Tricyclic compounds for the treatment of cancer, autoimmune disorders and inflammatory disorders

Abstract

The present application relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, as defined herein. The present application also describes pharmaceutical compositions comprising compounds of Formula (I) and pharmaceutically acceptable salts thereof, as well as methods of using the compounds and compositions to treat diseases such as cancer, autoimmune disorders, and inflammatory disorders.

Description

Technical Field

[0001] This application relates to tricyclic and other polycyclic compounds that can be used to treat proliferative diseases such as cancer, as well as autoimmune diseases and inflammatory diseases. Background Technology

[0002] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is an intracellular protein that participates in lymphocyte proliferation via upstream signaling of NF-κB, controlling lymphocyte activation, survival, proliferation, and differentiation. Along with CARMA or CARD scaffold proteins (e.g., CARD11 (caspase recruitment domain family member 11, also known as CARMA1), CARD14 (caspase recruitment domain family member 14, also known as CARMA2), CARD10 (caspase recruitment domain family member 10, also known as CARMA3), or CARD9 (caspase recruitment domain family member 9)) and BCL10 (B-cell CLL / lymphoma 10), MALT1 is one of the three subunits of the CBM complex formed upon activation of cell surface antigen receptors. See Jaworski et al., *Cell Mol Life Science*, 2016, 73, 459-473, and Julienland and Thome, *Frontiers in Immunology*, 2018, 9, 1927. MALT1 is known to mediate NF-κB signaling through at least two mechanisms: first, MALT1 functions as a scaffold protein, recruiting NF-κB signaling proteins such as TRAF6, TABs (e.g., TAB1, TAB2, TAB3), TAK1, and NEMO-IKKα / β; and second, as a cysteine ​​protease, it cleaves and inactivates negative regulators of NF-κB signaling, such as RelB, A20, or CYLD. See Rosebeck et al., *Science*, 2011, 331, 468-472.

[0003] MALT1 protease activity has become a potential therapeutic target, especially given the perceived important role of NF-κB and related pathways. Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoma typically characterized by NF-κB overactivation, and studies have shown that MALT1 protease inhibition can significantly suppress the growth of highly aggressive ABC-type DLBCL and promote its apoptosis. See Ferch U et al., *Journal of Experimental Medicine*, 2009, 206, 2313-2320; also see Hailfinger S et al., *Proceedings of the National Academy of Sciences of the United States of America*, 2009, 106, 19946-19951. Known peptide substrates of MALT1 or the fusion protein API2-MALT1 include A20, CYLD, BCL10, RelB, regnase-1, roquin-1, NIK, and LIMA1a. See Rebeaud et al., *Nature Immunology*, 2008, 9, 272-281; ​​see also Coornaert et al., *Nature Immunology*, 2008, 9, 263-271; Staal et al., *Journal of the European Molecular Biology Society (EMBO J)*, 2011, 30, 1742-1752; Hailfinger et al., *Proceedings of the National Academy of Sciences (PNAS)*, 2011, 108, 14596-14601; Jeltsch et al., *Nature Immunology*, 2014, 15, 1079-1089; Uehata et al., *Cell*, 2013, 153, 1036-1049; Nie et al., *Nature Communications*, 2015, 6, 5908; and Baens et al., *PLoS*, 2015. ONE)》2014,9,e103774. A general profile of MALT1 substrates is described in the following literature: Kasperkiewicz et al. Scientific Reports 8.1(2018):1-10.

[0004] Furthermore, several chromosomal translocations leading to constitutively active MALT1 have been identified in ABC-DLBCL, and the identification of the MALT1 fusion protein API2-MALT1 / IgH-MALT1 leading to upstream-stimuli-independent NF-κB activation further highlights the importance of this protein in cancer and various diseases. See Farinha et al., *Journal of Clinical Oncology*, 2005, 23, 6370-6378. Furthermore, MALT1 has been shown to be associated with several different types of cancer, such as hematologic malignancies (e.g., mantle cell lymphoma), chronic lymphocytic leukemia (CLL), and solid tumors (e.g., lung adenocarcinoma, breast cancer, pancreatic cancer, and glioblastoma). See Jiang et al., Cancer Research, 2011, 71, 2183-2192; see also Pan et al., Molecular Cancer Research, 2016, 14, 93-102; Penas et al., Blood, 2010, 115, 2214-2219; and J Cell Mol Med., July 2020, 24(13):7550-7562. MALT1, as an immunomodulatory protein, is also involved in innate and adaptive immunity and may affect several inflammatory conditions, such as psoriasis, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome, ulcerative colitis, and various types of allergic diseases caused by chronic inflammation. See Afofina et al., *FEBS Journal*, 2015, DOI:10.111 / febs.13325; also Lowes et al., *Annals of Immunology*, 2014, 32, 227-255; Jabara et al., *J Allergy Clin Immunology*, 2013, 132, 151-158; Streubel et al., *Clin Cancer Research*, 2004, 10, 476-480; and Liu et al., *Oncotarget*, 2016, 1-14. Recently, research has also demonstrated the importance of MALT1 in controlling regulatory T cell (Treg) function and homeostasis. Ongoing studies are investigating the potential of MALT1 inhibitors, alone or in combination with immune checkpoint mechanisms, for the treatment of patients with solid tumors. However, no MALT1 inhibitors have been approved for therapeutic use. Summary of the Invention

[0005] Therefore, this paper provides a compound of formula (I):

[0006]

[0007] Or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, Q, n, R X R 1 R 2 R 3 m and R 4 As defined in this article.

[0008] In some embodiments, the compound of formula (I) has the following structure:

[0009]

[0010] Or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, Q, n, R 1 R 2 R 3 m and R 4 As defined in this article.

[0011] This article also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0012] A method for treating CBM complex pathway-related cancers in subjects of need is also provided, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0013] A method for treating cancer in subjects in need is also provided, the method comprising:

[0014] (a) Identifying the cancer as a CBM complex pathway-related cancer; and

[0015] (b) Administer to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0016] A method for treating cancer in subjects in need is also provided, the method comprising:

[0017] Administer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein to a subject identified as having a CBM complex pathway-related cancer.

[0018] A method for treating a subject with MALT1-related cancer is also provided, the method comprising administering to a subject identified or diagnosed with MALT1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0019] A method for treating cancer in subjects in need is also provided, the method comprising:

[0020] (a) Determining that the cancer is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them; and

[0021] (b) Administer to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0022] A method for inhibiting transfer in a subject who requires such treatment is also provided, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0023] A method for treating an autoimmune disease in a subject in need is also provided, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0024] A method is also provided for treating a subject with a CBM complex pathway-related disease or condition, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0025] A method for treating a disease or condition in a subject in need is also provided, the method comprising:

[0026] (a) Identifying the disease or condition as a CBM complex pathway-related disease or condition; and

[0027] (b) Administer to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0028] A method for treating a disease or condition in a subject in need is also provided, the method comprising:

[0029] The subject is given an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein, to a subject identified as having a CBM complex pathway-related disease or condition.

[0030] A method for treating a subject with MALT1-related autoimmune disease is also provided, the method comprising administering to a subject identified or diagnosed with MALT1-related autoimmune disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0031] A method for treating a subject with MALT1-related autoimmune disease is also provided, the method comprising administering to a subject identified or diagnosed with MALT1-related autoimmune disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0032] A method for treating autoimmune diseases in subjects of need is also provided, the method comprising:

[0033] (a) Determine that the autoimmune disease is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them; and

[0034] (b) Administer to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0035] A method for treating a subject with MALT1-related autoimmune disease is also provided, the method comprising administering to a subject identified as having MALT1-related autoimmune disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0036] A method for treating inflammatory conditions in a subject in need is also provided, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0037] A method for treating a subject with MALT1-related inflammatory conditions is also provided, the method comprising administering to a subject identified or diagnosed with MALT1-related inflammatory conditions an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0038] A method for treating a subject with MALT1-related inflammatory conditions is also provided, the method comprising administering to a subject identified or diagnosed with MALT1-related inflammatory conditions an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0039] A method for treating inflammatory conditions in subjects in need is also provided, the method comprising:

[0040] (a) Determine that the inflammatory condition is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them; and

[0041] (b) Administer to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0042] A method for treating MALT1-related inflammatory conditions in subjects in need is also provided, the method comprising administering to a subject identified as having MALT1-related inflammatory conditions an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0043] A method for inhibiting the activity of the CBM complex pathway in mammalian cells is also provided, the method comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0044] A method for inhibiting the activity of the MALT1 protease in mammalian cells is also provided, the method comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0045] It also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of diseases or conditions related to the CBM complex pathway.

[0046] Also provided are compounds of formula (I) or pharmaceutically acceptable salts thereof, which are used to prepare medicaments for treating diseases or conditions related to the CBM complex pathway.

[0047] It also provides a method for treating an individual with MALT1-related cancer, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof before, during or after administration of other anticancer drugs (e.g., a first MALT1 inhibitor or another MALT1 inhibitor).

[0048] This article also provides a method for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0049] This document also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof obtained by a method for preparing compounds as defined herein.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. This document describes methods and materials used in this disclosure; other suitable methods and materials known in the art may also be used. These materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of conflict, this specification (including definitions) shall prevail.

[0051] Other features and advantages of this disclosure will become apparent from the following detailed description and the claims. Detailed Implementation

[0052] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the described structure. Unless otherwise stated, compounds identified herein as a particular tautomer by name or structure are intended to include other tautomers.

[0053] As used herein, the term "tautomer" refers to a compound whose structure differs significantly in atomic arrangement but exists readily and rapidly in equilibrium. It should be understood that the compounds described herein can be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of this disclosure, and the naming of compounds does not exclude any tautomer. The following are examples of included tautomeric forms:

[0054]

[0055] It should be understood that some of the compounds presented herein may contain one or more asymmetric centers, and therefore may be prepared and isolated as mixtures of isomers (such as racemic mixtures) or as enantiomeric pure forms.

[0056] The term "halogen" refers to one of the halogens in Group 17 of the periodic table. Specifically, this term refers to fluorine, chlorine, bromine, and iodine. Preferably, this term refers to fluorine or chlorine.

[0057] The term "C1-C6 alkyl" refers to a straight-chain or branched hydrocarbon chain containing one, two, three, four, five, or six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Similarly, C1-C3 alkyl refers to a straight-chain or branched hydrocarbon chain containing one, two, or three carbon atoms.

[0058] The term "C1-C6 haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom (e.g., fluorine, chlorine, bromine, and iodine) that is independently chosen each time it appears. The halogen atom can be present at any position on the hydrocarbon chain. Similarly, C1-C3 haloalkyl is a straight-chain or branched hydrocarbon chain containing one, two, or three carbon atoms substituted with at least one halogen atom. For example, C1-C3 haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloroethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl.

[0059] The term "C1-C6 alkoxy" refers to a C1-C6 alkyl group linked to a molecule by oxygen. This includes alkyl moieties that can be straight-chain or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0060] The term "C1-C6 haloalkoxy" refers to a C1-C6 alkyl group that is linked to a molecule by an oxygen atom and in which at least one hydrogen atom of the alkyl group is replaced by a halogen. This includes alkyl moieties that can be straight-chain or branched, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or trifluoropropoxy.

[0061] When valence is permissible Indicates a single or double bond. For example,

[0062]

[0063] As used herein, the term "cyano" refers to the -CN group.

[0064] As used herein, the term "hydroxyl group" refers to the -OH group.

[0065] As used herein, the term "amino" refers to the -NH2 group.

[0066] As used herein, the term "aryl" refers to a 6-10 all-carbon monocyclic or bicyclic group, wherein at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl. In bicyclic systems in which only one ring is aromatic, the non-aromatic ring may be a cycloalkyl group as defined herein.

[0067] As used herein, the term "heteroaryl" refers to a 5-10 membered monocyclic or bicyclic group in which at least one ring in the system is aromatic; wherein one or more carbon atoms in at least one ring in the system are independently replaced by heteroatoms selected from N, O, and S. Heteroaryls comprise rings in which one or more groups are oxidized (e.g., carbon, nitrogen, and sulfur), such as pyridone moieties. Non-limiting examples of heteroaryls include pyridine, pyrimidine, pyrrole, imidazole, and indole. In bicyclic systems in which only one ring is aromatic, the non-aromatic ring may be a cycloalkyl or heterocyclic group as defined herein.

[0068] As used herein, the term "cycloalkoxy" refers to 3-10 monocyclic or bicyclic hydrocarbon groups linked by an oxygen group (i.e., -O-); wherein bicyclic systems include fused ring systems, spirocyclic systems (optionally referred to as "spirocycloalkyl" groups), and bridged ring systems. Non-limiting examples of cycloalkoxy groups include cyclopropoxy, cyclohexoxy, spiro[2.3]hexoxy, and bicyclo[1.1.1]pentoxy.

[0069] As used herein, the term "cycloalkyl" refers to 3-10 monocyclic or bicyclic hydrocarbon groups that are saturated or partially unsaturated; wherein bicyclic systems include fused ring systems, spirocyclic systems (optionally referred to as "spirocycloalkyl" groups), and bridged ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclic[1.1.1]pentyl.

[0070] The term "heterocyclic group" refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic system that is not aromatic and has at least one heteroatom selected from N, O, and S within the ring. Bicyclic heterocyclic groups include fused ring systems, spirocyclic systems (optionally referred to as "spiroheterocyclic" groups), and bridged ring systems. Heterocyclic ring systems may contain oxygen substitutions at one or more C, N, or S ring members. Heterocyclic groups can be represented, for example, as "5-10 membered heterocyclic groups," which are ring systems containing 5, 6, 7, 8, 9, or 10 atoms, wherein at least one atom is a heteroatom. For example, one, two, or three heteroatoms may be present, optionally one or two. Heterocyclic groups can be bonded to the rest of the molecule via any carbon atom or via heteroatoms such as nitrogen. Exemplary heterocyclic groups include, but are not limited to, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, aziridine, oxaziridine, 2-azirospiro[3.3]heptyl, pyrrolidine-2-one, sulfolane, isothiazolin S,S-dioxide, and decahydronaphthyl.

[0071] As used herein, the term "paired" refers to a substituent atom or group that is attached to the same atom in the molecule.

[0072] As used herein, the term "ortho" refers to a substituent atom or group attached to an adjacent atom in a molecule. The stereochemical relationship between substituent atoms or groups can be cis, trans, undefined, or unresolved.

[0073] As used herein, the term “oxygen group” refers to the “=O” group attached to a carbon atom.

[0074] As used in this article, symbols It describes the connection points between an atom or part and a specified atom or group in the rest of the molecule.

[0075] It should be understood that the rings in the compound of formula (I) that include atoms X, Y and Z do not contain more than two adjacent nitrogen atoms.

[0076] Compounds of formula (I) contain their pharmaceutically acceptable salts. Additionally, compounds of formula (I) may contain other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and may be used as intermediates for the preparation and / or purification of compounds of formula (I) and / or for the isolation of enantiomers of compounds of formula (I). Non-limiting examples of pharmaceutically acceptable salts of compounds of formula (I) include trifluoroacetate and hydrochloride salts.

[0077] It will be further understood that compounds of formula (I) or their salts can be separated as solvates, and therefore any such solvates are included within the scope of this disclosure. For example, compounds of formula (I) and their salts can exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc.

[0078] In some embodiments, the compound of formula (I) comprises the compounds of Examples 1-203 and their stereoisomers and pharmaceutically acceptable salts. In some embodiments, the compound of formula (I) comprises the compounds of Examples 1-203 and their pharmaceutically acceptable salts. In some embodiments, the compounds of Examples 1-203 are in the form of a free base. In some embodiments, the compounds of Examples 1-203 are in the form of a pharmaceutically acceptable salt.

[0079] The term "pharmaceutically acceptable" means that the compound or its salt or composition is chemically and / or toxicologically compatible with the other components constituting the formulation and / or with the subject being treated with said formulation.

[0080] Protecting groups can be temporary substituents that protect potentially reactive functional groups from unwanted chemical transformations. The choice of a particular protecting group used is entirely within the skill of a person skilled in the art. Many factors can determine the choice of protecting group, including, but not limited to, the functional group being protected, other functional groups present in the molecule, the reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, the tolerance of the functional group to the conditions required to remove the protecting group, and the reaction conditions for the thermal decomposition of the compound provided herein. The field of protecting group chemistry has been reviewed (Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis, 2nd ed., Wiley: New York, 1991).

[0081] The nitrogen protecting group can be any temporary substituent that protects the amine moiety from undesirable chemical transformations. Examples of moieties formed when such a protecting group is bonded to an amine include, but are not limited to, allylamine, benzylamine (e.g., benzylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and triphenylmethylamine), acetamide, trichloroacetamide, trifluoroacetamide, pent-4-enamide, phthalimide, carbamates (e.g., methyl carbamate, tert-butyl carbamate, benzyl carbamate, allyl carbamate, 2,2,2-trichloroethyl carbamate, and 9-fluorenyl methyl carbamate), imines, and sulfonamides (e.g., benzenesulfonamide, p-toluenesulfonamide, and p-nitrobenzenesulfonamide).

[0082] The oxygen protecting group can be any temporary substituent that protects the hydroxyl moiety from unwanted chemical transformations. Examples of moieties formed when such a protecting group is bonded to the hydroxyl moiety include, but are not limited to, esters (e.g., acetyl, tert-butylcarbonyl, and benzoyl), benzyl (e.g., benzyl, p-methoxybenzyl, and 2,4-dimethoxybenzyl and triphenylmethyl), carbonates (e.g., methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate, and benzyl carbonate), ketals, acetals, and ethers.

[0083] The compounds described herein may also contain non-natural proportions of atomic isotopes on one or more atoms constituting such compounds. That is, an atom (especially when referred to with respect to compounds of formula (I)) includes all isotopes and mixtures of isotopes of that atom, which are naturally occurring or synthetically produced, and are either naturally abundant or in an isotopically enriched form. For example, unless otherwise explicitly stated, when referring to hydrogen, it should be understood to mean... 1 H, 2 H, 3 H or mixtures thereof; when referring to carbon, it should be understood as referring to 11 C 12 C13 C 14 C or mixtures thereof; when nitrogen is mentioned, it should be understood to refer to 13 N、 14 N、 15 N or mixtures thereof; when oxygen is mentioned, it should be understood to refer to 14 O、 15 O、 16 O、 17 O、 18 O or mixtures thereof; and when fluorine is mentioned, it should be understood to refer to 18 F, 19 F or mixtures thereof. For example, in deuteryl and deuteroxy groups, one or more hydrogen atoms are deuterated (F or a mixture thereof). 2 H) Specific substitution. Since some of the aforementioned isotopes are radioactive, the compounds provided herein also include compounds having one or more atoms of one or more isotopes and mixtures thereof, comprising radioactive compounds in which one or more non-radioactive atoms have been replaced by one of their radioactively rich isotopes. Radiolabeled compounds can be used as therapeutic agents, such as cancer therapeutic agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variations of the compounds provided herein, whether radioactive or non-radioactive, are intended to be covered within the scope of this disclosure.

[0084] For illustrative purposes, this document provides general methods for preparing the compounds and key intermediates. Detailed descriptions of each reaction step are provided in the Examples section below. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of this invention. Although specific starting materials and reagents are described in the embodiments and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified using conventional chemical methods well known to those skilled in the art according to this disclosure.

[0085] The ability of the selected compounds to act as MALT1 inhibitors can be demonstrated by the biological assays described in this paper. 50 The values ​​are shown in Tables A and B.

[0086] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be used to treat diseases and conditions that can be treated with MALT1 inhibitors, such as MALT1-related cancers, including blood cancers and solid tumors, MALT1-related autoimmune diseases, and MALT1-related inflammatory diseases.

[0087] As used herein, the term "treat" refers to a therapeutic or mitigating measure. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial relief of symptoms associated with the disease or condition, reduction of the severity of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or reduction of the disease state (e.g., one or more disease symptoms), and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean extended survival compared to expected survival without treatment.

[0088] As used herein, the term "subject" means any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or condition to be treated and / or prevented.

[0089] As used herein, the term “pediatric subject” refers to a subject who is under 21 years of age at the time of diagnosis or treatment. The term “pediatric” can be further subdivided into various subgroups, including: newborns (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 years to 21 years (up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. *Nelson Textbook of Pediatrics*, 15th ed., Philadelphia: WB Saunders Company, 1996; Rudolph AM et al. *Rudolph's Pediatrics*, 21st ed., New York: McGraw-Hill, 2002; and Avery MD, First LR. *Pediatric Medicine*, 2nd ed., Baltimore: Williams & Wilkins, 1994. In some embodiments, the age of the pediatric subjects is from birth to the first 28 days of life, from 29 days to under two years of age, from two years to under 12 years of age, or from 12 years to 21 years of age (up to but not including the twenty-second birthday). In some embodiments, the age of the pediatric subjects is defined as follows: from birth to the first 28 days of life, from 29 days to less than 1 year, from one month to less than four months, from three months to less than seven months, from six months to less than 1 year, from 1 year to less than 2 years, from 2 years to less than 3 years, from 2 years to less than 7 years, from 3 years to less than 5 years, from 5 years to less than 10 years, from 6 years to less than 13 years, from 10 years to less than 15 years, or from 15 years to less than 22 years.

[0090] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used to prevent diseases and conditions as defined herein (e.g., autoimmune diseases, inflammatory conditions, and cancer). As used herein, the term “prevention” means complete or partial prevention of the onset, recurrence, or spread of the disease or condition described herein, or its symptoms.

[0091] The term "regulatory agency" refers to a national agency that approves the medical use of drugs within that country. A non-restrictive example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0092] Signal transduction via the NF-κB pathway is involved in many cancers. See, for example, Staudt, Cold Spring Harbor Perspectives in Biology 2.6 (2010):a000109; Xia et al., Cancer Immunol. Res. 2.9 (2014):823-830; Xia et al., OncoTargets and Therapy 11 (2018):2063. NF-κB is a family of transcription factors including p50, p52, p65 (RelA), RelB, and c-Rel, which can bind to κB enhancer elements as various homodimers to induce transcription of many genes. Upon activation of certain cell surface receptors (e.g., CD28, BCR, HER1 (also known as EGFR (epidermal growth factor receptor) and ERBB1) or HER2 (also known as HER2 / neu or ERBB2)), the CBM complex is formed via CARD or CARMA proteins, possibly through phosphorylation of protein kinase C (e.g., protein kinase Cβ or protein kinase Cθ) and recruitment of the BCL10-MALT1 complex. See, for example, Xia et al. Tumor Targets and Therapies 11 (2018):2063, Shi and Sun. Molecular Immunology 68.2 (2015):546-557, Xia et al. Cancer Immunology Research 2.9 (2014):823-830, and Pan. Molecular Cancer Research 14.1 (2016):93-102.

[0093] As described above, the CBM complex can function as a scaffold protein in the activation of the NF-κB pathway. Upon formation, the CBM complex can activate the IKK complex (e.g., IKKγ (also known as NEMO), IKKα, and IKKβ), possibly through the ubiquitination of MALT1 (e.g., K63-linked ubiquitination), which induces the recruitment, ubiquitination (e.g., K63-linked ubiquitination), and degradation of IKKγ, thereby releasing IKKα and IKKβ to phosphorylate IκB, leading to IκB ubiquitination (e.g., K48-linked ubiquitination) and degradation, thus releasing NF-κB transcription factors (typically NF-κB1 isoforms: p50-RelA and p50-cRel) into the nucleus. This cascade reaction may be mediated by the ubiquitin ligase TRAF6 (tumor necrosis factor receptor (TNFR)-associated factor 6). The CBM complex may also affect NF-κB signaling through other protein complexes, such as TAB1 / 2-TAK and the linear ubiquitin chain assembly complex (LUBAC). See, for example, Cold Spring Harbor Biological Outlook 2.3 (2010):a000158, Xia et al. Tumor Targets and Therapies 11 (2018):2063, Julienland, Frontiers in Immunology 9 (2018):1927. MALT1 can also activate the JNK pathway (also known as the JNK / AP-1 pathway), although there is relatively little research in this area. See, for example, Julienland, Frontiers in Immunology 9 (2018):1927, and Wang et al., Oncogenesis 6.7 (2017):e365-e365.

[0094] In addition, MALT1 possesses cysteine ​​protease activity. Unrestricted examples of wild-type MALT1 substrates include BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, and HOIL1. Furthermore, the API2-MALT1 fusion protein (also known as cIAP2; the N-terminus of apoptosis inhibitor 2) has been shown to cleave NIK and LIMA1α. MALT1 cleavage of BCL10 is thought to lead to BCL10-independent NF-κB activation. By cleaving A20 (TNFα-inducible protein 3), MALT1 can reduce the negative regulation of the NF-κB pathway, as A20 is a deubiquitinating enzyme that has been suggested to reduce MALT1 ubiquitination, thereby reducing the recruitment and activation of the IKK complex. CYLD (CYLD lysine 63 deubiquitinase) is a deubiquitinating enzyme, and by cleaving this enzyme, MALT1 is believed to increase signaling via the NF-κB and / or JNK pathways. Cleavage of RelB typically alleviates the negative regulation of the NF-κB pathway because RelB forms a transcriptionally inactive complex with RelA and c-Rel. Cleavage of HOIL1 (also known as RBCK1) is believed to alleviate the negative regulation of NF-κB, as HOIL1 is thought to reduce linear ubiquitination. MALT1 can also be autoprocessed to promote signaling via the NF-κB pathway through a mechanism not yet fully understood. Cleavage of NIK (NF-κB-inducible kinase) generates the c-terminal fragment of NIK, which is resistant to proteasome degradation, thereby increasing non-canonical NF-κB signaling. Cleavage of LIMA1α (LIM domain and actin-binding protein 1) reduces the tumor-suppressive properties of this protein, and the remaining fragment is believed to have oncogenic properties and enhance cell proliferation, colony formation, and cell adhesion. Cleavage of Regnase 1 (regulatory RNase 1, also known as MCPIP-1 or Zc3h12a) and roquin-1 (also known as RC3H1) is thought to lead to the stabilization of mRNAs containing cytokines, chemokines, and co-stimulatory proteins such as ICOS, OX40, and TNF. This activity may be independent of MALT1 activity in the NF-κB and JNK pathways. See, for example, Afonina et al., *FEBS J.* 282.17(2015):3286-3297; Klein et al., *Nature Communications* 6.1(2015):1-17; Baens et al., *PLOS ONE* 9.8(2014):e103774; and Julien, *Frontiers in Immunology* 9(2018):1927.MALT1 is also involved in oncogenic BCR signaling in ibrutinib-responsive cell lines and biopsy samples, coordinated by a multi-protein supercomplex (hereinafter referred to as the My-T-BCR supercomplex) formed by MYD88, TLR9, and BCR. The My-T-BCR supercomplex co-localizes with mTOR on lysosomes, where it drives survival-promoting NF-κB and mTOR signaling. See Phelan et al., Nature, August 2018; 560(7718):387-391.

[0095] Therefore, inhibition of MALT1 can provide beneficial effects for many types of conditions associated with abnormal signaling in the NF-κB or JNK pathways. For example, inhibiting MALT1 can reduce flux through the NF-κB or JNK pathways caused by one or more of the following:

[0096] (1) Inactivated tumor suppressor genes. Non-restrictive examples of tumor suppressor genes that can be inactivated include BRCA1 and p53 (e.g., p53 H61L or I123T). See, for example, Sau et al. Cell Stem Cell 19.1 (2016):52-65, Xia et al. Cancer Immunology Research 2.9 (2014):823-830, Johansson et al. Tumor Targets 7.38 (2016):62627.

[0097] (2) Dysregulated cell surface receptors. Non-limiting examples of cell surface receptors include HER1 and HER2. See, for example, Xia et al., Cancer Immunology Research 2.9 (2014):823-830 and Pan, Molecular Cancer Research 14.1 (2016):93-102.

[0098] (3) Imbalance of one or more components of the CBM complex. Non-limiting examples of components of the CBM complex include MALT1, CARD11, CARD14, CARD10, CARD9 and BCL10.

[0099] (4) Dysregulation of one or more MALT1 protease substrates (e.g., wild-type MALT1 protease or dysregulated MALT1 protease). Non-limiting examples of MALT1 protease substrates include BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, HOIL1, NIK, and LIMA1α.

[0100] (5) Dysregulation of one or more components of the NF-κB pathway downstream of the CBM complex. Non-limiting examples of components of the NF-κB pathway downstream of the CBM complex include TRAF6, IKKα, IKKβ, IKKγ (also known as NEMO), IkBα, p50, p52, p65 (RelA), RelB, and c-Rel.

[0101] (6) Dysregulation of one or more components of the JNK pathway downstream of the CBM complex. Non-restricted examples of components of the JNK pathway downstream of the CBM complex include JNK1 (mitogen-activated protein kinase 8), JNK2 (mitogen-activated protein kinase 9), JNK3 (mitogen-activated protein kinase 10), or AP-1 transcription factor (e.g., a heterodimer of any of the c-Fos, c-Jun, ATF, or JDP families).

[0102] (7) Dysregulation of one or more fusion proteins caused by chromosomal translocation of the MALT1 gene. Non-limiting examples include the cIAP-MALT1 fusion protein.

[0103] (8) Imbalance of one or more components of the My-T-BCR supercomplex. Non-limiting examples of components of the My-T-BCR supercomplex include MYD88, TLR9 and mTOR.

[0104] As used herein, the term "CBM complex pathway" encompasses genes, transcripts, and proteins in signal transduction pathways that include CBM. For example, many aspects of the NF-κB pathway are part of the CBM complex pathway. The CBM complex pathway may include, for example, cell surface receptors (e.g., CD28, BCR, HER1, and HER2), signal transducers between cell surface receptors and CBM complexes (e.g., protein kinase Cβ or protein kinase Cθ), components of the CBM complex (e.g., MALT1, CARD11, CARD14, CARD10, CARD9, or BCL10), and substrates of the MALT1 protease (e.g., BCL10, A20, CYLD, RelB, Regnase). 1. Components of the NF-κB pathway downstream of the CBM complex (e.g., TAK1, TRAF6, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65(RelA) or c-Rel), components of the JNK pathway downstream of the CBM complex (e.g., JNK1, JNK2, JNK3 or AP-1 transcription factors), or components of the My-T-BCR supercomplex (e.g., MYD88, TLR9 or mTOR).

[0105] As used herein, the term “CBM complex pathway-related disease or condition” refers to a disease or condition associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of genes, proteins, or any of them in the CBM complex pathway, as described herein) in the CBM complex pathway. Non-limiting examples of CBM complex pathway-related diseases or conditions include, for example, CBM-related primary immunodeficiency diseases, autoimmune diseases, multiple sclerosis, colitis, psoriasis, and cancer. See, for example, McGuire et al., *Journal of Neuroinflamm.* 11.1 (2014):1-12; Lu et al., *Frontiers in Immunology* 9 (2018):2078; Jaworski et al., *Journal of the European Society for Molecular Biology* 33.23 (2014):2765-2781. Non-limiting examples of diseases or conditions related to the CBM complex pathway include MALT1-related diseases or conditions, such as MALT1-related cancers, MALT1-related autoimmune diseases, and MALT1-related inflammatory diseases.

[0106] As used herein, the term "CBM complex pathway-associated autoimmune disease" refers to an autoimmune disease associated with or having a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of CBM complex pathway genes, CBM complex pathway proteins, or any of them (e.g., one or more)). Non-limiting examples of CBM complex pathway-associated autoimmune diseases are described herein.

[0107] As used herein, the term "CBM complex pathway-associated inflammatory condition" refers to an inflammatory condition associated with or having a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of CBM complex pathway genes, CBM complex pathway proteins, or any of them (e.g., one or more)). Non-limiting examples of CBM complex pathway-associated inflammatory conditions are described herein.

[0108] In some embodiments, CBM complex pathway-related diseases or conditions are CBM complex pathway-related cancers, such as CBM complex pathway cell surface receptor-related cancers (e.g., CD28-related cancers, BCR-related cancers, HER1-related cancers, or HER2-related cancers), cancers related to signal transduction mechanisms between cell surface receptors and the CBM complex (e.g., protein kinase Cβ (PKCβ)-related cancers or protein kinase Cθ (PCKθ)-related cancers), components of CBM complex-related cancers (e.g., MALT1-related cancers, CARD11-related cancers, CARD14-related cancers, CARD10-related cancers, CARD9-related cancers, or BCL10-related cancers), and MALT1 protease substrate-related cancers (e.g., BCL10-related cancers, A20-related cancers, CYLD-related cancers, RelB-related cancers, Regnase). Cancers associated with CBM complexes include: 1-related cancers, roquin-1-related cancers, HOIL1-related cancers, NIK-related cancers, or LIMA1α-related cancers; cancers associated with components of the NF-κB pathway downstream of the CBM complex (e.g., TAK1-related cancers, TRAF6-related cancers, TAB1-related cancers, TAB2-related cancers, TAB3-related cancers, MKK7-related cancers, IKKα-related cancers, IKKβ-related cancers, IKKγ-related cancers, IkBα-related cancers, p50-related cancers, p65(RelA)-related cancers, or c-Rel-related cancers); cancers associated with components of the JNK pathway downstream of the CBM complex (e.g., JNK1-related cancers, JNK2-related cancers, JNK3-related cancers, or AP-1 transcription factor-related cancers); MYD88-related cancers, or combinations thereof.

[0109] As used herein, the term "CBM complex pathway-associated cancer" refers to cancer associated with or dysregulated (e.g., any type of dysregulation of the expression, activity, or level of genes, proteins, or any of them in the CBM complex pathway, as described herein) (e.g., post-diagnosis or after resistance to prior therapy). Non-limiting examples of CBM complex pathway-associated cancers are described herein. In some embodiments, CBM complex pathway-related cancers may be CBM complex pathway cell surface receptor-related cancers (e.g., CD28-related cancers, BCR-related cancers, HER1-related cancers, or HER2-related cancers), cancers related to signal transduction mechanisms between cell surface receptors and the CBM complex (e.g., protein kinase Cβ (PKCβ)-related cancers or protein kinase Cθ (PCKθ)-related cancers), components of CBM complex-related cancers (e.g., MALT1-related cancers, CARD11-related cancers, CARD14-related cancers, CARD10-related cancers, CARD9-related cancers, or BCL10-related cancers), or MALT1 protease substrate-related cancers (e.g., BCL10-related cancers, A20-related cancers, CYLD-related cancers, RelB-related cancers, Regnase). Cancers associated with CBM complexes, including cancers related to roquin-1, HOIL1, NIK, or LIMA1α; cancers associated with components of the NF-κB pathway downstream of the CBM complex (e.g., TAK1, TRAF6, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65(RelA), or c-Rel); and cancers associated with components of the JNK pathway downstream of the CBM complex (e.g., JNK1, JNK2, JNK3, or AP-1 transcription factor).

[0110] In some embodiments, dysregulation can be a dysregulation that results in abnormal activation of the expression, activity, or level of a gene, protein, or any of them. Activation can occur through any suitable mechanism, including but not limited to gene amplification, activation mutations, activation translocations, transcriptional activation, epigenetic alterations, and / or overexpression of the protein product of an oncogene. In some embodiments, dysregulation can be a dysregulation that results in abnormal inactivation of the expression, activity, or level of a gene, protein, or any of them. Inactivation can occur through any suitable mechanism, including but not limited to gene deletion, inactivation mutations, inactivation translocations, transcriptional silencing, epigenetic alterations, and degradation of the mRNA and / or protein product of a gene. Generally, as used herein, dysregulation (whether activation or inactivation) is a dysregulation that results in increased signal transduction via the NF-κB or JNK signaling pathway.

[0111] The term "wildtype" describes nucleic acids (e.g., the MALT1 gene or MALT1 mRNA) or proteins (e.g., the MALT1 protein) found in subjects who do not have a disease or condition related to nucleic acids or proteins (e.g., the MALT1 gene, MALT1 mRNA, or MALT1 protein) (and optionally do not have an increased risk of having a disease or condition related to nucleic acids or proteins and / or are not suspected of having a disease or condition related to nucleic acids or proteins), or from cells or tissues of subjects who do not have a disease or condition related to nucleic acids or proteins (e.g., MALT1-related cancer, autoimmune disease, or inflammatory disease) (and optionally do not have an increased risk of having a disease or condition related to nucleic acids or proteins and / or are not suspected of having a disease or condition related to nucleic acids or proteins).

[0112] In some embodiments, the subject has been identified or diagnosed with cancer that has dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or any of them (CBM complex pathway-related cancer) (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has cancer that is resistant to one or more prior therapies. In some embodiments, the subject has a tumor that is positive for dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). The subject may be a subject with a tumor that is positive for dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or any of them (e.g., identified as positive using a regulatory-approved (e.g., FDA-approved) assay or kit). The subject may be a subject whose tumor has dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or both (e.g., in cases where the tumor is identified using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has a tumor resistant to one or more prior therapies. In some embodiments, the subject is suspected of having CBM complex pathway-related cancer. In some embodiments, the subject has a suspected tumor resistant to one or more prior therapies. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or either of these (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has a clinical record indicating that the subject has a tumor resistant to one or more prior therapies. In some embodiments, the subject has been identified or diagnosed with cancer that has been determined based on histological examination to be associated with dysregulation of the expression, activity, or level of CBM complex pathway-related genes (e.g., the MALT1 gene), CBM complex pathway-related proteins (e.g., the MALT1 protein), or any of them (CBM complex pathway-related cancer).

[0113] In some embodiments, the subject has been identified or diagnosed with an autoimmune disease (CBM pathway-associated autoimmune disease) having dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject is suspected of having a CBM complex pathway-associated autoimmune disease. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subjects are pediatric subjects. In some embodiments, the subjects have been identified or diagnosed with an autoimmune disease that has been determined based on histological examination to be associated with dysregulation of the expression, activity, or level of CBM complex pathway-related genes (e.g., the MALT1 gene), CBM complex pathway-related proteins (e.g., the MALT1 protein), or any of them (CBM complex pathway-related autoimmune disease).

[0114] In some embodiments, the subject has been identified or diagnosed with an inflammatory condition (CBM pathway-associated inflammation) having dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject is suspected of having CBM complex pathway-associated inflammation. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with an inflammatory condition that has been determined based on histological examination to be associated with dysregulation of the expression, activity, or level of CBM complex pathway-related genes (e.g., the MALT1 gene), CBM complex pathway-related proteins (e.g., the MALT1 protein), or any of them (CBM complex pathway-related inflammatory condition).

[0115] As used herein, the term "CBM complex pathway cell surface receptor-associated cancer" refers to cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any of these (e.g., one or more), said dysregulation being associated with a CBM complex pathway cell surface receptor. In some embodiments, CBM complex pathway cell surface receptor-associated cancer is selected from the group consisting of: CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, HER2-associated cancer, and combinations thereof.

[0116] As used herein, the term “*-associated cancer” refers to cancer associated with or having a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the *gene, *protein, or any of them, as described herein) of the *gene, *protein, or any of them, and the *protein, as described herein”, where “*” refers to the specific CBM complex pathway gene or protein described herein. In some embodiments, *related cancers are selected from the group consisting of: CD28-related cancers, BCR-related cancers, HER1-related cancers, HER2-related cancers, PKCβ-related cancers, PKCθ-related cancers, MALT1-related cancers, CARD11-related cancers, CARD14-related cancers, A20-related cancers, CYLD-related cancers, RelB-related cancers, HOIL1-related cancers, NIK-related cancers, Regnase1-related cancers, LIMA1α-related cancers, roquin-1-related cancers, TRAF6-related cancers, TAK1-related cancers, TAB1-related cancers, TAB2-related cancers, TAB3-related cancers, MKK7-related cancers, IKKα-related cancers, IKKβ-related cancers, IKKγ-related cancers, IkBα-related cancers, p50-related cancers, p65-related cancers, c-Rel-related cancers, JNK1-related cancers, JNK2-related cancers, JNK3-related cancers, MYD88 transcription factor-related cancers, and AP-1 transcription factor-related cancers. In some embodiments, *related cancers are CD28-related cancers. In some embodiments, *related cancer is BCR-related cancer. In some embodiments, *related cancer is HER1-related cancer. In some embodiments, *related cancer is HER2-related cancer. In some embodiments, *related cancer is PKCβ-related cancer. In some embodiments, *related cancer is PKCθ-related cancer. In some embodiments, *related cancer is MALT1-related cancer. In some embodiments, *related cancer is CARD11-related cancer. In some embodiments, *related cancer is CARD14-related cancer. In some embodiments, *related cancer is A20-related cancer. In some embodiments, *related cancer is CYLD-related cancer. In some embodiments, *related cancer is RelB-related cancer. In some embodiments, *related cancer is HOIL1-related cancer. In some embodiments, *related cancer is NIK-related cancer. In some embodiments, *related cancer is Regnase 1-related cancer. In some embodiments, *related cancer is LIMA1α-related cancer. In some embodiments, *related cancer is roquin-1-related cancer. In some embodiments, *related cancer is TRAF6-related cancer. In some embodiments, *related cancer is TAK1-related cancer. In some embodiments, *related cancer is TAB1-related cancer. In some embodiments, *related cancer is TAB2-related cancer.In some embodiments, *related cancer is TAB3-related cancer. In some embodiments, *related cancer is MKK7-related cancer and IKKα-related cancer. In some embodiments, *related cancer is IKKβ-related cancer. In some embodiments, *related cancer is IKKγ-related cancer. In some embodiments, *related cancer is IkBα-related cancer. In some embodiments, *related cancer is p50-related cancer. In some embodiments, *related cancer is p65-related cancer. In some embodiments, *related cancer is c-Rel-related cancer. In some embodiments, *related cancer is JNK1-related cancer. In some embodiments, *related cancer is JNK2-related cancer. In some embodiments, *related cancer is JNK3-related cancer. In some embodiments, *related cancer is AP-1 transcription factor-related cancer. In some embodiments, *related cancer is MYD88 transcription factor-related cancer.

[0117] The phrase “dysregulation of expression, activity, or level of *gene, *protein, or any of them” (where * is a specific CBM complex pathway gene or protein described herein) refers to (e.g., compared to control non-cancer cells) a gene mutation of a wild-type *protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a *domain and a fusion chaperone; mutation in a *gene causing expression of a *protein containing at least one missing amino acid compared to wild-type *protein; mutation in a *gene causing expression of a *protein with one or more point mutations compared to wild-type *protein; mutation in a *gene causing expression of a *protein with at least one inserted amino acid compared to wild-type *protein; gene duplication causing elevated levels of *protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of *protein in cells); an alternative splicing form of *mRNA causing expression of a *protein with at least one missing amino acid compared to wild-type *protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling). As another example, an increased *gene copy number can cause overexpression of *proteins. For instance, dysregulation of the expression, activity, or level of *genes, *proteins, or any of them can be the result of gene or chromosomal translocations that cause the expression of fusion proteins containing a first portion of * and a second portion of a chaperone protein (i.e., not *). In some instances, dysregulation of the expression, activity, or level of *genes, *proteins, or any of them can be the result of a gene translocation between a *gene and another non-*gene. In some embodiments, the expression or activity or level of the gene, protein, or any of them is selected from the group consisting of: CD28, BCR, HER1, HER2, PKCβ, PKCθ, MALT1, CARD11, CARD14, A20, CYLD, RelB, HOIL1, NIK, Regnase 1, LIMA1α, roquin-1, TRAF6, TAK1, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65, c-Rel, JNK1, JNK2, JNK3, MYD88, and AP-1 transcription factors. In some embodiments, the gene or protein is CD28. In some embodiments, the gene or protein is BCR. In some embodiments, the gene or protein is HER1. In some embodiments, the gene or protein is HER2. In some embodiments, the gene or protein is PKCβ. In some embodiments, the gene or protein is PKCθ. In some embodiments, the gene or protein is MALT1.In some embodiments, the *gene or *protein is CARD11. In some embodiments, the *gene or *protein is CARD14. In some embodiments, the *gene or *protein is A20. In some embodiments, the *gene or *protein is CYLD. In some embodiments, the *gene or *protein is RelB. In some embodiments, the *gene or *protein is HOIL1. In some embodiments, the *gene or *protein is NIK. In some embodiments, the *gene or *protein is Regnase 1. In some embodiments, the *gene or *protein is LIMA1α. In some embodiments, the *gene or *protein is roquin-1. In some embodiments, the *gene or *protein is TRAF6. In some embodiments, the *gene or *protein is TAK1. In some embodiments, the *gene or *protein is TAB1. In some embodiments, the *gene or *protein is TAB2. In some embodiments, the *gene or *protein is TAB3. In some embodiments, the *gene or *protein is MKK7. In some embodiments, the *gene or *protein is IKKα. In some embodiments, the *gene or *protein is IKKβ. In some embodiments, the *gene or *protein is IKKγ. In some embodiments, the *gene or *protein is IkBα. In some embodiments, the *gene or *protein is p50. In some embodiments, the *gene or *protein is p65. In some embodiments, the *gene or *protein is c-Rel. In some embodiments, the *gene or *protein is JNK1. In some embodiments, the *gene or *protein is JNK2. In some embodiments, the *gene or *protein is JNK3. In some embodiments, the *gene or *protein is the MYD88 transcription factor. In some embodiments, the *gene or *protein is the AP-1 transcription factor.

[0118] In some embodiments, dysregulation of the expression, activity, or level of a gene, protein, or any of them can be a mutation in the gene encoding the protein, which is constitutively active or has increased activity compared to a protein encoded by a gene without the mutation. In some embodiments, an increased copy number of the gene can cause overexpression of the protein. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is CD28. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is BCR. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is HER1. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is HER2. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is PKCβ. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is PKCθ. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is CARD14. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is CARD9. In some embodiments, the expression, activity, or level of the *gene, *protein, or any of them is CARD10. In some embodiments, the expression, activity, or level of the *gene, *protein, or any of them is CARD11. In some embodiments, the expression, activity, or level of the *gene, *protein, or any of them is MALT1.

[0119] As another example, dysregulation of the expression, activity, or level of a gene, protein, or any of them can be a mutation in the gene encoding the protein, which is constitutively inactive or has reduced activity compared to a protein encoded by a gene that does not contain the mutation. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is A20. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is CYLD. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is RelB. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is HOIL1. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is NIK.

[0120] A disease or condition “associated with” a specific gene or protein described herein refers to a disease or condition that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the specific gene, protein, or any of the specific proteins described herein) in relation to or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the specific gene, protein, or any of the specific proteins described herein). Non-limiting examples of such diseases or conditions are described herein. Similarly, cancer “associated with” a specific gene or protein described herein refers to cancer that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the specific gene, protein, or any of the specific proteins described herein) in relation to or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the specific gene, protein, or any of the specific proteins described herein). Non-limiting examples of such cancers are described herein.

[0121] An exemplary sequence of the protein described in this article is shown below.

[0122] An example sequence of human CD28 is shown below:

[0123] SEQ ID NO:1 (UniParc Registry Number UPI0000043F4D)

[0124] MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIY FCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0125] Non-restrictive examples of CD28 gene or CD28 protein dysregulation can be found, for example, Rohr et al., Leukemia 30.5 (2016):1062-1070, Yoo et al., Haematologica 101.6 (2016):757-763, and Lee et al., Haematologica 100.12 (2015):e505.

[0126] An exemplary sequence of human BCR is shown below:

[0127] SEQ ID NO:2 (UniParc Registry Number UPI000016A088)

[0128]

[0129] Non-limiting examples of BCR gene or BCR protein (e.g., BCR-ABL fusion) dysregulation can be found, for example, Yang and Fu, Crit. Rev. Oncol. / Hematol. 93.3 (2015):277-292, Weisberg et al., Nat. Rev. Cancer 7.5 (2007):345-356, and Jabbour et al., Cancer 117.9 (2011):1800-1811.

[0130] An example sequence of human HER1 is shown below:

[0131] SEQ ID NO:3 (UniParc Registry Number UPI000003E750)

[0132]

[0133] Non-limiting examples of HER1 gene or HER1 protein dysregulation can be found, for example, Zhang et al., Targets for Tumors 7.48 (2016):78985; Ellison et al., Journal of Clinical Pathology 66.2 (2013):79-89; Midha et al., American Journal of Cancer Research 5.9 (2015):2892; and Yamamoto et al., Lung Cancer 63.3 (2009):315-321.

[0134] An example sequence of human HER2 is shown below:

[0135] SEQ ID NO:4 (UniParc Registry Number UPI000003F55F)

[0136]

[0137] Non-limiting examples of HER2 gene or HER2 protein dysregulation can be found in, for example, Petrelli, Fausto et al., Breast Cancer Research and Treatment 166.2 (2017):339-349; Yan et al., Cancer and Metastasis Reviews 34.1 (2015):157-164; Koshkin et al., Bladder Cancer 5.1 (2019):1-12; and Connell et al., ESMO Open 2.5 (2017).

[0138] As used herein, the term "cancer associated with a signal transducer between cell surface receptors and the CBM complex" refers to cancer associated with or having an dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more), said dysregulation being associated with a signal transducer between cell surface receptors and the CBM complex. In some embodiments, cancer associated with a signal transducer between cell surface receptors and the CBM complex is selected from the group consisting of PKCβ-associated cancers, PCKθ-associated cancers, and combinations thereof. Cancer "associated" with a specific gene or protein described in this paragraph refers to cancer associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein) related to the expression, activity, or level of that specific gene, protein, or any of them. Non-limiting examples of such cancers are described herein.

[0139] An example sequence of human PKCβ is shown below:

[0140] SEQ ID NO:5 (UniParc Registry Number UPI000012DF67)

[0141] MADPAAGPPPSEGEESTVRFARKGALRQKNVHEVKNHKFTARFFKQPTFCSHCTDFIWGFGKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPASDDPRSKHKFKIHTYSSPTFCDHCGSLLYGLIHQGMKCDTCMMNVHKRCVMNVPSLCGTDHTERRGRIYIQAHIDRDVLIVLVRDAKNLVPMDPNGLSDPYVKLKLIPDPKSESKQKTKTIKCSLNPEWNETFRFQLKESDKDRRLSVEIWDWDLTSRNDFMGSLSFGISELQKASVDGWFKLLSQEEGEYFNVPVPPEGSEANEELRQKFERAKISQGTKVPEEKTTNTVSKFDNNGNRDRMKLTDFNFLMVLGKGSFGKVMLSERKGTDELYAVKILKKDVVIQDDDVECTMVEKRVLALPGKPPFLTQLHSCFQTMDRLYFVMEYVNGGDLMYHIQQVGRFKEPHAVFYAAEIAIGLFFLQSKGIIYRDLKLDNVMLDSEGHIKIADFGMCKENIWDGVTTKTFCGTPDYIAPEIIAYQPYGKSVDWWAFGVLLYEMLAGQAPFEGEDEDELFQSIMEHNVAYPKSMSKEAVAICKGLMTKHPGKRLGCGPEGERDIKEHAFFRYIDWEKLERKEIQPPYKPKARDKRDTSNFDKEFTRQPVELTPTDKLFIMNLDQNEFAGFSYTNPEFVINV

[0142] Exemplary sequence of human PKCθ is shown as follows:

[0143] SEQ ID NO:6 (UniParc accession number UPI000012DF74)

[0144] MSPFLRIGLSNFDCGSCQSCQGEAVNPYCAVLVKEYVESENGQMYIQKKPTMYPPWDSTFDAHINKGRVMQIIVKGKNVDLISETTVELYSLAERCRKNNGKTEIWLELKPQGRMLMNARYFLEMSDTKDMNEFETEGFFALHQRRGAIKQAKVHHVKCHEFTATFFPQPTFCSVCHEFVWGLNKQGYQCRQCNAAIHKKCIDKVIAKCTGSAINSRETMFHKERFKIDMPHRFKVYNYKSPTFCEHCGTLLWGLARQGLKCDACGMNVHHRCQTKVANLCGINQKLMAEALAMIESTQQARCLRDTEQIFREGPVEIGLPPCSIKNEARPPPCLPTPGKREPQGISWESPLDEV DKMCHLPEPELNKERPSLQIKLKIEDFILHKMLGKGSFGKVFLAEFKKTNQFFAIKALKKDVVLMDDVECTMVEKRVLSLAWEHPFLTHMFCTFQTKENLFFVMEYLNGGDLMYHIQSCHKFDLSRATFYAAEIILGLQFLHSKGIVYRDLKLDNILLDKDGHIKIADFGMCKENMLGDAKTNTFCGTPDYIAPEILLGQKYNHSVDWWSFGVLLYEMLIGQSPFHGQDEELELFHSIRMDNPFYPRWLEKEAKDLLVKLFVREPEKRLGVRGDIRQHPLFREINWEELERKEIDPPFRPKVKSPFDCSNFDKEFLNEKPRLSFADRALINSMDQNMFRNFSFNMPGMERLIS

[0145] As used herein, the term "component of CBM complex-associated cancer" refers to cancer associated with or having an dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more), said dysregulation being associated with a component of the CBM complex. In some embodiments, the component of CBM complex-associated cancer is selected from the group consisting of: MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, CARD10-associated cancer, CARD9-associated cancer, BCL10-associated cancer, and combinations thereof. In some embodiments, the CBM complex-associated cancer is selected from the group consisting of: MALT1-associated cancer, CARD11-associated cancer, BCL10-associated cancer, and combinations thereof. Cancer "associated" with a specific gene or protein described in this paragraph refers to cancer associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein) being associated with or having an dysregulation. Non-limiting examples of such cancers are described herein.

[0146] As used herein, the term "MALT1-associated autoimmune disease" refers to an autoimmune disease associated with or having dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any of them (e.g., one or more)). Non-limiting examples of MALT1-associated autoimmune diseases are described herein.

[0147] As used herein, the term "MALT1-associated inflammatory condition" refers to an inflammatory condition associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any of them (e.g., one or more). Non-limiting examples of MALT1-associated inflammatory conditions are described herein.

[0148] As used herein, the term "MALT1-related cancer" refers to cancer associated with or dysregulated (e.g., any type of dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any of them (e.g., one or more). Non-limiting examples of MALT1-related cancers are described herein.

[0149] The phrase "dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein, or either of them" refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type MALT1 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a MALT1 protease domain and a fusion chaperone; mutation in the MALT1 gene causing expression of MALT1 protein containing at least one amino acid deletion compared to wild-type MALT1 protein; mutation in the MALT1 gene causing expression of MALT1 protein with one or more point mutations compared to wild-type MALT1 protein; mutation in the MALT1 gene causing expression of MALT1 protein with at least one inserted amino acid compared to wild-type MALT1 protein; gene duplication causing elevated MALT1 protein levels in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated MALT1 protein levels in cells); MALT1 Alternative splicing of mRNA resulting in a MALT1 protein with at least one amino acid deletion compared to the wild-type MALT1 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulation of autocrine / paracrine signaling. As another example, dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protein, or either thereof can be a mutation in the MALT1 gene encoding the MALT1 protein, which is constitutively active or has increased activity compared to a protein encoded by a non-mutated MALT1 gene. As yet another example, an increased copy number of the MALT1 gene can cause overexpression of the MALT1 protease. For example, dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protein, or either thereof can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first portion of MALT1 (which includes a functional protease domain) and a second portion of a chaperone protein (i.e., not MALT1). In some instances, dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein, or either of them can be the result of a gene translocation between a MALT1 gene and another non-MALT1 gene.

[0150] An example sequence of human MALT1 is shown below:

[0151] SEQ ID NO:7 (UniParc Registry No. UPI000004D05E)

[0152] MSLLGDPLQALPPSAAPTGPLAPPAGATLNRLREPLLRRLSELLDQAPEGRGWRRLAELAGSRGRLRLSCLDLEQCSLKVLEPEGSPLSLCLKLMGEKGCTVTELSDFLQAMEHTEVLQLLSPPGIKITVNPESKAVLAGQFVKLCCRATGHPFVQYQWFKMNKEIPNGNTSELIFNAVHVKDAGFYVCRVNNNFTFEFSQWSQL DVCDIPESFQRSVDGVSESKLQICVEPTSQKLMPGSTLVLQCVAVGSPIPHYQWFKNELPLTHETKKLYMVPYVDLEHQGTYWCHVYNDRDSQDSKKVEIIIGRTDEAVECTEDELNNLGHPDNKEQTTDQPLAKDKVALLIGNMNYREHPKLKAPLVDVYELTNLLRQLDFKVVSLLDLTEYEMRNAVDEFLLLDKGVYGLLYY AGHGYENFGNSFMVPVDAPNPYRSENCLCVQNILKLMQEKETGLNVFLLDMCRKRNDYDDTIPILDALKVTANIVFGYATCQGAEAFEIQHSGLANGIFMKFLKDRLLEDKKITVLLDEVAEDMGKCHLTKGKQALEIRSSLSEKRALTDPIQGTEYSAESLVRNLQWAKAHELPESMCLKFDCGVQIQLGFAAEFSNVMIIYTSI VYKPPEIIMCDAYVTDFPLDLDIDPKDANKGTPEETGSYLVSKDLKPHCLYTRLSSLQKLKEHLVFTVCLSYQYSGLEDTVEDKQEVNVGKPLIAKLDMHRGLGRKTCFQTCLMSNGPYQSSAATSGGAGHYHSLQDPFHGVYHSHPGNPSNVTPADSCHCSRTPDAFISSFAHHASCHFSRSNVPVETTDEIPFSDRLRISEK

[0153] Non-limiting examples of MALT1 gene or MALT1 protein perturbation are shown in the lower table B1.

[0154] Table B1.

[0155]

[0156] 1US Patent 10,711,036

[0157] 2 US Patent Application Publication US20190160045A1

[0158] 3 US Patent Application Publication US20130096021A1

[0159] 4 US Patent Application Publication US20150320754A1

[0160] As used herein, the term “CARD11-associated autoimmune disease” refers to an autoimmune disease that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them, as described herein) of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them.

[0161] As used herein, the term “CARD11-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them, as described herein) with respect to or with respect to the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them.

[0162] As used herein, the term “CARD11-related cancer” refers to cancer that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them, e.g., one or more) of the CARD11 gene, CARD11 protein, or any of them as described herein. Non-limiting examples of CARD11-related cancers are described herein.

[0163] The phrase “dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or either of them” refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type CARD11 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a CARD11 domain and a fusion chaperone; mutation in the CARD11 gene causing expression of a CARD11 protein containing at least one amino acid deletion compared to wild-type CARD11 protein; mutation in the CARD11 gene causing expression of a CARD11 protein with one or more point mutations compared to wild-type CARD11 protein; mutation in the CARD11 gene causing expression of a CARD11 protein with at least one inserted amino acid compared to wild-type CARD11 protein; gene duplication causing elevated levels of CARD11 protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of CARD11 protein in cells); CARD11 Alternative splicing forms of mRNA that result in a CARD11 protein with at least one amino acid deletion compared to the wild-type CARD11 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulation of autocrine / paracrine signaling. As another example, dysregulation of the expression, activity, or level of the CARD11 gene, the CARD11 protein, or either thereof can be a mutation in the CARD11 gene encoding the CARD11 protein, which is constitutively active or has increased activity compared to a protein encoded by a CARD11 gene without the mutation. As yet another example, an increased copy number of the CARD11 gene can cause overexpression of the CARD11 protein. For example, dysregulation of the expression, activity, or level of the CARD11 gene, the CARD11 protein, or either thereof can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first portion of CARD11 and a second portion of a chaperone protein (i.e., not CARD11). In some instances, dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or either of them can be the result of a gene translocation between a CARD11 gene and another non-CARD11 gene.

[0164] An example sequence of human CARD11 is shown below:

[0165] SEQ ID NO:8 (UniParc Registry No. UPI00003FED38)

[0166]

[0167] Non-restrictive examples of CARD11 gene or CARD11 protein dysregulation are shown in Table B2 below.

[0168] Table B2.

[0169]

[0170]

[0171] 1 Wu et al., Targeted Tumor Research, 7.25(2016):38180.

[0172] 2 Watt et al., The American Journal of Pathology, 185.9(2015):2354-2363.

[0173] As used herein, the term “CARD14-associated autoimmune disease” refers to an autoimmune disease that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them, as described herein) of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them.

[0174] As used herein, the term “CARD14-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them, as described herein) of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them.

[0175] As used herein, the term “CARD14-associated cancer” refers to cancer that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them, as described herein) with respect to or with an imbalance (e.g., any type of imbalance in the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them, as described herein).

[0176] An example sequence of human CARD14 is shown below:

[0177] SEQ ID NO:9 (UniParc Registry No. UPI000013D81B)

[0178]

[0179] As used herein, the term “CARD10-associated autoimmune disease” refers to an autoimmune disease that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them, as described herein) of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them.

[0180] As used herein, the term “CARD10-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them, as described herein) with respect to or with respect to the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them.

[0181] As used herein, the term “CARD10-associated cancer” refers to cancer that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them, as described herein) of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them.

[0182] The phrase “dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or either of them” refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type CARD10 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a CARD10 domain and a fusion chaperone; mutation in the CARD10 gene causing expression of a CARD10 protein containing at least one amino acid deletion compared to wild-type CARD10 protein; mutation in the CARD10 gene causing expression of a CARD10 protein with one or more point mutations compared to wild-type CARD10 protein; mutation in the CARD10 gene causing expression of a CARD10 protein with at least one inserted amino acid compared to wild-type CARD10 protein; gene duplication causing elevated levels of CARD10 protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of CARD10 protein in cells); CARD10 Alternative splicing of mRNA resulting in a CARD10 protein with at least one amino acid deletion compared to the wild-type CARD10 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, dysregulation of the expression, activity, or level of the CARD10 gene, the CARD10 protein, or either thereof can be a mutation in the CARD10 gene encoding the CARD10 protein, which is constitutively active or has increased activity compared to a protein encoded by a CARD10 gene without the mutation. As yet another example, an increased copy number of the CARD10 gene can cause overexpression of the CARD10 protein. For example, dysregulation of the expression, activity, or level of the CARD10 gene, the CARD10 protein, or either thereof can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first portion of CARD10 and a second portion of a chaperone protein (i.e., not CARD10). In some instances, dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or either of them can be the result of a gene translocation between a CARD10 gene and another non-CARD10 gene.

[0183] An example sequence of human CARD10 is shown below:

[0184] SEQ ID NO:10 (UniParc Registry Number UPI0000044645)

[0185]

[0186] As used herein, the term “CARD9-associated autoimmune disease” refers to an autoimmune disease that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein) of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them.

[0187] As used herein, the term “CARD9-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein) that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein).

[0188] As used herein, the term “CARD9-related cancer” refers to cancer that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein) with respect to or with an imbalance (e.g., any type of imbalance in the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein).

[0189] The phrase "dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or either of these" refers to (e.g., compared to control non-cancer cells) a gene mutation in the wild-type CARD9 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a CARD9 domain and a fusion chaperone; mutation in the CARD9 gene causing expression of a CARD9 protein containing at least one amino acid deletion compared to wild-type CARD9; mutation in the CARD9 gene causing expression of a CARD9 protein with one or more point mutations compared to wild-type CARD9; mutation in the CARD9 gene causing expression of a CARD9 protein with at least one inserted amino acid compared to wild-type CARD9; gene duplication causing elevated levels of CARD9 protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of CARD9 protein in cells); CARD9 Alternative splicing of mRNA resulting in a CARD9 protein with at least one amino acid deletion compared to the wild-type CARD9 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or either thereof can be a mutation in the CARD9 gene encoding the CARD9 protein, which is constitutively active or has increased activity compared to a protein encoded by a CARD9 gene without the mutation. As yet another example, an increased copy number of the CARD9 gene can cause overexpression of the CARD9 protein. For example, dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or either thereof can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first part of CARD9 and a second part of a chaperone protein (i.e., not CARD9). In some instances, dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or either of them can be the result of a gene translocation between a CARD9 gene and another non-CARD9 gene.

[0190] An example sequence of human CARD9 is shown below:

[0191] SEQ ID NO:11 (UniParc Registry Number UPI000013E4EB)

[0192] MSDYENDDECWSVLEGFRVTTLTSVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRKVGVLLDILQRTGHKGYVAFLESLELYYPQLYKKVTGKEPARVFSMIIDASGESGLTQLLMTEVMKLQKKVQDLT ALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECEAGSRELKRCKEENYDLAMRLAHQSEEKGAALMRNRDLQLEIDQLKHSLMKAEDDCKVERKHTLKLRHAMEQRPSQELLWELQQEKALLQARVQELEASV QEGKLDRSSPYIQVLEEDWRQALRDHQEQANTIFSLRKDLRQGEARRLRCMEEKEMFELQCLALRKDSKMYKDRIEAILLQMEEVAIERDQAIATREELHAQHARGLQEKDALRKQVRELGEKADELQLQVFQC EAQLLAVEGRLRRQQLETLVLSSDLEDGSPRRSQELSLPQDLEDTQLSDKGCLAGGGSPKQPFAALHQEQVLRNPHDAGLSSGEPPEKERRRLKESFENYRRKRALRKMQKGWRQGEEDRENTTGSDNTDTEGS

[0193] As used herein, the term “BCL10-associated autoimmune disease” refers to an autoimmune disease that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them, as described herein) of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them.

[0194] As used herein, the term “BCL10-associated inflammatory condition” refers to an inflammatory condition that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them, as described herein) of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them.

[0195] As used herein, the term “BCL10-associated cancer” refers to cancer that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them, as described herein) with respect to or with an imbalance (e.g., any type of imbalance in the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them, as described herein).

[0196] The phrase "dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or either thereof" refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type BCL10 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a BCL10 domain and a fusion chaperone; mutation in the BCL10 gene causing expression of a BCL10 protein with at least one amino acid deletion compared to wild-type BCL10 protein; mutation in the BCL10 gene causing expression of a BCL10 protein with one or more point mutations compared to wild-type BCL10 protein; mutation in the BCL10 gene causing expression of a BCL10 protein with at least one inserted amino acid compared to wild-type BCL10 protein; gene duplication causing elevated levels of BCL10 protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of BCL10 protein in cells); BCL10 Alternative splicing forms of mRNA that result in a BCL10 protein with at least one amino acid deletion compared to the wild-type BCL10 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling. For example, dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or either thereof can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion of BCL10 and a second portion of a chaperone protein (i.e., not BCL10). In some instances, dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or either thereof can be the result of a gene translocation of a BCL10 gene to another non-BCL10 gene.

[0197] An exemplary sequence of human BCL10 is shown below:

[0198] SEQ ID NO:12 (UniParc Registry Number UPI000012682F)

[0199] MEPTAPSLTEEDLTEVKKDALENLRVYLCEKIIAERHFDHLRAKKILSREDTEEEISCRTSSRKRAGKLLDYLQENPKGLDTLVESIRREKTQNFLIQKITDEVLKLRNIKLEHLKG LKCSSCEPFPDGATNNLSRSNSDESNFSEKLRASTVMYHPEGESSTTPFFSTNSSLNLPVLEVGRTENTIFSSTTLPRPGDPGAPPLPPDLQLEEEGTCANSSEMFLPLRSRTVSRQ

[0200] Non-restrictive examples of BCL10 gene or BCL10 protein dysregulation are shown in Table B3 below.

[0201] Table B3.

[0202]

[0203]

[0204] 1 Willis et al., Cell 96.1 (1999):35-45.

[0205] 2 Zhang et al., Nature Genetics, 22.1(1999):63-68.

[0206] As used herein, the term "MALT1 protease substrate-associated cancer" refers to cancer associated with or having an dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more), said dysregulation being associated with a MALT1 protease substrate. In some embodiments, MALT1 protease substrate-associated cancer is selected from the group consisting of: BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, RelB-associated cancer, Regnase1-associated cancer, roquin-1-associated cancer, HOIL1-associated cancer, NIK-associated cancer, LIMA1α-associated cancer, and combinations thereof. In some embodiments, MALT1 protease substrate-associated cancer is selected from the group consisting of: BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, and combinations thereof. Cancer "associated" with a specific gene or protein described in this paragraph refers to cancer associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein) being associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein). This article describes a non-limiting example of this type of cancer.

[0207] Exemplary sequences of human A20 are shown below:

[0208] SEQ ID NO:13 (UniParc accession number UPI000000D92D)

[0209] MAEQVLPQALYLSNMRKAVKIRERTPEDIFKPTNGIIHHFKTMHRYTLEMFRTCQFCPQFREIIHKALIDRNIQATLESQKKLNWCREVRKLVALKTNGDGNCLMHATSQYMWGVQDTDLVLRKALFSTLKETDTRNFKFRWQLESLKSQEFVETGLCYDTRNWNDEWDNLIKMASTDTPMARSGLQYNSLEEIHIFVLCNILRRPIIVISDKMLRSLESGSNFAPLKVGGIYLPLHWPAQECYRYPIVLGYDSHHFVPLVTLKDSGPEIRAVPLVNRDRGRFEDLKVHFLTDPENEMKEKLLKEYLMVIEIPVQGWDHGTTHLINAAKLDEANLPKEINLVDDYFELVQHEYKKWQENSEQGRREGHAQNPMEPSVPQLSLMDVKCETPNCPFFMSVNTQPLCHECSERRQKNQNKLPKLNSKPGPEGLPGMALGASRGEAYEPLAWNPEESTGGPHSAPPTAPSPFLFSETTAMKCRSPGCPFTLNVQHNGFCERCHNARQLHASHAPDHTRHLDPGKCQACLQDVTRTFNGICSTCFKRTTAEASSSLSTSLPPSCHQRSKSDPSRLVRSPSPHSCHRAGNDAPAGCLSQAARTPGDRTGTSKCRKAGCVYFGTPENKGFCTLCFIEYRENKHFAAASGKVSPTASRFQNTIPCLGRECGTLGSTMFEGYCQKCFIEAQNQRFHEAKRTEEQLRSSQRRDVPRTTQSTSRPKCARASCKNILACRSEELCMECQHPNQRMGPGAHRGEPAPEDPPKQRCRAPACDHFGNAKCNGYCNECFQFKQMYG

[0210] Non-limiting examples of A20 gene or A20 protein dysregulation are shown in Table B4 below.

[0211] Table B4.

[0212]

[0213] 1 Johansson et al., Targets of Tumors, 7.38(2016):62627.

[0214] 2 Novak et al. Blood 113.20 (2009):4918-4921.

[0215] An example sequence of human CYLD is shown below:

[0216] SEQ ID NO:14 (UniParc Registry Number UPI0000073A15)

[0217] MSSGLWSQEKVTSPYWEERIFYLLLQECSVTDKQTQKLLKVPKGSIGQYIQDRSVGHSRIPSAKGKKNQIGLKILEQPHAVLFVDEKDVVEINEKFTELLLAITNCEERFSLFKNRNRLSKGLQIDVGCPVKVQLRSGEEKFPGVVRFRGPLLAERTVSGIFFGVELLEEGRGQGFTDGVYQGKQLFQCDEDCGVFVALDKLELIEDDDTALESDYAGPGDTMQVELPPLEINSRVSLKVGETIESGTVIFCDVLPGKESLGYFVGVDMDNPIGNWDGRFDGVQLCSFACVESTILLHINDIIPALSESVTQERRPPKLAFMSRGVGDKGSSSHNKPKATGSTSDPGNRNRSELFYTLNGSSVDSQPQSKSKNTWYIDEVAEDPAKSLTEISTDFDRSSPPLQPPPVNSLTTENRFHSLPFSLTKMPNTNGSIGHSPLSLSAQSVMEELNTAPVQESPPLAMPPGNSHGLEVGSLAEVKENPPFYGVIRWIGQPPGLNEVLAGLELEDECAGCTDGTFRGTRYFTCALKKALFVKLKSCRPDSRFASLQPVSNQIERCNSLAFGGYLSEVVEENTPPKMEKEGLEIMIGKKKGIQGHYNSCYLDSTLFCLFAFSSVLDTVLLRPKEKNDVEYYSETQELLRTEIVNPLRIYGYVCATKIMKLRKILEKVEAASGFTSEEKDPEEFLNILFHHILRVEPLLKIRSAGQKVQDCYFYQIFMEKNEKVGVPTIQQLLEWSFINSNLKFAEAPSCLIIQMPRFGKDFKLFKKIFPSLELNITDLLEDTPRQCRICGGLAMYECRECYDDPDISAGKIKQFCKTCNTQVHLHPKRLNHKYNPVSLPKDLPDWDWRHGCIPCQNMELFAVLCIETSHYVAFVKYGKDDSAWLFFDSMADRDGGQNGFNIPQVTPCPEVGEYLKMSLEDLHSLDSRRIQGCARRLLCDAYMCMYQSPTMSLYK

[0218] Non-limiting examples of dysregulation of the CYLD gene or CYLD protein can be found, for example, Massoumi, Future Oncology 7.2 (2011):285-297; Alameda, JP et al., Oncogene 29.50 (2010):6522-6532; Williams et al., Modern Pathology (2020):1-13; and Courtois and Gilmore, Oncogene 25.51 (2006):6831-6843.

[0219] An example sequence of human RelB is shown below:

[0220] SEQ ID NO:15 (UniParc Registry Number UPI00000012B7)

[0221] MLRSGPASGPSVPTGRAMPSRRVARPPAAPELGALGSPDLSSLSLAVSRSTDELEIIDEYIKENGFGLDGGQPGPGEGLPRLVSRGAASLSTVTLGPVAPPATPPPWGCPLGRLVSPAPGPGPQPHLVITEQPKQRGMRFRYEC EGRSAGSILGESSTEASKTLPAIELRDCGGLREVEVTACLVWKDWPHRVHPHSLVGKDCTDGICRVRLRPHVSPRHSFNNLGIQCVRKKEIEAAIERKIQLGIDPYNAGSLKNHQEVDMNVVRICFQASYRDQQGQMRRMDPVLS EPVYDKKSTNTSELRICRINKESGPCTGGEELYLLCDKVQKEDISVVFSRASWEGRADFSQADVHRQIAIVFKTPPYEDLEIVEPVTVNVFLQRLTDGVCSEPLPFTYLPRDHDSYGVDKKRKRGMPDVLGELNSSDPHGIESKR RKKKPAILDHFLPNHGSGPFLPPSALLPDPDFFSGTVSLPGLEPPGGPDLLDDGFAYDPTAPTLFTMLDLLPPAPPHASAVVCSGGAGAVVGETPGPEPLTLDSYQAPGPGDGGTASLVGSNMFPNHYREAAFGGGLLSPGPEAT

[0222] An exemplary sequence of human Regnase 1 is shown below:

[0223] SEQ ID NO: 16 (UniParc accession number UPI000004D30E)

[0224] MSGPCGEKPVLEASPTMSLWEFEDSHSRQGTPRPGQELAAEEASALELQMKVDFFRKLGYSSTEIHSVLQKLGVQADTNTVLGELVKHGTATERERQTSPDPCPQLPLVPRGGGTPKAPNLEPPLPEEEKEGSDLRPVVIDGSNVAMSHGNKEVFSCRGILLAVNWFLERGHTDITVFVPSWRKEQPRPDVPITDQHILRELEKKKILVFTPSRRVGGKRVVCYDDRFIVKLAYESDGIVVSNDTYRDLQGERQEWKRFIEERLLMYSFVNDKFMPPDDPLGRHGPSLDNFLRKKPLTLEHRKQPCPYGRKCTYGIKCRFFHPERPSCPQRSVADELRANALLSPPRAPSKDKNGRRPSPSSQSSSLLTESEQCSLDGKKLGAQASPGSRQEGLTQTYAPSGRSLAPSGGSGSSFGPTDWLPQTLDSLPYVSQDCLDSGIGSLESQMSELWGVRGGGPGEPGPPRAPYTGYSPYGSELPATAAFSAFGRAMGAGHFSVPADYPPAPPAFPPREYWSEPYPLPPPTSVLQEPPVQSPGAGRSPWGRAGSLAKEQASVYTKLCGVFPPHLVEAVMGRFPQLLDPQQLAAEILSYKSQHPSE

[0225] An exemplary sequence of human roquin-1 is shown below:

[0226] SEQ ID NO: 17 (UniParc accession number UPI00001D7DA8)

[0227]

[0228] SEQ ID NO:17 (UniParc accession number UPI000006F045)

[0229] MDEKTKKAEEMALSLTRAVAGGDEQVAMKCAIWLAEQRVPLSVQLKPEVSPTQDIRLWVSVEDAQMHTVTIWLTVRPDMTVASLKDMVFLDYGFPPVLQQWVIGQRLARDQETLHSHGVRQNGDSAYLYLLSARNTSLNPQELQRERQLRMLEDLGFKDLTLQPRGPLEPGPPKPGVPQEPGRGQPDAVPEPPPVGWQCPGCTFINKPTRPGCEMCCRARPEAYQVPASYQPDEEERARLAGEEEALRQYQQRKQQQQEGNYLQHVQLDQRSLVLNTEPAECPVCYSVLAPGEAVVLRECLHTFCRECLQGTIRNSQEAEVSCPFIDNTYSCSGKLLEREIKALLTPEDYQRFLDLGISIAENRSAFSYHCKTPDCKGWCFFEDDVNEFTCPVCFHVNCLLCKAIHEQMNCKEYQEDLALRAQNDVAARQTTEMLKVMLQQGEAMRCPQCQIVVQKKDGCDWIRCTVCHTEICWVTKGPRWGPGGPGDTSGGCRCRVNGIPCHPSCQNCH

[0230] The exemplary sequence of human NIK is shown below:

[0231] SEQ ID NO:18 (UniParc accession number UPI0000074220)

[0232] MAVMEMACPGAPGSAVGQQKELPKAKEKTPPLGKKQSSVYKLEAVEKSPVFCGKWEILNDVITKGTAKEGSEAGPAAISIIAQAECENSQEFSPTFSERIFIAGSKQYSQSESLDQIPNNVAHATEGKMARVCWKGKRRSKARKKRKKKSSKSLAHAGVALAKPLPRTPEQESCTIPVQEDESPLGAPYVRNTPQFTKPLKEPGLGQLCFKQLGEGLRPALPRSELHKLISPLQCLNHVWKLHHPQDGGPLPLPTHPFPYSRLPHPFPFHPLQPWKPHPLESFLGKLACVDSQKPLPDPHLSKLACVDSPKPLPGPHLEPSCLSRGAHEKFSVEEYLVHALQGSVSSGQAHSLTSLAKTWAARGSRSREPSPKTEDNEGVLLTEKLKPVDYEYREEVHWATHQLRLGRGSFGEVHRMEDKQTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQLVKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVCLQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFFRGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNRALQQVGGLKSPWRGEYKEPRHPPPNQANYHQTLHAQPRELSPRAPGPRPAEETTGRAPKLQPPLPPEPPEPNKSPPLTLSKEESGMWEPLPLSSLEPAPARNPSSPERKATVPEQELQQLEIELFLNSLSQPFSLEEQEQILSCLSIDSLSLSDDSEKNPSKASQSSRDTLSSGVHSWSSQAEARSSSWNMVLARGRPTDTPSYFNGVKVQIQSLNGEHLHIREFHRVKVGDIATGISSQIPAAAFSLVTKDGQPVRYDMEVPDSGIDLQCTLAPDGSFAWSWRVKHGQLENRP

[0233] An exemplary sequence of human LIMA1α is shown below:

[0234] SEQ ID NO: 19 (UniParc accession number UPI000002A906)

[0235] MENCLGESRHEVEKSEISENTDASGKIEKYNVPLNRLKMMFEKGEPTQTKILRAQSRSASGRKISENSYSLDDLEIGPGQLSSSTFDSEKNESRRNLELPRLSETSIKDRMAKYQAAVSKQSSSTNYTNELKASGGEIKIHKMEQKENVPPGPEVCITHQEGEKISANENSLAVRSTPAEDDSRDSQVKSEVQQPVHPKPLSPDSRASSLSESSPPKAMKKFQAPARETCVECQKTVYPMERLLANQQVFHISCFRCSYCNNKLSLGTYASLHGRIYCKPHFNQLFKSKGNYDEGFGHRPHKDLWASKNENEEILERPAQLANARETPHSPGVEDAPIAKVGVLAASMEAKASSQQEKEDKPAETKKLRIAWPPPTELGSSGSALEEGIKMSKPKWPPEDEISKPEVPEDVDLDLKKLRRSSSLKERSRPFTVAASFQSTSVKSPKTVSPPIRKGWSMSEQSEESVGGRVAERKQVENAKASKKNGNVGKTTWQNKESKGETGKRSKEGHSLEMENENLVENGADSDEDDNSFLKQQSPQEPKSLNWSSFVDNTFAEEFTTQNQKSQDVELWEGEVVKELSVEEQIKRNRYYDEDEDEE

[0236] As used herein, the term "cancer associated with a component of the NF-κB pathway downstream of the CBM complex" refers to cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any of these (e.g., one or more), said dysregulation being associated with a component of the NF-κB pathway downstream of the CBM complex. In some embodiments, cancers associated with a component of the NF-κB pathway downstream of the CBM complex are selected from the group consisting of: TAK1-associated cancers, TRAF6-associated cancers, TAB1-associated cancers, TAB2-associated cancers, TAB3-associated cancers, MKK7-associated cancers, IKKα-associated cancers, IKKβ-associated cancers, IKKγ-associated cancers, IkBα-associated cancers, p50-associated cancers, p65(RelA)-associated cancers, c-Rel-associated cancers, and combinations thereof. In some embodiments, cancers associated with a component of the NF-κB pathway downstream of the CBM complex are IKKγ-associated cancers. Cancer “associated with” a particular gene or protein described in this paragraph refers to cancer that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the particular gene, protein, or any of them described herein) with the expression or activity or level of the particular gene, protein, or any of them. Non-limiting examples of such cancers are described herein.

[0237] An example sequence of human TAK1 is shown below:

[0238] SEQ ID NO:20 (UniParc Registry No. UPI000012EAD6)

[0239] MSTASAASSSSSSSAGEMIEAPSQVLNFEEIDYKEIEVEEVVGRGAFGVVCKAKWRAKDVAIKQIESESERKAFIVELRQLSRVNHPNIVKLYGACLNPVCLVMEYAEGGSLYNVLHGAEPLPYYTAAHAMSWCLQCSQGVAYLHSMQPKALIHRDLKPPNLLLVAGGTVLKICDFGTACDIQTHMTNNKGSAAWMAPEVFEGSNYSEKCDVFSWGIILWEVITRRKPFDEIGGPAFRIMWAVHNGTRPPLIKNLPKPIESLMTRCWSKDPSQRPSMEEIVKIMTHLMRYFPGADEPLQYPCQYSDEGQSNSATSTGSFMDIASTNTSNKSDTNMEQVPATNDTIKRLESKLLKNQAKQQSESGRLSLGASRGSSVESLPPTSEGKRMSADMSEIEARIAATTAYSKPKRGHRKTASFGNILDVPEIVISGNGQPRRRSIQDLTVTGTEPGQVSSRSSSPSVRMITTSGPTSEKPTRSHPWTPDDSTDTNGSDNSIPMAYLTLDHQLQPLAPCPNSKESMAVFEQHCKMAQEYMKVQTEIALLLQRKQELVAELDQDEKDQQNTSRLVQEHKKLLDENKSLSTYYQQCKKQLEVIRSQQQKRQGTS

[0240] An exemplary sequence of human TRAF6 is shown below:

[0241] SEQ ID NO:21 (UniParc accession number UPI000000D924)

[0242] MSLLNCENSCGSSQSESDCCVAMASSCSAVTKDDSVGGTASTGNLSSSFMEEIQGYDVEFDPPLESKYECPICLMALREAVQTPCGHRFCKACIIKSIRDAGHKCPVDNEILLENQLFPDNFAKREILSLMVKCPNEGCLHKMELRHLEDHQAHCEFALMDCPQCQRPFQKFHINIHILKDCPRRQVSCDNCAASMAFEDKEIHDQNCPLANVICEYCNTILIREQMPNHYDLDCPTAPIPCTFSTFGCHEKMQRNHLARHLQENTQSHMRMLAQAVHSLSVIPDSGYISEVRNFQETIHQLEGRLVRQDHQIRELTAKMETQSMYVSELKRTIRTLEDKVAEIEAQQCNGIYIWKIGNFGMHLKCQEEEKPVVIHSPGFYTGKPGYKLCMRLHLQLPTAQRCANYISLFVHTMQGEYDSHLPWPFQGTIRLTILDQSEAPVRQNHEEIMDAKPELLAFQRPTIPRNPKGFGYVTFMHLEALRQRTFIKDDTLLVRCEVSTRFDMGSLRREGFQPRSTDAGV

[0243] An exemplary sequence of human TAB1 is shown below:

[0244] SEQ ID NO:22 (UniParc Accession No. UPI0000136861)

[0245] MAAQRRSLLQSEQQPSWTDDLPLCHLSGVGSASNRSYSADGKGTESHPPEDSWLKFRSENNCFLYGVFNGYDGNRVTNFVAQRLSAELLLGQLNAEHAEADVRRVLLQAFDVVERSFLESIDDALAEKASLQSQLPEGVPQHQLPPQYQKILERLKTLEREISGGAMAVVAVLLNNKLYVANVGTNRALLCKSTVDGLQVTQLNVDHTTENEDELFRLSQLGLDAGKIKQVGIICGQESTRRIGDYKVKYGYTDIDLLSAAKSKPIIAEPEIHGAQPLDGVTGFLVLMSEGLYKALEAAHGPGQANQEIAAMIDTEFAKQTSLDAVAQAVVDRVKRIHSDTFASGGERARFCPRHEDMTLLVRNFGYPLGEMSQPTPSPAPAAGGRVYPVSVPYSSAQSTSKTSVTLSLVMPSQGQMVNGAHSASTLDEATPTLTNQSPTLTLQSTNTHTQSSSSSSDGGLFRSRPAHSLPPGEDGRVEPYVDFAEFYRLWSVDHGEQSVVTAP

[0246] An exemplary sequence of human TAB2 is shown below:

[0247] SEQ ID NO:23 (UniParc Accession No. UPI0000073C75)

[0248] MAQGSHQIDFQVLHDLRQKFPEVPEVVVSRCMLQNNNNLDACCAVLSQESTRYLYGEGDLNFSDDSGISGLRNHMTSLNLDLQSQNIYHHGREGSRMNGSRTLTHSISDGQLQGGQSNSELFQQEPQTAPAQVPQGFNVFGMSSSSGASNSAPHLGFHLGSKGTSSLSQQTPRFNPIMVTLAPNIQTGRNTPTSLHIHGVPPPVLNSPQGNSIYIRPYITTPGGTTRQTQQHSGWVSQFNPMNPQQVYQPSQPGPWTTCPASNPLSHTSSQQPNQQGHQTSHVYMPISSPTTSQPPTIHSSGSSQSSAHSQYNIQNISTGPRKNQIEIKLEPPQRNNSSKLRSSGPRTSSTSSSVNSQTLNRNQPTVYIAASPPNTDELMSRSQPKVYISANAATGDEQVMRNQPTLFISTNSGASAASRNMSGQVSMGPAFIHHHPPKSRAIGNNSATSPRVVVTQPNTKYTFKITVSPNKPPAVSPGVVSPTFELTNLLNHPDHYVETENIQHLTDPTLAHVDRISETRKLSMGSDDAAYTQALLVHQKARMERLQRELEIQKKKLDKLKSEVNEMENNLTRRRLKRSNSISQIPSLEEMQQLRSCNRQLQIDIDCLTKEIDLFQARGPHFNPSAIHNFYDNIGFVGPVPPKPKDQRSIIKTPKTQDTEDDEGAQWNCTACTFLNHPALIRCEQCEMPRHF

[0249] An exemplary sequence of human TAB3 is shown below:

[0250] SEQ ID NO:24 (UniParc Accession No. UPI0000071648)

[0251] MAQSSPQLDIQVLHDLRQRFPEIPEGVVSQCMLQNNNNLEACCRALSQESSKYLYMEYHSPDDNRMNRNRLLHINLGIHSPSSYHPGDGAQLNGGRTLVHSSSDGHIDPQHAAGKQLICLVQEPHSAPAVVAATPNYNPFFMNEQNRSAATPPSQPPQQPSSMQTGMNPSAMQGPSPPPPPPSYMHIPRYSTNPITVTVSQNLPSGQTVPRALQILPQIPSNLYGSPGSIYIRQTSQSSSGRQTPQSTPWQSSPQGPVPHYSQRPLPVYPHQQNYQPSQYSPKQQQIPQSAYHSPPPSQCPSPFSSPQHQVQPSQLGHIFMPPSPSTTPPHPYQQGPPSYQKQGSHSVAYLPYTASSLSKGSMKKIEITVEPSQRPGTAINRSPSPISNQPSPRNQHSLYTATTPPSSSPSRGISSQPKPPFSVNPVYITYTQPTGPSCTPSPSPRVIPNPTTVFKITVGRATTENLLNLVDQEERSAAPEPIQPISVIPGSGGEKGSHKYQRSSSSGSDDYAYTQALLLHQRARMERLAKQLKLEKEELERLKSEVNGMEHDLMQRRLRRVSCTTAIPTPEEMTRLRSMNRQLQINVDCTLKEVDLLQSRGNFDPKAMNNFYDNIEPGPVVPPKPSKKDSSDPCTIERKARRISVTSKVQADIHDTQAAAADEHRTGSTQSPRTQPRDEDYEGAPWNCDSCTFLNHPALNRCEQCEMPRYT

[0252] Exemplary sequence of human MKK7 is shown as follows:

[0253] SEQ ID NO:25 (UniParc accession number UPI000012F494)

[0254] MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPTLQLPLANDGGSRSPSSESSPQHPTPPARPRHMLGLPSTLFTPRSMESIEIDQKLQEIMKQTGYLTIGGQRYQAEINDLENLGEMGSGTCGQVWKMRFRKTGHVIAVKQMRRSGNKEENKRILMDLDVVLKSHDCPYIVQCFGTFITNTDVFIAMELMGTCAEKLKKRMQGPIPERILGKMTVAIVKALYYLKEKHGVIHRDVKPSNILLDERGQIKLCDFGISGRLVDSKAKTRSAGCAAYMAPERIDPPDPTKPDYDIRADVWSLGISLVELATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDCLTKDHRKRPKYNKLLEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR

[0255] An exemplary sequence of human IKKα is shown below:

[0256] SEQ ID NO:26 (UniParc accession number UPI000013D6C7)

[0257] MERPPGLRPGAGGPWEMRERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCHEIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTSFVGTLQYLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPKCIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRCFVLMDHILNLKIVHILNMTSAKIISFLLPPDESLHSLQSRIERETGINTGSQELLSETGISLDPRKPASQCVLDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPIIQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKLEFFHKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYAEVGVIGYLEDQIMSLHAEIMELQKSPYGRRQGDLMESLEQRAIDLYKQLKHRPSDHSYSDSTEMVKIIVHTVQSQDRVLKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQSSARSLVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHLSTIIHEANEEQGNSMMNLDWSWLTE

[0258] An exemplary sequence of human IKKβ is shown below:

[0259] SEQ ID NO:27 (UniParc Accession No. UPI0000033729)

[0260] MSWSPSLTTQTCGAWEMKERLGTGGFGNVIRWHNQETGEQIAIKQCRQELSPRNRERWCLEIQIMRRLTHPNVVAARDVPEGMQNLAPNDLPLLAMEYCQGGDLRKYLNQFENCCGLREGAILTLLSDIASALRYLHENRIIHRDLKPENIVLQQGEQRLIHKIIDLGYAKELDQGSLCTSFVGTLQYLAPELLEQQKYTVTVDYWSFGTLAFECITGFRPFLPNWQPVQWHSKVRQKSEVDIVVSEDLNGTVKFSSSLPYPNNLNSVLAERLEKWLQLMLMWHPRQRGTDPTYGPNGCFKALDDILNLKLVHILNMVTGTIHTYPVTEDESLQSLKARIQQDTGIPEEDQELLQEAGLALIPDKPATQCISDGKLNEGHTLDMDLVFLFDNSKITYETQISPRPQPESVSCILQEPKRNLAFFQLRKVWGQVWHSIQTLKEDCNRLQQGQRAAMMNLLRNNSCLSKMKNSMASMSQQLKAKLDFFKTSIQIDLEKYSEQTEFGITSDKLLLAWREMEQAVELCGRENEVKLLVERMMALQTDIVDLQRSPMGRKQGGTLDDLEEQARELYRRLREKPRDQRTEGDSQEMVRLLLQAIQSFEKKVRVIYTQLSKTVVCKQKALELLPKVEEVVSLMNEDEKTVVRLQEKRQKELWNLLKIACSKVRGPVSGSPDSMNASRLSQPGQLMSQPSTASNSLPEPAKKSEELVAEAHNLCTLLENAIQDTVREQDQSFTALDWSWLQTEEEEHSCLEQAS Exemplary sequences of human IKKγ are shown below:

[0261] SEQ ID NO:28 (UniParc Accession No. UPI0000000CC4)

[0262] MNRHLWKSQLCEMVQPSGGPAADQDVLGEESPLGKPAMLHLPSEQGAPETLQRCLEENQELRDAIRQSNQILRERCEELLHFQASQREEKEFLMCKFQEARKLVERLGLEKLDLKRQKEQALREVEHLKRCQQQMAEDKASVKAQVTSLLGELQESQSRLEAATKECQALEGRARAASEQARQLESEREALQQQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSERKRGMQLEDLKQQLQQAEEALVAKQEVIDKLKEEAEQHKIVMETVPVLKAQADIYKADFQAERQAREKLAEKKELLQEQLEQLQREYSKLKASCQESARIEDMRKRHVEVSQAPLPPAPAYLSSPLALPSQRRSPPEEPPDFCCPKCQYQAPDMDTLQIHVMECIE

[0263] Non-limiting examples of dysregulation of the IKKγ gene or IKKγ protein can be found in, for example, Courtois and Gilmore, Oncogene 25.51(2006): 6831-6843.

[0264] An exemplary sequence of human IkBα is shown below:

[0265] SEQ ID NO:29 (UniParc Accession No. UPI000004F0A9)

[0266] MFQAAERPQEWAMEGPRDGLKKERLLDDRHDSGLDSMKDEEYEQMVKELQEIRLEPQEVPRGSEPWKQQLTEDGDSFLHLAIIHEEKALTMEVIRQVKGDLAFLNFQNNLQQTPLHLAVITNQPEIAEALLGAGCDPELRDFRGNTPLHLACEQGCLASVGVLTQSCTTPHLHSILKATNYNGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVDLQNPDLVSLLLKCGADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQLTLENLQMLPESEDEESYDTESEFTEFTEDELPYDDCVFGGQRLTL

[0267] An exemplary sequence of human p105 processed into p50 is shown below:

[0268] SEQ ID NO:30 (UniParc Registry Number UPI000000D917)

[0269] MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYVCEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCEDGICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQAEGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIYDSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDFSPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQRKRQKLMPNFSDFGGSGAGAGGGGMFGSGGGGTGSTGPGYSFPHYGFPTYGGITFHPGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGEVTLT YATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQDENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVEDLLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMMSNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGTTPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMATSWQVFDILNGKPYEPEFTSDDLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLGLGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQAHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQEGPLEGKI

[0270] Exemplary sequences of human p65 are shown below:

[0271] SEQ ID NO:31 (UniParc accession number UPI000013ED68)

[0272] MDELFPLIFPAEPAQASGPYVEIIEQPKQRGMRFRYKCEGRSAGSIPGERSTDTTKTHPTIKINGYTGPGTVRISLVTKDPPHRPHPHELVGKDCRDGFYEAELCPDRCIHSFQNLGIQCVKKRDLEQAISQRIQTNNNPFQVPIEEQRGDYDLNAVRLCFQVTVRDPSGRPLRLPPVLSHPIFDNRAPNTAELKICRVNRNSGSCLGGDEIFLLCDKVQKEDIEVYFTGPGWEARGSFSQADVHRQVAIVFRTPPYADPSLQAPVRVSMQLRRPSDRELSEPMEFQYLPDTDDRHRIEEKRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAPQPYPFTSSLSTINYDEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQAPAPVPVLAPGPPQAVAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDLASVDNSEFQQLLNQGIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNGLLSGDEDFSSIADMDFSALLSQISS

[0273] Exemplary sequences of human c-Rel are shown below:

[0274] SEQ ID NO:32 (UniParc accession number UPI000013367B)

[0275] MASGAYNPYIEIIEQPRQRGMRFRYKCEGRSAGSIPGEHSTDNNRTYPSIQIMNYYGKGKVRITLVTKNDPYKPHPHDLVGKDCRDGYYEAEFGQERRPLFFQNLGIRCVKKKEVKEAIITRIKAGINPFNVPEKQLNDIEDCDLNVVRLCFQV FLPDEHGNLTTALPPVVSNPIYDNRAPNTAELRICRVNKNCGSVRGGDEIFLLCDKVQKDDIEVRFVLNDWEAKGIFSQADVHRQVAIVFKTPPYCKAITEPVTVKMQLRRPSDQEVSESMDFRYLPDEKDTYGNKAKKQKTTLLFQKLCQDHVE TGFRHVDQDGLELLTSGDPPTLASQSAGITVNFPERPRPGLLGSIGEGRYFKKEPNLFSHDAVVREMPTGVSSQAESYYPSPGPISSGLSHHASMAPLPSSSWSSVAHPTPRSGNTNPLSSFSTRTLPSNSQGIPPFLRIPVGNDLNASNACIYN NADDIVGMEASSMPSADLYGISDPNMLSNCSVNMMTTSSDSMGETDNPRLLSMNLENPSCNSVLDPRDLRQLHQMSSSSMSAGANSNTTVFVSQSDAFEGSDFSCADNSMINESGPSNSTNPNSHGFVQDSQYSGIGSMQNEQLSDSFPYEFFQV

[0276] As used herein, the term "cancer associated with a component of the JNK pathway downstream of the CBM complex" refers to cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more), said dysregulation being associated with a component of the JNK pathway downstream of the CBM complex. In some embodiments, cancers associated with a component of the JNK pathway downstream of the CBM complex are selected from the group consisting of: JNK1-associated cancers, JNK2-associated cancers, JNK3-associated cancers, MYD88 transcription factor-associated cancers, AP-1 transcription factor-associated cancers, and combinations thereof. Cancer "associated" with a specific gene or protein described in this paragraph refers to cancer associated with or having dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein) being associated with a specific gene, protein, or any of them (e.g., one or more). Non-limiting examples of such cancers are described herein.

[0277] An exemplary sequence of human JNK1 is shown below:

[0278] SEQ ID NO:33 (UniParc Registry Number UPI000012F17A)

[0279] MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRPFQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYI VMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAPEVILGMGYKENVDLWSVGC IMGEMVCHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARDLLSKMLVIDASKRISVDEALQHPY INVWYDPSEAEAPPPKIPDKQLDEREHTIEEWKELIYKEVMDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAAGPLGCCR

[0280] An example sequence of human JNK2 is shown below:

[0281] SEQ ID NO:34 (UniParc Registry Number UPI000006E3AD)

[0282] MSDSKCDSQFYSVQVADSTFTVLKRYQQLKPIGSGAQGIVCAAFDTVLGINVAVKKLSRPFQNQTHAKRAYRELVLLKCVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIHMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTACTNFMMTPYVVTRYYRAPEVILGMGYKENVDIWSVGCIMGELVKGCVIFQGTDHIDQWNKVIEQLGTPSAEFMKKLQPTVRNYVENRPKYPGIKFEELFPDWIFPSESERDKIKTSQARDLLSKMLVIDPDKRISVDEALRHPYITVWYDPAEAEAPPPQIYDAQLEEREHAIEEWKELIYKEVMDWEERSKNGVVKDQPSDAAVSSNATPSQSSSINDISSMSTEQTLASDTDSSLDASTGPLEGCR

[0283] The exemplary sequence of human JNK3 is shown as follows:

[0284] SEQ ID NO: 35 (UniParc accession number UPI0000049042)

[0285] MSLHFLYYCSEPTLDVKIAFCQGFDKQVDVSYIAKHYNMSKSKVDNQFYSVEVGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAVLDRNVAIKKLSRPFQNQTHAKRAYRELVLMK CVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAP EVILGMGYKENVDIWSVGCIMGEMVRHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRNYVENRPKYAGLTFPKLFPDSLFPADSEHNKLKASQARDLLSKMLVIDPAKRI SVDDALQHPYINVWYDPAEVEAPPPQIYDKQLDEREHTIEEWKELIYKEVMNSEEKTKNGVVKGQPSPSGAAVNSSESLPPSSSVNDISSMSTDQTLASDTDSSLEASAGPLGCCR

[0286] Compound of formula (I)

[0287] This article provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0288]

[0289] in:

[0290] Each It can be a single bond or a double bond;

[0291] Q is -CH2-, O, or NH;

[0292] X is N or C;

[0293] Y is either N or C;

[0294] Z is N or CR 5 ;

[0295] When one of X and Y is N, the other of X and Y is C;

[0296] n is 1, 2, or 3;

[0297] R X It is hydrogen or halogen;

[0298] R 1It can be hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or -NR. A R B Or optionally substituted with 1-3 C1-C3 alkyl groups selected from hydroxyl and C1-C3 alkoxy groups;

[0299] R 2 It is hydrogen, halogen, amino, or C1-C3 alkyl;

[0300] Each R 3 Independently, it is deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl; or two Rs. 3 Together with the carbon atom to which it is attached, it forms an oxo group, a 4-8 membered heterocyclic group, or a C3-C8 cycloalkyl group;

[0301] m can be 0, 1, 2, or 3;

[0302] R 4 It is a phenyl or a 5-9 membered heteroaryl group; wherein each R 4 The group is optionally composed of 1-3 independently selected R 6 Substituents of the substituents;

[0303] R 5 It can be hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or -NR. C R D Or C1-C3 alkyl; and

[0304] Each R 6 Independently selected from: halogen; cyano; amino; -N=(S=O)(C1-C3 alkyl)2; -S(=O) p (C1-C3 alkyl); -(C=O)NR E R F C1-C3 alkoxy group; C1-C3 haloalkyl group optionally substituted with a hydroxyl group; C1-C3 haloalkoxy group; 5-6 membered heteroaryl group optionally substituted with: halogen, cyano, hydroxyl, C1-C3 alkoxy group, C1-C3 haloalkoxy group, amino group, C1-C3 haloalkyl group, 4-6 membered heterocyclic group or optionally substituted with a hydroxyl group or -NR group. E R F Substituted C1-C3 alkyl groups; optionally substituted with hydroxyl groups, -NR E R F Or C1-C4 alkyl groups substituted with C1-C3 alkoxy groups; 3-8 membered heterocyclic groups; and C3-C6 cycloalkoxy groups;

[0305] p is 1 or 2; and

[0306] R A R B R C R D R E and R F Independently hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or R A and R B , or R C and R D , or R E and R F Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group that is optionally substituted with 1-2 halogens.

[0307] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0308]

[0309] in:

[0310] Each It can be a single bond or a double bond;

[0311] Q is -CH2-, O, or NH;

[0312] X is N or C;

[0313] Y is either N or C;

[0314] Z is N or CR 5 ;

[0315] When one of X and Y is N, the other of X and Y is C;

[0316] n is 1, 2, or 3;

[0317] R 1 It can be hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or -NR. A R B Or optionally substituted with 1-3 C1-C3 alkyl groups selected from hydroxyl and C1-C3 alkoxy groups;

[0318] R 2 It is hydrogen, halogen, amino, or C1-C3 alkyl;

[0319] Each R 3 Independently, it is deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl; or two Rs. 3Together with the carbon atom to which it is attached, it forms an oxo group, a 4-8 membered heterocyclic group, or a C3-C8 cycloalkyl group;

[0320] m can be 0, 1, 2, or 3;

[0321] R 4 It is a phenyl or a 5-9 membered heteroaryl group; wherein each R 4 The group is optionally composed of 1-3 independently selected R 6 Substituents of the substituents;

[0322] R 5 It can be hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or -NR. C R D Or C1-C3 alkyl; and

[0323] Each R 6 Independently selected from: halogen; cyano; amino; -N=(S=O)(C1-C3 alkyl)2; -S(=O) p (C1-C3 alkyl); -(C=O)NR E R F C1-C3 alkoxy group; C1-C3 haloalkyl group optionally substituted with a hydroxyl group; C1-C3 haloalkoxy group; 5-6 membered heteroaryl group optionally substituted with: halogen, cyano, hydroxyl, C1-C3 alkoxy group, C1-C3 haloalkoxy group, amino group, C1-C3 haloalkyl group, 4-6 membered heterocyclic group or optionally substituted with a hydroxyl group or -NR group. E R F Substituted C1-C3 alkyl groups; optionally substituted with hydroxyl groups, -NR E R F Or C1-C4 alkyl groups substituted with C1-C3 alkoxy groups; 3-8 membered heterocyclic groups; and C3-C6 cycloalkoxy groups;

[0324] p is 1 or 2; and

[0325] R A R B R C R D R E and R F Independently hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or R A and R B , or R C and R D , or R E and R F Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group that is optionally substituted with 1-2 halogens.

[0326] In some embodiments, Q is -CH2-. In some embodiments, Q is O. In some embodiments, Q is NH.

[0327] In some embodiments, the five-membered nitrogen-containing ring partially formed by X and Y is a heteroaromatic ring.

[0328] In some embodiments, X is C and Y is C.

[0329] In some embodiments, X is N and Y is C.

[0330] In some embodiments, X is C and Y is N.

[0331] In some embodiments, Z is N. In some embodiments, Z is CR. 5 .

[0332] In some embodiments, X is C; Y is C; and Z is CR. 5 In some embodiments, X is N; Y is C; and Z is CR. 5 In some embodiments, X is C; Y is N; and Z is CR. 5 In some embodiments, X is C; Y is C; and Z is N. In some embodiments, X is N; Y is C; and Z is N. In some embodiments, X is C; Y is N; and Z is N.

[0333] In some embodiments, R 1 Halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NR A R B Alternatively, it may be a C1-C3 alkyl group substituted with 1-3 substituents selected from hydroxyl and C1-C3 alkoxy groups.

[0334] In some embodiments, R 1 It is halogenated or cyano. In some embodiments, R 1 It is chlorinated or cyano. In some embodiments, R 1 It is hydrogen. In some embodiments, R is... 1 It is a halogen. In some embodiments, R 1 It is fluorine. In some embodiments, R 1 It is chlorine. In some embodiments, R 1 It is cyano. In some embodiments, R 1 It is a hydroxyl group.

[0335] In some embodiments, R 1 It is a C1-C3 alkoxy group. In some embodiments, R 1 It is methoxy or ethoxy.

[0336] In some embodiments, R1 It is a C1-C3 haloalkoxy group. In some embodiments, R 1 It is trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

[0337] In some embodiments, R 1 It is a C1-C3 haloalkyl group. In some embodiments, R 1 It is difluoromethyl, trifluoromethyl, or 2,2,2-trifluoroethyl.

[0338] In some embodiments, R 1 For -NR A R B In some embodiments, R A and R B Independently hydrogen or C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is methyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other component is ethyl. In some embodiments, R A and R B Both are hydrogen. In some embodiments, R A and R B Both are C1-C3 alkyl groups. In some embodiments, R A and R B Both are methyl groups. In some embodiments, R A and R B One of them is methyl and R A and R B The other one is ethyl. In some embodiments, R A and R B Both are ethyl.

[0339] In some embodiments, R A and R B Together with the nitrogen atom it is attached to, it forms a 4-6 membered heterocyclic group. In some embodiments, R A and R B Together with the nitrogen atom it is attached to, it forms a 4-membered heterocyclic group. In some embodiments, R A and R BTogether with the nitrogen atom it is attached to, it forms a 5-membered heterocyclic group. In some embodiments, R A and R B Together with the nitrogen atom it is attached to, it forms a 6-membered heterocyclic group.

[0340] In some embodiments, R 1 It is a C1-C3 alkyl group optionally substituted with 1-3 substituents selected from hydroxyl and C1-C3 alkoxy groups. In some embodiments, R 1 It is a C1-C3 alkyl group optionally substituted with one of the substituents selected from hydroxyl and C1-C3 alkoxy groups. In some of these embodiments, R 1 The methyl group is optionally substituted with one substituent selected from hydroxyl and C1-C3 alkoxy groups. In some embodiments, R 1 Ethyl group optionally substituted with one substituent selected from hydroxyl and C1-C3 alkoxy groups. In some embodiments, R 1 It is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R 1 C1-C3 alkyl groups optionally substituted with C1-C3 alkoxy groups (e.g., methoxy groups). In some embodiments, R 1 It is hydroxymethyl or methoxyethyl.

[0341] In some embodiments, R 1 It is an unsubstituted C1-C3 alkyl group (e.g., methyl or ethyl).

[0342] In some embodiments, R 2 It is hydrogen. In some embodiments, R is... 2 It is a halogen. In some embodiments, R 2 It is fluorine. In some embodiments, R 2 It is chlorine. In some embodiments, R 2 It is an amino group. In some embodiments, R is... 2 It is a C1-C3 alkyl group, such as methyl.

[0343] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0344] In some embodiments, m is 0, 1, 2, or 3. (This text is repeated 6 times in the original.)

[0345] In some embodiments, each R 3 It can be independently deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy.

[0346] In some embodiments, each R 3 It is deuterium.

[0347] In some embodiments, each R 3 Independently halogenated. In some embodiments, R 3 It is fluorine. In some embodiments, R 3 For chlorine. In some embodiments, each R 3 Independently, it is a hydroxyl group.

[0348] In some embodiments, each R 3 It is independently a C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 haloalkyl.

[0349] In some embodiments, each R 3 Independently, it is a C1-C3 alkyl group. For example, R 3 It is methyl or ethyl. In some embodiments, each R 3 Independently, it is a C1-C3 alkoxy group. For example, R 3 It is methoxy or ethoxy. In some embodiments, each R 3 Independently, it is a C1-C3 haloalkoxy group. For example, R 3 It is trifluoromethoxy, difluoromethoxy, or fluoromethoxy. In some embodiments, each R 3 Independently, each is a C1-C3 haloalkyl group. For example, each R 3 It is trifluoromethyl or 2,2,2-trifluoroethyl.

[0350] In some embodiments, Q is -CH2-, m is 1, and each R 3It is a C1-C3 alkyl group. In some embodiments, Q is -CH2-, m is 2, and each R 3 It is a C1-C3 alkyl group. In some embodiments, Q is -CH2-, m is 2, and R is C1-C3 alkyl. 3 It is a C1-C3 alkyl group, wherein R 3 The group is a C1-C3 alkyl group. In some embodiments, Q is -CH2- and each R 3 Independently, it is a C1-C3 alkyl group. In some embodiments, Q is -CH2-, m is 2, and R 3 The groups are at the homologous position. In some embodiments, Q is -CH2-, m is 2, and each R 3 It is a C1-C3 haloalkyl group. In some embodiments, Q is -CH2- and R is... 3 The group is a C1-C3 haloalkyl group. In some embodiments, Q is -CH2-, m is 2, and one R 3 It is a C1-C3 alkyl group and another R 3 It is a C1-C3 haloalkyl group. In some embodiments, Q is -CH2-, m is 2, and one R 3 It is a C1-C3 alkoxy group and another R 3 It is a C1-C3 haloalkyl group. In some embodiments, Q is -CH2-, R 3 The group is a C1-C3 alkyl or a C1-C3 haloalkyl. In some embodiments, Q is -CH2-, m is 2, and one R 3 It is a C1-C3 alkyl group and another R 3 It is a C3-C6 cycloalkyl group. In some embodiments, m is 2, and one R 3 It is trifluoromethyl and another R 3 It is an ethoxylated compound. In some embodiments, Q is -CH2-, and R is... 3 The group is a C1-C3 alkyl or a C3-C6 cycloalkyl. In some embodiments, Q is -CH2-, m is 2, and one R 3 It is a C1-C3 haloalkyl and another R 3 It is a C3-C6 cycloalkyl group. In some embodiments, Q is -CH2-, and R is... 3 The groups are C1-C3 haloalkyl and C3-C6 cycloalkyl.

[0351] In some embodiments, Q is -CH2-, m is 1, and each R 3 It is methyl. In some embodiments, Q is -CH2-, m is 2, and each R 3 It is methyl. In some embodiments, Q is -CH2-, m is 2, and each R 3 It is methyl, and both R 3The group is a geminate methyl group. In some embodiments, Q is -CH2-, and each R 3 Independently, it is methyl. In some embodiments, Q is -CH2-, m is 2, and R is... 3 The groups are at the homologous position. In some embodiments, Q is -CH2-, m is 2, and each R 3 It is trifluoromethyl. In some embodiments, Q is -CH2-, and R is trifluoromethyl. 3 The group is a trifluoromethyl group. In some embodiments, Q is -CH2-, m is 2, and one R 3 For methyl and another R 3 It is trifluoromethyl. In some embodiments, Q is -CH2-, and R is trifluoromethyl. 3 The group is a geminate methyl group or a trifluoromethyl group. In some embodiments, Q is -CH2-, m is 2, and one R 3 For methyl and another R 3 It is cyclopropyl. In some embodiments, Q is -CH2-, and R is... 3 The groups are methyl and cyclopropyl. In some embodiments, Q is -CH2-, m is 2, and one R 3 It is trifluoromethyl and another R 3 It is cyclopropyl. In some embodiments, Q is -CH2-, and R is... 3 The functional groups are trifluoromethyl and cyclopropyl.

[0352] In some embodiments, Q is -CH2-, m is 2, and the two Rs 3 Together with the carbon atom it is attached to, it forms an oxo group. In some embodiments, m is 2, and the two Rs... 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). In some embodiments, m is 2, and the two Rs 3 Together with the carbon atom it is attached to, it forms a cyclopropyl or cyclobutyl group.

[0353] In some embodiments, two R 3 Together with the carbon atom it is attached to, it forms a 4-8 membered heterocyclic group. In some embodiments, m is 2, and the two R atoms... 3 Together with the carbon atom it is attached to, it forms a 4-8 membered heterocyclic group. In some embodiments, the two R atoms... 3 Together with the carbon atom it is attached to, it forms a 4-6 membered heterocyclic group. In some embodiments, the two R atoms... 3 Together with the carbon atom it is attached to, it forms a 4-membered heterocyclic group, such as an oxetane or an azirone. In some embodiments, the two R... 3Together with the carbon atom it is attached to, it forms a 5-membered heterocyclic group. In some embodiments, the two R atoms... 3 Together with the carbon atom it is attached to, it forms a 6-membered heterocyclic group, such as a tetrahydropyranyl group. In some embodiments, m is 2, and the two R... 3 Together with the carbon atom it is attached to, it forms an oxocyclic butyl or tetrahydropyranyl group.

[0354] In some embodiments, m is 3, and two R 3 The group is methyl, and has one R 3 Choose from the group consisting of methyl and hydroxyl groups.

[0355] In some embodiments, Q is 0, m is 1, and each R 3 It is a C1-C3 alkyl group. In some embodiments, Q is 0, m is 2, and each R 3 It is a C1-C3 alkyl group. In some embodiments, Q is 0, m is 2, and R is C1-C3 alkyl. 3 It is a C1-C3 alkyl group, wherein R 3 The group is a C1-C3 alkyl group. In some embodiments, Q is O, and each R 3 Independently, it is a C1-C3 alkyl group. In some embodiments, Q is 0, m is 2, and R... 3 The groups are at the homologous position. In some embodiments, Q is 0, m is 2, and each R 3 It is a C1-C3 haloalkyl group. In some embodiments, Q is O, and R is... 3 The group is a C1-C3 haloalkyl group. In some embodiments, Q is 0, m is 2, and one R 3 It is a C1-C3 alkyl group and another R 3 It is a C1-C3 haloalkyl group. In some embodiments, Q is O, R is... 3 The groups are C1-C3 alkyl and C1-C3 haloalkyl groups. In some embodiments, Q is 0, m is 2, and one R 3 It is a C1-C3 alkyl group and another R 3 It is a C3-C6 cycloalkyl group. In some embodiments, Q is O, and R is C3-C6 cycloalkyl. 3 The group is a C1-C3 alkyl or a C3-C6 cycloalkyl group. In some embodiments, Q is 0, m is 2, and one R 3 It is a C1-C3 haloalkyl and another R 3 It is a C3-C6 cycloalkyl group. In some embodiments, Q is O, and R is C3-C6 cycloalkyl. 3 The groups are C1-C3 haloalkyl and C3-C6 cycloalkyl.

[0356] In some embodiments, Q is 0, m is 1, and each R 3It is methyl. In some embodiments, Q is O, m is 2, and each R 3 It is methyl. In some embodiments, Q is O, m is 2, and each R 3 It is methyl, and both R 3 The group is a geminate methyl group. In some embodiments, Q is O, and each R 3 Independently, it is methyl. In some embodiments, Q is O, m is 2, and R is... 3 The groups are at the homologous position. In some embodiments, Q is 0, m is 2, and each R 3 It is trifluoromethyl. In some embodiments, Q is O, and R is... 3 The group is a trifluoromethyl group at the geminal position. In some embodiments, Q is 0, m is 2, and one R 3 For methyl and another R 3 It is trifluoromethyl. In some embodiments, Q is O, and R is... 3 The group is a geminate methyl group or a trifluoromethyl group. In some embodiments, Q is 0, m is 2, and an R group is 0. 3 For methyl and another R 3 It is cyclopropyl. In some embodiments, Q is O, and R is... 3 The groups are geminal methyl and cyclopropyl. In some embodiments, Q is 0, m is 2, and one R 3 It is trifluoromethyl and another R 3 It is cyclopropyl. In some embodiments, Q is O, and R is... 3 The functional groups are trifluoromethyl and cyclopropyl.

[0357] In some embodiments, Q is 0, m is 2, and the two Rs 3 Together with the carbon atom it is attached to, it forms an oxo group. In some embodiments, m is 2, and the two Rs... 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

[0358] In some embodiments, Q is NH, m is 1, and each R 3 It is a C1-C3 alkyl group. In some embodiments, Q is NH, m is 2, and each R 3 It is a C1-C3 alkyl group. In some embodiments, Q is NH, m is 2, and R is C1-C3 alkyl. 3 It is a C1-C3 alkyl group, wherein R 3 The group is a C1-C3 alkyl group. In some embodiments, Q is NH, and each R 3 Independently, it is a C1-C3 alkyl group. In some embodiments, Q is NH, m is 2, and R is... 3The groups are at the homologous position. In some embodiments, Q is NH, m is 2, and each R 3 It is a C1-C3 haloalkyl group. In some embodiments, Q is NH, and R is C1-C3 haloalkyl. 3 The group is a C1-C3 haloalkyl group. In some embodiments, Q is NH, m is 2, and one R 3 It is a C1-C3 alkyl group and another R 3 It is a C1-C3 haloalkyl group. In some embodiments, Q is NH, R is NH. 3 The group is a C1-C3 alkyl or a C1-C3 haloalkyl. In some embodiments, Q is NH, m is 2, and one R 3 It is a C1-C3 alkyl group and another R 3 It is a C3-C6 cycloalkyl group. In some embodiments, Q is NH, and R is C3-C6 cycloalkyl. 3 The group is a C1-C3 alkyl or a C3-C6 cycloalkyl group. In some embodiments, Q is NH, m is 2, and one R 3 It is a C1-C3 haloalkyl and another R 3 It is a C3-C6 cycloalkyl group. In some embodiments, Q is NH, and R is C3-C6 cycloalkyl. 3 The groups are C1-C3 haloalkyl and C3-C6 cycloalkyl.

[0359] In some embodiments, Q is NH, m is 1, and each R 3 , is methyl. In some embodiments, Q is NH, m is 2, and each R 3 It is methyl. In some embodiments, Q is NH, m is 2, and each R 3 It is methyl, and both R 3 The group is a methyl group at the methyl position. In some embodiments, Q is NH, and each R 3 Independently, it is methyl. In some embodiments, Q is NH, m is 2, and R is methyl. 3 The groups are at the homologous position. In some embodiments, Q is NH, m is 2, and each R 3 It is trifluoromethyl. In some embodiments, Q is NH, and R is trifluoromethyl. 3 The group is a trifluoromethyl group at the methyl group. In some embodiments, Q is NH, m is 2, and one R 3 For methyl and another R 3 It is trifluoromethyl. In some embodiments, Q is NH, and R is trifluoromethyl. 3 The group is a methyl group or a trifluoromethyl group. In some embodiments, Q is NH, m is 2, and one R 3 For methyl and another R 3 It is cyclopropyl. In some embodiments, Q is NH, and R is cyclopropyl. 3The groups are methyl and cyclopropyl. In some embodiments, Q is NH, m is 2, and one R 3 It is trifluoromethyl and another R 3 It is cyclopropyl. In some embodiments, Q is NH, and R is cyclopropyl. 3 The functional groups are trifluoromethyl and cyclopropyl.

[0360] In some embodiments, Q is NH, m is 2, and the two Rs 3 Together with the carbon atom it is attached to, it forms an oxo group. In some embodiments, m is 2, and the two Rs... 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

[0361] In some embodiments, R 4 It is a phenyl or a 5-6 membered heteroaryl group; wherein each R 4 The group is optionally replaced by 1-2 independently selected R groups. 6 Replacement. In some embodiments, R 4 It is a phenyl or a 5-6 membered heteroaryl group; wherein each R 4 The group is optionally replaced by 2-3 independently selected R groups. 6 Replacement. In some embodiments, R 4 It is a phenyl or a 5-6 membered heteroaryl group; wherein each R 4 The group is optionally selected by one or three independently chosen R 6 Replacement. In some embodiments, R 4 It is a phenyl or a 5-6 membered heteroaryl group; wherein each R 4 The group is optionally selected by one independently chosen R 6 Replacement. In some embodiments, R 4 It is a phenyl or a 5-6 membered heteroaryl group; wherein each R 4 The group is optionally selected by two independently chosen R 6 Replacement. In some embodiments, R 4 It is a phenyl or a 5-6 membered heteroaryl group; wherein each R 4 The group is optionally selected by 3 independently chosen R 6 replace.

[0362] In some embodiments, R 4 It is a phenyl or a 5-membered heteroaryl group; wherein each R 4 The group is optionally composed of 1-3 independently selected R 6 Substituent substitution. In some embodiments, R 4 It is a phenyl or a 6-membered heteroaryl group; wherein each R 4 The group is optionally composed of 1-3 independently selected R6 Substituents are substituted.

[0363] In some embodiments, R 4 R is arbitrarily selected by 1-3 independent choices 6 Substituted phenyl groups. In some embodiments, R 4 To be arbitrarily assigned to 1 R 6 Substituted phenyl groups. In some embodiments, R 4 R is arbitrarily selected by two independent choices 6 Substituted phenyl groups. In some embodiments, R 4 R is arbitrarily selected by 3 independent choices 6 Substituted phenyl groups.

[0364] In some embodiments, R 4 It is an unsubstituted phenyl group.

[0365] In some embodiments, R 4 For being selected independently from 1-3 R 6 The substituted phenyl group. In some embodiments, R 4 For R 6 Substituted phenyl groups. In some embodiments, R 4 For R, which is selected by two independent choices 6 Substituted phenyl groups. In some embodiments, R 4 For R, which is selected independently by 3 people 6 Substituted phenyl groups.

[0366] In some embodiments, R 4 To be optionally selected independently from 1-3 (e.g., 2) R 6 The substituents are substituted into 5-6 heteroaryl groups. In some embodiments, R 4 To be optionally selected independently from 1-3 (e.g., 2) R 6 The substituents are substituted into the 6-membered heteroaryl group.

[0367] In some embodiments, R 4 It is an unsubstituted 5-6 aryl group.

[0368] In some embodiments, R 4 For being selected independently from 1-3 R 6 The substituents are substituted with 5-6 heteroaryl groups.

[0369] In some embodiments, R 4 For R, which is optionally selected independently by 1-3 (e.g., 1 or 2) 6 Substituted 5-9-membered heteroaryl groups. In some embodiments, R 4 For being selected independently from 1-3 (e.g., 2) R6 The substituents replace the 5-9 membered heteroaryl groups. In some embodiments, R 4 To be optionally selected independently from 1-3 (e.g., 2) R 6 The substituents replace the 9-membered heteroaryl group. In some embodiments, R 4 For being selected from R 6 The substituents replace the 9-membered heteroaryl group. In some embodiments, R 4 It is a 9-membered heteroaryl group containing a pyridinyl group. In some embodiments, R 4 for Where ring B is optionally selected from 1-2 (e.g., 1) rings from R. 6 The substituents replace the 4-5 membered heterocyclic group. In some embodiments, R 4 for

[0370] In some embodiments, R 4 It is an unsubstituted 5-6 membered heteroaryl group. In some embodiments, R 6 At least one of R6 is a halogen. In some embodiments, at least one of R6 is fluorine. In some embodiments, at least one of R6 is chlorine. In some embodiments, R 6 One of them is a halogen. In some embodiments, R 6 One of them is fluorine. In some embodiments, R 6 One of them is chlorine. In some embodiments, R 6 Two of them are halogens. In some embodiments, R 6 Two of them are fluorine. In some embodiments, R 6 Two of them are chlorine. In some embodiments, R 6 Three of them are halogens. In some embodiments, R 6 Three of them are fluorine. In some embodiments, R 6 Three of them are chlorine. In some embodiments, R 6 At least one of them is a cyano group. In some embodiments, R 6 At least one of them is an amino group.

[0371] In some embodiments, R 6 At least one of them is -(C=O)NR E R F In some embodiments, R E and R F Independently hydrogen or C1-C3 alkyl. In some embodiments, R E and R F One of them is hydrogen and R E and R FThe other one is a C1-C3 alkyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is a C3-C6 cycloalkyl group. In some embodiments, R E and R F One of them is a C1-C3 alkyl group and R E and R F The other one is a C3-C6 cycloalkyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is methyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is ethyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is cyclopropyl. In some embodiments, R E and R F One of them is methyl and R E and R F The other component is cyclopropyl. In some embodiments, R E and R F Both are hydrogen. In some embodiments, R E and R F Both are C1-C3 alkyl groups. In some embodiments, R E and R F Both are methyl groups. In some embodiments, R E and R F One of them is methyl and R E and R F The other one is ethyl. In some embodiments, R E and R F Both are ethyl.

[0372] In some embodiments, R E and R F Together with the nitrogen atom it is attached to, it forms a 4-6 membered heterocyclic group. In some embodiments, R E and R F Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group, optionally substituted with 1-2 halogens. In some embodiments, R E and R FTogether with the nitrogen atom it is attached to, it forms a 4-membered heterocyclic group. In some embodiments, R E and R F Together with the nitrogen atom to which it is attached, it forms an azirhecyl-1-yl or 3,3-difluoro-azirhecyl-1-yl. In some embodiments, R E and R F Together with the nitrogen atom it is attached to, it forms a 5-membered heterocyclic group. In some embodiments, R E and R F Together with the nitrogen atom it is attached to, it forms a 6-membered heterocyclic group.

[0373] In some embodiments, R 6 At least one of them is -N=(S=O)(C1-C3 alkyl)2. In some embodiments, each (C1-C3 alkyl) is the same. In some embodiments, each (C1-C3 alkyl) is different. In some embodiments, each (C1-C3 alkyl) is methyl.

[0374] In some embodiments, R 6 At least one of them is -S (=O) p (C1-C3 alkyl). In some embodiments, each (C1-C3 alkyl) is the same. In some embodiments, each (C1-C3 alkyl) is different. In some embodiments, each (C1-C3 alkyl) is methyl.

[0375] In some embodiments, p is 1. In some embodiments, p is 2.

[0376] In some embodiments, R 6 At least one of them is a C1-C3 alkoxy group. In some embodiments, R 6 At least one of them is methoxy or ethoxy.

[0377] In some embodiments, R 6 At least one of them is a C1-C3 haloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R 6 At least one of them is an unsubstituted C1-C3 haloalkyl group. In some embodiments, R 6 At least one of them is a C1-C3 haloalkyl group substituted with a hydroxyl group. In some embodiments, R 6 At least one of them is trifluoromethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl. In some embodiments, R 6 At least one of them is 1-hydroxy-2,2-difluoroethyl.

[0378] In some embodiments, R 6 At least one of them is a C1-C3 haloalkoxy group. In some embodiments, R 6At least one of them is a trifluoromethoxy group.

[0379] In some embodiments, R 6 At least one of them is a 5-6 membered heteroaryl group optionally substituted with: halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4-6 membered heterocyclic group or optionally substituted with hydroxyl or -NR. E R F Substituted C1-C3 alkyl groups. In some embodiments, R 6 At least one of them is a 5-6 membered heteroaryl group optionally substituted with: halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, optionally substituted with hydroxyl or -NR E R F Substituted C1-C3 alkyl, amino, or C1-C3 haloalkyl. In some embodiments, R 6 The C1-C3 alkyl group is a 5-6 membered heteroaryl group optionally substituted with a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted with a hydroxyl group or -NR. E R F Replacement. In some embodiments, R 6 At least one of them is a 5-6 membered heteroaryl group optionally substituted with: halogen, C1-C3 haloalkyl, or optionally substituted with hydroxyl or -NR. E R F Substituted C1-C3 alkyl groups. In some embodiments, R 6 It is a 5-6 membered heteroaryl group substituted with a C1-C3 alkyl group, wherein the C1-C3 alkyl group is replaced by a hydroxyl group or -NR. E R F Replacement. In some embodiments, R 6 The 5-6 membered heteroaryl group is substituted with the following: hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, propan-2-ol, or propan-2-amine. In some embodiments, R 6 At least one of them is a 5-6 membered heteroaryl group optionally substituted with a 4-6 membered heterocyclic group.

[0380] In some embodiments, R 6 At least one of them is a 5-membered heteroaryl group optionally substituted with: halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkyl, amino, or C1-C3 haloalkyl. In some embodiments, R 6 At least one of them is a 6-membered heteroaryl group optionally substituted with: halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, or optionally substituted with hydroxyl or -NR. E R F Substituted C1-C3 alkyl groups. In some embodiments, R 6The 5-membered heteroaryl group is substituted with the following: hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, propan-2-ol, or propan-2-amine. In some embodiments, R 6 The 6-membered heteroaryl group is substituted by the following: hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, prop-2-ol or prop-2-amine.

[0381] In some embodiments, R 6 At least one of them is optionally hydroxyl, -NR E R F Or a C1-C3 alkyl group substituted with a C1-C3 alkoxy group. In some embodiments, R 6 At least one of them is optionally hydroxyl, -NR E R F Or C1-C4 alkyl groups substituted with C1-C3 alkoxy groups. In some embodiments, R 6 At least one of them is optionally hydroxyl, -NR E R F Or a C1-C3 alkoxy-substituted methyl group. In some embodiments, R 6 At least one of them is hydroxymethyl, 2-aminoethyl, or methoxyethyl. In some embodiments, R 6 At least one of them is optionally hydroxyl, -NR E R F Or a C1-C3 alkoxy-substituted ethyl. In some embodiments, R 6 At least one of them is 1-hydroxyethyl or 2-hydroxypropane-2-yl.

[0382] In some embodiments, R E and R F Independently hydrogen or C1-C3 alkyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is a C1-C3 alkyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is a C3-C6 cycloalkyl group. In some embodiments, R E and R F One of them is a C1-C3 alkyl group and R E and R F The other one is a C3-C6 cycloalkyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R FThe other is methyl. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is ethyl. E and R F One of them is hydrogen and R E and R F The other is cyclopropyl. In some embodiments, one of RE and RF is methyl and the other of RE and RF is cyclopropyl. E and R F Both are hydrogen. In some embodiments, R E and R F Both are C1-C3 alkyl groups. In some embodiments, both RE and RF are methyl. In some embodiments, one of RE and RF is methyl and the other of RE and RF is ethyl. In some embodiments, R E and R F Both are ethyl.

[0383] In some embodiments, R E and R F Together with the nitrogen atom it is attached to, it forms a 4-6 membered heterocyclic group. In some embodiments, R E and R F Together with the nitrogen atom it is attached to, it forms a 4-membered heterocyclic group. In some embodiments, R E and R F Together with the nitrogen atom to which it is attached, it forms an aziridine or a 2-oxoaziridine-1-yl group. In some embodiments, R E and R F Together with the nitrogen atom it is attached to, it forms a 5-membered heterocyclic group. In some embodiments, R E and R F Together with the nitrogen atom it is attached to, it forms a 2-oxopyrrolidone-1-yl group. In some embodiments, R E and R F Together with the nitrogen atom it is attached to, it forms a 6-membered heterocyclic group.

[0384] In some embodiments, R 6 At least one of them is a 3-8 membered heterocyclic group. In some embodiments, R 6 At least one of them is a 3-membered heterocyclic group. In some embodiments, R 6 At least one of them is a 4-membered heterocyclic group. In some embodiments, R 6 At least one of them is a 5-membered heterocyclic group. In some embodiments, R 6 At least one of them is a 6-membered heterocyclic group. In some embodiments, R 6 At least one of them is a 7-membered heterocyclic group. In some embodiments, R 6At least one of them is an 8-membered heterocyclic group.

[0385] In some embodiments, R 6 At least one of them is a C3-C6 cycloalkoxy group. In some embodiments, R 6 At least one of them is cyclopropoxy or cyclobutoxy.

[0386] In some embodiments, R 4 It is pyridyl, pyrimidinyl, pyrazinyl, pyrroleyl, or imidazoleyl; each of which is divided by 2 R 6 Replace: an R 6 It is triazolyl, imidazolyl, oxazolyl, pyrazolyl, or pyrrolidinyl; and another R 6 It is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. In some embodiments, R 4 It is pyridinyl, pyrimidinyl, or pyrazinyl; each of which is divided by 2 R 6 Replace: an R 6 It is triazolyl, imidazolyl, oxazolyl, pyrazolyl, or pyrrolidinyl; and another R 6 It is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. In some embodiments, R 4 For being 2 R 6 Substituted pyridinyl group: an R 6 It is triazole, imidazole, or oxazolyl; and another R 6 It can be methyl, methoxy, trifluoromethyl, trifluoromethoxy, chlorine, or cyano.

[0387] In some embodiments, each R 6 It is independently selected from: halogen; cyano; amino; C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 haloalkoxy; C1-C3 alkyl; and C3-C6 cycloalkoxy.

[0388] In some embodiments, R 4 R is selected by 1-3 independent choices 6 Substituted 3-pyridyl or 4-pyridyl.

[0389] In some embodiments, R 4 for The wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0390] In some embodiments, R 4 for The wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0391] In some embodiments, R 4 for The wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0392] In some embodiments, R 4 for The wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0393] In some embodiments, R 4 for The wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0394] In some embodiments, R 4 for The wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0395] In some embodiments, when R 4 for At that time, R 6 Choose from the group consisting of: cyano, halogen, C1-C3 haloalkyl and C1-C3 alkoxy.

[0396] In some embodiments, when R 4 for At that time, R 6 Choose from the group consisting of: cyano, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy and C1-C3 alkoxy, optionally substituted with hydroxyl.

[0397] In some embodiments, when R 4 for At that time, R 6 Choose from the group consisting of: cyano, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, and methoxy. For example, when R... 4 for At that time, R 6 It is chlorine or trifluoromethyl (e.g., chlorine).

[0398] In some embodiments, R 4 for Where R 6A and R 6B Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0399] In some embodiments, R 4 for Where R 6A and R 6B Independently selected from R6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0400] In some embodiments, R 4 for Where R 6A and R 6B Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0401] In some embodiments, R 4 for Where R 6A and R 6B Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0402] In some embodiments, when R 4 for hour,

[0403] R 6A Choose from the group consisting of: cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; and

[0404] R 6B Choose from the group consisting of: 5-6 membered heteroaryl groups optionally substituted with: cyano, C1-C3 alkyl optionally substituted with hydroxyl, 4-6 membered heterocyclic or amino; -N=(S=O)(C1-C3 alkyl)2; -(C=O)NR E R F ; C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; cyano; C3-C6 cycloalkoxy; and C1-C3 alkyl optionally substituted with hydroxyl.

[0405] In some embodiments, when R 4 for At that time, R 6A Choose from the group consisting of: cyano, fluorine, chlorine, methyl, ethyl, methoxy, trifluoromethyl; and

[0406] R 6BSelect from the group consisting of: 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1, 2,4-Triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, 1,2,4-triazol-4-one-2-yl, tetrazol-5-yl, 2-methyl-tetrazol-5-yl, 1-methyl-tetrazol-5-yl, imidazole-1-yl, 1-methyl-imidazole-3-yl, 1-methyl-5-amino-imidazole-3-yl 3-Methylimidazol-2-one-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, pyrrolidin-1-yl, thiazol-2-yl, isothiazolidine-2-yl-1,1-dioxide, pyrrolidin-2-one-1-yl, oxazol-2-yl, oxadiazol-2-yl, 2-aminopyrimidine-4-yl, -(C=O)4-methyl Piperazin-1-yl, 2-oxozylidene-1-yl, aziridine-1-yl, -(C=O)N(CH3)2, -(C=O)NHCH3, -(C=O)NHCH2CH3, -(C=O)NHcyclopropyl, -(C=O)(3,3-difluoroaziridine-1-yl), 2-hydroxypropane-2-yl, 1-hydroxyethyl, dimethyl(oxo)-λ 6 - Thiodimethyl, methoxy, ethoxy, difluoromethoxy, methyl, cyano.

[0407] In some embodiments, when R 4 for hour,

[0408] R 6A Choose from the group consisting of: cyano, chloro, methyl, and trifluoromethyl; and

[0409] R 6B Choose from the group consisting of: 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, and 1,2,4-triazol-4-one-2-yl.

[0410] In some embodiments, when R 4 for hour,

[0411] R 6A It is chlorine; and

[0412] R 6B Choose from the group consisting of: 1,2,3-triazol-2-yl, 1,2,3-triazol-1-yl and 1,2,4-triazol-4-one-2-yl.

[0413] In some embodiments, R 4 for Where R 6A R 6B and R 6C Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0414] In some embodiments, R 4 for Where R 6A R 6B and R 6C Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

[0415] In some embodiments, when R 4 for hour,

[0416] R 6A Select from the group consisting of: cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl;

[0417] R 6B Choose from the group consisting of: 5-6 membered heteroaryl groups optionally substituted with cyano, C1-C3 alkyl, or amino groups; -(C=O)NR E R F ; C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 haloalkoxy; cyano; and C1-C3 alkyl; and

[0418] R 6C Choose from the group consisting of: cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl.

[0419] In some embodiments, when R 4 for hour,

[0420] R 6A Choose from the following groups: cyano, fluorine, chlorine, methyl, ethyl, methoxy, trifluoromethyl;

[0421] R 6B Select from the group consisting of: 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, 1,2,4-triazol-4-one-2-yl, tetrazol-5-yl, 2-methyl-tetrazole-5-yl, 1 -Methyl-tetrazole-5-yl, imidazole-1-yl, 1-methyl-imidazole-3-yl, 1-methyl-5-amino-imidazole-3-yl, 3-methylimidazole-2-one-1-yl, 1-methyl-pyrazole-3-yl, 1-methyl-pyrazole-5-yl, pyrrolo-1-yl, thiazolyl-2-yl, isothiazolidine-2-yl-1,1-dioxide, pyrrolo-2-one-1-yl, oxazol-2-yl, oxadiazol-2-yl, 2-amino-pyrimidin-4-yl, -(C=O)4-methylpiperazin-1-yl, -(C=O)N(CH3)2, -(C=O)NHCH3, methoxy, ethoxy, difluoromethoxy, methyl, cyano; and

[0422] R 6C Choose from the group consisting of: cyano, fluorine, chlorine, methyl, ethyl, methoxy, methyl, and trifluoromethyl.

[0423] In some embodiments, when R 4 for hour,

[0424] R 6A Choose from the following groups: cyano, chloro, and trifluoromethyl;

[0425] R 6B Select from the group consisting of: 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, and 1,2,4-triazol-4-one-2-yl; and

[0426] R 6C Choose from the following groups: cyano, chloro, methyl, and trifluoromethyl.

[0427] In some embodiments, when R 4 for hour,

[0428] R 6A It is chlorine;

[0429] R 6B The following groups were selected: 1,2,3-triazol-2-yl and 1,2,4-triazol-4-one-2-yl; and

[0430] R 6C Choose from the following groups: cyano, chloro, methyl, and trifluoromethyl.

[0431] In some embodiments, R 5 It is hydrogen.

[0432] In some embodiments, R 5 It is a halogen. For example, R 5 It is fluorine. For example, R 5 It is chlorine. In some embodiments, R 5 It is cyano. In some embodiments, R 5 It is a hydroxyl group.

[0433] In some embodiments, R 5 It is a C1-C3 alkoxy group. In some embodiments, R 5 It is methoxy or ethoxy.

[0434] In some embodiments, R 5 It is a C1-C3 haloalkoxy group. In some embodiments, R 5 It is trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

[0435] In some embodiments, R 5 It is a C1-C3 haloalkyl group. In some embodiments, R 5 It is trifluoromethyl or 2,2,2-trifluoroethyl.

[0436] In some embodiments, R 5 For -NR C R D In some embodiments, R C and R D Independently hydrogen or C1-C3 alkyl. In some embodiments, R C and R D One of them is hydrogen and R C and R D The other one is a C1-C3 alkyl group. In some embodiments, R C and R D One of them is hydrogen and R C and RD The other one is methyl. In some embodiments, R C and R D One of them is hydrogen and R C and R D The other component is ethyl. In some embodiments, R C and R D Both are hydrogen. In some embodiments, R C and R D Both are C1-C3 alkyl groups. In some embodiments, R C and R D Both are methyl groups. In some embodiments, R C and R D One of them is methyl and R C and R D The other one is ethyl. In some embodiments, R C and R D Both are ethyl.

[0437] In some embodiments, R C and R D Together with the nitrogen atom it is attached to, it forms a 4-6 membered heterocyclic group. In some embodiments, R C and R D Together with the nitrogen atom it is attached to, it forms a 4-membered heterocyclic group. In some embodiments, R C and R D Together with the nitrogen atom to which they are attached, they form a 5-membered heterocyclic group. In some embodiments, RC and RD together with the nitrogen atom to which they are attached form a 6-membered heterocyclic group.

[0438] In some embodiments, R 5 It is a C1-C3 alkyl group. In some embodiments, R 5 It can be methyl or ethyl.

[0439] In some embodiments, R X It is hydrogen. In some embodiments, R is... X It is a halogen. In some embodiments, R X It is fluorine. In some embodiments, R X It is chlorine.

[0440] In some embodiments, the compound is selected from the compounds in Table 1 or their pharmaceutically acceptable salts.

[0441] Table 1

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471] * For detailed information on isomer separation, please refer to the experimental procedures.

[0472] Preparation process

[0473] This document provides a method for preparing compounds of formula (I) (e.g., any compound described herein), the method comprising:

[0474] Compound of formula (IA)

[0475]

[0476] With R 4 -NH2 reaction;

[0477] To form a compound of formula (I).

[0478] In some embodiments, the compound of formula (IA) is reacted with R 4 The -NH2 (e.g., 5-chloro-6-(triazolyl)pyridine-3-amine) reaction is carried out in the presence of POCl3 and pyridine.

[0479] In some embodiments, the compound of formula (IA) is reacted with R 4 The -NH2 reaction was carried out in the presence of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH).

[0480] In some embodiments, the compound of formula (IA) is reacted with R 4 The -NH2 reaction is carried out in the presence of N-methylimidazole (NMI).

[0481] In some embodiments, the compound of formula (IA) is prepared from the compound of formula (IAN):

[0482]

[0483] In some embodiments (when the compound of formula (IA) is prepared from the compound of formula (IAN), the method includes making the compound of formula (IANi)

[0484]

[0485] Reaction with compounds of formula (IAN-ii)

[0486]

[0487] Compounds with the formula (IAN) are formed.

[0488] In some embodiments, the reaction of compound (IANi) with compound (IAN-ii) is carried out in the presence of an acid.

[0489] In some of these embodiments, the acid is selected from the group consisting of hydrochloric acid and acetic acid.

[0490] This document provides a method for preparing compounds of formula (I) (e.g., any compound described herein), the method comprising:

[0491] Compounds of formula (IB)

[0492]

[0493] With R 4 -Hal reaction, where Hal is selected from the group consisting of Cl, Br, I and OSO2CF3;

[0494] To form a compound of formula (I).

[0495] In some embodiments, the compound of formula (IB) is reacted with R 4 The -Hal reaction is carried out in the presence of a catalyst and ligands.

[0496] In some embodiments (when the compound of formula (IB) is combined with R) 4 -Hal reaction is carried out in the presence of a catalyst and a ligand, wherein the catalyst is tris(dibenzylacetone)dipalladium(O).

[0497] In some embodiments (when the compound of formula (IB) is combined with R) 4 -Hal reaction is carried out in the presence of a catalyst and a ligand, wherein the ligand is 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene.

[0498] In some embodiments, the compound of formula (IB) is prepared from the compound of formula (IAN):

[0499]

[0500] In some embodiments, the method includes using a compound of formula (IANi).

[0501]

[0502] Reaction with compounds of formula (IAN-ii)

[0503]

[0504] Compounds with the formula (IAN) are formed.

[0505] In some embodiments, the reaction of compound (IANi) with compound (IAN-ii) is carried out in the presence of an acid.

[0506] In some embodiments (when the reaction of compound (IANi) with compound (IAN-ii) is carried out in the presence of an acid), the acid is selected from the group consisting of hydrochloric acid and acetic acid.

[0507] Treatment

[0508] Some embodiments provide a method of treating an autoimmune condition (e.g., MALT1-related autoimmune disease) in a subject requiring such treatment, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the autoimmune condition is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE).

[0509] Some embodiments provide a method for treating an inflammatory condition (e.g., MALT1-related inflammatory condition) in a subject requiring such treatment, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the inflammatory condition is chronic graft-versus-host disease (cGVHD).

[0510] Some embodiments provide methods for treating a subject with cancer (e.g., MALT1-related cancer) requiring such treatment, the methods comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. For example, this document provides a method for treating a subject with MALT1-related cancer requiring such treatment, the method comprising: a) detecting dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of therein in a sample from the subject; and b) administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of therein comprises one or more fusion proteins.

[0511] In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is a blood cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma (e.g., sporadic medullary thyroid carcinoma or hereditary medullary thyroid carcinoma), differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland tumor, lung adenocarcinoma, bronchioloalveolar lung cancer, type 2A or 2B multiple endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast cancer, breast adenoma, breast tumor, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, inflammatory myofibroblastoma, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical malformation / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma. Lymphoma, carcinoid tumor, unknown primary cancer, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, tumors by location, tumors, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct cancer, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma Sarcoma, extracranial germ cell tumors, gonadal extragerminal tumors, extrahepatic bile duct carcinoma, ocular cancer, fallopian tube cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, glioma, pilocytoma, hairy cell leukemia, head and neck cancer, thoracic tumors, head and neck tumors, CNS tumors, primary CNS tumors, heart disease, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis.Cellhistiocytosis), laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, tumors by location, tumors, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung cancer, lung tumors, respiratory tract tumors. Bronchial cancer, bronchial tumors, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleural pulmonary blastoma, pregnancy-related breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon tumor, renal cell carcinoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome Syndrome), skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis, unknown primary cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0512] In some embodiments, the cancer is a blood cancer, such as leukemia or lymphoma. In some embodiments, blood cancers (e.g., blood cancers as MALT1-related cancers) are selected from the group consisting of: leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), and myeloma, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), lymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplastic syndromes (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDS), myelodysplastic syndromes (MPD), and multiple myeloma (MM). Other examples of blood cancers include myelodysplastic disorders (MPDs) such as polycythemia vera (PV), essential thrombocytopenic purpura (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, blood cancers (e.g., blood cancers as MALT1-related cancers) are AML or CMML.

[0513] In some embodiments, the cancer is glioblastoma, chronic myeloid leukemia, granulocytic leukemia, or non-Hodgkin's lymphoma.

[0514] In some embodiments, the cancer (e.g., MALT1-related cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are MALT1-related cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal carcinoma, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, neuroblastoma, and melanoma. See, for example, Jiang et al., Cancer Research 2011, 71, 2183-2192; also see Pan et al., Molecular Cancer Research 2016, 14, 93-102 and Penas et al., Blood 2010, 115, 2214-2219.

[0515] In some embodiments, the subject is a human being.

[0516] Compounds of formula (I) and their pharmaceutically acceptable salts may also be used to treat MALT1-related cancers. Compounds of formula (I) and their pharmaceutically acceptable salts may also be used to treat MALT1-related autoimmune diseases. Compounds of formula (I) and their pharmaceutically acceptable salts may also be used to treat MALT1-related inflammatory diseases.

[0517] Therefore, this document also provides a method for treating a subject diagnosed with or identified as having MALT1-related cancer (e.g., any exemplary MALT1-related cancer disclosed herein), the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0518] In some embodiments of any of the methods provided herein, the compound of formula (I) is selected from Examples 1-168.

[0519] Dysregulation of the expression, activity, or level of the MALT1 protease, the MALT1 gene, or any of them (e.g., one or more) can contribute to tumorigenesis. For example, fusion proteins may have increased protease activity compared to wild-type MALT1 protein; wild-type MALT1 protease may be expressed (e.g., at increased levels) in mammalian cells due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancer cells); and MALT1 mRNA splicing variants may also cause MALT1 dysregulation.

[0520] In some respects, this document provides a method for treating cancer in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. This document also provides a method for treating CBM complex pathway-related cancers (such as any cancers disclosed herein) in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method for treating cancer in a subject of need is also provided, the method comprising: (a) identifying the cancer as a CBM complex pathway-related cancer; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0521] Identifying a subject's cancer as CBM complex pathway-related cancer can be performed by any suitable method. In some embodiments, the step of identifying a subject's cancer as CBM complex pathway-related cancer includes performing an assay to detect dysregulation of the expression, activity, or level of a CBM complex pathway-related gene, a CBM complex pathway-related protease protein, or either of these in a sample from the subject. In some embodiments, the method further includes obtaining a sample from the subject (e.g., a biopsy sample). The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence in situ hybridization (FISH).

[0522] Furthermore, this article provides a method for treating cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject identified as having a CBM complex pathway-related cancer.

[0523] This article also provides a method for treating MALT1-related cancer in a subject, the method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject identified or diagnosed with MALT1-related cancer. This article also provides a method for treating cancer in a subject in need, the method comprising: (a) determining that the cancer is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them; and (b) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0524] Determining whether the cancer is associated with an dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them can be performed using any suitable method. In some embodiments, the step of determining that the subject's cancer is a MALT1-related cancer includes performing an assay to detect an dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease protein, or any of them in a sample from the subject. In some embodiments, the method further includes obtaining a sample (e.g., a biopsy sample) from the subject. The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence in situ hybridization (FISH).

[0525] As described herein, CBM complex pathway-related cancers can be any suitable CBM complex pathway-related cancer (as described herein). In some embodiments, CBM complex pathway-related cancers are selected from the group consisting of: CBM complex pathway cell surface receptor-related cancers, cancers associated with signal transducers between cell surface receptors and the CBM complex, components of CBM complex-related cancers, MALT1 protease substrate-related cancers, cancers associated with components of the NF-κB pathway downstream of the CBM complex, cancers associated with components of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, CBM complex pathway cell surface receptor-related cancers are selected from the group consisting of: CD28-related cancers, BCR-related cancers, HER1-related cancers, HER2-related cancers, and combinations thereof. In some embodiments, cancers associated with signal transducers between cell surface receptors and the CBM complex are protein kinase Cβ (PKCβ)-related cancers, protein kinase Cθ (PCKθ)-related cancers, or combinations thereof. In some embodiments, the components of CBM complex-related cancers are selected from the group consisting of: MALT1-related cancers, CARD11-related cancers, CARD14-related cancers, CARD10-related cancers, CARD9-related cancers, BCL10-related cancers, and combinations thereof. For exemplary dysregulations in MALT1, CARD11, and BCL10, see, for example, Tables B1, B2, and B3. In some embodiments, MALT1 protease substrate-related cancers are selected from the group consisting of: BCL10-related cancers, A20-related cancers, CYLD-related cancers, RelB-related cancers, Regnase 1-related cancers, roquin-1-related cancers, HOIL1-related cancers, NIK-related cancers, LIMA1α-related cancers, and combinations thereof. In some embodiments, MALT1 protease substrate-related cancers are selected from the group consisting of: BCL10-related cancers, A20-related cancers, CYLD-related cancers, and combinations thereof. For exemplary dysregulations in BCL10 and A20, see, for example, Tables B3 and B4. In some embodiments, cancers associated with components of the NF-κB pathway downstream of the CBM complex are selected from the group consisting of: TAK1-associated cancers, TRAF6-associated cancers, TAB1-associated cancers, TAB2-associated cancers, TAB3-associated cancers, MKK7-associated cancers, IKKα-associated cancers, IKKβ-associated cancers, IKKγ-associated cancers, IkBα-associated cancers, p50-associated cancers, p65(RelA)-associated cancers, c-Rel-associated cancers, and combinations thereof.In some embodiments, cancers associated with components of the NF-κB pathway downstream of the CBM complex are IKKγ-related cancers. In some embodiments, cancers associated with components of the JNK pathway downstream of the CBM complex are selected from the group consisting of: JNK1-related cancers, JNK2-related cancers, JNK3-related cancers, MYD88 transcription factor-related cancers, AP-1 transcription factor-related cancers, and combinations thereof.

[0526] In some embodiments, CBM complex pathway-associated cancers are MALT1-associated cancers. MALT1-associated cancers may have any suitable dysregulation, such as any of the dysregulations described herein. In some embodiments, MALT1-associated cancers include IAP2-MALT1 fusions. In some embodiments, MALT1-associated cancers include IGH-MALT1 fusions.

[0527] This article also provides methods for treating CBM complex pathway-related diseases or conditions, autoimmune conditions, and inflammatory conditions. Therefore, this article provides a method for treating an autoimmune condition in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. This article also provides a method for treating a subject with MALT1-related autoimmune disease, the method comprising administering to a subject identified or diagnosed with MALT1-related autoimmune disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some cases, this article provides a method for treating an autoimmune disease in a subject of need, the method comprising: (a) determining that the autoimmune disease is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. This article also provides a method for treating a subject with MALT1-related autoimmune disease, the method comprising administering to a subject identified with MALT1-related autoimmune disease an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Furthermore, this document provides a method for treating inflammatory conditions in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some cases, this document provides a method for treating MALT1-related inflammatory conditions in a subject, the method comprising administering to a subject identified or diagnosed with MALT1-related inflammatory conditions an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. This document also provides a method for treating inflammatory conditions in a subject in need, the method comprising: (a) determining that the inflammatory condition is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. This document also provides a method for treating MALT1-related inflammatory conditions in a subject, the method comprising administering to a subject identified as having MALT1-related inflammatory conditions an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0528] This article also provides a method for treating a CBM complex pathway-related disease or condition in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method for treating a disease or condition in a subject of need is also provided, the method comprising: (a) identifying the cancer as a CBM complex pathway-related disease or condition; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Furthermore, this article provides a method for treating a disease or condition in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject identified as having a CBM complex pathway-related disease or condition.

[0529] CBM complex pathway-related diseases or conditions can be any suitable CBM complex pathway-related disease or condition, as described herein. In some embodiments, CBM complex pathway-related diseases or conditions are autoimmune diseases. In some embodiments, CBM complex pathway-related diseases or conditions are inflammatory conditions. In some embodiments, the CBM complex pathway-related cancers are selected from the group consisting of: CBM complex pathway cell surface receptor-related cancers, diseases or conditions related to signal transduction mechanisms between cell surface receptors and the CBM complex, components of CBM complex-related cancers, MALT1 protease substrate-related cancers, diseases or conditions related to components of the NF-κB pathway downstream of the CBM complex, diseases or conditions related to components of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, CBM complex pathway-related diseases or conditions are MALT1-related diseases or conditions.

[0530] In some cases, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to inhibit cellular processes, such as inhibiting cell proliferation. Therefore, this document provides a method for inhibiting mammalian cell proliferation, the method comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. This document also provides a method for inhibiting CBM complex pathway activity in mammalian cells, the method comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. This document further provides a method for inhibiting MALT1 protease activity in mammalian cells, the method comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the contact occurs in vivo. In some embodiments, the contact occurs in vitro. The mammalian cells can be any suitable cells. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are mammalian CBM complex pathway-associated cancer cells. In some embodiments, the mammalian cancer cells are mammalian MALT1-associated cancer cells. In some embodiments, the mammalian cells have dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of these. In some embodiments, dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0531] Compounds of formula (I) or pharmaceutically acceptable salts thereof may also be used in the preparation of medicaments. Therefore, this document provides the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating CBM complex pathway-related diseases or conditions. CBM complex pathway-related diseases or conditions can be any suitable CBM complex pathway-related disease or condition as described herein. In some embodiments, the CBM complex pathway-related disease or condition is selected from the group consisting of: CBM complex pathway cell surface receptor-related cancers, diseases or conditions related to signal transduction mechanisms between cell surface receptors and the CBM complex, components of CBM complex-related cancers, MALT1 protease substrate-related cancers, diseases or conditions related to components of the NF-κB pathway downstream of the CBM complex, diseases or conditions related to components of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, the CBM complex pathway-related disease or condition is a CBM complex pathway-related autoimmune condition. In some embodiments, the CBM complex pathway-related disease or condition is a CBM complex pathway-related inflammatory condition. In some embodiments, the CBM complex pathway-related disease or condition is a CBM complex pathway-related cancer. In some embodiments, CBM complex pathway-related diseases or conditions are MALT1-related diseases or conditions. In some embodiments, MALT1-related diseases or conditions include dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them. In some embodiments, dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0532] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) permeability. Such compounds are capable of crossing the blood-brain barrier and inhibiting the MALT1 protease in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in an effective amount. For example, treatment of a subject with cancer (e.g., MALT1-related cancers, such as MALT1-related brain cancer or CNS cancer) may comprise administration (e.g., oral administration) of the compound to said subject. In some such embodiments, the compounds provided herein can be used to treat primary or metastatic brain tumors. For example, the compound can be used to treat one or more gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglioma, ependymoma and mixed glioma, meningioma, medulloblastoma, intracranial ganglion glioma, schwannomas / neurilemmomas and craniopharyngioma (see, for example, the tumors listed in the following literature: Louis, DN et al., Acta Neuropathol 131(6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the subject has been previously treated with another anticancer agent, for example, another protease inhibitor (e.g., a compound not of formula (I)). In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the subject has been previously treated with another anticancer agent, for example, another protease inhibitor (e.g., a compound not of formula (I)).

[0533] In some embodiments of any of the methods or uses described herein, an assay for determining whether a subject has an dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them, using a sample from a subject, may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, FISH separation analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment. The assay may utilize other detection methods known in the art to detect dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them. In some embodiments, the sample is a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having MALT1-related cancer, a subject with one or more symptoms of MALT1-related cancer, and / or a subject at increased risk of developing MALT1-related cancer.

[0534] In some embodiments, liquid biopsy (differently referred to as liquid biopsy or liquid phase biopsy) can be used to identify dysregulations in the expression, activity, or level of a gene (e.g., the MALT1 gene), a MALT1 protein (e.g., MALT1 protein), or any of them. Liquid biopsy methods can be used to detect dysregulations in the total tumor burden and / or the expression, activity, or level of a gene (e.g., the MALT1 protein), a MALT1 protein (e.g., MALT1 protein), or any of them. Liquid biopsy can be performed on biological samples that are relatively readily available from the subject (e.g., by a simple blood draw) and is less invasive than conventional methods used to detect dysregulations in the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., MALT1 protein), or any of them. In some embodiments, liquid biopsy can be used at an earlier stage to detect the presence of dysregulations in the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., MALT1 protein), or any of them, compared to conventional methods. In some embodiments, biological samples used for liquid biopsy may comprise blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cyst fluid, feces, ascites, and combinations thereof. In some embodiments, liquid biopsy may be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy may be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA), which is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) may be used to identify dysregulations in the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of these.

[0535] In some embodiments, liquid biopsy can be used to detect ctDNA derived from a single gene. In some embodiments, liquid biopsy can be used to detect ctDNA derived from multiple genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more genes, or any number of genes between these numbers). In some embodiments, any of a variety of commercially available test panels (e.g., commercially available test panels designed to detect dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of these) can be used to detect ctDNA derived from multiple genes. Liquid biopsy can be used to detect dysregulations in the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them, including but not limited to point mutations or single nucleotide variants (SNVs), copy number variants (CNVs), gene fusions (e.g., translocations or rearrangements), insertions, deletions, or any combination thereof. In some embodiments, liquid biopsy can be used to detect germline mutations. In some embodiments, liquid biopsy can be used to detect somatic mutations. In some embodiments, liquid biopsy can be used to detect primary gene mutations (e.g., primary mutations or primary fusions associated with the initial development of a disease (e.g., cancer). In some embodiments, dysregulations in the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them identified using liquid biopsy are also present in cancer cells (e.g., in a tumor) in the subject. In some embodiments, liquid biopsy can be used to detect dysregulations in the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them described herein. In some embodiments, gene mutations identified by liquid biopsy can be used to identify a subject as a candidate for a specific treatment. For example, the detection of dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or either of these in a subject can indicate that the subject will respond to treatment comprising an administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0536] Liquid biopsies can be performed multiple times during the diagnostic, monitoring, and / or treatment process to determine one or more clinically relevant parameters, including but not limited to disease progression and / or treatment efficacy. For example, a first liquid biopsy can be performed at a first time point during the diagnostic, monitoring, and / or treatment process, and a second liquid biopsy can be performed at a second time point. In some embodiments, the first time point can be a time point before a subject is diagnosed with the disease (e.g., when the subject is healthy), and the second time point can be a time point after the subject has the disease (e.g., the second time point can be used to diagnose a subject with the disease). In some embodiments, the first time point can be a time point before a subject is diagnosed with the disease (e.g., when the subject is healthy), followed by monitoring of the subject, and the second time point can be a time point after monitoring the subject. In some embodiments, the first time point can be a time point after a subject is diagnosed with the disease, followed by treatment of the subject, and the second time point can be a time point after treatment is administered; in this case, the second time point can be used to assess the efficacy of the treatment (e.g., whether one or more gene mutations detected at the first time point are significantly reduced or undetectable). In some embodiments, the treatment to be administered to a subject may comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0537] In some embodiments, the efficacy of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by assessing the frequency of dysregulated alleles of a gene (e.g., the MALT1 gene) in cfDNA obtained from a subject at different time points (e.g., cfDNA obtained from a subject at a first time point and cfDNA obtained from a subject at a second time point), wherein at least one dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject between the first and second time points. Some embodiments of these methods may further include administering at least one dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject between the first and second time points. For example, the frequency of dysregulated alleles (e.g., the MALT1 gene) in cfDNA obtained from the subject at the second time point is reduced (e.g., reduced by 1% to about 99%, reduced by 1% to about 95%, reduced by 1% to about 90%, reduced by 1% to about 85%, reduced by 1% to about 80%, reduced by 1% to about 75%, reduced by 1% to about 1% 70%, reduced by 1% to approximately 65%, reduced by 1% to approximately 60%, reduced by 1% to approximately 55%, reduced by 1% to approximately 50%, reduced by 1% to approximately 45%, reduced by 1% to approximately 40%, reduced by 1% to approximately 35%, reduced by 1% to approximately 30%, reduced by 1% to approximately 25%, reduced by 1% to approximately 20%, reduced by 1% to approximately 15%, reduced by 1% to approximately 10%, reduced by 1% to approximately 5%, reduced by approximately 5% to approximately 99%, reduced by approximately 10% to about 99%, reduced by about 15% to about 99%, reduced by about 20% to about 99%, reduced by about 25% to about 99%, reduced by about 30% to about 99%, reduced by about 35% to about 99%, reduced by about 40% to about 99%, reduced by about 45% to about 99%, reduced by about 50% to about 99%, reduced by about 55% to about 99%, reduced by about 60% to about 99%, reduced by about 65% to about 99%, reduced by about 70% to about 99%, reduced by about 75% to about 95%, reduced by about 80% to about 99%, reduced by about 90% to about 99%, reduced by about 95% to about 99%, reduced by about 5% to about 10%, reduced by about 5% to about 25%, reduced by about 10% to about 30%, reduced by about 20% to about 40%, reduced by about 25% to about 50%, reduced by about 35% to about 55%, reduced by about 40% to about 60%, reduced by about 50% to about 75%, reduced by about 60% to about 80%, or reduced by about 65% to about 85%), indicating that the compound of formula (I) or a pharmaceutically acceptable salt thereof is effective for the subject. In some embodiments, AF is reduced such that the level is below the detection limit of the instrument.Alternatively, an increase in the allele frequency (AF) of gene (e.g., MALT1 gene) dysregulation in cfDNA obtained from the subject at a second time point compared to the AF of gene (e.g., MALT1 gene) dysregulation in cfDNA obtained from the subject at a first time point indicates that the compound of formula (I) or a pharmaceutically acceptable salt thereof is ineffective for the subject. Some embodiments of these methods may further include administering an additional dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in which the compound of formula (I) or a pharmaceutically acceptable salt thereof has been determined to be effective. Some embodiments of these methods may further include administering a different treatment to a subject in which the compound of formula (I) or a pharmaceutically acceptable salt thereof has been determined to be ineffective (e.g., treatment not including the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof as a single therapy).

[0538] In some instances of these methods, the time difference between the first and second time points can be approximately 1 day to approximately 1 year, approximately 1 day to approximately 11 months, approximately 1 day to approximately 10 months, approximately 1 day to approximately 9 months, approximately 1 day to approximately 8 months, approximately 1 day to approximately 7 months, approximately 1 day to approximately 6 months, approximately 1 day to approximately 5 months, approximately 1 day to approximately 4 months, approximately 1 day to approximately 3 months, approximately 1 day to approximately 10 weeks, approximately 1 day to approximately 2 months, approximately 1 day to approximately 6 weeks, approximately 1 day to approximately 1 month, approximately 1 day to approximately 25 days, approximately 1 day to approximately 20 days, approximately 1 day to approximately 15 days, approximately 1 day to approximately 10 days, approximately 1 day to approximately 5 days, approximately 2 days to approximately 1 year, approximately 5 days to approximately 1 year, approximately 10 days to approximately 1 year, approximately 15 days to approximately 1 year, approximately 20 days to approximately 1 year, approximately 25... The timeframes for these methods are approximately 1 day to 1 year, 1 month to 1 year, 6 weeks to 1 year, 2 months to 1 year, 3 months to 1 year, 4 months to 1 year, 5 months to 1 year, 6 months to 1 year, 7 months to 1 year, 8 months to 1 year, 9 months to 1 year, 10 months to 1 year, 11 months to 1 year, 1 day to 7 days, 1 day to 14 days, 5 days to 10 days, 5 days to 20 days, 10 days to 20 days, 15 days to 1 month, 15 days to 2 months, 1 week to 1 month, 2 weeks to 1 month, 1 month to 3 months, 3 months to 6 months, 4 months to 6 months, 5 months to 8 months, or 7 months to 9 months. In some embodiments of these methods, the subject may be pre-identified as having cancer with a disordered gene (e.g., any instance of a disordered gene described herein) (e.g., the MALT1 gene). In some embodiments of these methods, the subject may be pre-diagnosed with any type of cancer described herein. In some embodiments of these methods, the subject may have one or more metastases (e.g., one or more brain metastases).

[0539] In some embodiments described above, cfDNA includes ctDNA, such as MALT1-associated ctDNA. For example, cfDNA is ctDNA, such as MALT1-associated ctDNA. In some embodiments, at least a portion of the cfDNA is determined to be MALT1-associated ctDNA, for example, by determining that a sequenced and / or quantified amount of total cfDNA has MALT1 fusion and / or MALT1 overexpression.

[0540] In the field of medical oncology, common practice is to treat each subject with cancer using a combination of different forms of therapy. In medical oncology, in addition to the compositions described herein, one or more other components of such combination therapies or treatments may be, for example, surgical procedures, radiation therapy, and chemotherapy agents, such as other protease inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies.

[0541] For example, the surgery can be open or minimally invasive. Therefore, the compound of formula (I) or a pharmaceutically acceptable salt thereof can also be used as an adjuvant in cancer treatment, i.e., it can be used in combination with one or more other therapies or therapeutic agents (e.g., chemotherapeutic agents acting through the same or different mechanisms of action). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered prior to the administration of other therapeutic agents or other therapies. For example, one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a subject in need over a period of time, and then the tumor may be at least partially removed. In some embodiments, treatment with one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof prior to at least partial removal of the tumor may reduce the size of the tumor (e.g., tumor burden). In some embodiments, one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a subject in need over a period of time and in one or more rounds of radiotherapy. In some embodiments, treatment with one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof prior to one or more rounds of radiotherapy may reduce the size of the tumor (e.g., tumor burden).

[0542] In some embodiments, the subject has refractory cancer or cancer that is intolerant to standard therapies (e.g., chemotherapy), such as a first MALT1 inhibitor, a kinase inhibitor, immunotherapy, cell or gene therapy, or radiation therapy (e.g., radioactive iodine). In some embodiments, the subject has refractory cancer or cancer that is intolerant to prior therapies (e.g., chemotherapy, such as a first MALT1 inhibitor or another protease inhibitor, immunotherapy, cell or gene therapy, or radiation therapy (e.g., radioactive iodine). In some embodiments, the subject has cancer for which there is no standard therapy (e.g., locally advanced or metastatic tumor). In some embodiments, the subject has not used a MALT1 protease inhibitor. For example, the subject has not been treated with a selective MALT1 protease inhibitor. In some embodiments, the subject has used a MALT1 protease inhibitor.

[0543] In some embodiments of any of the methods described herein, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one additional therapeutic agent selected from one or more other therapies or therapeutic agents (e.g., chemotherapy or immunomodulatory agents). The additional therapy or therapeutic agent can be any suitable additional therapy or therapeutic agent, as described herein.

[0544] Other non-limiting examples of therapeutic agents include: other MALT1-targeting therapies (i.e., first or second MALT1 protease inhibitors, such as JNJ-67856633 or CTX-177), other protease inhibitors, kinase inhibitors (e.g., receptor tyrosine kinase-targeting therapies, such as BTK or EGFR inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways (e.g., venetoclax or obataclax); cytotoxic chemotherapy agents, angiogenesis-targeting therapies, immunotherapies (including antibodies and cell-based immunotherapies, as well as antibody-drug conjugates), and radiotherapy.

[0545] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, along with other therapeutic agents, are administered simultaneously in separate doses. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, along with other therapeutic agents, are administered sequentially in separate doses in any order.

[0546] In some embodiments, other MALT1-targeting therapeutic agents are other protease inhibitors exhibiting MALT1 inhibitory activity. In some embodiments, other MALT1-targeting therapeutic inhibitors are selective for the MALT1 protease. Exemplary MALT1 protease inhibitors may exhibit inhibitory activity (IC50) against the MALT1 protease of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM. 50 As measured in the assays described herein. In some embodiments, the MALT1 protease inhibitor may exhibit inhibitory activity (IC50) against the MALT1 protease of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM. 50 ), as measured in the determinations provided herein.

[0547] Non-limiting examples of protease-targeting therapeutic agents (e.g., a first or second MALT1 inhibitor) include JNJ-67856633 and CTX-177.

[0548] Non-limiting examples of multi-kinase inhibitors include: alectinib (9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carboxynitrile); amuvatinib (MP470, HPK56) (N-(1,3-benzo[2-dioxane-5-ylmethyl]-4-([1]benzifuran[3,2-d]pyrimidin-4-yl)piperazine-1-carbosulfan); apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl)phenyl-2-(4-picoyl)amino-3-methanesulfonyl) Nicotinamide); Cabozantinib (Cometriq XL-184) (N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); Dovitinib (TKI258; GFKI-258; CHIR-258) ((3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-yl]quinoline-2-one); Famitinib (5-[2-(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indyl]) [N-(2-methyl-2-propionyl)-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one]; ferdalatinib (SAR302503, TG101348) (N-(2-methyl-2-propionyl)-3-{[5-methyl-2-({4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4-pyrimidinyl]amino}benzenesulfonamide); foretinib (XL880, EXEL-2880, GSK1363089, GSK089) (N1'-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolinyl]oxy]phenyl]-N 1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); fostamantinib (R788) (2H-pyrido[3,2-b]-1,4-oxazine-3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphoryloxy)methyl]-, sodium salt (1:2)); ilorasertib (ABT-348) (1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea);Lenvatinib (E7080, Lenvima) (4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline carboxamide); motesanib (AMG) 706)(N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide); (nintedanib)(3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolone); ponatinib)(AP24534)(3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[ (4-Methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide); PP242 (torkinib) (2-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indol-5-ol); quizartinib (1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazo-2-yl)phenyl)urea); regorafenib (BAY) 73-4506, Stivarga (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate); RXDX-105 (CEP-32496, Agerafenib) (1-(3-((6,7-dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazol-3-yl)urea); Semaxanib (SU5416)((3Z)-3-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-1,3-dihydro-2H-indol-2-one); Sitravatinib (MGCD516, MG516) (N-(3-fluoro-4-{[2-(5-{[(2-methoxyethyl)amino]methyl}-2-pyridyl)thieno[3,2-b]pyridin-7-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide); Sorafenib (BAY 43-9006) (4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide);Vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine); Vatalanib (PTK787, PTK / ZK, ZK222584) (N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazine-1-amine); AD-57 (N-[4-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-N′-[3-(trifluoromethyl)phenyl]-urea); AD-80 (1-[4-(4-amino-1-propyl-2-ylpyrazolo[3,4-d]pyrimidin-3-yl]pyrimidin-3-yl) [Phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea); AD-81(1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea); ALW-II-41-27(N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide); BPR1K871(1-(3-chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)propoxy)quinazolin-4-yl)amino)ethyl)thiazolyl)urea); CLM 3(1-Phenylacetyl-N-(1-Phenylacetyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); EBI-907(N-(2-chloro-3-(1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]isoquinoline-7-yl)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide); NVP-AST-487(N-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-N'-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]-urea); NVP-BBT594(BBT594)(5-((6-acetamidopyrimidin-4-yl)oxy)-N-(4-((4-methylpiperazin-1)-) -yl)methyl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide); PD173955(6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylthioalkylaniline)pyrido[2,3-d]pyrimidin-7-one); PP2(4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidin); PZ-1(N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1Hbenzi[d]imidazol-1-yl)phenyl)acetamide); RPI-1(1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indoline-2-one);(3E)-3-[(4-hydroxyphenyl)methylene]-5,6-dimethoxy-1H-indole-2-one); SGI-7079(3-[2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenylacetonitrile); SPP86(1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); SU4984(4-[4-[(E)-(2-oxo-1H-indole-3-]... (-methylene)[(Z)-(5-fluoro-2-oxo-1H-indole-3-methylene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide); TG101209 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide); Withaferin A A)((4β,5β,6β,22R)-4,27-dihydroxy-5,6:22,26-diepoxyergoster-2,24-diene-1,26-dione); XL-999((Z)-5-((1-ethylpiperidin-4-yl)amino)-3-((3-fluorophenyl)(5-methyl-1H-imidazol-2-yl)methylene)indololin-2-one); BPR1J373(5-phenyl Thiazol-2-ylamine-pyrimidine derivatives); CG-806 (CG'806); DCC-2157; GTX-186; HG-6-63-01 ((E)-3-(2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide); SW- 01 (Cyclobenzaline hydrochloride); XMD15-44 (N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide (derived from the structure)); ITRI-305 (D0N5TB, DIB003599); BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro -1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide); BLU6864; DS-5010; GSK3179106; GSK3352589; NMS-E668; TAS0286 / HM05; TPX0046;And N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide.

[0549] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeted therapies include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, and letatinib. estaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, l-((3S,4R)-4-(3-fluorophenyl)-l-(2-methoxyethyl)pyrrolidine-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazole-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, 6976, GNF-5837, GTx-186, GW 441756, LOXO-101, MGCD516, PLX7486, RXDX101, VM-902A, TPX-0005, TSR-011, GNF-4256, N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrolo-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]-urea, AZ623, AZ64, ( S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine, AZD7451, CEP-751, CT327, sunitinib, GNF-8625, and (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-[2,4′-dipyridin]-2′-yl)piperidin-4-ol.

[0550] In some embodiments, an additional therapeutic agent is a BRAF inhibitor. Non-limiting examples of BRAF inhibitors include: dabrafenib, vemurafenib (also known as RG7204 or PLX4032), sorafenib tosylate, PLX-4720, GDC-0879, BMS-908662 (Bristol-Meyers Squibb), LGX818 (Novartis), PLX3603 (Hofmann-LaRoche), RAF265 (Novartis), RO5185426 (Hofmann-LaRoche), and GSK2118436 (GlaxoSmithKline). Further examples of BRAF inhibitors are known in the art.

[0551] In some embodiments, an additional therapeutic agent is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors may include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0552] In some embodiments, additional therapeutic agents are Ras-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., everolimus, rapamycin, perifosine, and temsirolimus), and other kinase inhibitors such as baricitinib. Citinib, Brigatinib, Capmatinib, Danusertib, Ibrutinib, Milciclib, Quercetin, Regorafenib, Ruxolitinib, Smasani, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736((R)-amino-NN-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepine-8-yl]-cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106, RXDX108 and TG101209(N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide).

[0553] In some embodiments, the additional therapeutic agent is a BTK inhibitor. Non-limiting examples of BTK inhibitors include ibrutinib, acalabrutinib, and zanubrutinib.

[0554] In some embodiments, the additional therapeutic agent is a Bcl-2 inhibitor. Non-limiting examples of Bcl-2 inhibitors include venetoclax, navitoclax, oblimersen, octopok, and AT-101.

[0555] In some embodiments, the additional therapeutic agent is a PI3K inhibitor. Non-limiting examples of PI3K inhibitors include idelalisib, copanlisib, duvelisib, alpelisib, taselisib, buparlisib, umbralisib, and copanlisib.

[0556] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include everolimus, tesimolimus, and ridaforolimus.

[0557] In some embodiments, the additional therapeutic agent is an HDAC inhibitor. Non-limiting examples of HDAC inhibitors include vorinostat, romidepsin, belinostat, chidamide, panobinostat, CXD101, and abexinostat.

[0558] In some embodiments, an additional therapeutic agent is a checkpoint inhibitor. Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.

[0559] In some embodiments, an additional therapeutic agent is cytotoxic chemotherapy. In some embodiments, cytotoxic chemotherapy includes arsenic trioxide, bleomycin, bendamustine, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, and mitomycin C. C), oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

[0560] In some embodiments, the additional therapeutic agent is an angiogenesis-targeting therapeutic agent. Non-limiting examples of angiogenesis-targeting therapies include lenalidomide, enzastaurine, aflibercept, and bevacizumab.

[0561] In some embodiments, additional therapies or therapeutic agents may comprise a histidine-tRNA synthetase (HRS) polypeptide or an expressible nucleotide encoding an HRS polypeptide.

[0562] The term "immunotherapy" refers to agents that modulate the immune system. In some embodiments, immunotherapy may increase the expression and / or activity of immune system modulators. In some embodiments, immunotherapy may decrease the expression and / or activity of immune system modulators. In some embodiments, immunotherapy may recruit and / or enhance the activity of immune cells.

[0563] In some embodiments, the immunotherapy is a cellular immunotherapy (e.g., adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge). TM; Plosker (2011) Drugs 71(1):101-108). In some embodiments, cell immunotherapy comprises cells expressing chimeric antigen receptor (CAR). In some embodiments, cell immunotherapy is CAR-T cell therapy. In some embodiments, CAR-T cell therapy is tisagenlecleucel (Kymria). In some embodiments, CAR-T cell therapy is axicabtagene ciloleucel (Yescarta). In some embodiments, CAR-T cell therapy is brexucabtagene autoleucel (Tecartus). In some embodiments, CAR-T cell therapy is relmacabtagene autoleucel. In some embodiments, CAR-T cell therapy is ALLO-501.

[0564] In some embodiments, immunotherapy is antibody therapy (e.g., monoclonal antibodies, conjugated antibodies, or bispecific antibodies). In some embodiments, antibody therapy is bevacizumab (Mvasti). TM , trastuzumab Avelumab Rituximab (MabThera) TM , Rituxan Hycela contains human hyaluronidase. TM ), edrecolomab (Panorex), daratumuab olaratumab (Lartruvo) TM ofatumumab alemtuzumab cetuximab Oregomab and Pembrolizumab dinutiximab Atolizumab (obinutuzumab) Trimelimumab (CP-675, 206), Ramucirumab Ulituximab (TG-1101), Panitumumab Elotuzumab (Empliciti) TM Avelumab nexusutuzumab (Portrazza) TM Cituzumab (UC-961) and ibrutumomab Ixatuximab (SAR650984), Nimotuzumab, Fresolimumab (GC1008), Lirilumab (INN), Mogamulizumab Ficlatuzumab (AV-299) and denosumab Lenzilumab, acitumab, spartalizumab, pembrolizumab, utomilumab, blinatumomab, ganitumab, urelumab, pildizumab, amatuximab, mosunetuzumab (BTCT4465A), CD20-TCB, RO7082859, XmAb13676, glofitamab, CD20-TDB, odronextamab (REGN1979), IGM-2323, BTCT4465A, AMG-562, or TTI-621.

[0565] In some embodiments, immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg). TM ), inotuzumab ozogamicin vedotin (brentuximab vedotin) Ado-trastuzumab emtansine (TDM-1); ), mirvetuximab soravtansine (IMGN853), anetumabravtansine, polotuzumab vedotine, loncastuximab tesirine (ADCT-402), camidanlumab tesirine (ADCT-301), or naratuximab emtansine (Debio 1562).

[0566] In some embodiments, the immunotherapy includes bonatetumab (AMG103); Or midostaurin (Rydapt).

[0567] In some embodiments, the immunotherapy comprises a toxin. In some embodiments, the immunotherapy is denileukin diftitox.

[0568] In some embodiments, immunotherapy is cytokine therapy. In some embodiments, cytokine therapy is interleukin-2 (IL-2) therapy, interferon-alpha (IFNα) therapy, granulocyte colony-stimulating factor (G-CSF) therapy, interleukin-12 (IL-12) therapy, interleukin-15 (IL-15) therapy, interleukin-7 (IL-7) therapy, or erythropoietin-alpha (EPO) therapy. In some embodiments, IL-2 therapy is aldesleukin. In some embodiments, IFNα therapy is In some embodiments, G-CSF therapy is filgrastim.

[0569] In some embodiments, immunotherapy is an immune checkpoint inhibitor. In some embodiments, immunotherapy comprises one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab. Or trimemumab (CP-675, 206). In some embodiments, the PD-1 inhibitor is pembrolizumab. or nivolumab In some embodiments, the PD-L1 inhibitor is atozolizumab. Acimenone Or durvalumab (Imfinzi) TM ).

[0570] In some embodiments, the immunotherapy is an mRNA-based immunotherapy. In some embodiments, the mRNA-based immunotherapy is CV9104 (see, for example, Rausch et al. (2014) Human Vaccines and Immunotherapy 10(11):3146-52; and Kubler et al. (2015) Journal of Immunotherapy for Cancer 3:26).

[0571] In some embodiments, immunotherapy is Bacillus Calmette-Guerin (BCG) therapy.

[0572] In some embodiments, immunotherapy is oncolytic virus therapy. In some embodiments, oncolytic virus therapy is talimogene alherparepvec (T-VEC); ).

[0573] In some embodiments, immunotherapy is a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is... or In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is... Recombivax or GI-13020 In some embodiments, cancer vaccines are or In some embodiments, cancer vaccines are GVAX, ADXS11-001, ALVAC-CEA, CimaVax-EGF, lapuleucel-T (APC8024; Neuvenge TM ), GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlisimut-L(Hepko-V5), SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, DPX-Survivac or viagenpumatucel-L(HS-110).

[0574] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is nelipepimut-S(E75)(NeuVax TM ), IMA901 or SurVaxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic personal neoantigen vaccine (see, for example, Ott et al. (2017) Nature 547:217-221; Sahin et al. (2017) Nature 547:222-226). In some embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA-based vaccine is a lactoglobulin-A DNA vaccine (see, for example, Kim et al. (2016) OncoImmunology 5(2):e1069940).

[0575] In some embodiments, the immune targeting agent is selected from interleukin, interferon α-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

[0576] In some embodiments, an additional therapy is radiation therapy. Non-limiting examples of radiation therapy include radioactive iodine therapy, external beam radiation, and radium-223 therapy.

[0577] In some embodiments, additional therapeutic agents are GSK-3368715, PF-06821497, ceralasertib; AZD6738, BI-894999, MAK-683, AZD-6738, taminadenant, TAK-981, MIK-665, or danvatirsen.

[0578] Other kinase inhibitors include those described in the following patents: for example, U.S. Patent Nos. 7,514,446; 7,863,289; 8,026,247; 8,501,756; 8,552,002; 8,815,901; 8,912,204; 9,260,437; 9,273,051; U.S. Publication No. US2015 / 0018336; International Publication Nos. WO2007 / 002325; WO2007 / 002433; WO2008 / 080001; WO2008 / 079906; WO2008 / 079903; WO2008 / 079909; WO... No. 2008 / 080015; No. WO 2009 / 007748; No. WO2009 / 012283; No. WO 2009 / 143018; No. WO 2009 / 143024; No. WO 2009 / 014637; No. 2009 / 152083; No. WO No. 2010 / 111527; No. WO 2012 / 109075; No. WO 2014 / 194127; No. WO2015 / 112806; No. WO 2007 / 110344; No. WO 2009 / 071480; No. WO No. 2009 / 118411; No. WO2010 / 031816; No. WO No. 2010 / 145998; No. WO 2011 / 092120; No. WO 2012 / 101032; No. WO2012 / 139930; No. WO 2012 / 143248; No. WO 2012 / 152763; No. WO No. 2013 / 014039; No. WO2013 / 102059; No. WO 2013 / 050448; No. WO 2013 / 050446; No. WO 2014 / 019908; No. WO2014 / 072220; No. WO 2014 / 184069; No. WO No. 2016 / 075224; No. WO No. 2016 / 081450; No. WO2016 / 022569; No. WO 2016 / 011141; No. WO 2016 / 011144; No. WO 2016 / 011147; No. WO2015 / 191667; No. WO 2012 / 101029; No. WO 2012 / 113774; No. WO 2015 / 191666; No. WO2015 / 161277; No. WO 2015 / 161274; No. WO 2015 / 108992; No. WO 2015 / 061572; No. WO2015 / 058129; No. WO 2015 / 057873;WO 2015 / 017528; WO / 2015 / 017533; WO2014 / 160521; and WO 2014 / 011900, each of which is hereby incorporated herein by reference in its entirety.

[0579] In some embodiments, the subject has previously received one or more standard-of-care therapies for lymphoma. In some embodiments, the previously administered standard-of-care therapies are vetin-polotuluzumab, selinexor, yescarta, tesalonide, a combination of bendamustine with rituximab and vetin-polotuluzumab, a combination of tafasitamab with lenalidomide, or a combination of rituximab with human hyaluronidase.

[0580] In some embodiments, the subject also received standard care therapy for lymphoma. In some embodiments, standard care therapy is vetin-polotuluzumab, celiniso, akirenzab (Yescarta), tesalenzab (Kymria), a combination of bendamustine with rituximab and vetin-polotuluzumab, a combination of tanxitoumab with lenalidomide, or a combination of rituximab with human hyaluronidase (Rituxan Hycela).

[0581] Although the genetic basis of tumorigenesis may differ between different types of cancer, the cellular and molecular mechanisms required for metastasis appear to be similar for all types of solid tumors. In the metastatic cascade, cancer cells lose their growth-inhibiting responses, undergo adhesive alterations, and produce enzymes that can degrade components of the extracellular matrix. This leads to the separation of tumor cells from the original tumor, their infiltration into the circulatory system via newly formed vascular systems, and their migration and extravasation at favorable distal sites where colonies may form.

[0582] Therefore, this document also provides a method for inhibiting, preventing, aiding in the prevention of, or alleviating metastatic symptoms of cancer in a subject of need, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Such methods can be used to treat one or more cancers described herein. See, for example, U.S. Publication No. 2013 / 0029925; International Publication No. WO 2014 / 083567; and U.S. Patent No. 8,568,998. See also, for example, Hezam K et al., *Rev Neurosci*, Jan 26, 2018; 29:93-98; Gao L et al., *Pancreas*, Jan 2015; 44:134-143; Ding K et al., *Journal of Biochemistry*, June 6, 2014; 289:16057-71; and Amit M et al., *Oncogenes*, June 8, 2017; 36:3232-3239. In some embodiments, the cancer is MALT1-related cancer. In some embodiments, as described herein, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with another therapy or another therapeutic agent. For example, a first or second MALT1 protease inhibitor.

[0583] The term “metastasis” is a term known in the art and refers to the formation of an additional tumor (e.g., a solid tumor) in a subject at a site distant from the primary tumor, wherein the additional tumor contains cancer cells that are the same as or similar to the primary tumor.

[0584] A method for reducing the risk of metastasis or further metastasis in a subject with MALT1-related cancer is also provided, the method comprising: selecting, identifying, or diagnosing a subject with MALT1-related cancer, and administering to the selected, identified, or diagnosed subject with MALT1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method for reducing the risk of metastasis or further metastasis in a subject with MALT1-related cancer is also provided, the method comprising administering to the subject with MALT1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in the risk of metastasis or further metastasis in a subject with MALT1-related cancer can be compared to the risk of metastasis or further metastasis in a subject before treatment, or to a subject or group of subjects with similar or identical MALT1-related cancer who have not received any treatment or have received different treatments.

[0585] The phrase "risk of metastasis" refers to the risk that a subject with a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from the primary tumor within a specified time period, wherein the additional tumor contains cancer cells that are the same as or similar to the primary tumor. This article describes methods for reducing the risk of metastasis in subjects with cancer.

[0586] The phrase "risk of additional metastasis" refers to the risk that a subject with a primary tumor and one or more additional tumors at sites distant from the primary tumor (wherein the additional tumors contain cancer cells identical or similar to the primary tumor) will develop one or more additional tumors distant from the primary tumor, wherein the additional tumors contain cancer cells identical or similar to the primary tumor. This article describes methods for reducing the risk of additional metastasis.

[0587] Some embodiments described herein provide methods for treating autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and SLE (e.g., MALT1-associated autoimmune diseases), the methods comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0588] Some embodiments described herein provide methods for treating inflammatory conditions such as chronic graft-versus-host disease (e.g., MALT1-associated autoimmune diseases), the methods comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0589] A method for inhibiting the activity of the MALT1 protease in mammalian cells is also provided, the method comprising contacting the mammalian cells with a compound of formula (I). In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having mammalian cells with MALT1 protease activity. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer described herein. In some embodiments, the mammalian cancer cells are MALT1-associated mammalian cancer cells.

[0590] A method for inhibiting the activity of the MALT1 protease in mammalian cells is also provided, the method comprising contacting the mammalian cells with a compound of formula (I). In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal having mammalian cells with MALT1 protease activity. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer described herein. In some embodiments, the mammalian cancer cells are MALT1-associated mammalian cancer cells. In some embodiments, the mammalian cells are gastrointestinal mammalian cells.

[0591] As used herein, the term “contact” means bringing together the indicated portions of an in vitro or in vivo system. For example, “contacting” the MALT1 protease with a compound provided herein includes administering the compound provided herein to a subject (e.g., a human) having the MALT1 protease, and, for example, introducing the compound provided herein into a sample containing mammalian cells or a purified formulation containing the MALT1 protease.

[0592] This article also provides a method for inhibiting mammalian cell proliferation in vitro or in vivo, the method comprising contacting mammalian cells with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0593] As defined herein, “MALT1 protease inhibitor” includes any compound exhibiting MALT1 inhibitory activity. In some embodiments, the MALT1 protease inhibitor is selective for the MALT1 protease. Exemplary MALT1 protease inhibitors may exhibit inhibitory activity (IC50) against the MALT1 protease at less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM. 50 As measured in the assays described herein. In some embodiments, the MALT1 protease inhibitor may exhibit inhibitory activity (IC50) against the MALT1 protease of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM. 50 ), as measured in the determinations provided in this article.

[0594] As used herein, a “first MALT1 protease inhibitor” or “first MALT1 inhibitor” is a MALT1 protease inhibitor as defined herein, but does not contain a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof. As used herein, a “second MALT1 protease inhibitor” or “second MALT1 inhibitor” is a MALT1 protease inhibitor as defined herein, but does not contain a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof. When both first and second MALT1 inhibitors are present in the methods provided herein, the first and second MALT1 protease inhibitors are distinct.

[0595] This document describes exemplary first and second MALT1 protease inhibitors. In some embodiments, the first or second MALT1 protease inhibitor may be, for example, JNJ-67856633 or CTX-177.

[0596] The phrase “effective amount” means an amount of compound which, when administered to a subject requiring such treatment, is sufficient to (i) treat a MALT1-related disease or condition (such as MALT1-related cancer); (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or symptom; or (iii) delay the onset of one or more symptoms of a particular disease, condition, or symptom described herein. The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof corresponding to the stated amount will vary depending on factors such as the specific compound, the disease condition and its severity, and the identity of the subject requiring treatment (e.g., weight), but can still be routinely determined by those skilled in the art.

[0597] Pharmaceutical Composition

[0598] When used as a medicine, compounds of formula (I) (containing their pharmaceutically acceptable salts) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical industry and can be administered via a variety of routes, depending on whether local or systemic treatment is desired and depending on the site of treatment. Administration can be local (including transdermal, epidermal, ophthalmic, and mucosal administration, including intranasal, vaginal, and rectal delivery), pulmonary administration (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal or intranasal administration), oral, or parenteral administration. Oral administration can comprise dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for topical application may include transdermal patches, ointments, emulsions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous, powdered, or oily bases, thickeners, etc., may be necessary or desirable.

[0599] This document also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients. For example, pharmaceutical compositions prepared using a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions are suitable for oral administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated within a carrier, such as a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material that can act as a medium, carrier, or medium for the active ingredient. Therefore, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as tablets or capsules.

[0600] This document further provides pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by thoroughly mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical mixing techniques. Depending on the desired route of administration (e.g., oral, parenteral), the carrier may take various forms. In some embodiments, the composition is a solid oral composition.

[0601] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0602] Methods for preparing pharmaceutical compositions have been described in numerous publications, such as *Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded*, Volumes 1–3, edited by Lieberman et al.; *Pharmaceutical Dosage Forms: Parenteral Medications*, Volumes 1–2, edited by Avis et al.; and *Pharmaceutical Dosage Forms: Disperse Systems*, Volumes 1–2, edited by Lieberman et al., published by Marcel Dekker, Inc.

[0603] When preparing compositions for oral dosage forms, any conventional pharmaceutical medium can be used. Therefore, suitable carriers and additives for liquid oral formulations (such as suspensions, elixirs, and solutions) include water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.; for solid oral formulations (such as powders, capsules, and tablets), suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrants, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium oleate), sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Solid oral formulations can also be coated or enteric-coated with substances such as sugars to modulate the main absorption sites. For parenteral administration, the carrier will typically consist of sterile water, and other components may be added to increase solubility or preservation. Injectable suspensions or solutions can also be prepared using aqueous carriers and appropriate additives. The pharmaceutical compositions described herein will contain, in each dosage unit (e.g., tablet, capsule, powder, injection, teaspoon, etc.), a certain amount of the active ingredient necessary to deliver the effective dose described herein.

[0604] Compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated into unit dosage forms, each dose containing about 5 to about 1,000 mg (1 g) of the active ingredient, more typically about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other subjects, each unit containing a predetermined amount of the active substance (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof), the predetermined amount of which, when combined with suitable pharmaceutical excipients, is calculated to produce the desired therapeutic effect.

[0605] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of an active ingredient. Those skilled in the art will understand that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of an active ingredient.

[0606] In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of the active ingredient. Those skilled in the art will understand that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient.

[0607] In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of the active ingredient. Those skilled in the art will understand that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0608] The daily dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof may vary within a wide range or any range thereof from 1.0 to 10,000 mg or higher per adult per day. For oral administration, the composition is preferably provided in tablet form containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250, and 500 mg of the active ingredient for symptomatic dose adjustment in treated subjects. An effective amount of the drug is typically provided at a dose level of about 0.1 mg / kg to about 1000 mg / kg body weight per day (or any range thereof). Preferably, the range is about 0.5 to about 500 mg / kg body weight per day (or any range thereof). More preferably, the range is about 1.0 to about 250 mg / kg body weight per day (or any range thereof). More preferably, the range is from about 0.1 to about 100 mg / kg body weight per day, or any range thereof. In one example, the range may be from about 0.1 to about 50.0 mg / kg body weight per day, or any amount or range thereof. In another example, the range may be from about 0.1 to about 15.0 mg / kg body weight per day, or any range thereof. In yet another example, the range may be from about 0.5 to about 7.5 mg / kg body weight per day, or any amount or range thereof thereof. The pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in a regimen of 1 to 4 times daily or as a single daily dose.

[0609] Active compounds can be effective over a wide dose range and are typically administered at pharmaceutically effective amounts. Those skilled in the art can readily determine the optimal dose to be administered. Therefore, it should be understood that the amount of compound actually administered will generally be determined by a physician and will vary depending on relevant circumstances, including the route of administration, the compound actually administered, the strength of the formulation, the condition being treated, and the progression of the disease. Additionally, factors relevant to the specific subject being treated, including subject response, age, weight, diet, time of administration, and severity of the subject's symptoms, will necessitate dose adjustments.

[0610] In some embodiments, the compounds provided herein may be administered in amounts ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein may be administered in amounts ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 85 mg / kg, approximately 90 mg / kg, approximately 95 mg / kg, or approximately 100 mg / kg.

[0611] Those skilled in the art will recognize that in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models predict the ability of a compound to treat or prevent a given condition.

[0612] Those skilled in the art will further recognize that human clinical trials, including first-in-human trials, dose-range trials, and efficacy trials, can be conducted in healthy subjects and / or subjects with a given condition, based on methods known in the clinical and medical fields.

[0613] This document provides pharmaceutical kits for treating, for example, MALT1-related diseases or conditions (such as cancer), comprising one or more containers containing a pharmaceutical composition comprising an effective amount of the compounds provided herein. As will be apparent to those skilled in the art, such kits may further comprise one or more of a variety of conventional pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, additional containers, etc., if desired. The kits may also include instructions (as inserts or as labels) indicating the amount of the component to be administered, instructions for administration, and / or instructions for mixing the components.

[0614] Example

[0615] Materials and methods

[0616] The compounds (including their salts) presented herein can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic pathways.

[0617] The reactions used to prepare the compounds provided herein can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially non-reactive to the starting materials (reactants), intermediates, or products at temperatures in which the reaction is carried out (e.g., a range from the freezing point to the boiling point of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, the suitable solvent for that particular reaction step can be selected by those skilled in the art.

[0618] The preparation of the compounds presented herein may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection, as well as the selection of appropriate protecting groups. The chemistry of protecting groups can be found, for example, in the following literature: *Protecting Group Chemistry*, 1st ed., Oxford University Press, 2000; *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 5th ed., Wiley-Interscience Publication, 2001; and Petrussion, S. et al., “Protecting Groups in Carbohydrate Chemistry”, *J. Chem. Educ.*, 74(11), 1297 (1997).

[0619] Reactions sensitive to moisture or air are carried out under nitrogen or argon atmospheres using anhydrous solvents and reagents. Reaction progress is determined by analytical thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), typically using Sanpont pre-coated TLC plates, silica gel GF-254, and a layer thickness of 0.25 mm.

[0620] Typically, the analytical LC-MS system used consists of a Shimadzu LCMS-2020, featuring electrospray ionization with positive ion detection mode, equipped with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS2020MS detector. The column is typically a HALO a C18 30*5.0 mm, 2.7 μm. Mobile phase A is water containing 0.05% TFA, and mobile phase B is acetonitrile containing 0.05% TFA. The gradient is from 5% mobile phase B to 100% in 2.0 min, held for 0.7 min, then returned to 5% mobile phase B in 0.05 min and held for 0.25 min. The column oven (CTO-20AC) is operated at 40.0 °C. The flow rate is 1.5 mL / min, and the injection volume is 1 μL. The PDA (SPD-M20A) has a detection range of 190-400 nm. The MS detector is equipped with electrospray ionization as the ionizable source; acquisition mode: scan; nebulizer gas flow rate: 1.5 L / min; dry gas flow rate: 15 L / min; detector voltage: tuned voltage ±0.2 kV; DL temperature: 250℃; heating block temperature: 250℃; scan range: 90.00-900.00 m / z. The ELSD (Alltech 3300) detector parameters are: drift tube temperature: 60±5℃; N2 flow rate: 1.8±0.2 L / min. The mobile phase gradient was optimized for individual compounds.

[0621] The GC-MS system typically uses a Shimadzu GCMS-QP2010 Ultra with both an FID and an MS detector. MS detector in acquisition mode: Start time: 2.00 min; End time: 9.00 min; ACQ mode: Scan; Event time: 0.30 sec; Scan rate: 2000; Start m / z: 50.00; End m / z: 550.00; Ion source temperature: 200.00 °C; Interface temperature: 250.00 °C; Solvent cut-off time: 2.00 min.

[0622] Preparative HPLC purification was typically performed using a Waters Auto Purification System (2545-2767) equipped with a 2489 UV detector. The column was a Waters C18, 19 x 150 mm, 5 μm. The mobile phase consisted of a mixture of acetonitrile (5-95%) in water containing 0.1% FA. The flow rate was maintained at 25 mL / min, the injection volume was 1200 μL, and the UV detector used two channels: 254 nm and 220 nm. The mobile phase gradient was optimized for individual compounds.

[0623] Chiral analysis chromatography was performed on one of the following columns: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH (Daicel Chemical Industries, Ltd.); (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Registechnologies, Inc.); CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.), at different column sizes (50x4.6mm, 100x4.6mm, 150x4.6mm, 250x4.6mm, 50x3.0mm, 100x3.0mm), where the stated percentages of ethanol / hexane (%Et / Hex) or isopropanol / hexane (%IPA / Hex) were used as isocratic solvent systems.

[0624] Reactions using microwave irradiation are typically carried out using initiators manufactured by Biotage. The solution is concentrated under reduced pressure using a rotary evaporator. Rapid column chromatography is typically performed using Biotage rapid chromatography equipment (Dyax Corp.) on silica gel (40-60 μM). The aperture is (perforation) on a pre-assembled box of the stated size. Unless otherwise specified, 1¹H NMR spectra were obtained in DMSO-d6 solution using a 400 MHz spectrometer. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal control in DMSO-d6 solution, and the residual CH₃OH peak or TMS was used as an internal reference in CD₃OD solution. Coupling constants (J) are reported in Hertz (Hz). Chiral analysis was performed on one of the following columns (250 x 4.6 mm): Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ (Daicel Chemical Industry Co., Ltd.), with labeled percentages of ethanol / hexane (%Et / Hex) or isopropanol / heptane (%IPA / Hep) as isocratic solvent systems. Chiral preparative chromatography was performed on one of the following columns: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH (Daicel Chemical Industry Co., Ltd.); (R,R)-Whelk-O1, (S,S)-Whelk-O1 (Regis Technologies); CHIRALCellulose-SB, SC, SA (YMC Corporation), with different column sizes (250x20mm, 250x30mm, 250x50mm), wherein the desired isocratic solvent system was identified on chiral analytical chromatography.

[0625] The abbreviations used in this article include: -C(O)CH3(Ac); acetic acid (AcOH); -OC(O)CH3(OAc); aqueous solution (aq); Cbz (benzyloxycarbonyl); N,N-diisopropylethylamine (DIEA); N;N-dimethylformamide (DMF); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); EtOAc (EtOAc); diethyl ether (ethyl ether or Et2O); PE (PE); g; h or hr; 2-propanol (IPA); mass spectrum (ms or MS); μL; mg; mL; mmol; min; methyl tert-butyl ether (MTBE); hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidine phosphate (PyBOP); retention time (R t); room temperature (rt or RT); saturated sodium chloride aqueous solution (saline); trifluoroacetic acid (TFA); tetrahydrofuran (THF); rapid chromatography (FC); liquid chromatography (LC); liquid chromatography-mass spectrometry (LCMS or LC-MS); supercritical fluid chromatography (SFC); tert-butoxycarbonyl (Boc or BOC); diethylaminosulfur trifluoride (DAST); DCM (DCM); dimethylacetamide (DMA; DMAC); dimethyl sulfoxide (DMSO); 1,3-bis(diphenylphosphine)propane (DPPP); acetic acid (HOAc); 3-chloroperoxybenzoic acid (m-CPBA); methyl (Me); methanol (MeOH); N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH); N-methylimidazolium (NMI); N-bromosuccinamide (NBS); thin layer chromatography (TLC).

[0626] The following are representative procedures for preparing the compounds used in the examples below, or procedures that may replace compounds that may not be commercially available and used in the examples below.

[0627] Method A1

[0628]

[0629] Examples 1 and 2: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6Hcyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6Hcyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0630] Step 1: 3-Chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine

[0631]

[0632] 2,3-Dichloro-5-nitropyridine (22.8 g, 118.2 mmol, 1.0 equivalent), CH3CN (250 mL), 2H-1,2,3-triazole (9.0 g, 130.0 mmol, 1.1 equivalent), and K2CO3 (21.2 g, 153.6 mmol, 1.3 equivalent) were placed in a 500 mL flask. The resulting mixture was stirred at 40 °C for 15 hours. The mixture was then cooled to 25 °C. The mixture was poured into EtOAc (300 mL). The organic layer was washed with water (2 x 300 mL) and brine (1 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. DCM (50 mL) was added to the residue. The resulting mixture was then filtered. The filter cake was washed with CH2Cl2 (2 x 10 mL) and dried to give 3-chloro-5-nitro-2-(1,2,3-triazol-2-yl)pyridine (6.8 g, 26% yield) as a grayish-white solid. 1 HNMR(400MHz, DMSO-d6)δ:8.39(d,J=2.4Hz,1H),8.14(d,J=2.4Hz,1H),8.33(s,2H).LC-MS:m / z 226[M+H] + .

[0633] Step 2: 5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine

[0634]

[0635] 3-Chloro-5-nitro-2-(1,2,3-triazol-2-yl)pyridine (6.6 g, 29.3 mmol, 1.0 equivalent) and EtOH (200 mL) were placed in a 1.0 L flask. HCl (50 mL) was added at 0 °C, followed by a small-volume addition of SnCl₂·2H₂O (33.0 g, 146.3 mmol, 5.0 equivalent) at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (300 mL), and the pH was adjusted to 9 using a 3N NaOH aqueous solution. The resulting mixture was extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-chloro-6-(1,2,3-triazol-2-yl)pyridine-3-amine as a grayish-white solid (Method A1, step 2; 5.4 g, 94% yield). 1H NMR (300MHz, DMSO-d6) δ: 8.05 (s, 2H), 7.83 (d, J = 2.5Hz, 1H), 7.21 (d, J = 2.5Hz, 1H), 6.19 (s, 2H). LC-MS: m / z 196 [M+H] + .

[0636] Step 3: 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one

[0637]

[0638] A solution of 2,2-dimethylcyclopentanone (2 g, 17.8 mmol) in DMF-DMA (20 mL) was stirred at 100 °C for 16 hours. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. This yielded a yellow oil of 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one (Method A1, step 3; 2 g, crude product), which could be used directly in the next step without further purification. LCMS (ES, m / z): 168 [M+H] + .

[0639] Step 4: 2-Chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine

[0640]

[0641] Add 5-chloro-1H-pyrazole-3-amine (1.5 g, 12.7 mmol) and AcOH (2 mL) to a stirred solution of 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one (1.5 g, 8.9 mmol) in toluene (20 mL) at room temperature. Stir the resulting mixture at 95 °C for 16 hours. Allow the mixture to cool to room temperature. Concentrate the reaction mixture under reduced pressure. Dilute the residue with water (100 mL). Adjust the pH to 6–7 with a saturated aqueous sodium bicarbonate solution. Extract the resulting mixture with ethyl acetate (100 mL x 2). Dry the combined organic layers over anhydrous sodium sulfate and concentrate under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether (1:5) to give 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine (1.4 g, 63.3% yield). 1 HNMR(300MHz,DMSO-d6)δ:8.56(s,1H),6.86(s,1H),2.88-3.03(m,2H),2.01-2.12(m,1H),1.27(s,3H).LC-MS(ES,m / z):222[M+H]+ .

[0642] Step 5: 2-Chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxynitrile

[0643]

[0644] To a stirred solution of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine (1.4 g, 6.3 mmol) in toluene (30 mL), (4R)-4-benzyl-2-[1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (274 mg, 0.8 mmol), copper acetoxy (154 mg, 1.2 mmol), N-fluorobenzenesulfonamide (3 g, 9.4 mmol), and TMSCN (3.1 g, 31.5 mmol) were added. The reaction was stirred at room temperature under nitrogen for 16 hours. The solvent was removed under vacuum, and the residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:5) to give 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylonitrile (Method A1, step 5; 690 mg, 17.7% yield). 1 HNMR(300MHz,DMSO-d6)δ:8.74(s,1H),7.00(s,1H),4.71-4.76(m,1H),2.54-2. 67(m,H),2.32-2.45(m,1H),1.63(s,3H),1.51(s,3H).LC-MS(ES,m / z):247[M+H] + .

[0645] Step 6: 2-Chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0646]

[0647] AcOH (6 mL) and HCl (6 mL) containing 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-carboxynitrile (690 mg, 2.8 mmol) were added to a 30 mL vial. The resulting mixture was stirred at 100 °C for 2 hours. The mixture was then cooled to room temperature. The solvent was concentrated under vacuum, and the residue was diluted with water (100 mL) and the pH was adjusted to 5–6 with NaHCO3. The resulting solution was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with MeOH / DCM (1:10) to give 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Method A1, step 6; 300 mg, 32.3% yield). 1 HNMR(400MHz,DMSO-d6)δ:12.75(s,1H),8.63(s,1H),6.92(s,1H),4.26-4.29(m,1H),2. 40-2.45(m,1H),2.28-2.33(m,1H),1.56(s,3H),1.52(s,3H).LC-MS(ES,m / z):266[M+H] + .

[0648] Step 7: 2-Chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0649]

[0650] To a stirred solution of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (390 mg, 1.4 mmol) in ACN (20 mL), 5-chloro-6-(triazol-2-yl)pyridine-3-amine (430.69 mg, 2.2 mmol), TCFH (1.65 g, 5.8 mmol), and NMI (482.06 mg, 5.87 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL). The resulting solution was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was subjected to preparative HPLC and the collected fractions were lyophilized to give a racemic mixture (200 mg, 60% yield) of 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide as a white solid. LC-MS (ES, m / z): 443 [M+H].

[0651] Step 8: Separate the enantiomers to obtain (R)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0652]

[0653] 200 mg of racemic 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was purified by chiral HPLC (CHIRALPAK IE, 2x25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH3·MeOH), mobile phase B: EtOH; flow rate: 17 mL / min; isocratic coefficient: 50B; 220 / 254 nm; RT1: 8.332; RT2: 12.438; injection volume: 1 mL; runs: 5). The first eluted isomer was concentrated and lyophilized to give Example 1 (74.3 mg, 11.4% yield) as a white solid. The second eluted isomer was concentrated and lyophilized to give Example 2 (69.6 mg, 10.6% yield) as a white solid.

[0654] Example 1: 1 H NMR(300MHz, methanol-d4)δ:8.71(d,J=2.4Hz,1H),8.66(d,J=2.4Hz,1H),8.55(s,1H),8.04(s,2H),6.72(s,1H), 4.42-4.47(m,1H),2.62-2.70(m,1H),2.45-2.48(m,1H),1.76(s,3H),1.65(s,3H).LCMS(ES,m / z):443[M+H] + .

[0655] Example 2: 1 H NMR(300MHz, methanol-d4)δ:8.71(d,J=2.4Hz,1H),8.66(d,J=2.4Hz,1H),8.55(s,1H),8.04(s,2H),6.73(s,1H),4 .42-4.47(m,1H),2.62-2.66(m,1H),2.45-2.48(m,1H),1.76(s,3H),1.65(s,3H).LC-MS(ES,m / z):443[M+H] + .

[0656] The absolute stereochemistry of each isolated isomer was not determined.

[0657] Method B1

[0658]

[0659] Examples 3 and 4: Single enantiomers obtained from a racemic mixture containing (R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0660] Step 1: 8,8-Dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-2-carboxynitrile

[0661]

[0662] A solution of 3-amino-1H-pyrazol-5-carboxynitrile (258 mg, 2.4 mmol) and (Z)-5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one (Method A1, step 3; 400 mg, 2.4 mmol) in AcOH (1 mL) and toluene (10 mL) was stirred at 90 °C for 3 hours under nitrogen. The mixture was cooled to room temperature and concentrated under vacuum. The residue was applied to a silica gel column and eluted with PE containing 0–50% EtOAc to give 8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazol[1,5-a]pyrimidine-2-carboxynitrile (220 mg, 43% yield) as a brown solid. 1 H NMR(300MHz,DMSO-d6)δ8.71(s,1H),7.53(s,1H),3.09-2.98(m,2H),2.09-2.14(m,2H),1.52(s,6H).LC-MS:m / z 213[M+H] + .

[0663] Step 2: 8,8-Dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-2,6-dicarboxynitrile

[0664]

[0665] Trimethylsilyl cyanide (514 mg, 5.2 mmol) was added in portions to a stirred solution of 8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-2-carboxylonitrile (220 mg, 1 mmol), N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (490 mg, 1.6 mmol), (4R)-4-benzyl-2-[1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (45.1 mg, 124.4 μmol) and copper acetoxy (25 mg, 207.3 μmol) in toluene (10 mL), and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with water (100 mL), and extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine, dried, and concentrated under vacuum. The residue was applied to a silica gel column and eluted with PE containing 0-30% EtOAc to give 8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-2,6-dicarboxynitrile (130 mg, 53% yield) as a grayish-white solid. LC-MS: m / z 238 [M+H] + .

[0666] Step 3: 2-Cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0667]

[0668] A solution of 130 mg (547.9 μmol) of 8,8-dimethyl-7,8-dihydro-2,6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-dicarboxynitrile (HCl) in 1 mL and 3 mL of AcOH was stirred at room temperature for 6 hours. The resulting mixture was concentrated under vacuum. The residue was diluted with 2 mL of water and the pH was adjusted to 8–9 with NaHCO3. The resulting mixture was concentrated under vacuum and purified by HPLC to give 2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (60 mg, 43% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.67(s,1H),7.70(s,1H),7.55(s,1H),7.21(s,1H),4.20-4.03(m,1H), 2.41(dd,J=13.2,9.1Hz,1H),2.22(dd,J=13.2,6.3Hz,1H),1.59(s,3H),1.49(s,3H).LC-MS:m / z 256[M+H] + .

[0669] Step 4: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0670]

[0671] To a stirred mixture of 5-bromo-3-chloro-2-(triazol-2-yl)pyridine (60 mg, 235.0 μmol) and 2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (60 mg, 235.0 μmol) in toluene (1 mL), (5-diphenylphosphino-9,9-dimethyl-oxanthracene-4-yl)-diphenylphosphine (13 mg, 23.5 μmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (13 mg, 23.5 μmol), and cesium carbonate (114 mg, 352.6 μmol) were added. Aluminum trifluoromethanesulfonate (11 mg, 23.5 μmol) was added in portions under nitrogen at room temperature. The resulting mixture was stirred at 110 °C for 16 hours under nitrogen. The mixture was cooled to room temperature, diluted with water (50 mL), and then extracted with DCM (3 x 50 mL). The organic layers were combined, washed with brine, dried, and concentrated under vacuum. The crude product (70 mg) was purified by preparative HPLC (column: XBridge preparative OBD C18 column, 19 x 250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 46B to 66B over 7 min; 220 nm; RT1: 6.12; injection volume: 1.5 mL; runs: 2) to give N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (22 mg, 22% yield) as a white solid. LC-MS: m / z 434 [M+H] + .

[0672] Step 5: Separate the enantiomers to obtain (R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0673]

[0674] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (22 mg, 50.4 μmol) was purified by chiral HPLC (column: Chiralpak ID-2, 2*25 cm, 5 μm; mobile phase A: MTBE (2 mM NH3-MEOH), mobile phase B: EtOH; flow rate: 17 mL / min; isocratic coefficient: 30B; 254 / 220 nm; RT1: 6.593; RT2: 8.779; injection volume: 1 mL; runs: 2). The first eluted isomer was concentrated and lyophilized to give Example 3 (7.3 mg, 33% yield) as a white solid. The second eluted isomer was concentrated and lyophilized to give Example 4 (6.2 mg, 28% yield) as a white solid.

[0675] Example 3: 1 H NMR (400MHz, methanol-d4) δ8.69(s,1H),8.63(d,J=2.4Hz,1H),8.02(s,2H),7.29(s,1H),4.48(dd,J=9.2,6.8 Hz,1H),2.71(dd,J=13.2,9.2Hz,1H),2.48(dd,J=13.2,6.8Hz,1H),1.75(s,3H),1.65(s,3H).LC-MS:m / z 434[M+H] + .

[0676] Example 4: 1 H NMR (400MHz, methanol-d4) δ8.69(s,1H),8.63(d,J=2.4Hz,1H),8.02(s,2H),7.28(s,1H),4.48(dd,J=9.2,6.8 Hz,1H),2.71(dd,J=13.2,9.2Hz,1H),2.47(dd,J=13.2,6.8Hz,1H),1.75(s,3H),1.65(s,3H).LC-MS:m / z 434[M+H] + .

[0677] The absolute stereochemistry of each isolated isomer was not determined.

[0678] Method C1

[0679]

[0680] Examples 5 and 6: Single enantiomers obtained from a racemic mixture containing (R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0681] Step 1: 2-Bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine

[0682]

[0683] Add 5-bromo-1H-pyrazole-3-amine (11.6 g, 71.8 mmol) and AcOH (15 mL) to a stirred solution of 5-(dimethylaminomethylene)-2,2-dimethyl-cyclopentan-1-one (Method A1, step 3; 10 g, 59.8 mmol) in toluene (150 mL) at room temperature. Stir the resulting mixture at 90 °C for 16 hours. Allow the mixture to cool to room temperature. Concentrate the reaction mixture under reduced pressure. Dilute the residue with water (200 mL). Adjust the pH to 6-7 with sodium bicarbonate (saturated, aqueous solution). Extract the resulting solution with EtOAc (3 x 200 mL), dry to anhydrous sodium sulfate, and concentrate under vacuum. The residue was applied to a silica gel column and eluted with EtOAc / PE (1:2) to give 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine (4 g, 20% yield). 1 H NMR(300MHz, DMSO-d6)δ:8.54(s,1H),6.93(s,1H),2.94-3.05(m,2H),2.07-2.12(m,2H),1.52(s,6H).LC-MS:m / z 266[M+H] + .

[0684] Step 2: 2-Bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxynitrile

[0685]

[0686] To a stirred solution of 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine (440 mg, 1.65 mmol) in toluene (10 mL), (4R)-4-benzyl-2-[1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (72 mg, 198.4 μmol), copper acetoxy (40 mg, 330.7 μmol), N-fluorobenzenesulfonamide (782 mg, 2.5 mmol), and TMSCN (820 mg, 8.3 mmol) were added. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The solvent was removed under vacuum, and the residue was applied to a silica gel column and eluted with EtOAc / PE (1:2) to give 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxynitrile (390 mg, 41% yield). 1 H NMR (300MHz, DMSO-d6)δ:8.72(s,1H),7.06(s,1H),4.71-4.76(m,1H),2.54-2.64(m,H),2.35-2.47(m,1H),1.64(s,3H),1.51(s,3H).LC-MS:m / z 291[M+H] + .

[0687] Step 3: 2,8,8-Trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxynitrile

[0688]

[0689] Add 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (638 mg, 2.5 mmol), Pd(dppf)Cl2 (93 mg, 127.1 μmol), K2CO3 (351 mg, 2.5 mmol, 153.4 μL), and H2O (1 mL) to a mixture of 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-carboxynitrile (370 mg, 1.3 mmol), dioxane (4 mL), H2O (1 mL), and Pd(dppf)Cl2 (93 mg, 127.1 μmol), dioxane (351 mg, 2.5 mmol, 153.4 μL), and H2O (1 mL) to the mixture of 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-carboxynitrile (4 mL). Stir the mixture at 100 °C for 2 hours under nitrogen. Cool the mixture to room temperature and concentrate under reduced pressure. Dilute the residue with water (50 mL), extract with EtOAc (3 x 50 mL), dry to anhydrous sodium sulfate, and concentrate under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc / PE (1:2) to give 2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxynitrile (105 mg, 36% yield). 1 H NMR (300MHz, DMSO-d6)δ:8.58(s,1H),6.63(s,1H),4.66-4.73(m,1H),2.55-2.62(m,1H),2.33-2.43(m,1H),1.65(s,3H),1.53(s,3H).LC-MS:m / z 227[M+H] + .

[0690] Step 4: 2,8,8-Trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0691]

[0692] A solution of 2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (97 mg, 428.7 μmol) in AcOH (2 mL) and HCl (2 mL) was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature. The mixture was concentrated under vacuum, and the residue was diluted with water (50 mL) and the pH was adjusted to 5–6 with NaHCO3. The resulting solution was extracted with EtOAc (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with DCM / MeOH (10:1) to give 2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (56 mg, 182.6 μmol, 43% yield). LC-MS: m / z 246 [M+H] + .

[0693] Step 5. N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0694]

[0695] To a solution of 2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (56 mg, 228.3 μmol) in ACN (3 mL), 5-chloro-6-(triazol-2-yl)pyridine-3-amine (67 mg, 342.5 μmol), TCFH (320 mg, 1.1 mmol), and NMI (94 mg, 1.1 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL). The resulting solution was extracted with EtOAc (3 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was fed onto a silica gel column and eluted with EA / PE (1:1) to give the crude product. The crude product was purified by HPLC, and the collected fractions were lyophilized to obtain N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (30 mg, 31%) as a white solid. LC-MS: m / z 423 [M+H] + .

[0696] Step 6: Separate the enantiomers to obtain (S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0697]

[0698] 30 mg of N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was purified by chiral HPLC (column: Chiralpak ID-2, 2*25 cm, 5 μm; mobile phase A: MTBE (2 mM NH3-MEOH), mobile phase B: EtOH; flow rate: 14 mL / min; isocratic 50B; 254 / 220 nm; RT1: 11.394; RT2: 17.177; injection volume: 2 mL; runs: 2). The first eluted isomer was concentrated and lyophilized to give Example 5 (6 mg, 6.2% yield) as a white solid. The second eluted isomer was concentrated and lyophilized to give Example 6 (8.6 mg, 8.9% yield) as a white solid.

[0699] Example 5: 1 H NMR (300MHz, methanol-d4): 8.71 (d, J = 2.4Hz, 1H), 8.66 (d, J = 2.4Hz, 1H), 8.42 (s, 1H), 8.04 (s, 2H), 6.53 (s, 1H), 4.41-4.87(m,1H),2.60-2.67(m,1H),2.54(s,3H),2.40-2.47(m,1H),1.80(s,3H),1.66(s,3H).LC-MS:m / z 423[M+H] + .

[0700] Example 6: 1 H NMR (300MHz, methanol-d4): 8.71 (d, J = 2.4Hz, 1H), 8.66 (d, J = 2.4Hz, 1H), 8.42 (s, 1H), 8.04 (s, 2H), 6.53 (s, 1H), 4.41-4.87(m,1H),2.60-2.67(m,1H),2.54(s,3H),2.40-2.47(m,1H),1.80(s,3H),1.66(s,3H).LC-MS:m / z 423[M+H] + .

[0701] The absolute stereochemistry of each isolated isomer was not determined.

[0702] Example 7: 2-Chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazolin-6-carboxamide

[0703]

[0704] The title compound was prepared from 2,2-dimethylcyclohexanone using method A1 in a manner similar to Example 1. 1 HNMR(400MHz, DMSO-d6)δ:10.98(s,1H),8.71(d,J=2.4Hz,1H),8.56(d,J=2.4Hz,1H),8.45(s,1H),8.16(s,2H),6.88(s ,1H),4.11-4.16(m,1H),2.05-2.27(m,2H),1.87-1.99(m,1H),1.75-1.85(m,1H),1.64(s,3H),1.59(s,3H).LC-MS:m / z 457[M+H] + .

[0705] Examples 8 and 9: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline-6-carboxamide.

[0706]

[0707] 100 mg of 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazolin-6-carboxamide was purified by chiral HPLC (CHIRALPAK IE, 2x25 cm, 5 μm; mobile phase A: Hex (8 mmol / L NH3·MeOH), mobile phase B: EtOH; flow rate: 17 mL / min; isocratic coefficient: 50B; 220 / 254 nm; RT1: 8.332; RT2: 12.438; injection volume: 1 mL; runs: 5). The first eluted isomer was concentrated and lyophilized to give Example 8 (34.6 mg, 35% yield) as a white solid. The second eluted isomer was concentrated and lyophilized to give Example 9 (31.1 mg, 31% yield) as a white solid.

[0708] Example 8: 1H NMR (300MHz, DMSO-d6) δ11.00(s,1H),8.71(d,J=2.1Hz,1H),8.57(d,J=2.1Hz,1H),8.46(s,1H),8.17(s,2H) ,6.89(s,1H),4.10-4.18(m,1H),2.04-2.32(m,2H),1.74-2.03(m,2H),1.65(s,3H),1.59(s,3H).LC-MS:m / z 457[M+H] + .

[0709] Example 9: 1 HNMR (300MHz, DMSO-d6) δ11.00(s,1H),8.71(d,J=2.1Hz,1H),8.57(d,J=2.1Hz,1H),8.45(s,1H),8.17(s,2H ),6.89(s,1H),4.10-4.18(m,1H),2.04-2.32(m,2H),1.74-2.03(m,2H),1.65(s,3H),1.59(s,3H).LC-MS:m / z 457[M+H] + .

[0710] The absolute stereochemistry of each isolated isomer was not determined.

[0711] Method D1

[0712]

[0713] Examples 10 and 11: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0714] Step 1: 5-Chloro-6-(1-Methyl-1H-pyrazol-3-yl)pyridine-3-amine

[0715]

[0716] A solution of 5,6-dichloropyridin-3-amine (1 g, 6.1 mmol) in dioxane (16 mL) and H₂O (4 mL) was added to a solution of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (1.2 g, 6.1 mmol), Pd(dppf)Cl₂ (513 mg, 610 μmol), and Na₂CO₃ (2.6 g, 4 mmol) under N₂. The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (150 mL). The resulting solution was extracted with EtOAc (3 x 150 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was applied to a silica gel column and eluted with EtOAc / PE (1:3) to give 5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine (1.2 g, crude product) as a yellow oil. LC-MS: m / z 209 [M+H] + .

[0717] Step 2: 2-Chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0718]

[0719] To a solution of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-carboxylic acid (Method A1, step 6; 100 mg, 376.3 μmol) in ACN (6 mL), 5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine (117 mg, 564.5 μmol), TCFH (422 mg, 1.5 mmol), and NMI (123 mg, 1.5 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (100 mL). The resulting solution was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with DCM / MeOH (10:1). The obtained product was further purified by preparative HPLC to give 2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (28.6 mg, 17% yield) as a white solid. LC-MS: m / z 456 [M+H] + .

[0720] Step 3: Separate the enantiomers to obtain (R)-2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0721]

[0722] 28.6 mg of 2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was purified by chiral HPLC (column: Chiralpak ID-2, 2*25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 15 mL / min; isocratic coefficient: 50B; 254 / 220 nm; RT1: 12.336; RT2: 26.017; injection volume: 1.5 mL; run count: 1). The first eluted isomer was concentrated and lyophilized to give Example 10 (7.8 mg, 27% yield) as a white solid. The second eluted isomer was concentrated and lyophilized to give Example 11 (7.2 mg, 27% yield) as a white solid.

[0723] Example 10: 1 H NMR(400MHz, DMSO-d6)δ:10.79(s,1H),8.72(d,J=2.0Hz,1H),8.63(s,1H),8.34(d,J=2.0Hz,1H),7.77(d,J=2.0Hz,1H),6.94(s,1H ),6.72(d,J=2.0Hz,1H),4.39-4.44(m,1H),3.92(s,3H),2.50-2.52(m,1H),2.27-2.33(m,1H),1.64(s,3H),1.56(s,3H).LC-MS:m / z 456[M+H] + .

[0724] Example 11: 1H NMR(400MHz, DMSO-d6)δ:10.79(s,1H),8.72(d,J=2.0Hz,1H),8.64(s,1H),8.34(d,J=2.0Hz,1H),7.77(d,J=2.0Hz,1H),6.94(s,1H ),6.72(d,J=2.0Hz,1H),4.39-4.45(m,1H),3.92(s,3H),2.50-2.51(m,1H),2.28-2.35(m,1H),1.64(s,3H),1.56(s,3H).LC-MS:m / z 456[M+H] + .

[0725] The absolute stereochemistry of each isolated isomer was not determined.

[0726] Method E1

[0727]

[0728] Examples 12 and 13: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0729] Step 1: 3-Chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine

[0730]

[0731] Add 1H-pyrazole (7 g, 28.5 mmol) and K₂CO₃ (2 g, 51.8 mmol) to a stirred solution of 2,3-dichloro-5-nitro-pyridine (5 g, 25.9 mmol) in MeCN (100 mL). Stir the resulting mixture at 40 °C for 16 h. Allow the mixture to cool to room temperature. Filter the reaction mixture and wash the collected solid with EtOAc (3 x 50 mL). Concentrate the resulting solution under reduced pressure. Apply the residue to a silica gel column and elute with EtOAc / PE (1:10) to give 3-chloro-5-nitro-2-(1H-pyrazole-1-yl)pyridine (4 g, 68% yield) as a white solid. 1H NMR (300MHz, DMSO-d6) δ: 9.30 (d, J = 2.4Hz, 1H), 9.00 (d, J = 2.4Hz, 1H), 8.50-8.51 (m, 1H), 7.67-7.68 (m, 1H), 6.67-6.68 (m, 1H). LC-MS: m / z 225 [M+H] + .

[0732] Step 2: 5-Chloro-6-(1H-pyrazol-1-yl)pyridin-3-amine

[0733]

[0734] Ammonium chloride (3.8 g, 71.2 mmol) was added to a stirred solution of 3-chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine (2 g, 8.9 mmol) in THF (33 mL) and H₂O (33 mL). Fe (4.0 g, 71.2 mmol) was then added to the mixture at 80 °C for 1 hour. The mixture was cooled to room temperature and filtered through a diatomaceous earth mat, which was then washed with EtOAc (3 x 10 mL). The resulting solution was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was applied to a silica gel column and eluted with EtOAc / PE (1:1) to give 5-chloro-6-(1H-pyrazol-1-yl)pyridine-3-amine (0.38 g, 22% yield) as a yellow solid. 1 ¹H NMR (300MHz, chloroform-d) δ: 7.87–7.90 (m, 2H), 7.78 (d, J = 1.8 Hz, 1H), 7.15 (d, J = 2.6 Hz, 1H), 6.45–6.47 (m, 1H), 4.50 (s, 2H). LC-MS: m / z 195 [M+H] + .

[0735] Step 3: 2-Chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0736]

[0737] To a stirred solution of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Method A1, step 6; 50 mg, 188.2 μmol) in ACN (5 mL), 3-chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine (55 mg, 282.3 μmol), TCFH (211 mg, 752.7 μmol), and NMI (62 mg, 752.7 μmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL). The resulting solution was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC, and the collected fractions were lyophilized to give 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (60 mg, 84% yield) as a white solid. LC-MS: m / z 442 [M+H] + .

[0738] Step 4: Separate the enantiomers to obtain (R)-2-chloro-N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0739]

[0740] 60 mg of 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was purified by chiral HPLC (column: Chiralpak IA, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 18 mL / min; isocratic coefficient: 50B; 220 / 254 nm; RT1: 7.267; RT2: 12.331; injection volume: 2 mL; runs: 4). The fraction containing the first eluting isomer was concentrated and lyophilized to give Example 12 (25.8 mg, 31% yield) as a white solid. The fraction containing the second eluting isomer was concentrated and lyophilized to give Example 13 (32.1 mg, 38% yield) as a white solid.

[0741] Example 12: 1 H NMR (400MHz, methanol-d4) δ: 8.65 (d, J = 2.4Hz, 1H), 8.56 (d, J = 2.0Hz, 1H), 8.51 (s, 1H), 8.13 (d, J = 2.4Hz, 1H), 7.78 (d, J = 1.2Hz, 1H), 6.70(s,1H),6.55-6.56(m,1H),4.38-4.41(m,1H),2.60-2.65(m,1H),2.40-2.43(m,1H),1.73(s,3H),1.62(s,3H).LC-MS:m / z 442[M+H] + .

[0742] Example 13: 1 H NMR (400MHz, methanol-d4) δ: 8.65 (d, J = 2.4Hz, 1H), 8.56 (d, J = 2.0Hz, 1H), 8.51 (s, 1H), 8.13 (d, J = 2.4Hz, 1H), 7.78 (d, J = 1.2Hz, 1H), 6.70(s,1H),6.55-6.56(m,1H),4.38-4.41(m,1H),2.60-2.65(m,1H),2.40-2.43(m,1H),1.73(s,3H),1.62(s,3H).LC-MS:m / z 442[M+H] + .

[0743] The absolute stereochemistry of each isolated isomer was not determined.

[0744] Method F1

[0745]

[0746] Examples 14 and 15: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0747] Step 1: 1-(3-chloro-5-nitropyridin-2-yl)-1H-pyrazole-4-carboxynitrile

[0748]

[0749] A mixture of 2,3-dichloro-5-nitro-pyridine (3 g, 15.6 mmol), 1H-pyrazole-4-carboxylonitrile (1.59 g, 17.1 mmol), and potassium carbonate (6.45 g, 46.6 mmol) in DMF (40 mL) was stirred at 25 °C for 4 hours. The resulting mixture was poured into ice / water (100 mL). The precipitated solid was collected by filtration and washed with water (5 x 20 mL). The resulting solid was dried under infrared light. This gave 1-(3-chloro-5-nitro-2-pyridyl)pyrazole-4-carboxylonitrile (3.4 g, 88% yield) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ: 9.34 (d, J = 2.4Hz, 1H), 9.30 (s, 1H), 9.10 (d, J = 2.4Hz, 1H), 8.51 (s, 1H).

[0750] Step 2: 1-(5-amino-3-chloropyridin-2-yl)-1H-pyrazole-4-carboxynitrile

[0751]

[0752] Iron (940 mg, 16.8 mmol) and ammonium chloride (900 mg, 16.8 mmol) were added to a stirred mixture of 1-(3-chloro-5-nitro-2-pyridyl)pyrazole-4-carboxynitrile (1 g, 4.0 mmol) in EtOH (15 mL) and H₂O (15 mL). The resulting mixture was stirred at 95 °C for 1 hour. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to remove EtOH. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (92:8) to give 1-(5-amino-3-chloro-2-pyridyl)pyrazole-4-carboxynitrile (630 mg, 72% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.89 (s, 1H), 8.26 (s, 1H), 7.79 (d, J = 2.4Hz, 1H), 7.18 (d, J = 2.4Hz, 1H), 6.14 (s, 2H). LC-MS: m / z 220 [M+H] + .

[0753] Step 3: 2-Chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0754]

[0755] TCFH (383 mg, 1.37 mmol) and NMI (187 mg, 2.28 mmol) were added to a stirred mixture of 1-(5-amino-3-chloro-2-pyridyl)pyrazol-4-carboxylonitrile (100 mg, 0.46 mmol) and 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Method A1, Step 6; 121 mg, 0.46 mmol) in ACN (10 mL). The resulting mixture was stirred at 25 °C for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EtOAc / PE (7:3) to give a crude product, which was then purified by HPLC. The collected fractions were lyophilized to give 2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (34.3 mg, 16% yield) as a white solid. LC-MS: m / z 467 [M+H] + .

[0756] Step 4: Separate the enantiomers to obtain (R)-2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0757]

[0758] 30 mg of 2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was purified by chiral HPLC (column: Chiralpak ID-2, 2x25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH; flow rate: 18 mL / min; isocratic coefficient: 50B; 254 / 220 nm; RT1: 15.609; RT2: 19.773; injection volume: 0.7 mL; runs: 4). The fraction containing the first eluting isomer was concentrated and lyophilized to give Example 14 (5.7 mg, 19% yield) as a white solid. The fraction containing the second eluting isomer was concentrated and lyophilized to produce Example 15 (5.6 mg, 19% yield) as a white solid.

[0759] Example 14: 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),9.10(s,1H),8.70(d,J=2.4Hz,1H),8.65(s,1H),8.54(d,J=2.4Hz,1H),8.40 (s,1H),6.95(s,1H),4.42-4.48(m,1H),2.53-2.60(m,1H),2.29-2.37(m,1H),1.64(s,3H),1.56(s,3H).LC-MS:m / z 467[M+H] + .

[0760] Example 15: 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),9.10(s,1H),8.70(d,J=2.4Hz,1H),8.65(s,1H),8.54(d,J=2.4Hz,1H),8.40 (s,1H),6.95(s,1H),4.42-4.48(m,1H),2.53-2.60(m,1H),2.29-2.37(m,1H),1.64(s,3H),1.56(s,3H).LC-MS:m / z 467[M+H] + .

[0761] The absolute stereochemistry of each isolated isomer was not determined.

[0762] Method G1

[0763]

[0764] Examples 16 and 17: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(pyrrolidone-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(pyrrolidone-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide.

[0765] Step 1: 3-Chloro-5-nitro-2-(pyrrolidine-1-yl)pyridine

[0766]

[0767] Pyrrolidine (884...

Claims

1. A compound of formula (I): （I）， or its pharmaceutically acceptable salt in: Each It can be a single bond or a double bond; X is N; Y is C; Z is N; Q is –CH2–; or X is N; Y is C; Z is N; Q is O; or X is N; Y is C; Z is CR 5 ;Q is –CH2–; or X is C; Y is N; Z is N; Q is –CH2–; and R X It is hydrogen or halogen; n is 1 or 2; R 1 It can be hydrogen, halogen, cyano, hydroxyl, C1-C3 haloalkyl or C1-C3 alkyl; R 2 It is hydrogen, halogen, or C1-C3 alkyl; Each R 3 Independently hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl; or two R 3 Together with the carbon atom to which it is attached, it forms a 4-6 membered heterocyclic group or a C3-C6 cycloalkyl group; m is 2 or 3; R 4 The heteroaryl group is 5-9 nucleotides, wherein the heteroaryl group is optionally composed of 1-3 independently selected from R 6 Substituents of the substituents; R 5 It is hydrogen or halogen; and Each R 6 Selected independently from: (i) Halogens; (ii) Cyano group; (iii) -N=(S=O)(C1-C3 alkyl)2; (iv) -(C=O)NR E R F ; (v) C1-C3 alkoxy groups; (vi) Optionally, C1-C3 haloalkyl groups are substituted with hydroxyl groups; (vii) C1-C3 haloalkoxy groups; (viii) 5-6 membered heteroaryl groups optionally substituted with the following: cyano, hydroxyl, 4-6 membered heterocyclic or C1-C3 alkyl groups optionally substituted with hydroxyl; (ix) C1-C4 alkyl groups optionally substituted with hydroxyl groups; (x) 3-8 membered heterocyclic groups; and (xi) C3-C6 cycloalkoxy; and R E and R F Independently hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or R E and R F Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group that is optionally substituted with 1-2 halogens.

2. The compound according to claim 1, wherein R 1 It is hydrogen.

3. The compound according to claim 1, wherein R 1 It is a halogen.

4. The compound according to claim 1, wherein R 1 It is chlorine.

5. The compound according to claim 1, wherein R 1 It is fluorine.

6. The compound according to claim 1, wherein R 1 It is a cyano group.

7. The compound according to claim 1, wherein R 1 It is a hydroxyl group.

8. The compound according to claim 1, wherein R 1 It is a C1-C3 haloalkyl group.

9. The compound according to claim 1, wherein R 1 It is an unsubstituted C1-C3 alkyl group.

10. The compound according to claim 1, wherein R 2 It is hydrogen.

11. The compound according to claim 1, wherein R 2 It is a halogen.

12. The compound according to claim 1, wherein R 2 It is either fluorine or chlorine.

13. The compound according to claim 1, wherein R 2 It is a C1-C3 alkyl group.

14. The compound according to claim 1, wherein R 2 It is a methyl group.

15. The compound according to claim 1, wherein n is 1.

16. The compound according to claim 1, wherein n is 2.

17. The compound according to claim 1, wherein m is 2.

18. The compound according to claim 1, wherein m is 2, and each R 3 It is a methyl group.

19. The compound according to claim 1, wherein m is 2, and each R 3 It is trifluoromethyl.

20. The compound according to claim 1, wherein m is 2, and an R 3 For methyl and another R 3 It is trifluoromethyl.

21. The compound according to claim 1, wherein m is 2, and an R 3 It is trifluoromethyl and another R 3 It is an ethoxylated compound.

22. The compound according to claim 1, wherein R 3 The group is in the homologous position.

23. The compound according to claim 1, wherein m is 2, and the two Rs 3 Together with the carbon atom it is attached to, it forms a 4-6 membered heterocyclic group.

24. The compound according to claim 1, wherein m is 2, and the two Rs 3 Together with the carbon atom it is attached to, it forms an oxocyclic butyl or tetrahydropyranyl group.

25. The compound according to claim 1, wherein m is 2, and the two Rs 3 Together with the carbon atom it is attached to, it forms a C3-C6 cycloalkyl group.

26. The compound according to claim 1, wherein m is 2, and the two Rs 3 Together with the carbon atom it is attached to, it forms a cyclopropyl or cyclobutyl group.

27. The compound according to claim 1, wherein R 4 R is arbitrarily selected by 1-3 independent choices 6 Substituted 5-9 aryl groups.

28. The compound according to claim 1, wherein R 4 R is selected by 1-3 independent choices 6 Substituted 5-9 aryl groups.

29. The compound according to claim 1, wherein R 4 R is selected by 1-3 independent choices 6 Substituted 5-6 aryl groups.

30. The compound according to claim 1, wherein R 6 At least one of them is a halogen.

31. The compound according to claim 1, wherein R 6 At least one of them is a cyano group.

32. The compound according to claim 1, wherein R 6 At least one of them is -(C=O)NR E R F .

33. The compound according to claim 32, wherein R E and R F It is independently hydrogen, C1-C3 alkyl or C3-C6 cycloalkyl.

34. The compound according to claim 32, wherein R E and R F One of them is hydrogen and R E and R F The other one is a C1-C3 alkyl or a C3-C6 cycloalkyl.

35. The compound according to claim 32, wherein R E and R F One of them is a C1-C3 alkyl group and R E and R F The other one is a C3-C6 cycloalkyl group.

36. The compound according to claim 32, wherein R E and R F Both are hydrogen.

37. The compound according to claim 32, wherein R E and R F Both are C1-C3 alkyl groups.

38. The compound according to claim 32, wherein R E and R F Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group that is optionally substituted with 1-2 halogens.

39. The compound according to claim 1, wherein R 6 At least one of them is -N=(S=O)(C1-C3 alkyl)2.

40. The compound according to claim 39, wherein each C1-C3 alkyl group is methyl.

41. The compound according to claim 1, wherein R 6 At least one of them is a C1-C3 alkoxy group.

42. The compound according to claim 1, wherein R 6 At least one of them is a C1-C3 haloalkyl group optionally substituted with a hydroxyl group.

43. The compound according to claim 1, wherein R 6 At least one of them is a C1-C3 haloalkoxy group.

44. The compound according to claim 1, wherein R 6 At least one of them is a 5-6 membered heteroaryl group optionally substituted with the following: cyano, hydroxyl, C1-C3 alkyl group optionally substituted with hydroxyl, or C1-C3 haloalkyl group.

45. The compound according to claim 1, wherein R 6 At least one of them is a C1-C4 alkyl group.

46. ​​The compound according to claim 1, wherein R 6 At least one of them is a 3-8 membered heterocyclic group.

47. The compound according to claim 1, wherein R 6 At least one of them is a C3-C6 cycloalkoxy group.

48. The compound according to claim 1, wherein R 6 At least one of them is a cyclopropoxy group.

49. The compound according to claim 1, wherein R 4 R is selected by 1-3 independent choices 6 Substituted 3-pyridyl or 4-pyridyl.

50. The compound according to claim 1, wherein R 4 for The wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

51. The compound according to claim 50, wherein R 6 Choose from the group consisting of: cyano, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy and C1-C3 alkoxy, optionally substituted with hydroxyl.

52. The compound according to claim 50, wherein R 6 Choose from the following groups: cyano, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, and methoxy.

53. The compound according to claim 1, wherein R 4 for , where R 6A and R 6B Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

54. The compound according to claim 1, wherein R 4 for , where R 6A and R 6B Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

55. The compound according to claim 1, wherein R 4 for , where R 6A and R 6B Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

56. The compound according to claim 1, wherein R 4 for , where R 6A and R 6B Independently selected from R 6 And the wavy line crosses the bond connected to the -C(=O)NH- part of formula (I).

57. The compound according to any one of claims 53 to 56, wherein R 6A Choose from the group consisting of: cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; and R 6B Choose from the group consisting of: 5-6 membered heteroaryl groups optionally substituted with: cyano, C1-C3 alkyl, or 4-6 membered heterocyclic groups optionally substituted with hydroxyl; -N=(S=O)(C1-C3 alkyl)2; -(C=O)NR E R F ; C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; cyano; C3-C6 cycloalkoxy; and C1-C3 alkyl.

58. The compound according to any one of claims 53 to 56, wherein R 6A Choose from the group consisting of: cyano, fluorine, chlorine, methyl, ethyl, methoxy, trifluoromethyl; and R 6B Select from the group consisting of: 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1, 2,4-Triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, 1,2,4-triazol-4-one-2-yl, tetrazol-5-yl, 2-methyl-tetrazol-5-yl, 1-methyl-tetrazol-5-yl, imidazole-1-yl, 1-methyl-imidazole-3-yl, 1-methyl-5-amino-imidazole-3-yl 3-Methylimidazol-2-one-1-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, pyrrolidin-1-yl, thiazol-2-yl, isothiazolidine-2-yl-1,1-dioxide, pyrrolidin-2-one-1-yl, oxazol-2-yl, oxadiazol-2-yl, 2-aminopyrimidine-4-yl, -(C=O)4-methyl Piperazin-1-yl, 2-oxozylidene-1-yl, aziridine-1-yl, -(C=O)N(CH3)2, -(C=O)NHCH3, -(C=O)NHCH2CH3, -(C=O)NHcyclopropyl, -(C=O)(3,3-difluoroaziridine-1-yl), 2-hydroxypropane-2-yl, 1-hydroxyethyl, dimethyl(oxo)-λ 6 - Thiodimethyl, methoxy, ethoxy, difluoromethoxy, methyl, cyano.

59. The compound according to any one of claims 53 to 56, wherein R 6A Choose from the group consisting of: cyano, chloro, methyl, and trifluoromethyl; and R 6B Choose from the group consisting of: 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, and 1,2,4-triazol-4-one-2-yl.

60. The compound according to claim 1, wherein R 5 It is hydrogen.

61. The compound according to claim 1, wherein R 5 It is a halogen.

62. The compound according to claim 1, wherein R 5 It is fluorine.

63. The compound according to claim 1, wherein R X It is a halogen.

64. The compound according to claim 1, wherein R X It is fluorine.

65. The compound according to claim 1, wherein R X It is hydrogen.

66. The compound of claim 1, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a Chiralpak ID-2 column, 2x25cm, 5μm column. 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a Chiralpak ID-2 column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a Chiralpak ID-2 column, 2x25cm, 5µm column. 、 、 、 、 、 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a Chiralpak IC, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a Chiralpak ID-2 column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a Chiralpak ID-2 column, 2x25cm, 5μm column. 、 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a Chiralpak IE column, 2x25cm, 5μm column. 、 、 、 、 、 、 、 、 When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SB column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IA, 2x25cm, 5μm column. 、 When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SB column, 2x25cm, 10μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IF column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the third elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SB column, 2x25cm, 10μm column. 、 、 、 、 、 、 , 、 、 , 、 、 、 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IF column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IF column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IA, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IA, 2x25cm, 5μm column. 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IE column, 2x25cm, 5μm column. 、 , 、 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IG column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IG column, 2x25cm, 5μm column. 、 , 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SC column, 2x25cm, 5μm column. 、 、 、 、 、 、 When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SC column, 2x25cm, 5μm column. 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IA, 2x25cm, 20μm column. 、 、 、 、 、 、 、 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IG column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Amylose-SA column, 2x25cm, 5μm column. 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Amylose-SA column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a CHIRALPAK IG column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IG column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a CHIRALPAK IG column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK ID, 2x25cm, 5μm column. 、 、 When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a CHIRALPAK IG column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SA column, 2x25cm, 5μm column. 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SA column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SB column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SA column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SC column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the first elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SC column, 2x25cm, 5μm column. 、 、 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a DAICEL DCpak P4VP column (2x25cm, 5μm). 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRALPAK IG column, 2x25cm, 5μm column. 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Amylose-SA column, 2x25cm, 5μm column. When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Amylose-SA column, 2x25cm, 5μm column. 、 、 、 、 、 、 、 、 、 、 、 、 、 、 When compounds Compounds with absolute stereochemistry of the second elution isomer were separated by chiral HPLC purification using a CHIRAL ART Cellulose-SC column, 2x25cm, 5μm column. , , and .

67. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 66, and at least one pharmaceutically acceptable excipient.

68. Use of the compound of any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 67 in the preparation of a medicament for treating cancer in a subject in need.

69. The use according to claim 68, wherein the subject is administered an additional therapy or treatment agent.

70. The use according to claim 69, wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapy agents, protease-targeting therapy agents, kinase-targeting therapy agents, apoptosis regulators, signal transduction inhibitors, immunotherapy, and angiogenesis-targeting therapy.

71. Use of the compound of any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 67 in the preparation of a medicament for treating an autoimmune disease in a subject of need.

72. The use according to claim 71, wherein the subject is administered an additional therapy or treatment agent.

73. The use according to claim 72, wherein the additional therapy or treatment agent is immunotherapy.

74. Use of the compound of any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 67 in the preparation of a medicament for treating an inflammatory condition in a subject of need.

75. The use according to claim 74, wherein the subject is administered an additional therapy or treatment agent.

76. The use according to claim 75, wherein the additional therapy or treatment agent is immunotherapy.

Images