitis; serum sickness; Sjögren's syndrome; spondyloarthritis; stiff person syndrome; Still's disease; subacute bacterial endocarditis (SBE); Suzak syndrome; Sweet's syndrome; Sydenham chorea; sympathetic ophthalmitis; systemic lupus erythematosus; Takayasu's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; undifferentiated spondyloarthritis; urticarial vasculitis; vasculitis; vitiligo; viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus (VZV), and human papillomavirus (HPV); or Wegener's granulomatosis. In some embodiments, autoimmune diseases are allergic conditions, including asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[0611] Skin contact hypersensitivity and asthma are just two examples of immune responses that may have a significant prevalence. Other examples include atopic dermatitis, eczema, Sjögren's syndrome including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may present with one or more of the following symptoms or signs: itching, swelling, redness, blistering, crusting, ulceration, pain, desquamation, cracking, hair loss, scarring, or exudation of fluid from the skin, eyes, or mucous membranes.

[0612] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly mononuclear cells, lymphocytes, neutrophils, and eosinophils) generally plays a significant role in the development of these diseases. Chronic eczema is also associated with marked epidermal hyperplasia. Immune-mediated leukocyte infiltration can occur in areas other than the skin, such as the airways in asthma and the tear-producing glands in keratoconjunctivitis sicca.

[0613] The compounds described herein, or their pharmaceutically acceptable salts, isotopic variants, or prodrugs, may be used in effective amounts to treat hosts, such as humans, who have skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rashes, skin irritations, or skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances, including some pharmaceuticals, may cause skin sensitization when applied topically. In some embodiments, skin disorders are treated by topical administration of compounds known in the art in combination with the compounds disclosed herein. In one non-limiting embodiment, the compounds of the present invention are used as topical agents for the treatment of 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 bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This novel method may also be useful in reducing skin infiltration by malignant leukocytes in diseases such as mycosis fungoides.

[0614] Diseases or conditions that can be treated with the compounds according to the present invention include, for example, autoimmune diseases such as asthma and multiple sclerosis, various cancers, ciliary diseases, 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 anemia, Tay-Sachs disease, and Turner syndrome.

[0615] Further disease conditions or pathological states that can be treated with the compounds according to the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, 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.

[0616] Further additional disease conditions or pathologies that can be treated with the compounds according to the present invention include, in particular, aceruloplasminemia, achondroplasia type II, chondrodysplasia, acrocephaly, Gaucher disease type II, acute intermittent porphyria, Canavan disease, adenomatous polyposis of the colon, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric tissue browning, α1-antitrypsin deficiency, α-1 proteinase inhibitor deficiency, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, amelodysplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, and diffuse endokeratosis. Candidoma, retinal hemangioma (von Hippel-Lindau disease), Apert syndrome, arachnoid finger (Marfan syndrome), Stickler syndrome, congenital polyarthralgia (Ehlers-Danlos syndrome #polyarthralgia type), telangiectasia ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behle-Stevenson gyrus syndrome, familial Mediterranean fever, Benjamin syndrome, β-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden embolism, Bloch-Salzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnewi-Ulrich syndrome (Turner syndrome), Brunneville disease (tubular sclerosis), prion disease, Birt-Hogg-Duvet syndrome, osteoporosis (osteogenesis imperfecta), broad thumb-toe syndrome (Broad Thumb-Hallux syndrome (Rubin) Stein-Tayby syndrome, bronze diabetes / bronze cirrhosis (He Mochromatosis, spinal bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome (lipoprotein lipase deficiency), CGD (chronic granulomatous disease), flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat-meow syndrome, CAVD (congenital absence of the vas deferens), Keiler's cardiac face syndrome (CBAVD), CEP (congenital erythroblastic porphyria), sac Cystic fibrosis, congenital hypothyroidism, chondrodysplasia (chondrodysplasia), megaepiphysitis of the otospinal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, fatal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), congenital erythroblastic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, chondrodysplasia, X-linked sideroblastic anemia, connective tissue disease, conotibial stump anomalous facies syndrome, Cooley's anemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease Menkes disease, hereditary coproporphyria, Cowden syndrome, craniofacial joint abnormalities (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Cruschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Stevenson gyroscal syndrome, primary hyperoxaluria, spondyloeiophyseal dysplasia (Stradwick type), Duchenne and Becker muscular dystrophy (DBMD), degenerative neurological disorders including Usher syndrome, de Grouchy syndrome and Degerin-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, myeloid protoporphyria Porphyria, erythroblastic type 5-aminolevulinate synthase deficiency, pure red porphyria, myeloid protoporphyria, erythroblastic uroporphyria, Friedreich's ataxia - familial paroxysmal polyserositis, latent dermatosis, familial pressure hypersensitivity neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrous cyst, fragile X syndrome, galactosemia, hereditary brain disorder, giant cell hepatitis (neonatal hemochromatosis), Glenbrachyne Dorstrandbury syndrome (pseudoxanthoma elasticum), Günther's disease (congenital erythroblastic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatic myeloid porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, chondrodysplasia, hypochromic anemia,Immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniist dysplasia, mottled dementia, Langer-Sardino achondroplasia, telangiectatic ataxia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniist dysplasia, Marfan syndrome, motor disorders, Mowat-Wilson syndrome, cystic fibrosis, Muwenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney achondroplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Lange disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyosteid fibrous dysplasia (McKune-Albright syndrome), Poy Zu-Jegers syndrome, Prader-Raaphardt-Willi syndrome, hemochromatosis, primary hyperuricemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), chronic hereditary progressive chorea (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy Pulmonary arterial hypertension, PXE (pseudoxanthoma elastica), Rb (retinoblastoma), neurofibromatosis type 1, relapsing polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Licker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe chondrodysplasia with developmental delay and acanthosis nigricans (SADDAN), Lie-Fraumeni syndrome, sarcoma, breast, leukemia and adrenal gland (sarcoma, breast, leukemia, and adrenal gland) (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Stradwick type SED (Stradwick type spondyloepiphyseal dysplasia), SEDc (congenital spondyloepiphyseal dysplasia), Stradwick type SEMD (Stradwick type spondyloepiphyseal dysplasia), Sprinzen syndrome, cutaneous pigmentation disorder, Smith-Lemle-Opitz syndrome, South African hereditary porphyria (atypical porphyria), infantile onset ascending These include sex-hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, β-thalassemia, thyroid disorders, sausage-like neuropathy (hereditary pressure-fragility neuropathy), Treacher Collins syndrome, triplo X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Floric disease, Waardenburg syndrome, Warburg-Schöf-Frederius syndrome, Wolf-Hirschhorn syndrome, Wolf's periodic disorder, Weissenbacher-Zweimüller syndrome, and xeroderma pigmentosum.

[0617] In one embodiment, a method for treating multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof. In another embodiment, a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, is used in a method for treating multiple myeloma, comprising administering the compound to a patient.

[0618] In one embodiment, a method is provided for managing the progression of multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof. In another embodiment, a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, is used in a method for managing the progression of multiple myeloma, comprising administering the compound to a patient.

[0619] In one embodiment, a method is provided for inducing a therapeutic response in a patient with multiple myeloma, as assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (described in Durie BG M; et al. "International uniform response criteria for multiple myeloma. Leukemia 2006, 10(10):1-7"), comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0620] In another embodiment, a method is provided for achieving a severe complete response, complete response, or very good partial response as assessed by the IURC for multiple myeloma in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0621] In another embodiment, an effective dose of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof, is administered to a patient, thereby improving overall survival, progression-free survival, relapse-free survival, time to process, or time to progression in a patient with multiple myeloma. A method is provided to achieve an extension of the disease survival period.

[0622] In another embodiment, a method is provided for achieving an extension of overall survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof.

[0623] In another embodiment, a method is provided for achieving an extension of progression-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0624] In another embodiment, a method is provided for achieving an extension of relapse-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0625] In another embodiment, a method is provided for achieving an extension of time to progression in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof.

[0626] In another embodiment, a method is provided for achieving an extension of disease-free survival in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof.

[0627] In addition to patients who have not previously received treatment, methods are also provided for treating patients who have previously received treatment for multiple myeloma but have not responded to standard therapy. In addition to patients who have not undergone surgery, additional methods are provided for treating patients who have undergone surgery to treat multiple myeloma. In addition to patients who have not undergone transplant therapy, methods are also provided for treating patients who have previously undergone transplant therapy.

[0628] The compounds described herein can be used in the treatment or management of relapsed, refractory, or resistant multiple myeloma. In some embodiments, the multiple myeloma is primary, secondary, tertiary, quaternary, or quintuple relapse. In one embodiment, the compounds described herein can be used to reduce, maintain, or eliminate minimal residual disease (MRD).

[0629] The types of multiple myeloma that can be treated with the compounds described herein include, but are not limited to, monoclonal hypergammaglobulinemia of unspecified significance (MGUS), low-risk, intermediate-risk, or high-risk multiple myeloma, newly diagnosed multiple myeloma (including newly diagnosed low-risk, intermediate-risk, or high-risk multiple myeloma), transplant-eligible and non-transplant-eligible multiple myeloma, smoldering (painless) multiple myeloma (including low-risk, intermediate-risk, or high-risk smoldering multiple myeloma), active multiple myeloma, solitary plasmacytoma, plasma cell leukemia, central nervous system multiple myeloma, light chain myeloma, non-secretory myeloma, immunoglobulin D myeloma, and immunoglobulin E myeloma.

[0630] In some embodiments, the compounds described herein can be used to treat or manage multiple myeloma characterized by genetic abnormalities, such as, but not limited to, cyclin D translocations (e.g., t(11;14)(q13;q32), t(6;14)(p21;32), t(12;14)(p13;q32), or t(6;20)), MMSET translocations (e.g., t(4;14)(p16;q32)), MAF translocations (e.g., t(14;16)(q32;a32), t(20;22), t(16;22)(q11;q13), or t(14;20)(q32;q11)), or other chromosomal factors (e.g., 17p13 or deletion of chromosome 13, del(17 / 17p), non-hyperdiploidy, and (1q) amplification).

[0631] In one embodiment, as an induction therapy, a pharmaceutically acceptable composition for which a composition is optionally formed is used. A method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I or formula II in a suitable carrier, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof.

[0632] In one embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof, as a consolidation therapy.

[0633] In one embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof, as maintenance therapy.

[0634] In one embodiment, multiple myeloma is a plasma cell leukemia.

[0635] In one embodiment, the multiple myeloma is high-risk multiple myeloma. In several embodiments, the high-risk multiple myeloma is relapsing or refractory. In one embodiment, the high-risk multiple myeloma has relapsed within 12 months of the initial treatment. In another embodiment, the high-risk multiple myeloma is characterized by one or more genetic abnormalities, such as del(17 / 17p) and t(14;16)(q32;q32). In several embodiments, the high-risk multiple myeloma is relapsing or refractory to one, two, or three prior treatments.

[0636] In one embodiment, multiple myeloma has a p53 mutation. In one embodiment, the p53 mutation is a Q331 mutation. In one embodiment, the p53 mutation is an R273H mutation. In one embodiment, the p53 mutation is a K132 mutation. In one embodiment, the p53 mutation is a K132N mutation. In one embodiment, the p53 mutation is an R337 mutation. In one embodiment, the p53 mutation is an R337L mutation. In one embodiment, the p53 mutation is a W146 mutation. In one embodiment, the p53 mutation is an S261 mutation. In one embodiment, the p53 mutation is an S261T mutation. In one embodiment, the p53 mutation is an E286 mutation. In one embodiment, the p53 mutation is an E286K mutation. In one embodiment, the p53 mutation is an R175 mutation. In one embodiment, the p53 mutation is an R175H mutation. In one embodiment, the p53 mutation is an E258 mutation. In one embodiment, the p53 mutation is the E258K mutation. In one embodiment, the p53 mutation is the A161 mutation. In one embodiment, the p53 mutation is the A161T mutation.

[0637] In one embodiment, multiple myeloma has a homozygous deletion of p53. In one embodiment, multiple myeloma has a homozygous deletion of wild-type p53. In one embodiment, multiple myeloma has wild-type p53.

[0638] In one embodiment, multiple myeloma exhibits activation of one or more oncogenic drivers. In one embodiment, one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. In one embodiment, multiple myeloma exhibits activation of C-MAF. In one embodiment, multiple myeloma exhibits activation of MAFB. In one embodiment, multiple myeloma exhibits activation of FGFR3 and MMset. In one embodiment, multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. In one embodiment, multiple myeloma exhibits activation of cyclin D1. In one embodiment, multiple myeloma exhibits activation of MAFB and cyclin D1 It shows activation. In one embodiment, multiple myeloma shows cyclin D activation.

[0639] In one embodiment, multiple myeloma has one or more chromosomal translocations. In one embodiment, the chromosomal translocation is t(14;16). In one embodiment, the chromosomal translocation is t(14;20). In one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal translocations are t(4;14) and t(14;16). In one embodiment, the chromosomal translocation is t(11;14). In one embodiment, the chromosomal translocation is t(6;20). In one embodiment, the chromosomal translocation is t(20;22). In one embodiment, the chromosomal translocations are t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In one embodiment, the chromosomal translocations are t(14;16) and t(16;22). In one embodiment, the chromosomal translocations are t(14;20) and t(11;14).

[0640] In one embodiment, multiple myeloma has a Q331 p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma has a homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma has a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20). In one embodiment, multiple myeloma has wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma has wild-type p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma has a homozygous deletion of p53, activation of FGFR3, MMset, and C-MAF, and chromosomal translocations at t(4;14) and t(14;16). In one embodiment, multiple myeloma has a homozygous deletion of p53, activation of cyclin D1, and chromosomal translocation at t(11;14). In one embodiment, multiple myeloma has an R337L p53 mutation, activation of cyclin D1, and chromosomal translocation at t(11;14). In one embodiment, multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In one embodiment, multiple myeloma has an S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In one embodiment, multiple myeloma has an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma has an R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma has an E258K p53 mutation, activation of C-MAF, and chromosomal translocations at t(14;16) and t(16;22). In one embodiment, multiple myeloma has wild-type p53, activation of MAFB and cyclin D1, and chromosomal translocations at t(14;20) and t(11;14).In one embodiment, multiple myeloma has an A161T p53 mutation, cyclin D activation, and a chromosomal translocation at t(11;14).

[0641] In some embodiments, multiple myeloma is a newly diagnosed multiple myeloma that is suitable for transplantation. In other embodiments, multiple myeloma is a newly diagnosed multiple myeloma that is not suitable for transplantation.

[0642] In some embodiments, multiple myeloma shows early progression (e.g., less than 12 months) after initial treatment. In other embodiments, multiple myeloma shows early progression (e.g., less than 12 months) after autologous stem cell transplantation. In another embodiment, multiple myeloma is refractory to lenalidomide. In another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, Multiple myeloma is characterized by relapsed or refractory disease in patients who have been exposed to or are doubly refractory to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide, or avadomide). In yet another embodiment, multiple myeloma is relapsed or refractory to three or more prior therapies, including, for example, CD38 monoclonal antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide or avadomide), or is double refractory to proteasome inhibitors or immunomodulatory compounds and CD38 mAbs. In further embodiments, multiple myeloma is triple-refractory, for example, to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide, or avadomide), and another activator described herein.

[0643] In one embodiment, a method is provided for treating or managing relapsed or refractory multiple myeloma in a patient with renal impairment or symptoms thereof, comprising administering to the patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof.

[0644] In another embodiment, a method is provided for treating or managing relapsed or refractory multiple myeloma in a frail patient, comprising administering to the patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition, wherein the frail patient is unsuitable for induction therapy or intolerant to dexamethasone treatment. In another embodiment, the frail patient is elderly, for example, over 65 years of age.

[0645] In another embodiment, the treatment of fourth-line relapsed or intractable disease involves administering to a patient an effective dose of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof. Methods for treating or managing curable multiple myeloma are provided.

[0646] In another embodiment, a method is provided for treating or managing newly diagnosed transplant-unsuitable multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof.

[0647] In another embodiment, a method is provided for treating or managing newly diagnosed transplant-unsuitable multiple myeloma, comprising administering to a patient an effective amount of a compound of formula I or formula II in a pharmaceutically acceptable carrier for optionally forming a composition, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug thereof, as an alternative therapy or post-transplant maintenance therapy.

[0648] In another embodiment, a method is provided for treating or managing high-risk multiple myeloma that is relapsed or refractory to one, two, or three prior therapies, comprising administering to a patient an effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0649] In some embodiments, patients targeted for treatment with one of the compounds described herein have not been treated with multiple myeloma therapy prior to administration. In some embodiments, Patients eligible for treatment with one of the compounds described herein have been treated with multiple myeloma therapy prior to administration. In some embodiments, patients eligible for treatment with one of the compounds described herein have developed drug resistance to multiple myeloma therapy. In some embodiments, patients eligible for treatment with one of the compounds described herein have developed resistance to one, two, or three multiple myeloma therapies, therapies selected from CD38 antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib), and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdamide or avadomide).

[0650] The compounds described herein can be used to treat patients regardless of their age. In some embodiments, the subjects are 18 years of age or older. In other embodiments, the subjects are 18, 25, 35, 40, 45, 50, 55, 60, 65, or over 70 years of age. In other embodiments, the patient is under 65 years of age. In other embodiments, the patient is over 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, for example, over 65 years of age. In one embodiment, the patient is an elderly multiple myeloma patient, for example, over 75 years of age.

[0651] IV. Combination Therapy Any of the compounds described herein may be used alone or in combination in effective amounts to treat a host such as a human having one of the disorders described herein.

[0652] The terms “bioactive agent” or “additional therapeutic agent” are used to describe active substances other than the compounds of the present invention that can be used in combination with or alternately with the compounds of the present invention to achieve a desired therapeutic outcome. In one embodiment, the compounds of the present invention and the additional therapeutic agent are administered such that they have overlapping periods during which they are active in vivo, for example, Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compounds of the present invention and the additional therapeutic agent are administered to a host in need, where they do not have overlapping pharmacokinetic parameters, but one has a therapeutic effect on the therapeutic efficacy of the other.

[0653] In one embodiment of this invention, additional therapeutic activators include, but are not limited to, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, checkpoint inhibitors including V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, and small molecules. The immunomodulator includes, but is not limited to, peptides, nucleotides, or other inhibitors. In certain embodiments, the immunomodulator is an antibody, such as a monoclonal antibody.

[0654] Examples of PD-1 inhibitors that inhibit immunosuppression by blocking the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor include nivolumab (Opdivo), pembrolizumab (Keytruda), pidylizumab, and AMP-224 (AstraZeneca). PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro) Examples include the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor and inhibit immunosuppression include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include ipilimumab and tremelimumab. Examples of LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb) and GSK2831781 (GlaxoSmithKline). Examples include, but are not limited to, IMP321 (Prima BioMed), LAG525 (Novartis), and the PD-1 and LAG-3 dual inhibitor MGD013 (MacroGenics). No. An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In one embodiment, the PD-1 inhibitor is BGB-A317. In one embodiment, the PD-L1 inhibitor is MED14736. In one embodiment, the PD-L2 inhibitor is rHIgM12B7A.

[0655] In one embodiment, the checkpoint inhibitor is a B7 inhibitor, such as a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is MGA271.

[0656] In one embodiment, the checkpoint inhibitor is an OX40 agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody, such as anti-OX-40 or MEDI6469.

[0657] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the GITR agonist is an anti-GITR antibody, such as TRX518.

[0658] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the CD137 agonist is an anti-CD137 antibody, for example, PF-05082566.

[0659] In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the CD40 agonist is an anti-CD40 antibody, for example, CF-870893.

[0660] In one embodiment, the checkpoint inhibitor is an IDO inhibitor, such as INCB24360 or indoximod.

[0661] In another embodiment, the active compounds described herein may be administered in combination with or alternately in effective amounts of an androgen (e.g., testosterone) inhibitor, including but not limited to a selective androgen receptor modulator, selective androgen receptor degrader, complete androgen receptor degrader, or another form of partial or complete androgen antagonist, for the treatment of abnormal tissue of the male reproductive system, such as prostate cancer or testicular cancer. In one embodiment, prostate or testicular cancer is androgen-resistant. Non-limiting examples of antiandrogen compounds are presented in International Publication No. 2011 / 156518 and U.S. Patents No. 8,455,534 and No. 8,299,112. Additional non-limiting examples of antiandrogen compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiraterone acetate, and cimetidine.

[0662] In one embodiment, the additional therapeutic agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

[0663] In one embodiment, the additional therapeutic agent is an EGFR inhibitor. Examples include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rosiletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272;PB272); abitinib (AC0010), EAI045, tarloxotinib (TH-4000;PR-610), PF-06459988 (Pfizer), and tesevatinib (XL Examples include transtinib (647; EXEL-7647; KD-019), WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

[0664] In one embodiment, the additional therapeutic agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0665] In one embodiment, the additional therapeutic agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tocitumomab, and ocrelizumab.

[0666] In one embodiment, the additional therapeutic agent is a JAK3 inhibitor. An example of a JAK3 inhibitor is tasocitinib.

[0667] In one embodiment, the additional therapeutic agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]aminophenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridine-5-yl)oxy]benzamide), and ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]pi [Perazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide)(navitoclax), ABT-263((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((tri Fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrole-2-yl)methylidene]-4-methoxypyrrole-2-ylidene]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazole-2-ylamino)-phenyl ester), pogosin, ethyl 2- Examples include amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossiporone (ApoG2), HA14-1, AT101, sabutoclax, gumbognate, or G3139 (oblimersene).

[0668] In one embodiment, the additional therapeutic agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a splenic tyrosine kinase (Syk) inhibitor, or A selection is made from those combinations.

[0669] Examples of PI3 kinase inhibitors include wartmannin, demethoxypyridine, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS- 9820, BKM120, GDC-0032 (Taselicib), (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazole-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-9-yl]pyrazole-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen(S)-methylphosphonate; or methyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458(2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridazinyl) Dinyl benzenesulfonamide) (omiparisib), TGX-221 ((±)-7-methyl-2-(morpholine-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidine-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate dihydrochloride), KIN-193 ( (R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-mohydroxypropan(mohydroxypropan)-1-one), GS-1101(5-fluoro-3-phenyl-2-([ S)-1-[9H-purine-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS 252424(5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]meth-(Z)-ylidene]-thiazolidin-2,4-dione), CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridin-3-sulfonamide), Buparlicib(5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941(2-(1H-indazole-4-yl)-6-[ [4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980((S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (RG7422 and Also known as SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18- Oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazine-2-yl)phenyl]urea) (gedatricib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-Dihydro-1H-imidazo[4,5-c]quinoline-1-yl]phenyl}propanenitrile)(Ductricidal(, dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR, 6E,9S,9aR,10R,11aS)-6-[[bis(propa-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib) ru)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441(KU- 57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpericib, IC-87114, TGI100713, CH5132799, PKI-402, copanlicib (BAY 80-6946), XL Examples include, but are not limited to, structures described in International Publication No. 2014 / 071109, 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitricib (GDC-0980;RG7422), and international publication No. 2014 / 071109.

[0670] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica®) (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-yl]propa-2-en-1-one), dianilinopyrimidine inhibitors, such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidine-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see U.S. Patent Application Publication No. 2011 / 0117073, which in whole forms part of this specification), dasatinib (N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidine-4-ylamino)thiazole-5-carboxamide), LFM-A13 (α-cyano-β -Hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834(RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazine-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazine-2-yl)phenyl)benzamide), CNX-774(4-(4- ((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056(7-benzyl-1-(3-(piperidine-1-yl)propyl)-2-(4-(pyridine-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline-6(5H)-one), GDC-0834((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahi, Drobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-( 2H-1,2,3-triazole-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47(1-(1-acryloylindoline-6-yl)-9-(1-methyl-1H-pyrazole-4-yl)benzo[h][1,6]naphthyrizine-2(1H)-one), and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridine-3-yl}phenyl)-2H-isoquinoline-1-one), as well as other molecules capable of inhibiting BTK activity, e.g., Akinleye et al., Journal of Hematology & Oncology, Examples include BTK inhibitors disclosed in 2013, 6:59 (which in whole constitutes part of this specification by reference).

[0671] Syk inhibitors include, for example, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazine-1-yl)phenyl)aminopyrimidine-5-carboxamide) and entospletinib (6 -(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidine-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridine-2-ylamino)-pyridazine-3-carboxylic acid amide), Imatinib (Gleevac; 4-[(4-methylpiperazine-1-yl)methyl]-N-(4- Methyl-3-{[4-(pyridine-3-yl)pyrimidine-2-yl]amino}phenyl)benzamide), staurosporine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine) ), PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607(4-((3-(2H-1,2,3-triazole-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112(3,3'-((5-fluoropyrimidine (See Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (See Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (See Singh et al. Discovery and Development of Spleen See Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire article is incorporated herein by reference), Compound D (Singh et al. See Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire article is incorporated herein by reference). See also PRT060318 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire article is incorporated herein by reference)), Luteolin (Singh et al. See also: al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire article is incorporated herein by reference)), apigenin (see also: Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire article is incorporated herein by reference)), quercetin (Singh et al. See Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire text is incorporated herein by reference)), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire text is incorporated herein by reference)), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. See also 2012, 55, 3614-3643 (which in whole forms part of this specification by reference) and Morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which in whole forms part of this specification by reference)).

[0672] In one embodiment, the additional therapeutic agent is a MEK inhibitor. MEK inhibitors are known, such as trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H)-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), and pimacertib / AS703026 / MSC 1935369((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidine-2-yl]azetidine-3-ol), refametinib / BAY869766 / RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901(N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-flu Oro-4-iodophenyl)amino]-benzamide), TAK733((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162(5-[(4-bromo-2-fluorophenyl)amino ]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidine-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655(3,Examples include 4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxadinan-2yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, binimetinib, SL-327, TAK-733, and PD318088.

[0673] In one embodiment, the additional therapeutic agent is a Raf inhibitor. Known Raf inhibitors include, for example, vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-ylamino)phenyl)benzamide), NVP-BHG712(4-methyl-3-(1-methyl-6-(pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265(1-methyl-5-[2-[5-(trifluoro Methyl)-1H-imidazole-2-yl]pyridine-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazole-2-amine), 2-bromoardicine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridine-4-yl)-1H-imidazole-4-yl)phenol), sorafenib N-oxide ( Examples include 4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib).

[0674] In one embodiment, additional therapeutic activators include, but are not limited to, AKT inhibitors comprising MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, trisirivine, AZD5363, honokiol, PF-04691502, and miltefosine; FLT-3 inhibitors comprising, but are not limited to, P406, dovitinib, quizartinib (AC220), amvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449; or combinations thereof.

[0675] In one embodiment, the additional therapeutic agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogues, everolimus (Afinitor), temsirolimus, ridafololimus, sirolimus, and defololimus. Examples of MEK inhibitors include trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimacertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GD C-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidine-2-yl]azetidine-3-ol)(cobimetinib), refametinib / BAY869766 / RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901(N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733((R)-3-(2,3-dihydroxyprop (L)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162(5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidine-2-ylo Examples include, but are not limited to, xycyclomen-2-one, WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxadinan-2-yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

[0676] In one embodiment, the additional therapeutic agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0677] In one embodiment, the additional therapeutic agent is an HSP inhibitor. Examples of HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol.

[0678] Additional bioactive compounds include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, and AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, Aurora kinase inhibitor, PIK-1 modulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, Anti-HGF antibody, Focal adhesion plaque kinase inhibitor, Map kinase (mek) inhibitor, VEGF trap antibody, Pemetrexed, Panitumumab, Amrubicin, Olegobomab, Lep-etu, Noratexide, azd2171, Batabulin, Ofatumumab, Zanolimumab, Edoteca Phosphorus, tetrandrin, lubitecan, tesmilifene, oblimersen Ticilimumab, Ipilimumab, Gosipol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Sericiclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, Disodium Salt Heptahydrate Camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazine methyl)-indolyl-quinolone, batalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydrocaproate Roxyprogesterone, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ronafarnib, BMS-214662, tipifarnib; amifostin, NVP-LAQ824, suberoyl analide hydroxamic acid (acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrin, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyprote Lon, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechloretamine, melphalan, 6-mercaptopurine, mesna, methotrex Sart, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-Cis-Retinoic Acid, Phenylalanine Mustard, Uracil Mustard, Estramustine, Altretamine, Phloxuridine, 5-Deoxyuridine, Cytosine Arabinoside, 6-Mercaptopurine, Deoxycoformycin, Calcitriol, Barrubicin, Mitramycin, Vinblastine, Vinorelbine, Topotecan, Lazoxin, Marimast, COL-3, Neovastat, BMS-275291, Squalamine, En Dostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifen, Id Idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin difutitox, gefitinib, bortezomib, pachyphene Ritaxel, paclitaxel without cremofol, docetaxel, epotilon B, BMS-247550, BMS-310705, droloxifen, 4-hydroxytamoxifen, pipendoxifen, ERA-923, alzoxifen, fulvestrant, acorbifen, rasofoxifen, idoxifen, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wartmannin, ZM336372, L-779, 450, PEG-filgrastim, Darbepoetin erythropoetin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone Sodium, Interleukin-11, Dexrazoxane, Alemtuzumab, All-trans Retinoic Acid, Ketoconazole, Interleukin-2, Megestrol, Immunoglobulin, Nitrogen Mustard, Methylprednisolone, Ibritumomab Diuxetan, Androgen, Decitabine, Hexamethylmelamine, Bexarotene, Tositumomab, Arsenic Trioxide, Cortisone, Etidronate, Mitotane, Cyclosporine, Liposomal Daunorubicin, Edwina-Asparaginase, Strontium-89, Casopitant, Netupitant, NK-1 Receptor Antagonist, Palonosetron, Aprepitant, Diphenhydramine, Hydroxyzine, Metoclopramide, Lorazepam, Alprazolam, Haloperidol, Droperi Examples include Dol, Dronabinol, Dexamethasone, Methylprednisolone, Prochlorperazine, Granisetron, Ondansetron, Dracetron, Tropicetron, Pegfilgrastim, Erythropoetin, Epoetin α, Darbepoetin α, and mixtures thereof.

[0679] In one embodiment, additional therapeutic activators include imatinib mesylate (Gleevac®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), trastuzumab (Herceptin®), trastuzumab-DM1, pertuzumab (Perjeta®), lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), panitumumab (Vectibix®), vandetanib (Caprelsa®), vemurafenib (Zelboraf®), and vorinostat (Zoli). Selected from, but not limited to, nza(trademark), romidepsin (Istodax(trademark)), bexarotene (Tagretin(trademark)), alitretinoin (Panretin(trademark)), tretinoin (Vesanoid(trademark)), carfilzomib (Kyprolis(trademark)), pralatrexate (Folotyn(trademark)), bevacizumab (Avastin(trademark)), Ziv-aflibercept (Zaltrap(trademark)), sorafenib (Nexavar(trademark)), sunitinib (Sutent(trademark)), pazopanib (Votrient(trademark)), regorafenib (Stivarga(trademark)), and cabozantinib (Cometriq(trademark)).

[0680] In certain embodiments, the additional therapeutic agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant.

[0681] Suitable additional therapeutic activators for chemotherapy include, but are not limited to, radiomolecules, cytotoxins, or toxins also known as cytotoxic agents, as well as any active substance harmful to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer drugs include vincristine (Oncovin®) or liposomal vincristine (Marqibo®), daunorubicin (Daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), cytarabine (cytosine arabinoside, ara-C or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (Pegasparagase or Oncaspar®), et Examples include poside (VP-16), teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), methotrexate, cyclophosphamide (Cytoxan®), prednisone, dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig®).Examples of suitable additional chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altoretamine, amiphostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamine platinum(II) (DDP) (cisplatin), diaminodichloroplatin, anthracyclines, antibiotics, antimetabolites, asparaginase, and BCG bacteria (BCG). (live) (in the bladder), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogen, cyclophosphamide, cyclotosphamide, cytarabi. , cytarabine, cytochalasin B, cytoxane, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin difutitox, dexrazoxane, dibromomannitol, dihydroxyanthracin dione, docetaxel, mesylate Lasetron, Doxorubicin HCl, Dronabinol, Escherichia coli (E. coli) L-Asparagus Ginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogen, estradiol, estramustine sodium phosphate, ethidium bromide, ethinylestradiol, etidronate, etoposide, citroborum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoid, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferon α-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidocaine, lomustine, metansinoid, mechloretamine Ondansetron HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate, methyltestosterone, mitramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, disodium pamidronate, pentostatin, pilocarpine HCl, plimycin, polyfeprozan 20 carmustine implant, porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, salglamostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testactone, tetracaine, thioepachlorambucil Examples include, but are not limited to, chlorambucil, thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, tretinoin, barrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0682] Additional therapeutic agents that can be administered in combination with the degrading agents disclosed herein include bevacizumab, sutinib, sorafenib, and 2-methoxyestradiol. 2ME2, finasunate, batalanib, vandetanib, aflibercept, boroximab, etalacizumab (MEDI-522), sirengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figtumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atrizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dasetuzumab, HLL1, huN901-DM1, ateph Remode, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, ta Examples include talmapimod (P276-00), enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0683] In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs "coat" the surface of cancer cells and can induce their destruction by the immune system. It is possible. For example, bevacizumab is a protein secreted by tumor cells and other cells in the tumor microenvironment that targets vascular endothelial growth factor (VEGF), which promotes the development of tumor blood vessels. When VEGF binds to bevacizumab, it is unable to interact with its cell receptor, thus interfering with the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the target receptors from sending normal growth-promoting signals. They may also induce apoptosis and activate the immune system to destroy tumor cells.

[0684] In one embodiment of the present invention, the additional therapeutic activator is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, such as cyclosporine A (NEORAL®), FK506 (tacrolimus), or pimecrolimus; an mTOR inhibitor, such as rapamycin or its derivatives, such as sirolimus (RAPAMUNE®), everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9; apalog, such as ridafololimus; azathioprine; camphopurine 1H; an S1P receptor modulator, such as fingolimod or its analogues; an anti-IL-8 antibody; a mycophenolic acid or its salt, such as sodium salt or its prodrug, such as mycophenolate mofetil (CELLCEPT®), or OKT3 (ORTHOCLONE OKT3(trademark), prednisone, ATGAM(trademark), THYMOGLOBULIN(trademark), Brequinal sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxysperguarine, tresperimus, leflunomide (ARAVA(trademark)), CTLAI-Ig, anti-CD25, anti- IL2R, basiliximab (SIMULECT®), daclizumab (ZENAPAX®), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4Ig (abatacept), belatacept, LFA3Ig, etanercept (Enb by Immunex) (Sold as rel (trademark)), adalimumab (Humira (trademark)), infliximab (Remicade (trademark)), anti-LFA-1 antibody, natalizumab (Antegren (trademark)), enrimomab, gavilimomab, anti-thymocyte immunoglobulin These may be brin, cyprizumab, alefacept, ephalizumab, pentasa, mesalazine, asacol, codeine phosphate, benolilate, fenbufen, naprosin, diclofenac, etodolac, and indomethacin, aspirin, and ibuprofen.

[0685] In one embodiment, the additional therapy is bendamustine. In one embodiment, the additional therapy is obinutuzumab. In one embodiment, the additional therapy is a proteasome inhibitor, such as ixazomib or oprozomib. In one embodiment, the additional therapy is a histone deacetylase inhibitor, such as ACY241. In one embodiment, the additional therapy is a BET inhibitor, such as GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, BI 894999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117, 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinoline-1(2H)-one, EP11313, and EP11336. In one embodiment, the additional therapy is an MCL-1 inhibitor, such as AZD5991, AMG176, MIK665, S64315, or S63845. In one embodiment, the additional therapy is an LSD-1 inhibitor, such as ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-amino-piperidine-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydro The agent is pyrimidine-4-yl]-2-fluorobenzonitrile or a salt thereof. In one embodiment, the additional therapy is a CS1 antibody, e.g., elotuzumab. In one embodiment, the additional therapy is a CD38 antibody, e.g., daratumumab or isatuximab. In one embodiment, the additional therapy is a BCMA antibody or antibody conjugate, e.g., GSK2857916 or BI 836909.

[0686] In some embodiments, the degradation inducers described herein are administered in combination with or alternately with one or more cellular immunotherapies. In some embodiments, the cellular immunotherapy is modified immune cells. Modified immune cells include, but are not limited to, modified T cell receptor (TCR) cells and modified chimeric antigen receptor (CAR) cells. Modified T cell receptor (TCR) therapy generally involves introducing modified T cell receptors that target specific cancer antigens into patient- or donor-derived immune effector cells, such as T cells or natural killer cells. Alternatively, chimeric antigen receptor (CAR) therapy generally involves introducing chimeric antigen receptors that target specific cancer antigens into patient- or donor-derived immune effector cells, such as T cells, natural killer cells, or macrophages. One important advantage of CARs compared to TCRs is their ability to bind to cancer cells even when their antigens are not presented on the surface by MHC, potentially making the cancer cells more susceptible to their attack. However, CAR cells can only recognize antigens that are naturally expressed on their cell surface, and their range of potential antigen targets is smaller than that of TCRs.

[0687] In some embodiments, immunotherapy is a modified TCR or CAR immune cell, where TCR or CAR is a receptor found naturally on mature B cells and often expressed by lymphoma and myeloma cells; CD19 is found on the surface of almost all B cells and affects their growth, development and activity, and is often expressed by leukemia, lymphoma and myeloma cells; CD22 is found mainly on the surface of mature B cells and is often expressed by leukemia and lymphoma cells; CD30 is expressed on certain types of activated immune cells and is often expressed by leukemia and lymphoma cells; CD33 is found on several types of immune cells and is often expressed by leukemia cells; CD56 is a protein found on both neuronal and natural killer immune cells; CD123 (also known as IL-3R) is found on immune cells, is involved in proliferation and differentiation, and is often expressed by leukemia and lymphoma cells; and CD22 is involved in cell adhesion, is usually produced only before birth, and is abnormally expressed in cancer. CEA, a protein that is often overexpressed and can contribute to metastasis; EBV-related antigen, an exogenous viral protein expressed by Epstein-Barr virus (EBV) infected cancer cells; EGFR, a pathway that controls cell growth and is often mutated in cancer; GD2, a pathway that controls cell growth, adhesion, and migration and is often abnormally overexpressed in cancer cells; GPC3, a cell surface protein thought to be involved in the regulation of growth and cell division; HER2, a pathway that controls cell growth and is generally overexpressed in some cancers, especially breast cancer, and is associated with metastasis; HPV-related antigen, an exogenous viral protein expressed by cancer cells that develop as a result of human papillomavirus (HPV) infection; MAGE antigen (the genes that produce these proteins are normally turned off in adult cells but are reactivated in cancer cells and can flag them as abnormal to the immune system); mesothelin, a protein that is generally overexpressed in cancer and can assist in metastasis; MUC-1, a glycosphingated protein that is generally overexpressed in cancer; and although usually produced only before birth,NY-ESO-1, a protein often abnormally expressed in cancer; PSCA, a surface protein found in several cell types and often overexpressed by cancer cells; PSMA, a surface protein found on prostate cells and often overexpressed by prostate cancer cells; ROR1, a tyrosine kinase-like orphan receptor that is mainly expressed before birth rather than in adult tissue, but is often abnormally expressed in cancer and may promote cancer cell metastasis and prevent cancer cell death; cancer, The modified CAR therapy targets one or more tumor-associated antigens selected from WT1, a protein that promotes the progression of cancer and is abnormally expressed in patients with cancer, particularly leukemia, and Claudin 18.2, a surface protein that is overexpressed in some esophageal cancers and is involved in invasion and survival. In some embodiments, the modified CAR therapy is axicapbutagen silolucel (Yescarta®), a CD19-targeted CAR T-cell immunotherapy approved for a subset of patients with lymphoma. In some embodiments, the modified CAR therapy is tisagenlecleucel (Kymriah®), a CD19-targeted CAR T-cell immunotherapy approved for a subset of patients with leukemia and lymphoma. In some embodiments, the modified CAR therapy is lysokabutagen maralucel (Bristol-Myers Squibb Co.), a CD19-targeted CAR T-cell immunotherapy used to treat relapsed / refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL). In some embodiments, the modified CAR therapy is a BCMA CAR-T therapy, for example, but not limited to, JNJ-4528 (Johnson & Johnson) and KITE-585 (Gilead). CAR-T therapy is a bispecific CAR-T cell therapy targeting BCMA and CD38. In some embodiments, modified CAR therapy is CD20 / CD22 bitargeted CAR-T cell therapy. Compositions and methods for inducing CAR immune cells are, for example, U.S. Patent No. 5,359,046 (Cell Genesys), U.S. Patent No. 5,712,149 (Cell Genesys), U.S. Patent No. 6,103,521 (Cell Genesys), U.S. Patent No. 7,446,190 (Memorial Sloan Kettering Cancer Center), U.S. Patent No. 7,446,179 (City of Hope), U.S. Patent No. 7,638,325 (University of Pennsylvania), U.S. Patent No. 8,911,993 (University of Pennsylvania), and U.S. Patent No. 8,399,645 (St. Jude's Children's). (Hospital), U.S. Publication No. 8,906,682 (University of Pennsylvania), U.S. Publication No. 8,916,381 (University of Pennsylvania), U.S. Publication No. 8,975,071 (University of Pennsylvania), U.S. Publication No. 9,102,760 (University of Pennsylvania), U.S. Publication No. 9,4644 (University of Pennsylvania), U.S. Publication No. 9,855,298 (Gilead), U.S. Publication No. 10,144,770 (St. Jude Children's Hospital), U.S. Publication No. 10,266,580 (University of Pennsylvania), U.S. Publication No. 10,189,903 (Seattle Children's Hospital), International Publication No. 2014 / 011988 ( (University of Pennsylvania), International Publication No. 2014 / 145252, International Publication No. 2014 / 153270 (Novartis AG), U.S. Patent Application Publication No. 2018 / 0360880 (Memorial Sloan Kettering Cancer Center), International Publication No. 2017 / 0243 (Dana Farber) This information is described in International Publication No. 2016 / 115177 (Juno Therapeutics, Inc.) of the Cancer Institute, and each of these publications constitutes part of this specification by reference.

[0688] In some embodiments, immunotherapy is unmodified adoptive cell therapy. Adoptive cell therapy is an approach used to enhance the immune system's ability to fight diseases such as tumors and viral infections. According to this approach, immune cells, such as T cells or NK cells, are collected from a patient or donor, stimulated in the presence of antigen-presenting cells with tumor or virus-associated antigens, and then increased ex vivo. In some embodiments, adoptive cell therapy is tumor-infiltrating lymphocyte (TIL) therapy, in which spontaneously generated T cells that have already infiltrated the patient's tumor are collected, activated, increased, and then reinjected into the patient. In some embodiments, unmodified adoptive cell therapy includes autologous or allogeneic immune cells, such as αβ T cells, that have been activated to target multiple latent antigens. One strategy used to generate targeted unmodified T cells involves ex vivo increase of T cells by antigen-specific stimulation of patient-derived (autologous) or donor-derived (allogeneic) T cells ex vivo. These strategies generally involve the isolation of peripheral blood mononuclear cells (PBMCs) and exposure of the cells to one or more tumor-associated antigens. In particular, approaches to generating multi-antigen-specific T cells involve priming and activating T cells using multiple libraries of targeted antigen overlap peptides, such as multiple libraries of 15-mer peptides that overlap by 11 amino acids across the entire amino acid sequences of several target antigens. The focus was on the compounding process (see, for example, overlap peptide library products commercially available from JPT Technologies or Miltenyi). Strategies for activating ex vivo autologous or allogeneic immune effector cells to target tumor-associated antigens include, for example, U.S. Patent Publication No. 2011 / 0182870 (Baylor College of Medicine), U.S. Patent Publication No. 2015 / 0010519 (Baylor College of Medicine), U.S. Patent Publication No. 2015 / 0017723 (Baylor College of Medicine), International Publication No. 2006026746 (U.S. Department of Health and Human Services), U.S. Patent Publication No. 2015 / 0044258 (Cell Medica / Kurr Therapeutics), International Publication No. 2016 / 154112 (Children's National Medical Center), International Publication No. 2017 / 203356 (Queensland Institute of Medical Research), International Publication No. 2018 / 005712 (Geneius Biotechnology, Inc.), Vera et al. al. Accelerated Production of Antigen-Specific T Cells for Pre-clinical and Clinical Applications using Gas-permeable Rapid Expansion Cultureware (G-Rex), April 2010 Journal of Immunotherapy 33(3):305-315, Shafer et al. Antigen-specific Cytotoxic T Lymphocytes can Target Chemoresistant Side-Population Tumor Cells in Hodgkin's Lymphoma; May 2010 Leukemia Lymphoma 51(5): 870-880, Quintarelli et al. High Avidity Cytotoxic T Lymphocytes Specific for a New PRAME-derived Peptide can Target Leukemic and Leukemic-precursor cells, March 24, 2011 Blood 117(12): 3353-3362、Bollard et al. Manufacture of GMP-grade Cytotoxic T Lymphocytes Specific for LMP1 and LMP2 for Patients with EBV-associated Lymphoma, May 2011 Cytotherapy 13(5): 518-522、Ramos et al. Human Papillomavirus Type 16 E6 / E7-Specific Cytotoxic T Lymphocytes for Adoptive Immunotherapy of HPV-associated Malignancies, January 2013 Immunotherapy 36(1): 66-76、Weber et al. Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia - implications for immunotherapy, Clinical Cancer Research 2013 September 15; This information is described in 19(18): 5079-5091 and Ngo et al. Complementation of antigen presenting cells to generate T lymphocytes with broad target specificity, Journal of Immunotherapy. 2014 May; 37(4): 193-203, each of which is incorporated herein by reference. In some embodiments, the unmodified activated immune cells administered in combination with or alternately with the degradation-inducing agent compositions described herein are selected from activated CD4+ T cells (T helper cells), CD8+ T cells (cytotoxic T lymphocytes), CD3+ / CD56+ natural killer T cells (CD3+NKT), and γδ T cells (γδ T cells), or combinations thereof. In some embodiments, the adoptive cell therapy is a composition comprising CD4+ T cells (T helper cells). In some embodiments, the adoptive cell therapy is a composition comprising CD8+ T cells (cytotoxic T lymphocytes). In some embodiments, adoptive cell therapy is a composition comprising CD3+ / CD56+ natural killer T cells (CD3+NKT). In some embodiments, adoptive cell therapy is a composition comprising CD4+ T cells (T helper cells), CD8+ T cells (cytotoxic T lymphocytes), CD3+ / CD56+ natural killer T cells (CD3+NKT), and γδ T cells (γδ T cells).

[0689] In some embodiments, immunotherapy is a bispecific T cell engager (BiTE). A bispecific T cell engager induces T cells to target and bind to specific antigens on the surface of cancer cells. For example, blinatumomab (Amgen) is a BiTE. Blinatumomab has recently been approved as a second-line therapy for relapsed or refractory acute lymphoblastic leukemia with Philadelphia chromosome negative. Blinatumomab is administered by continuous intravenous infusion in 4-week cycles.

[0690] In a particular embodiment, the additional therapeutic agent is an additional inhibitor of Ikaros ("IKZF1") and / or Aiolos ("IKZF3"). In another embodiment, the additional therapeutic agent is an inhibitor of Helios ("IKZF2"). In one embodiment, the additional therapeutic activator is an inhibitor of Eos ("IKZF4"). In another embodiment, the additional therapeutic activator is an inhibitor of Pegasus ("IKZF5"). In yet another embodiment, the additional therapeutic activator is a cereblon ligand.

[0691] Non-limiting examples of cerebron ligands that can be used in combination with the compounds of the present invention include thalidomide, lenalidomide, pomalidomide, and iverdamide.

[0692] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are selected from the compounds described in International Publication No. 2012 / 175481, International Publication No. 2015 / 085172, International Publication No. 2015 / 085172, International Publication No. 2017 / 067530, International Publication No. 2017 / 121388, International Publication No. 2017 / 201069, International Publication No. 2018 / 108147, International Publication No. 2018 / 118947, International Publication No. 2019 / 038717, International Publication No. 2019 / 191112, International Publication No. 2020 / 006233, Patent Document 25, International Publication No. 2020 / 006265, or International Publication No. 2020 / 012334.

[0693] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are selected from the compounds described in International Publication No. 2019 / 060693, International Publication No. 2019 / 060742, International Publication No. 2019 / 133531, International Publication No. 2019 / 140380, International Publication No. 2019 / 140387, International Publication No. 2010 / 010177, International Publication No. 2020 / 010210, or International Publication No. 2020 / 010227.

[0694] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are described in International Publication Nos. 2015 / 160845, 2016 / 118666, 2016 / 149668, 2016 / 197032, 2016 / 197114, 2017 / 011371, 2017 / 0115901, 2017 / 030814, 2017 / 176708, 2018 / 053354, 2018 / 0716060, 2018 / 102067, and International Publication Nos. 2017 / 176708. The compounds are selected from those listed in International Publication No. 2018 / 118598, International Publication No. 2018 / 119357, International Publication No. 2018 / 119441, International Publication No. 2018 / 119448, International Publication No. 2018 / 140809, International Publication No. 2018 / 226542, International Publication No. 2019 / 023553, International Publication No. 2019 / 099926, International Publication No. 2019 / 195201, International Publication No. 2019 / 195609, International Publication No. 2019 / 199816, International Publication No. 2020 / 023851, International Publication No. 2020 / 041331, or International Publication No. 2020 / 051564.

[0695] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are described in International Publication Nos. 2016 / 105518, 2017 / 007612, 2017 / 024317, 2017 / 024318, 2017 / 024319, 2017 / 117473, 2017 / 117474, 2017 / 185036, 2018 / 064589, and 2018 / 148. Publication No. 440, International Publication No. 2018 / 148443, International Publication No. 2018 / 226978, International Publication No. 2019 / 014429, International Publication No. 2019 / 079701, International Publication No. 2019 / 094718, International Publication No. 2019 / 094955, International Publication No. 2019 / 118893, International Publication No. 2019 / 165229, Patent Document 25, International Publication No. 2020 / 018788, International Publication No. 2020 / 069105, International Publication No. 2020 / 069117 or International Publication No. 2020 The compounds are selected from those listed in issue / 069125.

[0696] In another embodiment, additional compounds that can be used in combination with the compounds of the present invention are described in International Publication Nos. 2017 / 197036, 2017 / 197046, 2017 / 197051, 2017 / 197055, 2017 / 197056, 2017 / 115218, and 2018 / 2201. The compounds are selected from those described in International Publication No. 49, International Publication No. 2018 / 237026, International Publication No. 2019 / 099868, International Publication No. 2019 / 121562, International Publication No. 2019 / 149922, International Publication No. 2019 / 191112, International Publication No. 2019 / 204354, International Publication No. 2019 / 236483, or International Publication No. 2020 / 051235.

[0697] V. Pharmaceutical Compositions While any of the compounds disclosed herein can be administered as a pure (neat) chemical substance, they are more typically administered as a pharmaceutical composition containing an effective amount to a host, typically a human, who requires such treatment for any of the disorders described herein. Accordingly, this disclosure provides pharmaceutical compositions comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof for any of the uses described herein, together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain only the compound or salt as an activator, or, in alternative embodiments, the compound and at least one additional activator.

[0698] In a particular embodiment, the pharmaceutical composition is a dosage form containing about 0.0005 mg to about 2000 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 600 mg, or about 0.001 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 300 mg of the active compound. In another embodiment, the pharmaceutical composition is a dosage form containing about 0.01 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg or 100 mg, about 0.05 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg or 100 mg, about 0.1 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 50 mg, about 0.02 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 50 mg, or about 0.5 mg to about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 50 mg of the active compound. In another embodiment, the pharmaceutical composition is a dosage form containing about 0.01 mg to about 10 mg, about 0.05 mg to about 8 mg, or about 0.05 mg to about 6 mg, or about 0.05 mg to about 5 mg of the active compound. In another embodiment, the pharmaceutical composition is a dosage form containing about 0.1 mg to about 10 mg, about 0.5 mg to about 8 mg, or about 0.5 mg to about 6 mg, or about 0.5 mg to about 5 mg of the active compound. Non-limiting examples include dosage forms containing at least about 0.0005 mg, 0.001 mg, 0.01 mg, 0.1 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of the active compound or a salt thereof. Alternative, non-limiting examples include dosage forms containing the active compound or its salt in amounts of approximately 0.01 mg, 0.1 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg or less.

[0699] The pharmaceutical composition may also comprise an active compound in a certain molar ratio and additional therapeutic agents. In non-limiting exemplary embodiments, the pharmaceutical composition may contain an anti-inflammatory or immunosuppressant in a molar ratio of up to about 0.5:1, up to about 1:1, up to about 2:1, up to about 3:1, or up to about 1.5:1 to up to about 4:1 relative to the compound of the present invention. The compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implant including an ocular implant, percutaneously, orally, rectally, or as eye drops. The injectable preparation, including the intraocular injection agent, can be administered intravenously, intra-aortally, intracranially, subdermally, intraperitoneally, subcutaneously, nasally, sublingually, or rectally, or by other means, in a dosage unit formulation containing a conventionally pharmaceutically acceptable carrier. For intraocular delivery, the compound can be administered as desired, for example, intravitreously, intramammally, anteriorly, subtenon's capsule, subretinal, retrobulbar, peribulbar, superchoroidally, conjunctiva, subconjunctival, superscleral, periocular, transscleral, retrobulbar, near the posterior sclera, pericorneal, or lacrimal duct injection, or via mucus, mucin, or the mucosal barrier in an immediate or controlled release manner, or by an intraocular device.

[0700] Pharmaceutical compositions can be formulated in any pharmaceutically useful form, such as aerosols, creams, gels, pills, injections or infusions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhalation formulations in medical devices, suppositories, oral or sublingual formulations, parenteral formulations, or eye drops. Some dosage forms, such as tablets and capsules, can be divided into appropriate-sized unit doses containing an appropriate amount of the active ingredient, for example, an effective amount to achieve the desired purpose.

[0701] The carrier, containing excipients and diluents, must be sufficiently pure and sufficiently low in toxicity to be suitable for administration to the patient being treated. The carrier may be inert or may have its own pharmaceutically active properties. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0702] Examples of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, glidentifiers, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be of two or more types; for example, vegetable oil can be used as a lubricant in some formulations and as a diluent in others. A pharmaceutically acceptable carrier is one that, when administered in the amounts used in the corresponding pharmaceutical composition, does not cause any serious adverse reactions in the human body. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin; talc, and vegetable oils. Any activator that does not substantially interfere with the activity of the compounds of the present invention may be included in the pharmaceutical composition.

[0703] Pharmaceutical compositions / combinations can be formulated for oral administration. These compositions may contain any amount of the active compound to achieve the desired result, for example, 0.1% to 99% (wt.%) of the compound (e.g., including at least about 5 wt.%) of the compound. Some embodiments contain about 25 wt.% to about 50 wt.% or about 5 wt.% to about 75 wt.% of the compound.

[0704] Formulations suitable for rectal administration are typically provided as unit-dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then molding the resulting mixture.

[0705] Formulations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Suitable carriers include petrolatum, lanolin, polyethylene glycol, alcohol, transdermal enhancers, and combinations of two or more of these.

[0706] Formulations suitable for transdermal administration can be delivered as individual patches adapted to remain in close contact with the recipient's epidermis for extended periods. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3 (6):318 (1986)), typically in the form of an optionally buffered aqueous solution of the active compound. In one embodiment, a microneedle patch or device penetrates biological tissue, particularly the skin. or provided for the delivery of drugs into or therein. Microneedle patches or devices enable drug delivery at clinically relevant rates across or into the barriers of skin or other tissues with little or no damage, pain, or irritation to the tissue.

[0707] Formulations suitable for pulmonary administration can be delivered by a wide range of passive and active single / multiple dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of a suitable lung delivery device depends on parameters such as the properties of the drug and its formulation, the site of action, and the pathophysiology of the lung.

[0708] Many methods and devices for drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications (which, by full reference, constitute part of this specification): Examples include U.S. Patent No. 8,192,408, titled "Ocular trocar assembly" (Psivida Us, Inc.); U.S. Patent No. 7,585,517, titled "Transcleral delivery" (Macusight, Inc.); and U.S. Patents No. 5,710,182 and 5, titled "Ophthalmic composition". U.S. Patent No. 795,913 (Santen OY); U.S. Patent No. 8,663,6,913, entitled “Formulations for treating ocular diseases and conditions”. Issue 39, titled "Formulations and methods for vascular permeability-related diseases or conditions" U.S. Patent No. 8,486,960, entitled "Liquid formulations for treatment of diseases or conditions," U.S. Patent No. 8,367, U.S. Patent No. 097 and U.S. Patent No. 8,927,005, U.S. Patent No. 7,455,855 (Santen Pharmaceutical Co., Ltd.) titled "Delivering substance and drug delivery system using the same"; "Vision and pain" International Publication No. 2011 / 050365 entitled "Conformable Therapeutic Shield For Vision and Pain", and International Publication No. 2011 / 050365 entitled "Therapeutic Device for Pain Management and Vision". U.S. Patent No. 2009 / 145842 (Forsight Labs, LLC); U.S. Patents No. 9,066,779 and 8,623,395 entitled “Implantable therapeutic device”, International Publication No. 2014 / 160884 entitled “Ophthalmic Implant for Delivering Therapeutic Substances”, U.S. Patent Publication No. 2009 / 145842 entitled “Posterior segment drug delivery” Patent No. 8,399,006, U.S. Patent No. 8,277,830, U.S. Patent No. 8,795,712, U.S. Patent No. 8,808,727, U.S. Patent No. 8,298,578 and International Publication No. 2010 / 088548, titled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant," International Publication No. 2014 / 152959 and U.S. Patent Application Publication No. 20140276482, titled "Injector apparatus and method for drug delivery" U.S. Patent No. 8,905,963 and U.S. Patent No. 9,033,911, "Formulations and Methods for Increasing or Reducing Mucus" International Publication No. 2015 / 057554, titled "Ocular insert apparatus and methods", and U.S. Patent No. 8,715,712 and U.S. International Publication No. 8,939,948, entitled "Insertion and Removal Methods and Apparatus for Therapeutic Devices" (International Publication No. 20) International Publication No. 2014 / 066775, titled "Ophthalmic System for Sustained Release of Drug to the Eye," No. 13 / 116061, titled "Implantable Therapeutic Device" International Publication Nos. 2015 / 085234 and 2012 / 019176, International Publication No. 2012 / 065006 titled "Methods and Apparatus to determine Porous Structures for Drug Delivery", International Publication No. 2010 / 141729 titled "Anterior Segment Drug Delivery", International Publication No. 2011 / 050327 titled "Corneal Denervation for Treatment of Ocular Pain", International Publication No. 2013 / 022801 titled "Small Molecule Delivery with Implantable Therapeutic Device", and "Posterior Segment Drug Delivery International Publication No. 2012 / 019047, entitled "Subconjunctival Implant for Posterior Segment Drug Delivery," International Publication No. 2012 / 068549, titled "Therapeutic Agent Formulations for Implanted Devices," and International Publication No. 2012 / 019139, titled "Combined Delivery Methods and Apparatus," and "Intraocular Implantation International Publication No. 2013 entitled "Ocular Insert Apparatus and Methods" International Publication No. 2012 / 019136, entitled "Injector Apparatus and Method for Drug Delivery," is titled / 040426, and is titled "Fluid Exchange." International Publication No. 2013 / 040247 (ForSight Vision4, Inc.) entitled "Fluid Exchange Apparatus and Methods," U.S. Patent Application Publication No. 2014 / 0352690 entitled "Inhalation Device with Feedback System," U.S. Patent Nos. 8,910,625 and 2015 / 0165137 (Vectura GmbH) entitled "Inhalation Device for Use in Aerosol Therapy," U.S. Patent No. 6,948,496 entitled "Inhalers," U.S. Patent Application Publication No. 2005 / 0152849 entitled "Powder comprising anti-adherent materials for use in dry powder inhalers," U.S. Patent Nos. 6,582,678, 8,137,657, U.S. Patent Publication No. 2003 / 0202944, and U.S. Patent Publication No. 2010 / 0330188, titled "Carrier particles for use in dry powder inhalers," U.S. Patent No. 6,221,338, titled "Method of producing particles for use in dry powder inhalers," and U.S. Patent No. 6,989,155, titled "Powder," and "To treat premature ejaculation by lung inhalation." U.S. Patent Application Publication No. 2007 / 0043030, titled "Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation," and U.S. Patent No. 7,845,349, titled "Inhaler," are used in inhaler devices. U.S. patent application titled "Formulations for Use in Inhaler Devices" U.S. Patent Publication No. 2012 / 0114709 and U.S. Patent No. 8,101,160, U.S. Patent Application Publication No. 2013 / 028785, entitled "Compositions and Uses" No. 4, U.S. Patent Application Publication No. 2014 / 0037737, entitled "Particles for Use in a Pharmaceutical Composition" and U.S. Patent No. 8, U.S. Patent Application Publication No. 580,306, “Mixing Channel for an Inhalation Device,” published in 2015 / 0174343, “Used in a Pharmaceutical Composition.” U.S. Patent No. 7,744,855 and U.S. Patent Publication No. 2010 / 0285142, entitled "Method of making particles for use in a pharmaceutical composition", and U.S. Patent No. 7,541,022, entitled "Pharmaceutical formulations for dry powder inhalers", U.S. Patent These are Patent Application Publication No. 2009 / 0269412 and U.S. Patent Application Publication No. 2015 / 0050350 (Vectura Limited).

[0709] An additional, non-limiting example of a method for delivering active compounds is titled "Intracameral Implant for Treatment of an Ocular Condition". International Publication No. 2015 / 085251 (Envisia Therapeutics, Inc.); International Publication No. 2011 / 008737, titled "Engineered Aerosol Particles, and Associated Methods," and "Geometrically Engineered Particles and Methods for Modulating Macrophages or Immune Responses." International Publication No. 2013 / 082111 entitled "for Modulating Macrophage or Immune Responses," International Publication No. 2009 / 132265 entitled "Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates," International Publication No. 2010 / 099321 entitled "Interventional drug delivery system and associated methods," and "Polymer particle composite having high fidelity, size and shape of particles." International Publication No. 2008 / 100304 titled "fidelity order, size, and shape particles"), and International Publication No. 2007 / 024323 titled "Nanoparticle fabrication methods, systems, and materials" (Liquidia) Technologies, Inc. and the University of North Carolina at Chapel Hill; “Intraocular controlled release” International Publication No. 2010 / 009087 entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and "Intracellular Delivery and Release of Cargo" These are presented in International Publication No. 2009 / 132206, titled "Compositions and Methods for Intracellular Delivery and Release of Cargo," International Publication No. 2007 / 133808, titled "Nano-particles for cosmetic applications," International Publication No. 2007 / 056561, titled "Medical device, materials, and methods," International Publication No. 2010 / 065748, titled "Method for producing patterned materials," and International Publication No. 2007 / 081876, titled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.).

[0710] An additional, non-limiting example of a drug delivery device and method is, for example, U.S. Patent Application Publication 20090 entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor". No. 203709 (Abbott Laboratories); "Subconjunctival or periocular delivery of prodrugs" A US publication titled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug" U.S. Patent Application Publication No. 20050009910, titled "Biodegradable polymers for lowering intraocular pressure", U.S. Patent No. 8,481,069, titled "Tyrosine kinase microspheres", and "Method of making tyrosine kinase microspheres" U.S. Patent No. 8,465,778, titled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods," U.S. Patent No. 8,409,607, titled "Biodegradable intravitreal tyrosine kinase implants," and U.S. Patent Publication No. 8,512,738. U.S. Patent Application Publication No. 2014 / 0031408, entitled "Microsphere Drug Delivery System for Sustained Intraocular Release," and U.S. Patent Application Publication No. 2014 / 0294986, entitled "Methods for Treating Retinopathy With Extended Therapeutic Effect." U.S. Patent No. 8,911,768 (Allergan, Inc.), titled "Improved injectability" U.S. Patent No. 6,495,164 (Alkermes Controlled Therapeutics, Inc.), titled "Preparation of injectable suspensions having improved injectability"; International Publication No. 2014 / 047439 (Akina, Inc.), titled "Biodegradable Microcapsules Containing Filling Material"; International Publication No. 2010 / 132664 (Baxter International Inc. Baxter Healthcare SA), titled "Compositions and Methods for Drug Delivery"; "Polymer nanoparticles with improved drug carrying capacity and their use" U.S. Patent Application Publication No. 20120052041, entitled "Polymeric nanoparticles with enhanced drug loading and methods of use thereof" (The Brigham and Women's Hospital, Inc.); U.S. Patent Application Publication No. 20140178475, entitled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same" (USA). National Patent Application Publication No. 20140248358 and U.S. Patent Application Publication No. 20140249158 (BIND Therapeutics, Inc.); U.S. Patent No. 5,869,103 titled "Polymer microparticles for drug delivery" (Danbiosyst UK Ltd.); U.S. Patent No. 8628801 titled "Pegylated Nanoparticles" (University of Navarra); U.S. Patent Application Publication No. 2014 / 0107025 titled "Ocular drug delivery system" (Jade Therapeutics, LLC); "Composed of microparticles and biodegradable gel having an improved release profile" U.S. Patent No. 6,287,588, titled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof"; U.S. Patent No. 6,589,549 (Macromed, Inc.), titled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles"; U.S. Patent No. 6,007,845 and U.S. Patent No. 5,578,3, titled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers" Issue 25 (Massachusetts Institute of Technology); "For periorbital or subconjunctival administration" U.S. Patent Application Publication Nos. 20040234611, 20080305172, 20120269894, and 20130122064 (Novartis Ag) entitled "Ophthalmic depot formulations for periocular or subconjunctival administration"; "Block polymer U.S. Patent No. 6,413,539 (Poly-Med, Inc.), titled "Block polymer"; U.S. Patent Application Publication No. 20070071756 (Peyman), entitled "Delivery of an agent to ameliorate inflammation"; "Depot for injection" - A method for achieving sustained release of poorly soluble drugs, including formulations and nanoparticles (Injectable Depot U.S. Patent Application Publication No. 20080166411 (Pfizer, Inc.) entitled "Formulations and Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles"; U.S. Patent Application Publication No. 20080166411 entitled "Methods and compositions for enhanced delivery of bioactive molecules" Patent No. 6,706,289 (PR Pharmaceuticals, Inc.); and "Microparticle containing matrices for drug delivery" One example is U.S. Patent No. 8,663,674 (Surmodics), titled "...".

[0711] VI. General synthesis The compounds described herein can be prepared by methods known to those skilled in the art. In a non-limiting example, the compounds disclosed may be prepared using the following scheme.

[0712] For convenience, the compounds of the present invention having stereocenters can be depicted without stereochemistry. Those skilled in the art will recognize that concentrated enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following:

[0713] i) Physical separation of crystals - a technique for manually separating the visible crystals of individual enantiomers. This technique can be used when separate enantiomer crystals exist, i.e., the material is a conglomerate and the crystals are visually distinguishable.

[0714] ii) Simultaneous crystallization - This is a technique for separately crystallizing individual enantiomers from a racemic solution, and is only possible if the enantiomers are conglomerates in the solid state.

[0715] iii) Enzyme resolution - A technique for partially or completely separating a racemic mixture by the difference in reaction rates between enantiomer enzymes.

[0716] iv) Enzymatic asymmetric synthesis - A synthetic technique that uses an enzymatic reaction in at least one step of synthesis to obtain a synthetic precursor of a desired enantiomer, either pure as an enantiomer or concentrated as an enantiomer.

[0717] v) Chemical asymmetric synthesis - A synthetic technique for synthesizing a desired enantiomer from an achiral precursor under conditions that result in asymmetricity (i.e., chirality) in the product, which can be achieved by a chiral catalyst or chiral auxiliary agent.

[0718] vi) Diastereomer Separation - A technique for converting racemic compounds into individual enantiomers by reacting them with a pure reagent (chiral auxiliary) as enantiomers. Subsequently, the resulting diastereomers are separated by chromatography or crystallization based on clearer structural differences, and the chiral auxiliary is removed to obtain the desired enantiomers.

[0719] vii) Primary and secondary asymmetric transformations - rapidly equilibrate diastereomers derived from racemates and provide preponderance for dissolving diastereomers derived from desired enantiomers. A technique that causes the formation of a crystalline diastereomer from a desired enantiomer, or disrupts the equilibrium through preferential crystallization of the diastereomer derived from the desired enantiomer, ultimately converting all materials from the desired enantiomer to the crystalline diastereomer. Subsequently, the desired enantiomer is released from the diastereomer.

[0720] viii) Kinetic resolution - This technique refers to the achievement of partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by the uneven reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions.

[0721] ix) Enantiospecific synthesis from non-racemic precursors - during synthesis A synthetic technique for obtaining desired enantiomers from non-chiral starting materials without significant or complete loss of stereochemical integrity.

[0722] x) Chiral liquid chromatography—a technique for separating enantiomers of a racemic mixture in a liquid mobile phase by different interactions with the stationary phase (including by chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to induce different interactions.

[0723] xi) Chiral gas chromatography - A technique for separating enantiomers from racemates by their different interactions in a gas mobile phase using a column equipped with a fixed non-racemic chiral adsorbent phase.

[0724] xii) Extraction with chiral solvents - A technique in which enantiomers are separated by selective dissolution of one enantiomer in a specific chiral solvent.

[0725] xiii) Transport across chiral membranes - a technique for placing racemates in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing a racemate, and a driving force such as a difference in concentration or pressure results in preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral properties of the membrane, which allow only one enantiomer of the racemate to pass through.

[0726] xiv) Pseudo-mobile bed chromatography is used in one embodiment. A variety of chiral stationary phases are commercially available.

[0727] General Synthesis Scheme 1 [ka] In some embodiments, compounds of formula I or II can be synthesized according to the route presented in general synthesis scheme 1. In step 1, compound G1-1 is reacted with butyllithium (or alternatively, another organolithium reagent such as tert-butyllithium, sec-butyllithium, phenyllithium, or methyllithium, or a Grignard reagent such as isopropylmagnesium bromide or ethylmagnesium bromide) in an organic solvent (e.g., tetrahydrofuran or diethyl ether) at a low temperature (usually -78°C to -40°C), and then G1-2 is added to obtain G1-3. In step 2, compound G1-3 is reacted with trifluoroacetic acid (or alternatively, another strong oxyacid such as trifluic acid) and triethylsilane (or alternatively, another organosilane such as phenylsilane, or an organotin hydride such as tributyltin hydride) in an organic solvent (e.g., 1,2-dichloroethane) while heating (e.g., about 60°C, or alternatively, by microwave irradiation) to obtain G1-4. In step 3, compound G1-4 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), and then G1-5 is added to obtain G1-6.

[0728] General Synthesis Scheme 2 [ka] In some embodiments, compounds of formula I or II can be synthesized according to the routes presented in General Synthesis Scheme 2. In step 1, compound G2-1 (prepared according to the procedure outlined in General Synthesis Scheme 1 for compounds G1-3) is reacted with an oxidizing agent (e.g., manganese dioxide, or other reagents suitable for the oxidation of alcohols) in an organic solvent (e.g., acetonitrile) to obtain G2-2. In step 2, G2-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of G2-3 to obtain G2-4. In step 3, G2-4 is reacted with a suitable carbonyl reducing agent (e.g., sodium cyanoborohydride) in an organic solvent (e.g., ethanol or methanol) to obtain G2-5.

[0729] General Synthesis Scheme 3 [ka] In some embodiments, compounds of formula I or II can be synthesized according to the routes presented in general synthesis scheme 3. In step 1, compound G3-1 (prepared according to the procedure outlined in general synthesis scheme 2 for compound G2-2) and DAST (or example G3-2 is obtained by reacting it with another suitable nucleophilic fluorinating reagent (for example, Deoxo-Fluor) in an organic solvent (e.g., dichloromethane). In step 2, compound G3-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), and then G3-3 is added to obtain G3-4.

[0730] General Synthesis Scheme 4 [ka] In some embodiments, compounds of formula I or II can be synthesized according to the routes presented in General Synthesis Scheme 4. In step 1, compound G4-1 (prepared according to the procedure outlined in General Synthesis Scheme 1 for compounds G1-3) is reacted with DAST (or other suitable nucleophilic fluorinating reagent such as Deoxo-Fluor) in an organic solvent (e.g., dichloromethane) to obtain G4-2. In step 2, compound G4-2 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), followed by the addition of G4-3 to obtain G4-4.

[0731] General Synthesis Scheme 5 [ka] In some embodiments, compounds of formula I or II can be synthesized according to the route presented in general synthesis scheme 5. In step 1, compounds G5-1 and G5-2 are reacted at high temperature in an organic solvent (e.g., toluene, THF, dioxane, or DMF) in the presence of a palladium catalyst (e.g., palladium(II) acetate, Pd2(dba)3, or other suitable palladium catalysts used under Buchwald-Hartwig coupling conditions), a phosphine ligand (e.g., BINAP, xanthophos, or other suitable phosphine ligands used under Buchwald-Hartwig coupling conditions), and a base (e.g., potassium tert-butoxide, cesium carbonate, or other suitable bases used under Buchwald-Hartwig coupling conditions) to obtain G5-3. In step 2, compound G5-3 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide, or dichloromethane), followed by the addition of G5-4 to obtain G5-5.

[0732] General Synthesis Scheme 6 [ka] In some embodiments, compounds of formula I or II can be synthesized according to the routes presented in general synthesis scheme 6. In step 1, compound G6-1 is reacted with a metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) in an organic solvent (e.g., dioxane) and water in the presence of a palladium catalyst (e.g., Pd2(dba)3) and a phosphine ligand (e.g., xanthophos) to obtain G6-2. In step 2, G6-2 is protected with a suitable protecting group (e.g., Boc or Cbz group) using standard conditions to obtain compound G6-3. In step 3, G6-3 and G6-5 are reacted at a high temperature (e.g., about 80°C) in an organic solvent (e.g., 1,2-dichloroethane) in the presence of a copper catalyst (e.g., copper acetate) and a base (e.g., pyridine or DMAP) to obtain compound G6-6. In step 4, the protecting group PG in G6-6 is removed using standard conditions suitable for a particular group to obtain G6-7. In step 5, compound G6-7 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., dimethylformamide or dichloromethane), and then G6-8 is added to obtain G6-9.

[0733] Non-limiting examples of the present invention When chirality is indicated in the following synthesis scheme, the specification represents the relative chirality of the stereocenter, not an absolute specification. For example, [ka] This is indicated using a wedge-shaped bond to show that the specified chiral center has been split by chiral chromatography. However, the absolute chirality of that stereocenter is instead [ka] This is a possibility. In this case, if intermediate 3a is reacted with racemicromoglutarimide, the resulting compound 280 may be a mixture of diastereomers. [ka]

[0734] Similarly, when an achiral lactam is reacted with racemiclutarimide in the experiment described below, the resulting compound may be a mixture of enantiomers. For example, when intermediate 7 is reacted with racemibromoglutarimide, the resulting intermediate 9 may be a mixture of enantiomers. [ka]

[0735] The resulting compounds may be a mixture of enantiomers unless otherwise indicated, having a specified stereochemistry. For example, as follows: [ka]

[0736] Those skilled in the art can separate mixtures of these enantiomers using methods known in the art, including chiral chromatography, crystallization, transport across chiral membranes, or extraction with chiral solvents. In fact, some of the following compounds have been separated using these methods. For example, intermediates [ka] The compounds were separated by chiral chromatography using preparative HPLC. Similarly, enantiomer mixtures of glutarimide can be separated by these methods, including chiral chromatography. For example, a mixture of compounds 67 and 68 was separated by chiral chromatography using preparative HPLC. The resulting separated compounds had an enantiomer excess of 99%. [ka]

[0737] After separation, absolute chirality is determined by known methods, including structural determination of various crystal forms. It can be specified as follows. For example, X-ray diffraction can be used on crystals of compounds such as compound 67 and compound 68 to determine whether they are (R) or (S).

[0738] The enantiomer mixture can also be divided in a synthetic sequence using methods known in the art. For example, the chiral centers can be divided using enzymatic resolution and enzymatic asymmetric synthesis. Additionally, the enantiomer mixture can be divided by incorporating protecting groups or using chiral salts. When using chiral protecting groups or salts, the enantiomer mixture temporarily becomes a diastereomer mixture, which can then be physically separated using known methods.

[0739] If the compound of the present invention is a mixture of diastereomers, they can also be separated by methods known in the art. For example, a mixture of diastereomers can be separated by chromatographic methods including reversed-phase or normal-phase HPLC, silica gel chromatography, mobile-bed chromatography, and preparative TLC. A mixture of diastereomers can also be separated by crystallization. [Examples]

[0740] Example 1: Synthesis of 3-(2-oxobenzo[cd]indole-1-yl)piperidine-2,6-dione (compound 1): [ka] To a stirred solution of 1H-benzo[cd]indole-2-one 1 (100.0 mg, 591.09 μmol) in DMF (2 mL), sodium hydride (60% dispersion in mineral oil, 24.91 mg, 650.20 μmol, 60% purity) was added at 0°C, and the reaction mixture was heated at 60°C for 30 minutes. 3-bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 μmol) was added, and the reaction mixture was heated at 60°C for 24 hours. New spots formed with unreacted starting material. Additional 3-bromopiperidine-2,6-dione 2 (113.50 mg, 591.09 μmol) was added, and the reaction mixture was heated again for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic fraction was separated. Next, the reaction mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound, which was purified by preparative TLC plate (elution with 2% MeOH-DCM) to obtain 3-(2-oxobenzo[cd]indole-1-yl)piperidine-2,6-dione (compound 1) (10 mg, 34.35 μmol, yield 5.81%, purity 96.28%) as a pale yellow solid. 1 H NMR (d6-DMSO, 400 MHZ) δ 11.13 (s, 1H), 8.24 (d, J = 8.08 Hz, 1H), 8.11 (d, J = 6.92 Hz, 1H), 7.84 (t, J = 7.56 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.76 Hz, 1H), 7.17 (d, J = 7.12 Hz, 1H), 5.46 (dd, J = 12.76, 5.08 Hz, 1H), 3.00-2.91 (m, 1H), 2.82-2.71 (m, 1H), 2.67-2.63 (m, 1H), 2.12-2.09 (m, 1H); LC MS: ES+ 281.2.

[0741] Example 2: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (Compound 2) [ka] Step 1: Preparation of 6-bromobenzo[cd]indole-2(1H)-one(2): To a stirred suspension of 1H-benzo[cd]indole-2-one 1 (3.0 g, 17.73 mmol) in CHCl3 (50.0 mL), bromine (2.15 g, 26.60 mmol, 1.44 mL) was added dropwise while cooling, and the reaction mixture was stirred at room temperature for 48 hours. Sodium thiosulfate solution was poured into the reaction mixture while cooling, and the resulting yellow solid was filtered through a sintered funnel. The obtained solid was washed with cold water and pentane, and azeotropically reacted with toluene to obtain 6-bromo-1H-benzo[cd]indole-2-one 2-2 (4 g, 16.12 mmol, yield 90.93%) as a yellow solid. LC MS: ES+ 248.1, 250.0 (bromopa turn).

[0742] Step 2: Preparation of tert-butyl 4-(4-(hydroxy(2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)-1H-pyrazole-1-yl)piperidine-1-carboxylate (4): Butyllithium (2.2 M, 9.38 mL) was added at -78°C to a stirred solution of 6-bromo-1H-benzo[cd]indole-2-one 2-2 (1.6 g, 6.45 mmol) in THF (7 mL). After the addition was complete, the temperature was raised to -40°C and the reaction mixture was stirred at the same temperature for 30 minutes. Lumilpyrazole-1-yl)piperidine-1-carboxylate 3 (1.80 g, 6.45 mmol) was added at -78°C, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and diluted with ethyl acetate. The layers were separated, and the organic layer was washed with water. The organic layer was then dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude compound, which was purified by flash chromatography using 0% → 5% MeOH-DCM to obtain tert-butyl 4-[4-[hydroxy-(2-oxo-1H-benzo[cd]indole-6-yl)methyl]pyrazole-1-yl]piperidine-1-carboxylate 4 (527 mg, 1.17 mmol, yield 18.22%) as a brown solid. 1H NMR (d6-DMSO, 400 MHz) δ 10.70 (s, 1H), 8.34 (d, J = 8.28 Hz, 1H), 7.95 (d, J = 6.96 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.59-7.52 (m, 2H), 7.28 (s, 1H), 6...

Claims

1. A pharmaceutical composition for treating a disorder selected from peripheral T-cell lymphoma and adult T-cell leukemia / lymphoma in humans, comprising the formula: 【Chemistry 1】 (In the formula, R3 is selected from hydrogen, halogen, alkyl, haloalkyl, -OR8 and -NR8 R8', R 3' is selected from hydrogen, halogen, alkyl and haloalkyl, Alternatively, R3 and R3' can integrate with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring. In each case, R2 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R8, -C(O)OR8, -C(O)-NR8R8', -S(O)R8, -SO2R8, -SO2-OR8, and -SO2-NR8R8'. R7 is independently selected in each case from hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8, -NR 8 R 8', -C(O)R 8, -C(O)OR 8, -C(O)-NR 8 R 8', -OC(O)R 8, -NR 2-C(O)R 8, -S(O)R 8, -SO2 R 8, -SO2-OR 8 and -SO2-NR 8 R 8', Alternatively, two R7 groups on the same carbon may unite to form an oxo group. R8 and R8' are independently selected in both cases from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. R9 is independently hydrogen, halogen, cyano, nitro, R10, -CH2 R10, -OR10, -NR2 R10, -C(O)R10, -C(O)CH2 R10, -C(O)CH2 OR10, -C(O)CH2NR2 R10, -OC(O)R10, -NR2 -C(O)R10, -C(O)OR10, -C(O)NR2 R10, -S(O)R10, -SO2 R10, SO2CH2 R10, -SO2CH2 OR10, -SO2CH2NR2 R Selected from 10, -NR 2 SO 2 R 10, -SO 2 -OR 10 and -SO 2 -NR 2 R 10, R10 is selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, and each R10 is optionally substituted with one, two, three, or four groups independently selected from R11. Two R11 groups on the same carbon may combine to form an oxo group. Or R 11 is independently a halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -CH2 aryl, -CH2 heteroaryl, -OR 8, -NR 8 R 8', -C(O)R 8, -C(O)OR 8, -C(O)-NR 8 R 8', -C(O)CH2 R 8, -C(O)CH2 OR 8, -C(O)CH2-NR 8 R 8', -OC(O)R 8, -NR2-C(O)R 8, -CH2-OC(O)R 8, -CH2-NR2-C(O)R 8, -S(O)R 8 Selected from -SO₂R₁₈, -SO₂-OR₁₈, oxo, and -SO₂-NR₁₈R₁₈', each of the R₁¹ groups is optionally replaced by one, two, three, or four groups independently selected from R₁². R 12 is independently a halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -CH2 aryl, -CH2 heteroaryl, -OR 8, -NR 8 R 8', -C(O)R 8, -C(O)OR 8, -C(O)-NR 8 R 8', -C(O)CH2 R 8, -C(O)CH2 OR 8, -C(O)CH2-NR 8 R 8', -OC(O)R 8, -NR2-C(O)R 8, -CH2-OC(O)R 8, -CH2-NR2-C(O)R 8, -S(O)R 8 A pharmaceutical composition comprising a compound of -SO₂R₅, -SO₂-OR₅, oxo, and -SO₂-NR₅R₅' selected from -SO₂R₅, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the disorder is peripheral T-cell lymphoma.

3. The pharmaceutical composition according to claim 1, wherein the disorder is angioimmunoblastic lymphoma.

4. The pharmaceutical composition according to claim 1, wherein the disorder is anaplastic large cell lymphoma.

5. The pharmaceutical composition according to claim 1, wherein the disorder is adult T-cell leukemia / lymphoma.

6. The pharmaceutical composition according to claim 1, wherein the disorder is enteropathy-associated T-cell lymphoma.

7. The pharmaceutical composition according to claim 1, wherein the disorder is nasal natural killer / T-cell lymphoma.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein R 7 is selected from hydrogen, halogen, cyano, alkyl, haloalkyl, -OR 8 and -NR 8 R 8'.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein one of the R7 substituents is hydrogen.

10. The pharmaceutical composition according to any one of claims 1 to 7, wherein the two R7 substituents are hydrogen.

11. The pharmaceutical composition according to any one of claims 1 to 7, wherein the three R7 substituents are hydrogen.

12. The pharmaceutical composition according to any one of claims 1 to 7, wherein each R7 substituent is hydrogen.

13. The pharmaceutical composition according to claim 12, wherein R3 is hydrogen.

14. The pharmaceutical composition according to claim 13, wherein R 3' is hydrogen.

15. The pharmaceutical composition according to any one of claims 1 to 7, wherein R 9 is selected from hydrogen, alkyl, and haloalkyl.

16. The pharmaceutical composition according to any one of claims 1 to 7, wherein each R9 is hydrogen.

17. The pharmaceutical composition according to claim 16, wherein R3 is hydrogen.

18. The pharmaceutical composition according to claim 17, wherein R 3' is hydrogen.

19. The compound has the structure: 【Chemistry 2】 A pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. The compound has the structure: 【Transformation 3】 A pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is or a pharmaceutically acceptable salt thereof.

21. The compound has the structure: 【Chemistry 4】 A pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is or a pharmaceutically acceptable salt thereof.

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