Cyclic compounds and methods of using them

Abstract

This application relates to compounds of formula (I) as defined herein, and pharmaceutically acceptable salts thereof. This application also describes pharmaceutical compositions comprising a compound of formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for treating diseases such as cancer, autoimmune disorders, and inflammatory disorders. Also provided is a method for treating CBM complex pathway-related cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. JPEG2025524002000149.jpg2947

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 391,548, filed Jul. 22, 2022, which is hereby incorporated by reference in its entirety.

[0002] This application relates to tricyclics that are useful for treating cancer and proliferative disorders such as autoimmune and inflammatory disorders.

Background Art

[0003] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is an intracellular protein involved in lymphocyte proliferation through upstream signaling of NF-κB to control lymphocyte activation, survival, proliferation, and differentiation. Together 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 that is formed in response to activation of cell surface antigen receptors. See Jaworski et al., Cell Mol Life Science 2016, 73, 459-473, and Juilland and Thome, Frontiers in Immunology 2018, 9, 1927. MALT1 is known to mediate NF-κB signaling by at least two mechanisms. First, MALT1 functions as a scaffold protein to recruit NF-κB signaling proteins such as TRAF6, TAB (e.g., TAB1, TAB2, TAB3), TAK1, and NEMO-IKKβ, 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.

[0004] The protease activity of MALT1 has emerged as a potential therapeutic target, particularly in cases where NF-κB and related pathways are thought to play important roles. Activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL) is an aggressive lymphoma often characterized by hyperactivation of NF-κB, and it has been shown that MALT1 protease inhibition can dramatically inhibit growth and promote apoptosis in very aggressive ABC-type DLBCL. See Ferch U, et al., J Exp Med 2009, 206, 2313-2320. See also Hailfinger S, et al., Proc Natl Acad Sci USA 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 LIMAla. See Rebeaud et al., Nat Immunol 2008, 9, 272-281. See also Coornaert et al., Nat Immunol 20008, 9, 263-271, Staal et al., EMBO J 2011, 30, 1742-1752, Hailfinger et al., PNAS 2011, 108, 14596-14601, Jeltsch et al., Nat Immunol 2014, 15, 1079-1089, Uehata et al., Cell 2013, 153, 1036-1049, Nie et al., Nat Commun 2015, 6, 5908, and Baens et al., PLoS ONE 2014, 9, e103774. One general profile of MALT1 substrates is described in Kasperkiewicz, et al. Scientific Reports 8.1 (2018): 1-10. Additionally, several chromosomal translocations leading to the constitutive production of active MALT1 have been identified in ABC-DLBCL, and the identification of the MALT1 fusion proteins API2-MALT1 / IgH-MALT1, which lead to NF-κB activation independently of upstream stimuli, further emphasizes the importance of this protein in cancer and various diseases. See Farinha et al., J Clinical Oncology 2005, 23, 6370-6378. Furthermore, MALT1 has been shown to be involved in several different types of cancer, such as blood malignancies like mantle cell lymphoma, chronic lymphocytic leukemia (CLL), as well as solid tumors like lung adenocarcinoma, breast cancer, pancreatic cancer, and glioblastoma. See Jiang et al., Cancer Research 2011, 71, 2183-2192. Also see Pan et al., Mol Cancer Res 2016, 14, 93-102, Penas et al., Blood 2010, 115, 2214-2219, and J Cell Mol Med. 2020 Jul;24(13):7550-7562. MALT1 as an immunomodulatory protein is also involved in innate and adaptive immunity and may be effective in several inflammatory disorders, such as psoriasis, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome, ulcerative colitis, and different types of allergic disorders resulting from chronic inflammation. See Afofina et al., FEBS Journal 2015, DOI:10.1 111 / febs.13325. Also see Lowes et al., Ann Review 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. In recent years, findings have also suggested the importance of MALT1 in regulatory T cell (Treg) function and the control of homeostasis.Studies are underway to confirm the potential of MALT1 inhibitors for treating patients with solid tumors, either alone or in combination with immune checkpoint mechanisms. However, MALT1 inhibitors are not currently approved for therapeutic use.

Prior Art Documents

Non-Patent Documents

[0005]

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Summary of the Invention

[0006] Therefore, in this specification, a compound of formula (I):

Chemical formula

[0007] This specification also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0008] A method for treating CBM complex pathway-related cancer in a subject in need of treatment for CBM complex pathway-related cancer, comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is also provided.

[0009] A method for treating cancer in a subject in need of treatment for cancer, 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, or a pharmaceutical composition described herein, is also provided.

[0010] A method for treating cancer in a subject in need thereof, comprising administering to a subject identified as having a CBM complex pathway-related cancer an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Also provided is a method comprising administering to a subject identified or diagnosed as having a MALT1-related cancer an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for treating MALT1-related cancer in the subject.

[0011] Also provided is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with deregulation of the MALT1 gene, MALT1 protease, or the expression or activity or level of any of them; and (b) administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0012] A method for treating cancer in a subject in need thereof, (a) determining that the cancer is associated with deregulation of the MALT1 gene, MALT1 protease, or the expression or activity or level of any of them; and (b) administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0013] Also provided is a method for inhibiting metastasis in a cancer-bearing subject in need of treatment for inhibiting metastasis, comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0014] Also provided is a method for treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0015] A method for treating a CBM complex pathway-related disease or disorder in a subject in need of treatment for a CBM complex pathway-related disease or disorder, 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 described herein, is also provided.

[0016] A method for treating a disease or disorder in a subject in need of treatment for a disease or disorder, comprising: (a) identifying the disease or disorder as a CBM complex pathway-related disease or disorder; and (b) administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. The method is also provided.

[0017] A method for treating a disease or disorder in a subject in need of treatment for a disease or disorder, comprising: administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to a subject identified as having a CBM complex pathway-related disease or disorder. The method is also provided.

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

[0019] A method for treating a MALT1-related autoimmune disorder in a subject, comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to a subject identified or diagnosed as having a MALT1-related autoimmune disorder. The method is also provided.

[0020] A method for treating an autoimmune disorder in a subject in need of treatment for an autoimmune disorder, comprising: (a) determining that an autoimmune disorder is associated with a dysregulation of the MALT1 gene, MALT1 protease, or the expression or activity or level of any of them; (b) administering to a subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is also provided.

[0021] A method for treating a MALT1-related autoimmune disorder in a subject, comprising administering to a subject determined to have a MALT1-related autoimmune disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is also provided.

[0022] A method for treating an inflammatory disorder in a subject in need of treatment for an inflammatory disorder, comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is also provided.

[0023] A method for treating a MALT1-related inflammatory disorder in a subject, comprising administering to a subject identified or diagnosed as having a MALT1-related inflammatory disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is also provided.

[0024] A method for treating a MALT1-related inflammatory disorder in a subject, comprising administering to a subject identified or diagnosed as having a MALT1-related inflammatory disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is also provided.

[0025] A method for treating an inflammatory disorder in a subject in need of treatment for an inflammatory disorder, comprising (a) determining that an inflammatory disorder is associated with a dysregulation of the MALT1 gene, MALT1 protease, or the expression or activity or level of any of them; (b) administering to a subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. A method is also provided that includes these steps.

[0026] A method for treating a MALT1-related inflammatory disorder in a subject, comprising administering to a subject determined to have a MALT1-related inflammatory disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. A method is also provided that includes this step.

[0027] A method for inhibiting CBM complex pathway activity in mammalian cells, comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method is also provided that includes this step.

[0028] A method for inhibiting MALT1 protease activity in mammalian cells, comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method is also provided that includes this step.

[0029] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a CBM complex pathway-related disease or disorder is also provided.

[0030] A compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided for use in the manufacture of a medicament for the treatment of a CBM complex pathway-related disease or disorder.

[0031] A method for treating an individual having MALT1-related cancer, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof before, during, or after administration of another anti-cancer agent(s) (e.g., a first MALT1 inhibitor or another MALT1 inhibitor) is also provided.

[0032] Also provided herein is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0033] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof obtained by a process for preparing a compound as defined herein.

[0034] 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 belongs. Methods and materials are described herein for use in the present disclosure, and other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0035] Other features and advantages of the present disclosure will become apparent from the following detailed description of the invention and the claims. DETAILED DESCRIPTION OF THE INVENTION

[0036] As used herein, the term "compound" means to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures shown. In this specification, a compound identified by a name or structure as a particular tautomeric form is intended to include other tautomeric forms unless otherwise specified.

[0037] The term "tautomer" as used herein refers to compounds that have significantly different structures in the arrangement of atoms but exist in easy and rapid equilibrium. The compounds provided herein may be shown as different tautomers, and when a compound has tautomeric forms, it is intended that all tautomeric forms are within the scope of this disclosure, and it should be understood that the naming of the compound does not exclude any tautomer. The following is an example of the tautomeric forms included. [Chem.]

[0038] Certain compounds provided herein may contain one or more centers of asymmetry and, therefore, it will be understood that they can be prepared and isolated in a mixture of isomers such as a racemic mixture or in enantiomerically pure form.

[0039] The term "halo or halogen" refers to a halogen, one of Group 17 of the periodic table. Specifically, this term refers to fluorine, chlorine, bromine, and iodine. Preferably, this term refers to fluorine or chlorine.

[0040] The term "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Similarly, a C1-C3 alkyl group is a straight or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms.

[0041] The term "C1-C6 haloalkyl" refers to a hydrocarbon chain substituted by at least one halogen atom, such as fluorine, chlorine, bromine, and iodine, which is independently selected at each occurrence. The halogen atom may be present at any position on the hydrocarbon chain. Similarly, a C1-C3 haloalkyl group is a straight-chain or branched-chain hydrocarbon chain containing 1, 2, or 3 carbon atoms substituted by at least one halogen atom. For example, C1-C3 haloalkyl can refer to chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloroethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl and 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0042] The term "C1-C3 alkoxy" refers to a C1-C3 alkyl group bonded to a molecule through oxygen. This includes moieties where the alkyl portion can be straight-chain or branched-chain, such as methoxy, ethoxy, n-propoxy, and isopropoxy.

[0043] The term "C1-C3 haloalkoxy" refers to a C1-C3 alkyl group bonded to a molecule through oxygen, in which at least one hydrogen atom of the alkyl group is replaced by a halogen. This includes moieties where the alkyl portion can be straight-chain or branched-chain, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or trifluoropropoxy.

[0044]

Chemical formula

Chemical formula

[0045] As used herein, the term "cyano" refers to the -CN radical.

[0046] As used herein, the term "hydroxyl" refers to the -OH radical.

[0047] As used herein, the term "amino" refers to the -NH2 group.

[0048] As used herein, the term "aryl" refers to a 6- to 10-membered monocyclic or bicyclic group in which at least one ring in the system is aromatic and all carbon atoms are single-bonded. Non-limiting examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl. In a bicyclic ring system in which only one ring is aromatic, the non-aromatic ring can be a cycloalkyl group as defined herein.

[0049] As used herein, the term "heteroaryl" refers to a 5- to 10-membered or 5- to 9-membered monocyclic or bicyclic group in which at least one ring in the system is aromatic, and one or more carbon atoms in at least one ring in the system are replaced by heteroatoms independently selected from N, O, and S. The heteroaryl group includes rings in which one or more atoms (e.g., carbon, nitrogen, and sulfur) are oxidized, such as a pyridone moiety. Non-limiting examples of heteroaryl groups include pyridine, pyrimidine, pyridazine, pyrimidinone, pyrrole, pyrazole, imidazole, triazole, thiazole, and indole. In a bicyclic ring system in which only one ring is aromatic, the non-aromatic ring can be a cycloalkyl or heterocyclyl group as defined herein.

[0050] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 or 3 to 7 members, or a monocyclic hydrocarbon group of 3 to 6 members, and the bicyclic system includes fused, spiro (optionally referred to as a "spirocycloalkyl" group), and bridged ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0051] The term "heterocyclyl" refers to an aromatic-free, saturated or partially unsaturated monocyclic or bicyclic hydrocarbon ring system of 3 to 12 members, 3 to 8 members, or 4 to 6 members having at least one heteroatom within the ring selected from N, O, and S. The bicyclic heterocyclyl group includes fused, spiro (optionally referred to as a "spiroheterocyclyl" group), and bridged ring systems. The heterocyclyl ring system may include oxo substitution at one or more C, N, or S ring members. The heterocyclyl group may be represented, for example, as a "5- to 10-membered heterocyclyl group", which is a ring system containing 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. For example, 1, 2, or 3 heteroatoms may optionally be present, one or two of which may be present. The heterocyclyl group may be attached to the remainder of the molecule through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidin-2-one, sulfolane, isothiazoline S,S-dioxide, and decahydronaphthalenyl.

[0052] As used herein, the term "oxo" refers to the "=O" group attached to a carbon atom.

[0053] As used herein, the symbol

Chemical formula

[0054] It should be understood that the rings in the compounds of formula (I) containing atoms X, Y, and Z do not contain more than two adjacent nitrogen atoms.

[0055] The compounds of formula (I) include their pharmaceutically acceptable salts. In addition, the compounds of formula (I) may not necessarily be pharmaceutically acceptable salts, and other salts of such compounds that are useful as intermediates for preparing and / or purifying the compounds of formula (I) and / or for separating enantiomers of the compounds of formula (I) are also included. Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula (I) include trifluoroacetic acid and hydrochloride.

[0056] Furthermore, the compounds of formula (I) or their salts may be isolated in the form of solvates, and thus it will be understood that any such solvates are included within the scope of the present disclosure. For example, the compounds of formula (I) and their salts may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc.

[0057] In some embodiments, the compounds of formula (I) include the compounds of Examples 1-196, as well as their stereoisomers and pharmaceutically acceptable salts. In some embodiments, the compounds of formula (I) include the compounds of Examples 1-196 and their pharmaceutically acceptable salts. In some embodiments, the compounds of Examples 1-196 are in the free base form. In some embodiments, the compounds of Examples 1-196 are in the form of pharmaceutically acceptable salts.

[0058] The term "pharmaceutically acceptable" indicates that a compound, or its salt, or composition is chemically and / or toxicologically compatible with other ingredients in a formulation and / or the subject being treated therewith.

[0059] A protecting group can be a temporary substituent that protects a potentially reactive functional group from unwanted chemical transformations. The choice of the specific protecting group to be used is within the sufficient scope of the skill of one of ordinary skill in the art. Some considerations can determine the choice of protecting group, including, but not limited to, the functional group to be protected, other functionality present within the molecule, the reaction conditions at each step of the synthetic sequence, other protecting groups present within the molecule, the functional group tolerance to the conditions necessary to remove the protecting group, and the reaction conditions for the thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed (Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed. Wiley: New York, 1991).

[0060] A nitrogen protecting group can be any temporary substituent that protects an amine moiety from unwanted chemical transformations. Examples of moieties formed when such a protecting group is attached to an amine include, but are not limited to, allylamine, benzylamine (e.g., vegylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and tritylamine), acetylamide, trichloroacetamide, trifluoroacetamide, pent-4-enamide, phthalimide, carbamate (e.g., methyl carbamate, t-butyl carbamate, benzyl carbamate, allyl carbamate, 2,2,2-trichloroethyl carbamate, and 9-fluorenylmethyl carbamate), imine, and sulfonamide (e.g., benzenesulfonamide, p-toluenesulfonamide, and p-nitrobenzenesulfonamide).

[0061] An 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 attached to a hydroxyl include esters (e.g., acetyl, t-butylcarbonyl, and benzoyl), benzyl (e.g., benzyl, p-methoxybenzyl, and 2,4-dimethoxybenzyl, and trityl), carbonates (e.g., methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate, and benzyl carbonate), ketals, and acetals, and ethers, but are not limited thereto.

[0062] The compounds provided herein may also contain non-natural proportions of atomic isotopes in one or more of the atoms that make up such compounds. That is, the atoms, specifically when referring to compounds according to formula (I), are either naturally occurring or synthetically produced, and have either natural abundances or are in isotopically enriched forms, including all isotopes and mixtures of isotopes of that atom. For example, unless otherwise specified, when hydrogen is referred to, 1 H, 2 H, 3 H, or mixtures thereof are understood to be meant, and when carbon is referred to, 11 C, 12 C, 13 C, 14 C, or mixtures thereof are understood to be meant, and when nitrogen is referred to, 13 N, 14 N, 15 N, or mixtures thereof are understood to be meant, and when oxygen is referred to, 14 O, 15 O, 16 O, 17 O, 18 O, or mixtures thereof are understood to be meant, and when fluoro is referred to, 18 F, 19 F, or mixtures thereof are understood to be meant. For example, in deuterated alkyl and deuterated alkoxy groups, one or more hydrogen atoms are deuterium ( 2It is specifically replaced by (H). Since some of the aforementioned isotopes are radioactive, therefore, the compounds provided herein also include compounds having one or more isotopes of one or more of the atoms, including radioactive compounds, and mixtures thereof, wherein one or more non-radioactive atoms are replaced by one of its radioactively enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, such as cancer therapeutic agents, research reagents, such as assay reagents, and diagnostic agents, such as in vivo imaging agents. All isotope modifications of the compounds provided herein are intended to be encompassed within the scope of the present disclosure, whether radioactive or not.

[0063] For illustrative purposes, general methods for preparing compounds and key intermediates are provided herein. For more detailed descriptions of the individual reaction steps, see the Examples section below. One of ordinary skill in the art will understand that other synthetic routes can be used to synthesize the compounds of the present invention. Specific starting materials and reagents are shown in the schemes and discussed below, but other starting materials and reagents can be readily substituted to provide various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of the present disclosure using conventional chemistry well known to those of ordinary skill in the art.

[0064] The ability of the selected compound to act as a MALT1 inhibitor can be demonstrated by the biological assays described herein. The IC 50 values are shown in Table A.

[0065] The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful for treating diseases and disorders that can be treated by MALT1 inhibitors, such as MALT1-related cancers, including blood cancers and solid tumors, MALT1-related autoimmune disorders, and MALT1-related inflammatory disorders.

[0066] As used herein, the terms "treating" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of all or part of the symptoms associated with a disease, disorder or condition, whether detectable or not, diminishment of the extent of the disease, stabilization (i.e., not worsening) of the state of the disease, delay or slowing of the progression of the disease, improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete). "Treatment" can also mean prolonging the survival period as compared to the expected survival period if not receiving treatment.

[0067] As used herein, the term "subject" refers to any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented.

[0068] As used herein, the term "pediatric subject" refers to a subject less than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations including neonates (from birth to 1 month of age), infants (from 1 month to 2 years of age), children (from 2 years to 12 years of age), and adolescents (from 12 years to 21 years of age (including up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. 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 pediatric subject is from birth to 28 days of age, from 29 days to less than 2 years of age, from 2 years to less than 12 years of age, or from 12 years to 21 years of age (including up to but not including the 22nd birthday). In some embodiments, the pediatric subject is from birth to 28 days of age, from 29 days to less than 1 year of age, from 1 month to less than 4 months of age, from 3 months to less than 7 months of age, from 6 months to less than 1 year of age, from 1 year to less than 2 years of age, from 2 years to less than 3 years of age, from 2 years to less than 7 years of age, from 3 years to less than 5 years of age, from 5 years to less than 10 years of age, from 6 years to less than 13 years of age, from 10 years to less than 15 years of age, or from 15 years to less than 22 years of age.

[0069] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is useful for preventing diseases and disorders as defined herein (e.g., autoimmune disorders, inflammatory disorders, and cancer). As used herein, the term "preventing" means preventing the onset, recurrence, or spread of all or a portion of a disease or condition described herein, or its symptoms.

[0070] The term "regulatory agency" refers to a national agency for approving the medical use of pharmaceutical agents by the state. For example, a non-limiting example of a regulatory agency is the US Food and Drug Administration (FDA).

[0071] Signaling through 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 kB enhancer elements as various homo- and hetero-dimers and induce the transcription of several genes. Following the 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, presumably, via phosphorylation of CARD or CARMA proteins by the recruitment of protein kinase C (e.g., protein kinase C beta or protein kinase C theta) and the BCL10-MALT1 complex. See, for example, Xia, et al. OncoTargets and Therapy 11 (2018): 2063, Shi, and Sun. Mol. Immunol. 68.2 (2015): 546-557, Xia, et al. Cancer Immunol. Res. 2.9 (2014): 823-830, and Pan, Mol. Cancer Res. 14.1 (2016): 93-102.

[0072] As described above in this specification, the CBM complex can function as a scaffold protein in the activation of the NF-κB pathway. Once formed, the CBM complex can likely activate the IKK complex (e.g., IKKγ (also called NEMO), IKKα, and IKKβ) by ubiquitination of MALT1 (e.g., K63-linked ubiquitination), which results in the recruitment, ubiquitination (e.g., K63-linked ubiquitination), and degradation of IKKγ, thereby releasing IKKα and IKKβ to phosphorylate IκB, resulting in ubiquitination (e.g., K48-linked ubiquitination) and degradation of IκB and releasing the NF-κB transcription factors (typically, NF-κB1 subtypes: p50-RelA and p50-cRel) to the nucleus. This cascade is likely mediated by the ubiquitin ligase TRAF6 (tumor necrosis factor receptor (TNFR)-associated factor 6). The CBM complex can also affect NF-κB signaling through additional protein complexes such as TAB1 / 2-TAK and the linear ubiquitin chain assembly complex (LUBAC). See, e.g., Israeel, Cold Spring Harbor Perspectives in Biology 2.3 (2010): a000158, Xia, et al., OncoTargets and Therapy 11 (2018): 2063, Juilland, Front. Immunol. 9 (2018): 1927. MALT1 can also activate the JNK pathway (also called the JNK / AP-1 pathway), but little research has been done to study this area. See, e.g., Juilland, Front. Immunol. 9 (2018): 1927, and Wang, et al., Oncogenesis 6.7 (2017): e365-e365.

[0073] In addition, MALT1 has cysteine protease activity. Non-limiting examples of substrates of wild-type MALT1 include BCL10, A20, CYLD, RelB, Regnase-1, Rokkin-1, and HOIL1. In addition, the API2-MALT1 (amino terminus of the inhibitor of apoptosis 2, also called cIAP2) fusion protein has also been shown to cleave NIK and LIMA1α. Cleavage of BCL10 by MALT1 is thought to result in activation of BCL10-independent NF-κB. By cleaving A20 (TNF alpha-induced protein 3), since A20 is a deubiquitinating enzyme that has been shown to reduce ubiquitination of MALT1 and thus recruitment and activation of the IKK complex, MALT1 can reduce negative regulation of the NF-κB pathway. CYLD (CYLD lysine 63 deubiquitinating enzyme) is a deubiquitinating enzyme, and cleavage of this enzyme is thought to increase signaling through the NF-κB pathway and / or the JNK pathway by MALT1. Cleavage of RelB typically results in alleviation of negative regulation of the NF-κB pathway because RelB forms a transcriptionally inactive complex with RelA and c-Rel. By cleaving HOIL1 (also known as RBCK1), since HOIL1 is thought to reduce linear ubiquitination, negative regulation of NF-κB is thought to be alleviated. MALT1 can also auto-process, which promotes signaling through the NF-κB pathway through a mechanism that is not fully understood. By cleaving NIK (NF-κB-inducing kinase), the API2-MALT1 protease generates a C-terminal fragment of NIK that is resistant to proteasomal degradation, thereby increasing non-canonical NF-κB signaling. By cleaving LIMA1α (LIM domain and actin-binding protein 1), the tumor suppressor properties of this protein are reduced and the remaining fragment has oncogenic properties and is thought to promote cell proliferation, colony formation, and cell adhesion.Cleavage of Regnase-1 (also known as MCPIP-1 or Zc3h12a, a regulatory RNase) and Roquin-1 (also known as RC3H1) is thought to result in the stabilization of mRNAs, including those of cytokines, chemokines, and costimulatory proteins such as ICOS, OX40, and TNF. This activity may be independent of MALT1 activity within the NF-κB and JNK pathways. See, for example, Afonina, et al. FEBS J. 282.17 (2015): 3286-3297; Klein et al. Nat. Comm. 6.1 (2015): 1-17; Baens, et al. PloS one 9.8 (2014): e103774; and Juilland, Front. Immunol. 9 (2018): 1927. MALT1 is also involved in oncogenic BCR signaling in ibrutinib-responsive cell lines and biopsy samples, which is regulated by a multi-protein supercomplex formed by MYD88, TLR9, and BCR (hereinafter referred to as the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endosomes and drives survival-promoting NF-κB and mTOR signaling. See Phelan et al., Nature 2018 Aug;560(7718):387-391.

[0074] Thus, inhibition of MALT1 can provide a beneficial effect on many types of disorders associated with abnormal signaling in the NF-κB or JNK pathways. For example, inhibition of MALT1 can reduce flux through the NF-κB or JNK pathways resulting from one or more of the following. (1) Inactivated tumor suppressor genes. Non-limiting 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 Immunol. Res. 2.9 (2014): 823-830; Johansson, et al. Oncotarget 7.38 (2016): 62627.

[0075] (2) Dysregulated cell surface receptors. Non-limiting examples of cell surface receptors include HER1 and HER2. See, for example, Xia, et al. Cancer Immunol. Res. 2.9 (2014): 823-830, and Pan, Mol. Cancer Res. 14.1 (2016): 93-102.

[0076] (3) Dysregulation 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.

[0077] (4) Dysregulation of one or more substrates of MALT1 protease (e.g., wild-type MALT1 protease or dysregulated MALT1 protease). Non-limiting examples of substrates of MALT1 protease include BCL10, A20, CYLD, RelB, Regnase-1, Rok-1, HOIL1, NIK, and LIMA1α.

[0078] (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 called NEMO), IkBα, p50, p52, p65 (RelA), RelB, and c-Rel.

[0079] (6) Dysregulation of one or more components of the JNK pathway downstream of the CBM complex. Non-limiting 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 an AP-1 transcription factor (e.g., a heterodimer of any of the c-Fos, c-Jun, ATF, or JDP family).

[0080] (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.

[0081] (8)Dysregulation 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.

[0082] As used herein, the term "CBM complex pathway" includes genes, transcripts, and proteins within a signaling pathway that includes CBM. For example, many aspects of the NF-κB pathway are part of the CBM complex pathway. The CBM complex pathway can include, for example, cell surface receptors (e.g., CD28, BCR, HER1, and HER2), signal transducers between the cell surface receptor and the CBM complex (e.g., protein kinase C beta or protein kinase C theta), components of the CBM complex (e.g., MALT1, CARD11, CARD14, CARD10, CARD9, or BCL10), substrates of the MALT1 protease (e.g., BCL10, A20, CYLD, RelB, Regnase-1, Rok-1, HOIL1, NIK, and LIMA1α), 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 factor), or components of the My-T-BCR supercomplex (e.g., MYD88, TLR9, or mTOR).

[0083] As used herein, the term "CBM complex pathway-related disease or disorder" refers to a disease or disorder associated with or having dysregulation of a gene within the CBM complex pathway, a protein within the CBM complex pathway, or any (e.g., one or more) of their expression or activity or levels (e.g., any of the types of dysregulation of the expression or activity or levels of a gene within the CBM complex pathway, a protein within the CBM complex pathway, or any of them described herein). Non-limiting examples of CBM complex pathway-related diseases or disorders include, for example, CBM-related primary immunodeficiency, autoimmune disorders, multiple sclerosis, colitis, psoriasis, and cancer. See, for example, McGuire, et al. J. Neuroinflamm. 11.1 (2014): 1-12, Lu, et al., Front. Immunol. 9 (2018): 2078, Jaworski, et al., EMBO J. 33.23 (2014): 2765-2781. Non-limiting examples of CBM complex pathway-related diseases or disorders include MALT1-related diseases or disorders such as MALT1-related cancer, MALT1-related autoimmune disorders, and MALT1-related inflammatory disorders.

[0084] As used herein, the term "CBM complex pathway-related autoimmune disorder" refers to an autoimmune disorder associated with or having dysregulation of a CBM complex pathway gene, a CBM complex pathway protein, or any (e.g., one or more) of their expression or activity or levels (e.g., any of the types of dysregulation of the expression or activity or levels of a CBM complex pathway gene, a CBM complex pathway protein, or any of them described herein). Non-limiting examples of CBM complex pathway-related autoimmune disorders are described herein.

[0085] As used herein, the term "CBM complex pathway-related inflammatory disorder" refers to an inflammatory disorder associated with, or having a dysregulation of (e.g., any of the types of dysregulation of the expression, activity, or level of a CBM complex pathway gene, a CBM complex pathway protein, or any of them (e.g., one or more)), a CBM complex pathway gene, a CBM complex pathway protein, or any of them. Non-limiting examples of CBM complex pathway-related inflammatory disorders are described herein.

[0086] In some embodiments, the CBM complex pathway-related disease or disorder is a CBM complex pathway cell surface receptor-related cancer (e.g., CD28-related cancer, BCR-related cancer, HER1-related cancer, or HER2-related cancer), a cancer associated with a signal transducer between a cell surface receptor and the CBM complex (e.g., protein kinase C beta (PKCβ)-related cancer or protein kinase C theta (PCKθ)-related cancer), a component of a CBM complex-related cancer (e.g., MALT1-related cancer, CARD11-related cancer, CARD14-related cancer, CARD10-related cancer, CARD9-related cancer, or BCL10-related cancer), a MALT1 protease substrate-related cancer (e.g., BCL10-related cancer, A20-related cancer, CYLD-related cancer, RelB-related cancer, Regnase-1-related cancer, Rok-1-related cancer, HOIL1-related cancer, NIK-related cancer, or LIMA1α-related cancer), a cancer associated with a component of the NF-κB pathway downstream of the CBM complex (e.g., TAK1-related cancer, TRAF6-related cancer, TAB1-related cancer, TAB2-related cancer, TAB3-related cancer, MKK7-related cancer, IKKα-related cancer, IKKβ-related cancer, IKKγ-related cancer, IkBα-related cancer, p50-related cancer, p65 (RelA)-related cancer, or c-Rel-related cancer), a cancer associated with a component of the JNK pathway downstream of the CBM complex (e.g., JNK1-related cancer, JNK2-related cancer, JNK3-related cancer, or AP-1 transcription factor-related cancer), MYD88-related cancer, or a combination thereof, such as a CBM complex pathway-related cancer.

[0087] The term "CBM complex pathway-related cancer", as used herein, refers to a cancer that is associated with, or has a dysregulation of, (e.g., at the time of diagnosis, or after developing resistance to a previous therapy) a gene within the CBM complex pathway, a protein within the CBM complex pathway, or the expression or activity or level of any of them (e.g., one or more), such as any of the types of dysregulation of the expression or activity or level of a gene within the CBM complex pathway, a protein within the CBM complex pathway, or any of them described herein. Non-limiting examples of CBM complex pathway-related cancers are described herein. In some embodiments, the CBM pathway-related cancer is a CBM complex pathway cell surface receptor-related cancer (e.g., CD28-related cancer, BCR-related cancer, HER1-related cancer, or HER2-related cancer), a cancer associated with a signal transducer between a cell surface receptor and the CBM complex (e.g., protein kinase C beta (PKCβ)-related cancer or protein kinase C theta (PCKθ)-related cancer), a component of the CBM complex-related cancer (e.g., MALT1-related cancer, CARD11-related cancer, CARD14-related cancer, CARD10-related cancer, CARD9-related cancer, or BCL10-related cancer), a MALT1 protease substrate-related cancer (e.g., BCL10-related cancer, A20-related cancer, CYLD-related cancer, RelB-related cancer, Regnase-1-related cancer, Rok1-related cancer, HOIL1-related cancer, NIK-related cancer, or LIMA1α-related cancer), a cancer associated with a component of the NF-κB pathway downstream of the CBM complex (e.g., TAK1-related cancer, TRAF6-related cancer, TAB1-related cancer, TAB2-related cancer, TAB3-related cancer, MKK7-related cancer, IKKα-related cancer, IKKβ-related cancer, IKKγ-related cancer, IkBα-related cancer, p50-related cancer, p65 (RelA)-related cancer, or c-Rel-related cancer), a cancer associated with a component of the JNK pathway downstream of the CBM complex (e.g., JNK1-related cancer, JNK2-related cancer, JNK3-related cancer, or AP-1 transcription factor-related cancer), or a combination thereof.

[0088] In some embodiments, deregulation can be deregulation that results in abnormal activation of a gene, protein, or the expression or activity or level of any of them. Activation can be through any suitable mechanism, including, but not limited to, gene amplification, activating mutations, activating translocations, transcriptional activation, epigenetic changes, and / or overexpression of the protein product of an oncogene. In some embodiments, deregulation can be deregulation that results in abnormal inactivation of a gene, protein, or the expression or activity or level of any of them. Inactivation can be through any suitable mechanism, including, but not limited to, gene deletion, inactivating mutations, inactivating translocations, transcriptional silencing, epigenetic changes, and degradation of the gene's mRNA and / or protein product. Typically, as used herein, deregulation is deregulation that results in increased signaling through the NF-κB or JNK signaling pathway, whether it is activation or inactivation.

[0089] The term "wild type" describes a nucleic acid or protein (e.g., the MALT1 gene, MALT1 mRNA, or MALT1 protein) that is found in a subject that does not have (and optionally also does not have an increased risk of developing, and / or is not suspected of having) a disease or disorder associated with the nucleic acid or protein (e.g., MALT1-related cancer, autoimmune disorder, or inflammatory disorder), or that is found in a cell or tissue from a subject that does not have (and optionally also does not have an increased risk of developing, and / or is not suspected of having) a disease or disorder associated with the nucleic acid or protein (e.g., MALT1-related cancer, autoimmune disorder, or inflammatory disorder).

[0090] In some embodiments, the subject has been identified or diagnosed as having a cancer (CBM complex pathway-related cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit) associated with dysregulation of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of any of them. In some embodiments, the subject has a cancer that is resistant to one or more previous therapies. In some embodiments, the subject has a tumor that is positive for dysregulation of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). The subject can be a subject having a tumor (s) that is positive for dysregulation of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). The subject can be a subject in which the tumor has dysregulation of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of them (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an FDA-approved assay or kit). In some embodiments, the subject has a tumor that is resistant to one or more previous therapies. In some embodiments, the subject is suspected of having a CBM complex pathway-related cancer. In some embodiments, the subject has a tumor that is suspected of being resistant to one or more previous therapies.In some embodiments, the subject has a clinical record indicating that the subject has a tumor having dysregulation of an CBM complex pathway-related gene (e.g., the MALT1 gene), an CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of any of them (and optionally, the clinical record indicates that the subject should be treated by 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 previous therapies. In some embodiments, the subject is identified or diagnosed as having a cancer associated with dysregulation of an CBM complex pathway-related gene (e.g., the MALT1 gene), an CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of any of them, as determined based on histological examination (CBM complex pathway-related cancer).

[0091] In some embodiments, the subject is identified or diagnosed as having an autoimmune disorder associated with dysregulation of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of any of them (an autoimmune disorder associated with the CBM complex pathway) (e.g., as determined using an assay or kit approved by a regulatory agency, such as the FDA). In some embodiments, the subject has a tumor that is positive for dysregulation of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as the FDA). In some embodiments, the subject is suspected of having an autoimmune disorder associated with the CBM complex pathway. In some embodiments, the subject has a clinical record indicating that the subject has a tumor having dysregulation of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of 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 is identified or diagnosed as having an autoimmune disorder associated with the CBM complex pathway (an autoimmune disorder associated with the CBM complex pathway) determined to be associated with dysregulation of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or the expression or activity or level of any of them based on histological examination.

[0092] In some embodiments, the subject is identified or diagnosed as having an inflammatory disorder associated with dysregulation of CBM complex pathway-related genes (e.g., MALT1 gene), CBM complex pathway-related proteins (e.g., MALT1 protein), or the expression or activity or level of any of them (inflammatory disorder associated with CBM complex pathway, e.g., as determined using an assay or kit approved by a regulatory agency, e.g., an assay or kit approved by the FDA). In some embodiments, the subject has a tumor that is positive for dysregulation of CBM complex pathway-related genes (e.g., MALT1 gene), CBM complex pathway-related proteins (e.g., MALT1 protein), or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., an assay or kit approved by the FDA). In some embodiments, the subject is suspected of having an inflammatory disorder associated with CBM complex pathway. In some embodiments, the subject has a clinical record indicating that the subject has a tumor having dysregulation of CBM complex pathway-related genes (e.g., MALT1 gene), CBM complex pathway-related proteins (e.g., MALT1 protein), or the expression or activity or level of 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 is identified or diagnosed as having an inflammatory disorder associated with CBM complex pathway-related genes (e.g., MALT1 gene), CBM complex pathway-related proteins (e.g., MALT1 protein), or the expression or activity or level of any of them, as determined based on histological examination.

[0093] As used herein, the term "CBM complex pathway cell surface receptor-related cancer" refers to a cancer associated with, or having dysregulation of, the expression, activity, or level of a gene, protein, or any (e.g., one or more) of them related to the CBM complex pathway cell surface receptor. In some embodiments, the CBM complex pathway cell surface receptor-related cancer is selected from the group consisting of CD28-related cancer, BCR-related cancer, HER1-related cancer, HER2-related cancer, and combinations thereof.

[0094] The term "**-associated cancer" as used herein refers to a cancer that is associated with or has dysregulation (e.g., any of the types of dysregulation of the expression or activity or level of a gene, protein, or any of them (e.g., one or more) as described herein) of a gene, protein, or any of them, and "**" refers to a specific CBM complex pathway gene or protein described herein. In some embodiments, the **-associated cancer is selected from the group consisting of CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, HER2-associated cancer, PKCβ-associated cancer, PKCθ-associated cancer, MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, A20-associated cancer, CYLD-associated cancer, RelB-associated cancer, HOIL1-associated cancer, NIK-associated cancer, Legumain1-associated cancer, LIMA1α-associated cancer, Rockin-1-associated cancer, TRAF6-associated cancer, TAK1-associated cancer, TAB1-associated cancer, TAB2-associated cancer, TAB3-associated cancer, MKK7-associated cancer, IKKα-associated cancer, IKKβ-associated cancer, IKKγ-associated cancer, IkBα-associated cancer, p50-associated cancer, p65-associated cancer, c-Rel-associated cancer, JNK1-associated cancer, JNK2-associated cancer, JNK3-associated cancer, MYD88 transcription factor-associated cancer, and AP-1 transcription factor-associated cancer. In some embodiments, the **-associated cancer is CD28-associated cancer. In some embodiments, the **-associated cancer is BCR-associated cancer. In some embodiments, the **-associated cancer is HER1-associated cancer. In some embodiments, the **-associated cancer is HER2-associated cancer. In some embodiments, the **-associated cancer is PKCβ-associated cancer. In some embodiments, the **-associated cancer is PKCθ-associated cancer. In some embodiments, the **-associated cancer is MALT1-associated cancer. In some embodiments, the **-associated cancer is CARD11-associated cancer. In some embodiments, the **-associated cancer is CARD14-associated cancer. In some embodiments, the **-associated cancer is A20-associated cancer. In some embodiments, the **-associated cancer is CYLD-associated cancer. In some embodiments, the **-associated cancer is RelB-associated cancer. In some embodiments, the **-associated cancer is HOIL1-associated cancer.In some embodiments, the related cancer is an NIK-related cancer. In some embodiments, the related cancer is a Regnase-1-related cancer. In some embodiments, the related cancer is an LIMA1α-related cancer. In some embodiments, the related cancer is a Rok-in-1-related cancer. In some embodiments, the related cancer is a TRAF6-related cancer. In some embodiments, the related cancer is a TAK1-related cancer. In some embodiments, the related cancer is a TAB1-related cancer. In some embodiments, the related cancer is a TAB2-related cancer. In some embodiments, the related cancer is a TAB3-related cancer. In some embodiments, the related cancers are MKK7-related cancer and IKKα-related cancer. In some embodiments, the related cancer is an IKKβ-related cancer. In some embodiments, the related cancer is an IKKγ-related cancer. In some embodiments, the related cancer is an IkBα-related cancer. In some embodiments, the related cancer is a p50-related cancer. In some embodiments, the related cancer is a p65-related cancer. In some embodiments, the related cancer is a c-Rel-related cancer. In some embodiments, the related cancer is a JNK1-related cancer. In some embodiments, the related cancer is a JNK2-related cancer. In some embodiments, the related cancer is a JNK3-related cancer. In some embodiments, the related cancer is an AP-1 transcription factor-related cancer. In some embodiments, the related cancer is a MYD88 transcription factor-related cancer.

[0095] The phrase "dysregulation of a gene, protein, or the expression, activity, or level of any of them" (*being a specific CBM complex pathway gene or protein described herein) refers to gene mutations (e.g., chromosomal translocations that result in the expression of a fusion protein including a domain and a fusion partner, mutations in a *gene that result in the expression of a *protein containing at least one amino acid deletion compared to the wild-type *protein, mutations in a *gene that result in the expression of a *protein with one or more point mutations compared to the wild-type *protein, mutations in a *gene that result in the expression of a *protein with at least one inserted amino acid compared to the wild-type *protein, gene duplications that result in an increase in the level of a *protein within a cell, or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in an increase in the level of a *protein within a cell), an alternative splice version of an mRNA that results in a *protein having at least one amino acid deletion in the *protein compared to the wild-type *protein, or an increase (e.g., an increase in level) in the expression of a wild-type *protein within a mammalian cell due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As a further example, an increase in the copy number of a *gene can result in overexpression of the *protein. For example, dysregulation of a *gene, *protein, or the expression, activity, or level of any of them can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion of * and a second portion of a partner protein (i.e., one that is not *). In some examples, dysregulation of a *gene, *protein, or the expression, activity, or level of any of them can be the result of a gene translocation between one *gene and another non-* gene.In some embodiments, the gene, protein, or the expression or activity or level of any of them is selected from the group consisting of CD28, BCR, HER1, HER2, PKCβ, PKCθ, MALT1, CARD11, CARD14, A20, CYLD, RelB, HOIL1, NIK, Legumain1, LIMA1α, Rockin-1, TRAF6, TAK1, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65, c-Rel, JNK1, JNK2, JNK3, MYD88, and AP-1 transcription factor. 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 Legumain1. In some embodiments, the gene or protein is LIMA1α. In some embodiments, the gene or protein is Rockin-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.

[0096] In some embodiments, dysregulation of the expression, activity, or level of a gene, protein, or any of them may be a mutation in a gene that encodes a protein that is constitutively active or has increased activity compared to a protein encoded by a gene without a mutation. In some embodiments, an increase in the copy number of a gene can result in 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 a gene, protein, or any of them is CARD10. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is CARD11. In some embodiments, the expression, activity, or level of a gene, protein, or any of them is MALT1.

[0097] As another example, dysregulation of a *gene, *protein, or the expression or activity or level of any of them may be a mutation in a *gene that encodes a *protein that is constitutively inactive or has reduced activity compared to a protein encoded by a *gene that does not contain a mutation. In some embodiments, the *gene, *protein, or the expression or activity or level of any of them is A20. In some embodiments, the *gene, *protein, or the expression or activity or level of any of them is CYLD. In some embodiments, the *gene, *protein, or the expression or activity or level of any of them is RelB. In some embodiments, the *gene, *protein, or the expression or activity or level of any of them is HOIL1. In some embodiments, the *gene, *protein, or the expression or activity or level of any of them is NIK.

[0098] A disease or disorder "associated with" a particular gene or protein described herein refers to a disease or disorder that is associated with or has dysregulation of a particular gene, a particular protein, or the expression or activity or level of any of them (e.g., any of the types of dysregulation of a particular gene, a particular protein, or the expression or activity or level of any of them described herein). Non-limiting examples of such diseases or disorders are described herein. Similarly, a cancer "associated with" a particular gene or protein described herein refers to a cancer that is associated with or has dysregulation of a particular gene, a particular protein, or the expression or activity or level of any of them (e.g., any of the types of dysregulation of a particular gene, a particular protein, or the expression or activity or level of any of them described herein). Non-limiting examples of such cancers are described herein.

[0099] Exemplary sequences of the proteins described in this specification are shown below.

[0100] Exemplary sequences of human CD28 are shown below. SEQ ID NO: 1 (UniParc accession number UPI0000043F4D) MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLD SAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIYFCKIEVMYPP PYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVR SKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0101] Non-limiting examples of dysregulation of the CD28 gene or CD28 protein can be found, for example, in 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.

[0102] Exemplary sequences of human BCR are shown below. SEQ ID NO: 2 (UniParc accession number UPI000016A088) MVDPVGFAEAWKAQFPDSEPPRMELRSVGDIEQELERCKASIRRLEQEVNQERFRMIYLQ TLLAKEKKSYDRQRWGFRRAAQAPDGASEPRASASRPQPAPADGADPPPAEEPEARPDGE GSPGKARPGTARRPGAAASGERDDRGPPASVAALRSNFERIRKGHGQPGADAEKPFYVNV EFHHERGLVKVNDKEVSDRISSLGSQAMQMERKKSQHGAGSSVGDASRPPYRGRSSESSC GVDGDYEDAELNPRFLKDNLIDANGGSRPPWPPLEYQPYQSIYVGGMMEGEGKGPLLRSQ STSEQEKRLTWPRRSYSPRSFEDCGGGYTPDCSSNENLTSSEEDFSSGQSSRVSPSPTTY RMFRDKSRSPSQNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDGEG AFHGDADGSFGTPPGYGCAADRAEEQRRHQDGLPYIDDSPSSSPHLSSKGRGSRDALVSG ALESTKASELDLEKGLEMRKWVLSGILASEETYLSHLEALLLPMKPLKAAATTSQPVLTS QQIETIFFKVPELYEIHKEFYDGLFPRVQQWSHQQRVGDLFQKLASQLGVYRAFVDNYGV AMEMAEKCCQANAQFAEISENLRARSNKDAKDPTTKNSLETLLYKPVDRVTRSTLVLHDL LKHTPASHPDHPLLQDALRISQNFLSSINEEITPRRQSMTVKKGEHRQLLKDSFMVELVE GARKLRHVFLFTDLLLCTKLKKQSGGKTQQYDCKWYIPLTDLSFQMVDELEAVPNIPLVP DEELDALKIKISQIKNDIQREKRANKGSKATERLKKKLSEQESLLLLMSPSMAFRVHSRN GKSYTFLISSDYERAEWRENIREQQKKCFRSFSLTSVELQMLTNSCVKLQTVHSIPLTIN KEDDESPGLYGFLNVIVHSATGFKQSSNLYCTLEVDSFGYFVNKAKTRVYRDTAEPNWNE EFEIELEGSQTLRILCYEKCYNKTKIPKEDGESTDRLMGKGQVQLDPQALQDRDWQRTVI AMNGIEVKLSVKFNSREFSLKRMPSRKQTGVFGVKIAVVTKRERSKVPYIVRQCVEEIER RGMEEVGIYRVSGVATDIQALKAAFDVNNKDVSVMMSEMDVNAIAGTLKLYFRELPEPLF TDEFYPNFAEGIALSDPVAKESCMLNLLLSLPEANLLTFLFLLDHLKRVAEKEAVNKMSL HNLATVFGPTLLRPSEKESKLPANPSQPITMTDSWSLEVMSQVQVLLYFLQLEAIPAPDS KRQSILFSTEV

[0103] Non-limiting examples of dysregulation of the BCR gene or BCR protein (e.g., BCR-ABL fusion) can be found, for example, in 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.

[0104] An exemplary sequence of human HER1 is shown below. SEQ ID NO: 3 (UniParc accession number UPI000003E750) MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEV VLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALA VLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDF QNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGC TGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYV VTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFK NCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAF ENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKL FGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCN LLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVM GENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVV ALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGS GAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGI CLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAA RNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPK FRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQ QGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTED SIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLN TVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRV APQSSEFIGA

[0105] Non-limiting examples of deregulation of the HER1 gene or HER1 protein can be found, for example, in Zhang, et al., Oncotarget 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.

[0106] Exemplary sequences of human HER2 are shown below. SEQ ID NO: 4 (UniParc accession number UPI000003F55F) MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNL ELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNG DPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLA LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQC AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSAN IQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLP DLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQEC VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVG ILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETEL RKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSP YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVR LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWM IDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDA EEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEG AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYV NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV

[0107] Non-limiting examples of deregulation of the HER2 gene or HER2 protein can be found, for example, in 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).

[0108] As used herein, the term "cancer associated with a signal transducer between a cell surface receptor and a CBM complex" refers to a cancer associated with or having a dysregulation of the expression, activity, or level of a gene, protein, or any (e.g., one or more) of them between a cell surface receptor and a CBM complex. In some embodiments, the cancer associated with a signal transducer between a cell surface receptor and a CBM complex is selected from the group consisting of PKCβ-related cancer, PCKθ-related cancer, and combinations thereof. A cancer "associated with" a particular gene or protein described in this paragraph refers to a cancer associated with or having a dysregulation (e.g., any of the types of dysregulation of the expression, activity, or level of a particular gene, a particular protein, or any of them described herein) of the expression, activity, or level of a particular gene, a particular protein, or any of them. Non-limiting examples of such cancers are described herein.

[0109] An exemplary sequence of human PKCβ is shown below. SEQ ID NO: 5 (UniParc accession number UPI000012DF67) MADPAAGPPPSEGEESTVRFARKGALRQKNVHEVKNHKFTARFFKQPTFCSHCTDFIWGF GKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPASDDPRSKHKFKIHTYSSPTFCDHCGS LLYGLIHQGMKCDTCMMNVHKRCVMNVPSLCGTDHTERRGRIYIQAHIDRDVLIVLVRDA KNLVPMDPNGLSDPYVKLKLIPDPKSESKQKTKTIKCSLNPEWNETFRFQLKESDKDRRL SVEIWDWDLTSRNDFMGSLSFGISELQKASVDGWFKLLSQEEGEYFNVPVPPEGSEANEE LRQKFERAKISQGTKVPEEKTTNTVSKFDNNGNRDRMKLTDFNFLMVLGKGSFGKVMLSE RKGTDELYAVKILKKDVVIQDDDVECTMVEKRVLALPGKPPFLTQLHSCFQTMDRLYFVM EYVNGGDLMYHIQQVGRFKEPHAVFYAAEIAIGLFFLQSKGIIYRDLKLDNVMLDSEGHI KIADFGMCKENIWDGVTTKTFCGTPDYIAPEIIAYQPYGKSVDWWAFGVLLYEMLAGQAP FEGEDEDELFQSIMEHNVAYPKSMSKEAVAICKGLMTKHPGKRLGCGPEGERDIKEHAFF RYIDWEKLERKEIQPPYKPKARDKRDTSNFDKEFTRQPVELTPTDKLFIMNLDQNEFAGF SYTNPEFVINV

[0110] An exemplary sequence of human PKCθ is shown below. SEQ ID NO: 6 (UniParc accession number UPI000012DF74) MSPFLRIGLSNFDCGSCQSCQGEAVNPYCAVLVKEYVESENGQMYIQKKPTMYPPWDSTF DAHINKGRVMQIIVKGKNVDLISETTVELYSLAERCRKNNGKTEIWLELKPQGRMLMNAR YFLEMSDTKDMNEFETEGFFALHQRRGAIKQAKVHHVKCHEFTATFFPQPTFCSVCHEFV WGLNKQGYQCRQCNAAIHKKCIDKVIAKCTGSAINSRETMFHKERFKIDMPHRFKVYNYK SPTFCEHCGTLLWGLARQGLKCDACGMNVHHRCQTKVANLCGINQKLMAEALAMIESTQQ ARCLRDTEQIFREGPVEIGLPCSIKNEARPPCLPTPGKREPQGISWESPLDEVDKMCHLP EPELNKERPSLQIKLKIEDFILHKMLGKGSFGKVFLAEFKKTNQFFAIKALKKDVVLMDD DVECTMVEKRVLSLAWEHPFLTHMFCTFQTKENLFFVMEYLNGGDLMYHIQSCHKFDLSR ATFYAAEIILGLQFLHSKGIVYRDLKLDNILLDKDGHIKIADFGMCKENMLGDAKTNTFC GTPDYIAPEILLGQKYNHSVDWWSFGVLLYEMLIGQSPFHGQDEEELFHSIRMDNPFYPR WLEKEAKDLLVKLFVREPEKRLGVRGDIRQHPLFREINWEELERKEIDPPFRPKVKSPFD CSNFDKEFLNEKPRLSFADRALINSMDQNMFRNFSFMNPGMERLIS

[0111] As used herein, the term "constituent of CBM complex-related cancer" refers to a cancer that is associated with dysregulation of the expression, activity, or level of a gene, protein, or any one (e.g., one or more) of them that is associated with the constituents of the CBM complex, or has dysregulation. In some embodiments, the constituent of CBM complex-related cancer is selected from the group consisting of MALT1-related cancer, CARD11-related cancer, CARD14-related cancer, CARD10-related cancer, CARD9-related cancer, BCL10-related cancer, and combinations thereof. In some embodiments, the CBM complex-related cancer is selected from the group consisting of MALT1-related cancer, CARD11-related cancer, BCL10-related cancer, and combinations thereof. A cancer "associated with" a particular gene or protein described in this paragraph refers to a cancer that is associated with or has dysregulation of the expression, activity, or level of a particular gene, a particular protein, or any one (e.g., one or more) of them (e.g., any one of the types of dysregulation of the expression, activity, or level of a particular gene, a particular protein, or any one of them described herein). Non-limiting examples of such cancers are described herein.

[0112] The term "MALT1-related autoimmune disorder", as used herein, refers to an autoimmune disorder that is associated with or has dysregulation (e.g., any of the types of dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as the MALT1 protease protein or MALT1 protease), or any one or more thereof, such as those described herein for the MALT1 gene, MALT1 protease, MALT1 protease domain, or any of them) of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as the MALT1 protease protein or MALT1 protease), or any one or more thereof. Non-limiting examples of MALT1-related autoimmune disorders are described herein.

[0113] The term "MALT1-related inflammatory disorder", as used herein, refers to an inflammatory disorder that is associated with or has dysregulation (e.g., any of the types of dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as the MALT1 protease protein or MALT1 protease), or any one or more thereof, such as those described herein for the MALT1 gene, MALT1 protease, MALT1 protease domain, or any of them) of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as the MALT1 protease protein or MALT1 protease), or any one or more thereof. Non-limiting examples of MALT1-related inflammatory disorders are described herein.

[0114] As used herein, the term "MALT1-related cancer" refers to a cancer that is associated with, or has deregulation of, the MALT1 gene, the MALT1 protein (also referred to herein as the MALT1 protease protein or MALT1 protease), or any (e.g., one or more) of their expression or activity or level (e.g., any of the types of deregulation of the expression or activity or level of the MALT1 gene, the MALT1 protein, the MALT1 protease domain, or any of them as described herein). Non-limiting examples of MALT1-related cancers are described herein.

[0115] The term "dysregulation of the MALT1 gene, MALT1 protein, or the expression or activity or level of any of them" refers to gene mutations (e.g., chromosomal translocations that result in the expression of a fusion protein including the MALT1 protease domain and a fusion partner, mutations in the MALT1 gene that result in the expression of a MALT1 protein containing at least one amino acid deletion compared to the wild-type MALT1 protein, mutations in the MALT1 gene that result in the expression of a MALT1 protein with one or more point mutations compared to the wild-type MALT1 protein, mutations in the MALT1 gene that result in the expression of a MALT1 protein with at least one inserted amino acid compared to the wild-type MALT1 protein, gene duplications that result in an increase in the level of intracellular MALT1 protein, or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in an increase in the level of intracellular MALT1 protein), alternative splice versions of MALT1 mRNA that result in a MALT1 protein having at least one amino acid deletion in the MALT1 protein compared to the wild-type MALT1 protein, or an increase (e.g., an increase in level) in the expression of wild-type MALT1 protein in mammalian cells due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the MALT1 gene, MALT1 protein, or the expression or activity or level of any of them can be a mutation in the MALT1 gene that encodes a MALT1 protein that is constitutively active or has increased activity compared to the protein encoded by the MALT1 gene without the mutation. As a further example, an increase in the copy number of the MALT1 gene can result in overexpression of MALT1 protease. For example, dysregulation of the MALT1 gene, MALT1 protein, or the expression or activity or level of any of them can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion of MALT1 containing a functional protease domain and a second portion of a partner protein (i.e., it is not MALT1).In some cases, dysregulation of the MALT1 gene, the MALT1 protein, or the expression or activity or level of any of them can be the result of a gene translocation between one MALT1 gene and another non-MALT1 gene.

[0116] Exemplary sequences of human MALT1 are shown below. SEQ ID NO: 7 (UniParc accession number UPI000004D05E) MSLLGDPLQALPPSAAPTGPLLAPPAGATLNRLREPLLRRLSELLDQAPEGRGWRRLAEL AGSRGRLRLSCLDLEQCSLKVLEPEGSPSLCLLKLMGEKGCTVTELSDFLQAMEHTEVLQ LLSPPGIKITVNPESKAVLAGQFVKLCCRATGHPFVQYQWFKMNKEIPNGNTSELIFNAV HVKDAGFYVCRVNNNFTFEFSQWSQLDVCDIPESFQRSVDGVSESKLQICVEPTSQKLMP GSTLVLQCVAVGSPIPHYQWFKNELPLTHETKKLYMVPYVDLEHQGTYWCHVYNDRDSQD SKKVEIIIGRTDEAVECTEDELNNLGHPDNKEQTTDQPLAKDKVALLIGNMNYREHPKLK APLVDVYELTNLLRQLDFKVVSLLDLTEYEMRNAVDEFLLLLDKGVYGLLYYAGHGYENF GNSFMVPVDAPNPYRSENCLCVQNILKLMQEKETGLNVFLLDMCRKRNDYDDTIPILDAL KVTANIVFGYATCQGAEAFEIQHSGLANGIFMKFLKDRLLEDKKITVLLDEVAEDMGKCH LTKGKQALEIRSSLSEKRALTDPIQGTEYSAESLVRNLQWAKAHELPESMCLKFDCGVQI QLGFAAEFSNVMIIYTSIVYKPPEIIMCDAYVTDFPLDLDIDPKDANKGTPEETGSYLVS KDLPKHCLYTRLSSLQKLKEHLVFTVCLSYQYSGLEDTVEDKQEVNVGKPLIAKLDMHRG LGRKTCFQTCLMSNGPYQSSAATSGGAGHYHSLQDPFHGVYHSHPGNPSNVTPADSCHCS RTPDAFISSFAHHASCHFSRSNVPVETTDEIPFSFSDRLRISEK

[0117] Non-limiting examples of dysregulation of the MALT1 gene or MALT1 protein are shown in Table B1 below.

Table B1

[0118] The term "CARD11-related autoimmune disorder", as used herein, refers to an autoimmune disorder that is associated with or has dysregulation of the CARD11 gene, the CARD11 protein, or any (e.g., one or more) of their expression or activity or level of expression or activity or level (e.g., any of the types of dysregulation of the CARD11 gene, the CARD11 protein, or any of them described herein).

[0119] The term "CARD11-related inflammatory disorder", as used herein, refers to an inflammatory disorder that is associated with or has dysregulation of the CARD11 gene, the CARD11 protein, or any (e.g., one or more) of their expression or activity or level of expression or activity or level (e.g., any of the types of dysregulation of the CARD11 gene, the CARD11 protein, or any of them described herein).

[0120] As used herein, the term "CARD11-related cancer" refers to a cancer that is associated with, or has deregulation (e.g., any of the types of deregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any one or more thereof as described herein) of the CARD11 gene, CARD11 protein, or any one or more thereof. Non-limiting examples of CARD11-related cancers are described herein.

[0121] The phrase "dysregulation of the CARD11 gene, CARD11 protein, or the expression or activity or level of any of them" refers to gene mutations (e.g., chromosomal translocations that result in the expression of a fusion protein including the CARD11 domain and a fusion partner, mutations in the CARD11 gene that result in the expression of a CARD11 protein containing at least one amino acid deletion compared to the wild-type CARD11 protein, mutations in the CARD11 gene that result in the expression of a CARD11 protein with one or more point mutations compared to the wild-type CARD11 protein, mutations in the CARD11 gene that result in the expression of a CARD11 protein with at least one inserted amino acid compared to the wild-type CARD11 protein, gene duplications that result in an increase in the level of the CARD11 protein within the cell, or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in an increase in the level of the CARD11 protein within the cell), alternative splice versions of CARD11 mRNA that result in a CARD11 protein having at least one amino acid deletion in the CARD11 protein compared to the wild-type CARD11 protein, or an increase (e.g., an increase in level) in the expression of the wild-type CARD11 protein within mammalian cells due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the CARD11 gene, CARD11 protein, or the expression or activity or level of any of them can be a mutation in the CARD11 gene that encodes a CARD11 protein that is constitutively active or has increased activity compared to the protein encoded by the CARD11 gene without the mutation. As a further example, an increase in the copy number of the CARD11 gene can result in overexpression of the CARD11 protein. For example, dysregulation of the CARD11 gene, CARD11 protein, or the expression or activity or level of any of them can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion of CARD11 and a second portion of a partner protein (i.e., it is not CARD11).In some cases, dysregulation of the CARD11 gene, CARD11 protein, or the expression or activity or level of any of them can be the result of a gene translocation between a CARD11 gene and another non-CARD11 gene.

[0122] An exemplary sequence of human CARD11 is shown below. SEQ ID NO: 8 (UniParc accession number UPI00003FED38) MPGGGPEMDDYMETLKDEEDALWENVECNRHMLSRYINPAKLTPYLRQCKVIDEQDEDEV LNAPMLPSKINRAGRLLDILHTKGQRGYVVFLESLEFYYPELYKLVTGKEPTRRFSTIVV EEGHEGLTHFLMNEVIKLQQQMKAKDLQRCELLARLRQLEDEKKQMTLTRVELLTFQERY YKMKEERDSYNDELVKVKDDNYNLAMRYAQLSEEKNMAVMRSRDLQLEIDQLKHRLNKME EECKLERNQSLKLKNDIENRPKKEQVLELERENEMLKTKNQELQSIIQAGKRSLPDSDKA ILDILEHDRKEALEDRQELVNRIYNLQEEARQAEELRDKYLEEKEDLELKCSTLGKDCEM YKHRMNTVMLQLEEVERERDQAFHSRDEAQTQYSQCLIEKDKYRKQIRELEEKNDEMRIE MVRREACIVNLESKLRRLSKDSNNLDQSLPRNLPVTIISQDFGDASPRTNGQEADDSSTS EESPEDSKYFLPYHPPQRRMNLKGIQLQRAKSPISLKRTSDFQAKGHEEEGTDASPSSCG SLPITNSFTKMQPPRSRSSIMSITAEPPGNDSIVRRYKEDAPHRSTVEEDNDSGGFDALD LDDDSHERYSFGPSSIHSSSSSHQSEGLDAYDLEQVNLMFRKFSLERPFRPSVTSVGHVR GPGPSVQHTTLNGDSLTSQLTLLGGNARGSFVHSVKPGSLAEKAGLREGHQLLLLEGCIR GERQSVPLDTCTKEEAHWTIQRCSGPVTLHYKVNHEGYRKLVKDMEDGLITSGDSFYIRL NLNISSQLDACTMSLKCDDVVHVRDTMYQDRHEWLCARVDPFTDHDLDMGTIPSYSRAQQ LLLVKLQRLMHRGSREEVDGTHHTLRALRNTLQPEEALSTSDPRVSPRLSRASFLFGQLL QFVSRSENKYKRMNSNERVRIISGSPLGSLARSSLDATKLLTEKQEELDPESELGKNLSL IPYSLVRAFYCERRRPVLFTPTVLAKTLVQRLLNSGGAMEFTICKSDIVTRDEFLRRQKT ETIIYSREKNPNAFECIAPANIEAVAAKNKHCLLEAGIGCTRDLIKSNIYPIVLFIRVCE KNIKRFRKLLPRPETEEEFLRVCRLKEKELEALPCLYATVEPDMWGSVEELLRVVKDKIG EEQRKTIWVDEDQL

[0123] Non-limiting examples of dysregulation of the CARD11 gene or CARD11 protein are shown in Table B2 below.

Table B2

[0124] As used herein, the term "CARD14-related autoimmune disorder" refers to an autoimmune disorder associated with or having dysregulation (e.g., any of the types of dysregulation of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any one or more thereof as described herein) of the CARD14 gene, CARD14 protein, or any one or more thereof.

[0125] As used herein, the term "CARD14-related inflammatory disorder" refers to an inflammatory disorder associated with or having dysregulation (e.g., any of the types of dysregulation of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any one or more thereof as described herein) of the CARD14 gene, CARD14 protein, or any one or more thereof.

[0126] As used herein, the term "CARD14-related cancer" refers to a cancer associated with or having dysregulation (e.g., any of the types of dysregulation of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any one or more thereof as described herein) of the CARD14 gene, CARD14 protein, or any one or more thereof.

[0127] Exemplary sequences of human CARD14 are shown below. SEQ ID NO: 9 (UniParc accession number UPI000013D81B) MGELCRRDSALTALDEETLWEMMESHRHRIVRCICPSRLTPYLRQAKVLCQLDEEEVLHS PRLTNSAMRAGHLLDLLKTRGKNGAIAFLESLKFHNPDVYTLVTGLQPDVDFSNFSGLME TSKLTECLAGAIGSLQEELNQEKGQKEVLLRRCQQLQEHLGLAETRAEGLHQLEADHSRM KREVSAHFHEVLRLKDEMLSLSLHYSNALQEKELAASRCRSLQEELYLLKQELQRANMVS SCELELQEQSLRTASDQESGDEELNRLKEENEKLRSLTFSLAEKDILEQSLDEARGSRQE LVERIHSLRERAVAAERQREQYWEEKEQTLLQFQKSKMACQLYREKVNALQAQVCELQKE RDQAYSARDSAQREISQSLVEKDSLRRQVFELTDQVCELRTQLRQLQAEPPGVLKQEART REPCPREKQRLVRMHAICPRDDSDCSLVSSTESQLLSDLSATSSRELVDSFRSSSPAPPS QQSLYKRVAEDFGEEPWSFSSCLEIPEGDPGALPGAKAGDPHLDYELLDTADLPQLESSL QPVSPGRLDVSESGVLMRRRPARRILSQVTMLAFQGDALLEQISVIGGNLTGIFIHRVTP GSAADQMALRPGTQIVMVDYEASEPLFKAVLEDTTLEEAVGLLRRVDGFCCLSVKVNTDG YKRLLQDLEAKVATSGDSFYIRVNLAMEGRAKGELQVHCNEVLHVTDTMFQGCGCWHAHR VNSYTMKDTAAHGTIPNYSRAQQQLIALIQDMTQQCTVTRKPSSGGPQKLVRIVSMDKAK ASPLRLSFDRGQLDPSRMEGSSTCFWAESCLTLVPYTLVRPHRPARPRPVLLVPRAVGKI LSEKLCLLQGFKKCLAEYLSQEEYEAWSQRGDIIQEGEVSGGRCWVTRHAVESLMEKNTH ALLDVQLDSVCTLHRMDIFPIVIHVSVNEKMAKKLKKGLQRLGTSEEQLLEAARQEEGDL DRAPCLYSSLAPDGWSDLDGLLSCVRQAIADEQKKVVWTEQSPR

[0128] As used herein, the term "CARD10-related autoimmune disorder" refers to an autoimmune disorder associated with, or having, dysregulation of the CARD10 gene, CARD10 protein, or any of them (e.g., one or more) in terms of expression, activity, or level (e.g., any of the types of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them described herein).

[0129] As used herein, the term "CARD10-related inflammatory disorder" refers to an inflammatory disorder associated with, or having, dysregulation of the CARD10 gene, CARD10 protein, or any of them (e.g., one or more) in terms of expression, activity, or level (e.g., any of the types of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them described herein).

[0130] As used herein, the term "CARD10-related cancer" refers to a cancer associated with, or having, dysregulation of the CARD10 gene, CARD10 protein, or any of them (e.g., one or more) in terms of expression, activity, or level (e.g., any of the types of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them described herein).

[0131] The phrase "dysregulation of the CARD10 gene, CARD10 protein, or the expression or activity or level of any of them" refers to gene mutations (e.g., chromosomal translocations that result in the expression of a fusion protein containing the CARD10 domain and a fusion partner, mutations in the CARD10 gene that result in the expression of a CARD10 protein containing at least one amino acid deletion compared to the wild-type CARD10 protein, mutations in the CARD10 gene that result in the expression of a CARD10 protein with one or more point mutations compared to the wild-type CARD10 protein, mutations in the CARD10 gene that result in the expression of a CARD10 protein with at least one inserted amino acid compared to the wild-type CARD10 protein, gene duplications that result in an increase in the level of the CARD10 protein in the cell, or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in an increase in the level of the CARD10 protein in the cell), alternative splice versions of CARD10 mRNA that result in a CARD10 protein with at least one amino acid deletion in the CARD10 protein compared to the wild-type CARD10 protein, or an increase (e.g., an increase in level) in the expression of the wild-type CARD10 protein in mammalian cells due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the CARD10 gene, CARD10 protein, or the expression or activity or level of any of them can be a mutation in the CARD10 gene that encodes a CARD10 protein that is constitutively active or has increased activity compared to the protein encoded by the CARD10 gene without the mutation. As a further example, an increase in the copy number of the CARD10 gene can result in overexpression of the CARD10 protein. For example, dysregulation of the CARD10 gene, CARD10 protein, or the expression or activity or level of any of them can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion of CARD10 and a second portion of a partner protein (i.e., it is not CARD10).In some cases, dysregulation of the CARD10 gene, the CARD10 protein, or the expression or activity or level of any of them can be the result of a gene translocation between a CARD10 gene and another non-CARD10 gene.

[0132] An exemplary sequence of human CARD10 is shown below. SEQ ID NO: 10 (UniParc accession number UPI0000044645) MPGRAEAGEAEEEAGAGSGSEAEEDALWERIEGVRHRLARALNPAKLTPYLRQCRVIDEQ DEEEVLSTYRFPCRVNRTGRLMDILRCRGKRGYEAFLEALEFYYPEHFTLLTGQEPAQRC SMILDEEGPEGLTQFLMTEVRRLREARKSQLQREQQLQARGRVLEEERAGLEQRLRDQQQ AQERCQRLREDWEAGSLELLRLKDENYMIAMRLAQLSEEKNSAVLRSRDLQLAVDQLKLK VSRLEEECALLRRARGPPPGAEEKEKEKEKEKEPDNVDLVSELRAENQRLTASLRELQEG LQQEASRPGAPGSERILLDILEHDWREAQDSRQELCQKLHAVQGELQWAEELRDQYLQEM EDLRLKHRTLQKDCDLYKHRMATVLAQLEEIEKERDQAIQSRDRIQLQYSQSLIEKDQYR KQVRGLEAERDELLTTLTSLEGTKALLEVQLQRAQGGTCLKACASSHSLCSNLSSTWSLS EFPSPLGGPEATGEAAVMGGPEPHNSEEATDSEKEINRLSILPFPPSAGSILRRQREEDP APPKRSFSSMSDITGSVTLKPWSPGLSSSSSSDSVWPLGKPEGLLARGCGLDFLNRSLAI RVSGRSPPGGPEPQDKGPDGLSFYGDRWSGAVVRRVLSGPGSARMEPREQRVEAAGLEGA CLEAEAQQRTLLWNQGSTLPSLMDSKACQSFHEALEAWAKGPGAEPFYIRANLTLPERAD PHALCVKAQEILRLVDSAYKRRQEWFCTRVDPLTLRDLDRGTVPNYQRAQQLLEVQEKCL PSSRHRGPRSNLKKRALDQLRLVRPKPVGAPAGDSPDQLLLEPCAEPERSLRPYSLVRPL LVSALRPVVLLPECLAPRLIRNLLDLPSSRLDFQVCPAESLSGEELCPSSAPGAPKAQPA TPGLGSRIRAIQESVGKKHCLLELGARGVRELVQNEIYPIVIHVEVTEKNVREVRGLLGR PGWRDSELLRQCRGSEQVLWGLPCSWVQVPAHEWGHAEELAKVVRGRILQEQARLVWVEC GSSRGCPSSSEA

[0133] As used herein, the term "CARD9-related autoimmune disorder" refers to an autoimmune disorder associated with or having dysregulation of the CARD9 gene, the CARD9 protein, or any (e.g., one or more) of their expression or activity or level (e.g., any of the types of dysregulation of the expression or activity or level of the CARD9 gene, the CARD9 protein, or any of them described herein).

[0134] As used herein, the term "CARD9-related inflammatory disorder" refers to an inflammatory disorder associated with, or having a dysregulation of, the CARD9 gene, the CARD9 protein, or any (e.g., one or more) of their expression, activity, or levels (e.g., any of the types of dysregulation of the expression, activity, or levels of the CARD9 gene, the CARD9 protein, or any of them described herein).

[0135] As used herein, the term "CARD9-related cancer" refers to a cancer associated with, or having a dysregulation of, the CARD9 gene, the CARD9 protein, or any (e.g., one or more) of their expression, activity, or levels (e.g., any of the types of dysregulation of the expression, activity, or levels of the CARD9 gene, the CARD9 protein, or any of them described herein).

[0136] The phrase "dysregulation of the CARD9 gene, CARD9 protein, or the expression or activity or level of any of them" refers to gene mutations (e.g., chromosomal translocations that result in the expression of a fusion protein including the CARD9 domain and a fusion partner, mutations in the CARD9 gene that result in the expression of a CARD9 protein containing at least one amino acid deletion compared to the wild-type CARD9 protein, mutations in the CARD9 gene that result in the expression of a CARD9 protein with one or more point mutations compared to the wild-type CARD9 protein, mutations in the CARD9 gene that result in the expression of a CARD9 protein with at least one inserted amino acid compared to the wild-type CARD9 protein, gene duplications that result in an increase in the level of the CARD9 protein in the cell, or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in an increase in the level of the CARD9 protein in the cell), alternative splice versions of CARD9 mRNA that result in a CARD9 protein having at least one amino acid deletion in the CARD9 protein compared to the wild-type CARD9 protein, or an increase (e.g., an increase in level) in the expression of the wild-type CARD9 protein in mammalian cells due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the CARD9 gene, CARD9 protein, or the expression or activity or level of any of them can be a mutation in the CARD9 gene that encodes a CARD9 protein that is constitutively active or has increased activity compared to the protein encoded by the CARD9 gene that does not contain the mutation. As a further example, an increase in the copy number of the CARD9 gene can result in overexpression of the CARD9 protein. For example, dysregulation of the CARD9 gene, CARD9 protein, or the expression or activity or level of any of them can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion of CARD9 and a second portion of a partner protein (i.e., it is not CARD9).In some instances, dysregulation of the CARD9 gene, the CARD9 protein, or the expression or activity or level of any of them can be the result of a gene translocation between a CARD9 gene and another non-CARD9 gene.

[0137] An exemplary sequence of human CARD9 is shown below. SEQ ID NO: 11 (UniParc accession number UPI000013E4EB) MSDYENDDECWSVLEGFRVTLTSVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRK VGVLLDILQRTGHKGYVAFLESLELYYPQLYKKVTGKEPARVFSMIIDASGESGLTQLLM TEVMKLQKKVQDLTALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECEAGSRELKRCKE ENYDLAMRLAHQSEEKGAALMRNRDLQLEIDQLKHSLMKAEDDCKVERKHTLKLRHAMEQ RPSQELLWELQQEKALLQARVQELEASVQEGKLDRSSPYIQVLEEDWRQALRDHQEQANT IFSLRKDLRQGEARRLRCMEEKEMFELQCLALRKDSKMYKDRIEAILLQMEEVAIERDQA IATREELHAQHARGLQEKDALRKQVRELGEKADELQLQVFQCEAQLLAVEGRLRRQQLET LVLSSDLEDGSPRRSQELSLPQDLEDTQLSDKGCLAGGGSPKQPFAALHQEQVLRNPHDA GLSSGEPPEKERRRLKESFENYRRKRALRKMQKGWRQGEEDRENTTGSDNTDTEGS

[0138] The term "BCL10-related autoimmune disorder", as used herein, refers to an autoimmune disorder associated with, or having a dysregulation of, the BCL10 gene, the BCL10 protein, or any of them (e.g., one or more), such as dysregulation of the expression, activity, or level of the BCL10 gene, the BCL10 protein, or any of them (e.g., any of the types of dysregulation of the expression, activity, or level of the BCL10 gene, the BCL10 protein, or any of them described herein).

[0139] The term "BCL10-related inflammatory disorder", as used herein, refers to an inflammatory disorder associated with, or having a dysregulation of, the BCL10 gene, the BCL10 protein, or any of them (e.g., one or more), such as dysregulation of the expression, activity, or level of the BCL10 gene, the BCL10 protein, or any of them (e.g., any of the types of dysregulation of the expression, activity, or level of the BCL10 gene, the BCL10 protein, or any of them described herein).

[0140] The term "BCL10-related cancer", as used herein, refers to a cancer associated with, or having a dysregulation of, the BCL10 gene, the BCL10 protein, or any of them (e.g., one or more), such as dysregulation of the expression, activity, or level of the BCL10 gene, the BCL10 protein, or any of them (e.g., any of the types of dysregulation of the expression, activity, or level of the BCL10 gene, the BCL10 protein, or any of them described herein).

[0141] The phrase "dysregulation of the BCL10 gene, BCL10 protein, or the expression or activity or level of any of them" refers to gene mutations (e.g., chromosomal translocations that result in the expression of a fusion protein containing the BCL10 domain and a fusion partner, mutations in the BCL10 gene that result in the expression of a BCL10 protein containing at least one amino acid deletion compared to the wild-type BCL10 protein, mutations in the BCL10 gene that result in the expression of a BCL10 protein with one or more point mutations compared to the wild-type BCL10 protein, mutations in the BCL10 gene that result in the expression of a BCL10 protein with at least one inserted amino acid compared to the wild-type BCL10 protein, gene duplications that result in an increase in the level of BCL10 protein in the cell, or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in an increase in the level of BCL10 protein in the cell), alternative splice versions of BCL10 mRNA that result in a BCL10 protein having at least one amino acid deletion in the BCL10 protein compared to the wild-type BCL10 protein, or an increase (e.g., an increase in level) in the expression of wild-type BCL10 protein in mammalian cells due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). For example, dysregulation of the BCL10 gene, BCL10 protein, or the expression or activity or level of any of them can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing the first part of BCL10 and the second part of a partner protein (i.e., it is not BCL10). In some examples, dysregulation of the BCL10 gene, BCL10 protein, or the expression or activity or level of any of them can be the result of a gene translocation between one BCL10 gene and another non-BCL10 gene.

[0142] An exemplary sequence of human BCL10 is shown below. SEQ ID NO: 12 (UniParc accession number UPI000012682F) MEPTAPSLTEEDLTEVKKDALENLRVYLCEKIIAERHFDHLRAKKILSREDTEEISCRTS SRKRAGKLLDYLQENPKGLDTLVESIRREKTQNFLIQKITDEVLKLRNIKLEHLKGLKCS SCEPFPDGATNNLSRSNSDESNFSEKLRASTVMYHPEGESSTTPFFSTNSSLNLPVLEVG RTENTIFSSTTLPRPGDPGAPPLPPDLQLEEEGTCANSSEMFLPLRSRTVSRQ

[0143] Non-limiting examples of dysregulation of the BCL10 gene or BCL10 protein are shown in Table B3 below.

Table B3

[0144] As used herein, the term "MALT1 protease substrate-related cancer" refers to a cancer that is associated with, or has dysregulation of the expression, activity, or level of, a gene, protein, or any one (e.g., one or more) of them related to the MALT1 protease substrate. In some embodiments, the MALT1 protease substrate-related cancer is selected from the group consisting of BCL10-related cancer, A20-related cancer, CYLD-related cancer, RelB-related cancer, Regnase-1-related cancer, Rok-in-1-related cancer, HOIL1-related cancer, NIK-related cancer, LIMA1α-related cancer, and combinations thereof. In some embodiments, the MALT1 protease substrate-related cancer is selected from the group consisting of BCL10-related cancer, A20-related cancer, CYLD-related cancer, and combinations thereof. A cancer "related to" a particular gene or protein described in this paragraph refers to a cancer that is associated with, or has dysregulation of the expression, activity, or level of, a particular gene, a particular protein, or any one (e.g., one or more) of them (e.g., any one of the types of dysregulation of the expression, activity, or level of a particular gene, a particular protein, or any one of them described herein). Non-limiting examples of such cancers are described herein.

[0145] An exemplary sequence of human A20 is shown below. SEQ ID NO: 13 (UniParc accession number UPI000000D92D) MAEQVLPQALYLSNMRKAVKIRERTPEDIFKPTNGIIHHFKTMHRYTLEMFRTCQFCPQF REIIHKALIDRNIQATLESQKKLNWCREVRKLVALKTNGDGNCLMHATSQYMWGVQDTDL VLRKALFSTLKETDTRNFKFRWQLESLKSQEFVETGLCYDTRNWNDEWDNLIKMASTDTP MARSGLQYNSLEEIHIFVLCNILRRPIIVISDKMLRSLESGSNFAPLKVGGIYLPLHWPA QECYRYPIVLGYDSHHFVPLVTLKDSGPEIRAVPLVNRDRGRFEDLKVHFLTDPENEMKE KLLKEYLMVIEIPVQGWDHGTTHLINAAKLDEANLPKEINLVDDYFELVQHEYKKWQENS EQGRREGHAQNPMEPSVPQLSLMDVKCETPNCPFFMSVNTQPLCHECSERRQKNQNKLPK LNSKPGPEGLPGMALGASRGEAYEPLAWNPEESTGGPHSAPPTAPSPFLFSETTAMKCRS PGCPFTLNVQHNGFCERCHNARQLHASHAPDHTRHLDPGKCQACLQDVTRTFNGICSTCF KRTTAEASSSLSTSLPPSCHQRSKSDPSRLVRSPSPHSCHRAGNDAPAGCLSQAARTPGD RTGTSKCRKAGCVYFGTPENKGFCTLCFIEYRENKHFAAASGKVSPTASRFQNTIPCLGR ECGTLGSTMFEGYCQKCFIEAQNQRFHEAKRTEEQLRSSQRRDVPRTTQSTSRPKCARAS CKNILACRSEELCMECQHPNQRMGPGAHRGEPAPEDPPKQRCRAPACDHFGNAKCNGYCN ECFQFKQMYG

[0146] Non-limiting examples of dysregulation of the A20 gene or A20 protein are shown in Table B4 below.

Table B4

[0147] Exemplary sequences of human CYLD are shown below. SEQ ID NO: 14 (UniParc accession number UPI0000073A15) MSSGLWSQEKVTSPYWEERIFYLLLQECSVTDKQTQKLLKVPKGSIGQYIQDRSVGHSRI PSAKGKKNQIGLKILEQPHAVLFVDEKDVVEINEKFTELLLAITNCEERFSLFKNRNRLS KGLQIDVGCPVKVQLRSGEEKFPGVVRFRGPLLAERTVSGIFFGVELLEEGRGQGFTDGV YQGKQLFQCDEDCGVFVALDKLELIEDDDTALESDYAGPGDTMQVELPPLEINSRVSLKV GETIESGTVIFCDVLPGKESLGYFVGVDMDNPIGNWDGRFDGVQLCSFACVESTILLHIN DIIPALSESVTQERRPPKLAFMSRGVGDKGSSSHNKPKATGSTSDPGNRNRSELFYTLNG SSVDSQPQSKSKNTWYIDEVAEDPAKSLTEISTDFDRSSPPLQPPPVNSLTTENRFHSLP FSLTKMPNTNGSIGHSPLSLSAQSVMEELNTAPVQESPPLAMPPGNSHGLEVGSLAEVKE NPPFYGVIRWIGQPPGLNEVLAGLELEDECAGCTDGTFRGTRYFTCALKKALFVKLKSCR PDSRFASLQPVSNQIERCNSLAFGGYLSEVVEENTPPKMEKEGLEIMIGKKKGIQGHYNS CYLDSTLFCLFAFSSVLDTVLLRPKEKNDVEYYSETQELLRTEIVNPLRIYGYVCATKIM KLRKILEKVEAASGFTSEEKDPEEFLNILFHHILRVEPLLKIRSAGQKVQDCYFYQIFME KNEKVGVPTIQQLLEWSFINSNLKFAEAPSCLIIQMPRFGKDFKLFKKIFPSLELNITDL LEDTPRQCRICGGLAMYECRECYDDPDISAGKIKQFCKTCNTQVHLHPKRLNHKYNPVSL PKDLPDWDWRHGCIPCQNMELFAVLCIETSHYVAFVKYGKDDSAWLFFDSMADRDGGQNG FNIPQVTPCPEVGEYLKMSLEDLHSLDSRRIQGCARRLLCDAYMCMYQSPTMSLYK

[0148] Non-limiting examples of dysregulation of the CYLD gene or CYLD protein can be found, for example, in Massoumi, Future Oncology 7.2 (2011): 285-297, Alameda, J.P., 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.

[0149] An exemplary sequence of human RelB is shown below. SEQ ID NO: 15 (UniParc accession number UPI00000012B7) MLRSGPASGPSVPTGRAMPSRRVARPPAAPELGALGSPDLSSLSLAVSRSTDELEIIDEY IKENGFGLDGGQPGPGEGLPRLVSRGAASLSTVTLGPVAPPATPPPWGCPLGRLVSPAPG PGPQPHLVITEQPKQRGMRFRYECEGRSAGSILGESSTEASKTLPAIELRDCGGLREVEV TACLVWKDWPHRVHPHSLVGKDCTDGICRVRLRPHVSPRHSFNNLGIQCVRKKEIEAAIE RKIQLGIDPYNAGSLKNHQEVDMNVVRICFQASYRDQQGQMRRMDPVLSEPVYDKKSTNT SELRICRINKESGPCTGGEELYLLCDKVQKEDISVVFSRASWEGRADFSQADVHRQIAIV FKTPPYEDLEIVEPVTVNVFLQRLTDGVCSEPLPFTYLPRDHDSYGVDKKRKRGMPDVLG ELNSSDPHGIESKRRKKKPAILDHFLPNHGSGPFLPPSALLPDPDFFSGTVSLPGLEPPG GPDLLDDGFAYDPTAPTLFTMLDLLPPAPPHASAVVCSGGAGAVVGETPGPEPLTLDSYQ APGPGDGGTASLVGSNMFPNHYREAAFGGGLLSPGPEAT

[0150] An exemplary sequence of human Regnase-1 is shown below. SEQ ID NO: 16 (UniParc accession number UPI000004D30E) MSGPCGEKPVLEASPTMSLWEFEDSHSRQGTPRPGQELAAEEASALELQMKVDFFRKLGY SSTEIHSVLQKLGVQADTNTVLGELVKHGTATERERQTSPDPCPQLPLVPRGGGTPKAPN LEPPLPEEEKEGSDLRPVVIDGSNVAMSHGNKEVFSCRGILLAVNWFLERGHTDITVFVP SWRKEQPRPDVPITDQHILRELEKKKILVFTPSRRVGGKRVVCYDDRFIVKLAYESDGIV VSNDTYRDLQGERQEWKRFIEERLLMYSFVNDKFMPPDDPLGRHGPSLDNFLRKKPLTLE HRKQPCPYGRKCTYGIKCRFFHPERPSCPQRSVADELRANALLSPPRAPSKDKNGRRPSP SSQSSSLLTESEQCSLDGKKLGAQASPGSRQEGLTQTYAPSGRSLAPSGGSGSSFGPTDW LPQTLDSLPYVSQDCLDSGIGSLESQMSELWGVRGGGPGEPGPPRAPYTGYSPYGSELPA TAAFSAFGRAMGAGHFSVPADYPPAPPAFPPREYWSEPYPLPPPTSVLQEPPVQSPGAGR SPWGRAGSLAKEQASVYTKLCGVFPPHLVEAVMGRFPQLLDPQQLAAEILSYKSQHPSE

[0151] An exemplary sequence of human interleukin-1 is shown below. Accession number 17 (UniParc accession number UPI00001D7DA8) MPVQAPQWTDFLSCPICTQTFDETIRKPISLGCGHTVCKMCLNKLHRKACPFDQTTINTD IELLPVNSALLQLVGAQVPEQQPITLCSGVEDTKHYEEAKKCVEELALYLKPLSSARGVG LNSTTQSVLSRPMQRKLVTLVHCQLVEEEGRIRAMRAARSLGERTVTELILQHQNPQQLS SNLWAAVRARGCQFLGPAMQEEALKLVLLALEDGSALSRKVLVLFVVQRLEPRFPQASKT SIGHVVQLLYRASCFKVTKRDEDSSLMQLKEEFRTYEALRREHDSQIVQIAMEAGLRIAP DQWSSLLYGDQSHKSHMQSIIDKLQTPASFAQSVQELTIALQRTGDPANLNRLRPHLELL ANIDPSPDAPPPTWEQLENGLVAVRTVVHGLVDYIQNHSKKGADQQQPPQHSKYKTYMCR DMKQRGGCPRGASCTFAHSQEELEKFRKMNKRLVPRRPLSASLGQLNEVGLPSAAILPDE GAVDLPSRKPPALPNGIVSTGNTVTQLIPRGTDPSYDSSLKPGKIDHLSSSAPGSPPDLL ESVPKSISALPVNPHSIPPRGPADLPPMPVTKPLQMVPRGSQLYPAQQTDVYYQDPRGAA PPFEPAPYQQGMYYTPPPQCVSRFVRPPPSAPEPAPPYLDHYPPYLQERVVNSQYGTQPQ QYPPIYPSHYDGRRVYPAPSYTREEIFRESPIPIEIPPAAVPSYVPESRERYQQIESYYP VAPHPTQIRPSYLREPPYSRLPPPPQPHPSLDELHRRRKEIMAQLEERKVISPPPFAPSP TLPPTFHPEEFLDEDLKVAGKYKGNDYSQYSPWSCDTIGSYIGTKDAKPKDVVAAGSVEM MNVESKGMRDQRLDLQRRAAETSDDDLIPFGDRPTVSRFGAISRTSKTIYQGAGPMQAMA PQGAPTKSINISDYSPYGTHGGWGASPYSPHQNIPSQGHFSERERISMSEVASHGKPLPS AEREQLRLELQQLNHQISQQTQLRGLEAVSNRLVLQREANTLAGQSQPPPPPPPKWPGMI SSEQLSLELHQVEREIGKRTRELSMENQCSLDMKSKLNTSKQAENGQPEPQNKVPAEDLT LTFSDVPNGSALTQENISLLSNKTSSLNLSEDPEGGGDNNDSQRSGVTPSSAP

[0152] An exemplary sequence of human HOIL1 is shown below. Sequence number 18 (UniParc accession number UPI000006F045) MDEKTKKAEEMALSLTRAVAGGDEQVAMKCAIWLAEQRVPLSVQLKPEVSPTQDIRLWVS VEDAQMHTVTIWLTVRPDMTVASLKDMVFLDYGFPPVLQQWVIGQRLARDQETLHSHGVR QNGDSAYLYLLSARNTSLNPQELQRERQLRMLEDLGFKDLTLQPRGPLEPGPPKPGVPQE PGRGQPDAVPEPPPVGWQCPGCTFINKPTRPGCEMCCRARPEAYQVPASYQPDEEERARL AGEEEALRQYQQRKQQQQEGNYLQHVQLDQRSLVLNTEPAECPVCYSVLAPGEAVVLREC LHTFCRECLQGTIRNSQEAEVSCPFIDNTYSCSGKLLEREIKALLTPEDYQRFLDLGISI AENRSAFSYHCKTPDCKGWCFFEDDVNEFTCPVCFHVNCLLCKAIHEQMNCKEYQEDLAL RAQNDVAARQTTEMLKVMLQQGEAMRCPQCQIVVQKKDGCDWIRCTVCHTEICWVTKGPR WGPGGPGDTSGGCRCRVNGIPCHPSCQNCH

[0153] An exemplary sequence of human NIK is shown below. Accession number 19 (UniParc accession number UPI0000074220) MAVMEMACPGAPGSAVGQQKELPKAKEKTPPLGKKQSSVYKLEAVEKSPVFCGKWEILND VITKGTAKEGSEAGPAAISIIAQAECENSQEFSPTFSERIFIAGSKQYSQSESLDQIPNN VAHATEGKMARVCWKGKRRSKARKKRKKKSSKSLAHAGVALAKPLPRTPEQESCTIPVQE DESPLGAPYVRNTPQFTKPLKEPGLGQLCFKQLGEGLRPALPRSELHKLISPLQCLNHVW KLHHPQDGGPLPLPTHPFPYSRLPHPFPFHPLQPWKPHPLESFLGKLACVDSQKPLPDPH LSKLACVDSPKPLPGPHLEPSCLSRGAHEKFSVEEYLVHALQGSVSSGQAHSLTSLAKTW AARGSRSREPSPKTEDNEGVLLTEKLKPVDYEYREEVHWATHQLRLGRGSFGEVHRMEDK QTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQL VKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVC LQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFF RGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNRALQQVGG LKSPWRGEYKEPRHPPPNQANYHQTLHAQPRELSPRAPGPRPAEETTGRAPKLQPPLPPE PPEPNKSPPLTLSKEESGMWEPLPLSSLEPAPARNPSSPERKATVPEQELQQLEIELFLN SLSQPFSLEEQEQILSCLSIDSLSLSDDSEKNPSKASQSSRDTLSSGVHSWSSQAEARSS SWNMVLARGRPTDTPSYFNGVKVQIQSLNGEHLHIREFHRVKVGDIATGISSQIPAAAFS LVTKDGQPVRYDMEVPDSGIDLQCTLAPDGSFAWSWRVKHGQLENRP

[0154] An exemplary sequence of human LIMA1α is shown below. Accession number 20 (UniParc accession number UPI000002A906) MENCLGESRHEVEKSEISENTDASGKIEKYNVPLNRLKMMFEKGEPTQTKILRAQSRSAS GRKISENSYSLDDLEIGPGQLSSSTFDSEKNESRRNLELPRLSETSIKDRMAKYQAAVSK QSSSTNYTNELKASGGEIKIHKMEQKENVPPGPEVCITHQEGEKISANENSLAVRSTPAE DDSRDSQVKSEVQQPVHPKPLSPDSRASSLSESSPPKAMKKFQAPARETCVECQKTVYPM ERLLANQQVFHISCFRCSYCNNKLSLGTYASLHGRIYCKPHFNQLFKSKGNYDEGFGHRP HKDLWASKNENEEILERPAQLANARETPHSPGVEDAPIAKVGVLAASMEAKASSQQEKED KPAETKKLRIAWPPPTELGSSGSALEEGIKMSKPKWPPEDEISKPEVPEDVDLDLKKLRR SSSLKERSRPFTVAASFQSTSVKSPKTVSPPIRKGWSMSEQSEESVGGRVAERKQVENAK ASKKNGNVGKTTWQNKESKGETGKRSKEGHSLEMENENLVENGADSDEDDNSFLKQQSPQ EPKSLNWSSFVDNTFAEEFTTQNQKSQDVELWEGEVVKELSVEEQIKRNRYYDEDEDEE

[0155] As used herein, the term "cancer associated with components of the NF-κB pathway downstream of the CBM complex" refers to a cancer associated with, or having dysregulation of, the expression, activity, or level of a gene, protein, or any (e.g., one or more) of them that are components of the NF-κB pathway downstream of the CBM complex. 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-associated cancers. A "cancer associated with" a particular gene or protein described in this paragraph refers to a cancer associated with, or having dysregulation of, the expression, activity, or level of a particular gene, a particular protein, or any (e.g., one or more) of them (e.g., any of the types of dysregulation of the expression, activity, or level of a particular gene, a particular protein, or any of them described herein). Non-limiting examples of such cancers are described herein.

[0156] An exemplary sequence of human TAK1 is shown below. SEQ ID NO: 21 (UniParc accession number UPI000012EAD6) MSTASAASSSSSSSAGEMIEAPSQVLNFEEIDYKEIEVEEVVGRGAFGVVCKAKWRAKDV AIKQIESESERKAFIVELRQLSRVNHPNIVKLYGACLNPVCLVMEYAEGGSLYNVLHGAE PLPYYTAAHAMSWCLQCSQGVAYLHSMQPKALIHRDLKPPNLLLVAGGTVLKICDFGTAC DIQTHMTNNKGSAAWMAPEVFEGSNYSEKCDVFSWGIILWEVITRRKPFDEIGGPAFRIM WAVHNGTRPPLIKNLPKPIESLMTRCWSKDPSQRPSMEEIVKIMTHLMRYFPGADEPLQY PCQYSDEGQSNSATSTGSFMDIASTNTSNKSDTNMEQVPATNDTIKRLESKLLKNQAKQQ SESGRLSLGASRGSSVESLPPTSEGKRMSADMSEIEARIAATTAYSKPKRGHRKTASFGN ILDVPEIVISGNGQPRRRSIQDLTVTGTEPGQVSSRSSSPSVRMITTSGPTSEKPTRSHP WTPDDSTDTNGSDNSIPMAYLTLDHQLQPLAPCPNSKESMAVFEQHCKMAQEYMKVQTEI ALLLQRKQELVAELDQDEKDQQNTSRLVQEHKKLLDENKSLSTYYQQCKKQLEVIRSQQQ KRQGTS

[0157] An exemplary sequence of human TRAF6 is shown below. Accession number 22 (UniParc accession number UPI000000D924) MSLLNCENSCGSSQSESDCCVAMASSCSAVTKDDSVGGTASTGNLSSSFMEEIQGYDVEF DPPLESKYECPICLMALREAVQTPCGHRFCKACIIKSIRDAGHKCPVDNEILLENQLFPD NFAKREILSLMVKCPNEGCLHKMELRHLEDHQAHCEFALMDCPQCQRPFQKFHINIHILK DCPRRQVSCDNCAASMAFEDKEIHDQNCPLANVICEYCNTILIREQMPNHYDLDCPTAPI PCTFSTFGCHEKMQRNHLARHLQENTQSHMRMLAQAVHSLSVIPDSGYISEVRNFQETIH QLEGRLVRQDHQIRELTAKMETQSMYVSELKRTIRTLEDKVAEIEAQQCNGIYIWKIGNF GMHLKCQEEEKPVVIHSPGFYTGKPGYKLCMRLHLQLPTAQRCANYISLFVHTMQGEYDS HLPWPFQGTIRLTILDQSEAPVRQNHEEIMDAKPELLAFQRPTIPRNPKGFGYVTFMHLE ALRQRTFIKDDTLLVRCEVSTRFDMGSLRREGFQPRSTDAGV

[0158] An exemplary sequence of human TAB1 is shown below. Accession number 23 (UniParc accession number UPI0000136861) MAAQRRSLLQSEQQPSWTDDLPLCHLSGVGSASNRSYSADGKGTESHPPEDSWLKFRSEN NCFLYGVFNGYDGNRVTNFVAQRLSAELLLGQLNAEHAEADVRRVLLQAFDVVERSFLES IDDALAEKASLQSQLPEGVPQHQLPPQYQKILERLKTLEREISGGAMAVVAVLLNNKLYV ANVGTNRALLCKSTVDGLQVTQLNVDHTTENEDELFRLSQLGLDAGKIKQVGIICGQEST RRIGDYKVKYGYTDIDLLSAAKSKPIIAEPEIHGAQPLDGVTGFLVLMSEGLYKALEAAH GPGQANQEIAAMIDTEFAKQTSLDAVAQAVVDRVKRIHSDTFASGGERARFCPRHEDMTL LVRNFGYPLGEMSQPTPSPAPAAGGRVYPVSVPYSSAQSTSKTSVTLSLVMPSQGQMVNG AHSASTLDEATPTLTNQSPTLTLQSTNTHTQSSSSSSDGGLFRSRPAHSLPPGEDGRVEP YVDFAEFYRLWSVDHGEQSVVTAP

[0159] An exemplary sequence of human TAB2 is shown below. Accession number 24 (UniParc accession number UPI0000073C75) MAQGSHQIDFQVLHDLRQKFPEVPEVVVSRCMLQNNNNLDACCAVLSQESTRYLYGEGDL NFSDDSGISGLRNHMTSLNLDLQSQNIYHHGREGSRMNGSRTLTHSISDGQLQGGQSNSE LFQQEPQTAPAQVPQGFNVFGMSSSSGASNSAPHLGFHLGSKGTSSLSQQTPRFNPIMVT LAPNIQTGRNTPTSLHIHGVPPPVLNSPQGNSIYIRPYITTPGGTTRQTQQHSGWVSQFN PMNPQQVYQPSQPGPWTTCPASNPLSHTSSQQPNQQGHQTSHVYMPISSPTTSQPPTIHS SGSSQSSAHSQYNIQNISTGPRKNQIEIKLEPPQRNNSSKLRSSGPRTSSTSSSVNSQTL NRNQPTVYIAASPPNTDELMSRSQPKVYISANAATGDEQVMRNQPTLFISTNSGASAASR NMSGQVSMGPAFIHHHPPKSRAIGNNSATSPRVVVTQPNTKYTFKITVSPNKPPAVSPGV VSPTFELTNLLNHPDHYVETENIQHLTDPTLAHVDRISETRKLSMGSDDAAYTQALLVHQ KARMERLQRELEIQKKKLDKLKSEVNEMENNLTRRRLKRSNSISQIPSLEEMQQLRSCNR QLQIDIDCLTKEIDLFQARGPHFNPSAIHNFYDNIGFVGPVPPKPKDQRSIIKTPKTQDT EDDEGAQWNCTACTFLNHPALIRCEQCEMPRHF

[0160] An exemplary sequence of human TAB3 is shown below. Accession number 25 (UniParc accession number UPI0000071648) MAQSSPQLDIQVLHDLRQRFPEIPEGVVSQCMLQNNNNLEACCRALSQESSKYLYMEYHS PDDNRMNRNRLLHINLGIHSPSSYHPGDGAQLNGGRTLVHSSSDGHIDPQHAAGKQLICL VQEPHSAPAVVAATPNYNPFFMNEQNRSAATPPSQPPQQPSSMQTGMNPSAMQGPSPPPP PPSYMHIPRYSTNPITVTVSQNLPSGQTVPRALQILPQIPSNLYGSPGSIYIRQTSQSSS GRQTPQSTPWQSSPQGPVPHYSQRPLPVYPHQQNYQPSQYSPKQQQIPQSAYHSPPPSQC PSPFSSPQHQVQPSQLGHIFMPPSPSTTPPHPYQQGPPSYQKQGSHSVAYLPYTASSLSK GSMKKIEITVEPSQRPGTAINRSPSPISNQPSPRNQHSLYTATTPPSSSPSRGISSQPKP PFSVNPVYITYTQPTGPSCTPSPSPRVIPNPTTVFKITVGRATTENLLNLVDQEERSAAP EPIQPISVIPGSGGEKGSHKYQRSSSSGSDDYAYTQALLLHQRARMERLAKQLKLEKEEL ERLKSEVNGMEHDLMQRRLRRVSCTTAIPTPEEMTRLRSMNRQLQINVDCTLKEVDLLQS RGNFDPKAMNNFYDNIEPGPVVPPKPSKKDSSDPCTIERKARRISVTSKVQADIHDTQAA AADEHRTGSTQSPRTQPRDEDYEGAPWNCDSCTFLNHPALNRCEQCEMPRYT

[0161] An exemplary sequence of human MKK7 is shown below. Accession number 26 (UniParc accession number UPI000012F494) MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPTLQLPLANDGGSRSPSSES SPQHPTPPARPRHMLGLPSTLFTPRSMESIEIDQKLQEIMKQTGYLTIGGQRYQAEINDL ENLGEMGSGTCGQVWKMRFRKTGHVIAVKQMRRSGNKEENKRILMDLDVVLKSHDCPYIV QCFGTFITNTDVFIAMELMGTCAEKLKKRMQGPIPERILGKMTVAIVKALYYLKEKHGVI HRDVKPSNILLDERGQIKLCDFGISGRLVDSKAKTRSAGCAAYMAPERIDPPDPTKPDYD IRADVWSLGISLVELATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDC LTKDHRKRPKYNKLLEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR

[0162] An exemplary sequence of human IKKα is shown below. Accession number 27 (UniParc accession number UPI000013D6C7) MERPPGLRPGAGGPWEMRERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCH EIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQ ILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTS FVGTLQYLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPK CIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRC FVLMDHILNLKIVHILNMTSAKIISFLLPPDESLHSLQSRIERETGINTGSQELLSETGI SLDPRKPASQCVLDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPI IQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKL EFFHKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYAEVGVIGYLEDQIMSLHAE IMELQKSPYGRRQGDLMESLEQRAIDLYKQLKHRPSDHSYSDSTEMVKIIVHTVQSQDRV LKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQ SSARSLVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHL STIIHEANEEQGNSMMNLDWSWLTE

[0163] An exemplary sequence of human IKKβ is shown below. Accession number 28 (UniParc accession number UPI0000033729) MSWSPSLTTQTCGAWEMKERLGTGGFGNVIRWHNQETGEQIAIKQCRQELSPRNRERWCL EIQIMRRLTHPNVVAARDVPEGMQNLAPNDLPLLAMEYCQGGDLRKYLNQFENCCGLREG AILTLLSDIASALRYLHENRIIHRDLKPENIVLQQGEQRLIHKIIDLGYAKELDQGSLCT SFVGTLQYLAPELLEQQKYTVTVDYWSFGTLAFECITGFRPFLPNWQPVQWHSKVRQKSE VDIVVSEDLNGTVKFSSSLPYPNNLNSVLAERLEKWLQLMLMWHPRQRGTDPTYGPNGCF KALDDILNLKLVHILNMVTGTIHTYPVTEDESLQSLKARIQQDTGIPEEDQELLQEAGLA LIPDKPATQCISDGKLNEGHTLDMDLVFLFDNSKITYETQISPRPQPESVSCILQEPKRN LAFFQLRKVWGQVWHSIQTLKEDCNRLQQGQRAAMMNLLRNNSCLSKMKNSMASMSQQLK AKLDFFKTSIQIDLEKYSEQTEFGITSDKLLLAWREMEQAVELCGRENEVKLLVERMMAL QTDIVDLQRSPMGRKQGGTLDDLEEQARELYRRLREKPRDQRTEGDSQEMVRLLLQAIQS FEKKVRVIYTQLSKTVVCKQKALELLPKVEEVVSLMNEDEKTVVRLQEKRQKELWNLLKI ACSKVRGPVSGSPDSMNASRLSQPGQLMSQPSTASNSLPEPAKKSEELVAEAHNLCTLLE NAIQDTVREQDQSFTALDWSWLQTEEEEHSCLEQAS

[0164] An exemplary sequence of human IKKγ is shown below. Accession number 29 (UniParc accession number UPI0000000CC4) MNRHLWKSQLCEMVQPSGGPAADQDVLGEESPLGKPAMLHLPSEQGAPETLQRCLEENQE LRDAIRQSNQILRERCEELLHFQASQREEKEFLMCKFQEARKLVERLGLEKLDLKRQKEQ ALREVEHLKRCQQQMAEDKASVKAQVTSLLGELQESQSRLEAATKECQALEGRARAASEQ ARQLESEREALQQQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQE YDNHIKSSVVGSERKRGMQLEDLKQQLQQAEEALVAKQEVIDKLKEEAEQHKIVMETVPV LKAQADIYKADFQAERQAREKLAEKKELLQEQLEQLQREYSKLKASCQESARIEDMRKRH VEVSQAPLPPAPAYLSSPLALPSQRRSPPEEPPDFCCPKCQYQAPDMDTLQIHVMECIE

[0165] Non-limiting examples of dysregulation of the IKKγ gene or IKKγ protein are described, for example, in Courtois and Gilmore, Oncogene 25.51(2006):6831-6843.

[0166] An exemplary sequence of human IkBα is shown below. SEQ ID NO: 30 (UniParc accession number UPI000004F0A9) MFQAAERPQEWAMEGPRDGLKKERLLDDRHDSGLDSMKDEEYEQMVKELQEIRLEPQEVP RGSEPWKQQLTEDGDSFLHLAIIHEEKALTMEVIRQVKGDLAFLNFQNNLQQTPLHLAVI TNQPEIAEALLGAGCDPELRDFRGNTPLHLACEQGCLASVGVLTQSCTTPHLHSILKATN YNGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVDLQNPDLVSLLLKCG ADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQLTLENLQMLPESEDEESYDTESEFTEFTE DELPYDDCVFGGQRLTL

[0167] An exemplary sequence of human p105 processed to p50 is shown below. SEQ ID NO: 31 (UniParc accession number UPI000000D917) MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYV CEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCED GICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQA EGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIY DSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDF SPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQ RKRQKLMPNFSDSFGGGSGAGAGGGGMFGSGGGGGGTGSTGPGYSFPHYGFPTYGGITFH PGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGE VTLTYATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQD ENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVED LLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMM SNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGT TPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMAT SWQVFDILNGKPYEPEFTSDDLLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLG LGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQ AHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQ EGPLEGKI

[0168] An exemplary sequence of human p65 is shown below. Accession number 32 (UniParc accession number UPI000013ED68) MDELFPLIFPAEPAQASGPYVEIIEQPKQRGMRFRYKCEGRSAGSIPGERSTDTTKTHPT IKINGYTGPGTVRISLVTKDPPHRPHPHELVGKDCRDGFYEAELCPDRCIHSFQNLGIQC VKKRDLEQAISQRIQTNNNPFQVPIEEQRGDYDLNAVRLCFQVTVRDPSGRPLRLPPVLS HPIFDNRAPNTAELKICRVNRNSGSCLGGDEIFLLCDKVQKEDIEVYFTGPGWEARGSFS QADVHRQVAIVFRTPPYADPSLQAPVRVSMQLRRPSDRELSEPMEFQYLPDTDDRHRIEE KRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAPQPYPFTSSLSTINY DEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQAPAPVPVLAPGPPQA VAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDLASVDNSEFQQLLNQ GIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNGLLSGDEDFSSIADM DFSALLSQISS

[0169] An exemplary sequence of human c-Rel is shown below. Accession number 33 (UniParc accession number UPI000013367B) MASGAYNPYIEIIEQPRQRGMRFRYKCEGRSAGSIPGEHSTDNNRTYPSIQIMNYYGKGK VRITLVTKNDPYKPHPHDLVGKDCRDGYYEAEFGQERRPLFFQNLGIRCVKKKEVKEAII TRIKAGINPFNVPEKQLNDIEDCDLNVVRLCFQVFLPDEHGNLTTALPPVVSNPIYDNRA PNTAELRICRVNKNCGSVRGGDEIFLLCDKVQKDDIEVRFVLNDWEAKGIFSQADVHRQV AIVFKTPPYCKAITEPVTVKMQLRRPSDQEVSESMDFRYLPDEKDTYGNKAKKQKTTLLF QKLCQDHVETGFRHVDQDGLELLTSGDPPTLASQSAGITVNFPERPRPGLLGSIGEGRYF KKEPNLFSHDAVVREMPTGVSSQAESYYPSPGPISSGLSHHASMAPLPSSSWSSVAHPTP RSGNTNPLSSFSTRTLPSNSQGIPPFLRIPVGNDLNASNACIYNNADDIVGMEASSMPSA DLYGISDPNMLSNCSVNMMTTSSDSMGETDNPRLLSMNLENPSCNSVLDPRDLRQLHQMS SSSMSAGANSNTTVFVSQSDAFEGSDFSCADNSMINESGPSNSTNPNSHGFVQDSQYSGI GSMQNEQLSDSFPYEFFQV

[0170] As used herein, the term "cancer associated with components of the JNK pathway downstream of the CBM complex" refers to a cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any one or more of them (e.g., one or more) that are components of the JNK pathway downstream of the CBM complex. In some embodiments, cancers associated with components 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. A cancer "associated with" a particular gene or protein described in this paragraph refers to a cancer associated with or having dysregulation of the expression, activity, or level of a particular gene, a particular protein, or any one or more of them (e.g., one or more) (e.g., any one of the types of dysregulation of the expression, activity, or level of a particular gene, a particular protein, or any one of them described herein). Non-limiting examples of such cancers are described herein.

[0171] An exemplary sequence of human JNK1 is shown below. SEQ ID NO: 34 (UniParc accession number UPI000012F17A) MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRP FQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYIVMELMDANLCQVIQ MELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSF MMTPYVVTRYYRAPEVILGMGYKENVDLWSVGCIMGEMVCHKILFPGRDYIDQWNKVIEQ LGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARDLLSK MLVIDASKRISVDEALQHPYINVWYDPSEAEAPPPKIPDKQLDEREHTIEEWKELIYKEV MDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAA GPLGCCR

[0172] An exemplary sequence of human JNK2 is shown below. SEQ ID NO: 35 (UniParc accession number UPI000006E3AD) MSDSKCDSQFYSVQVADSTFTVLKRYQQLKPIGSGAQGIVCAAFDTVLGINVAVKKLSRP FQNQTHAKRAYRELVLLKCVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIH MELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTACTNF MMTPYVVTRYYRAPEVILGMGYKENVDIWSVGCIMGELVKGCVIFQGTDHIDQWNKVIEQ LGTPSAEFMKKLQPTVRNYVENRPKYPGIKFEELFPDWIFPSESERDKIKTSQARDLLSK MLVIDPDKRISVDEALRHPYITVWYDPAEAEAPPPQIYDAQLEEREHAIEEWKELIYKEV MDWEERSKNGVVKDQPSDAAVSSNATPSQSSSINDISSMSTEQTLASDTDSSLDASTGPL EGCR

[0173] An exemplary sequence of human JNK3 is shown below. SEQ ID NO: 36 (UniParc accession number UPI0000049042) MSLHFLYYCSEPTLDVKIAFCQGFDKQVDVSYIAKHYNMSKSKVDNQFYSVEVGDSTFTV LKRYQNLKPIGSGAQGIVCAAYDAVLDRNVAIKKLSRPFQNQTHAKRAYRELVLMKCVNH KNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHL HSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAPEVILGMGY KENVDIWSVGCIMGEMVRHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRNYVEN RPKYAGLTFPKLFPDSLFPADSEHNKLKASQARDLLSKMLVIDPAKRISVDDALQHPYIN VWYDPAEVEAPPPQIYDKQLDEREHTIEEWKELIYKEVMNSEEKTKNGVVKGQPSPSGAA VNSSESLPPSSSVNDISSMSTDQTLASDTDSSLEASAGPLGCCR

[0174] Compound of formula (I) The present specification provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

[0175] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

[0176] In some embodiments, Q is -CH2-. In some embodiments, Q is O. In some embodiments, Q is NH.

[0177] In some embodiments, the five-membered nitrogen-containing ring partially formed by X and Y is a heteroaromatic ring.

[0178] In some embodiments, X is C and Y is C.

[0179] In some embodiments, X is N and Y is C.

[0180] In some embodiments, X is C and Y is N.

[0181] In some embodiments, Z is N. In some embodiments, Z is CR 6 and in some embodiments, Z is CR 6 and R 6 is hydrogen.

[0182] In some embodiments, X is C, Y is C, and Z is CR 6 In some embodiments, X is N, Y is C, and Z is CR 6 In some embodiments, X is C, Y is N, and Z is CR 6 In some embodiments, X is C, Y is N, and Z is CR 6 and R 6 is hydrogen. 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.

[0183] In some embodiments, R 6 is hydrogen.

[0184] In some embodiments, R 6 is halogen. For example, R 6 is fluoro. For example, R 6is chloro. In some embodiments, R 6 is cyano. In some embodiments, R 6 is hydroxyl.

[0185] In some embodiments, R 6 is C1-C3 alkoxy. In some embodiments, R 6 is methoxy or ethoxy.

[0186] In some embodiments, R 6 is C1-C3 haloalkoxy. In some embodiments, R 6 is trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

[0187] In some embodiments, R 6 is C1-C3 haloalkyl. In some embodiments, R 6 is trifluoromethyl or 2,2,2-trifluoroethyl.

[0188] In some embodiments, R 1 is alkyl optionally substituted with one to three substituents selected from halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NR A R B , or hydroxyl and C1-C3 alkoxy.

[0189] In some embodiments, R 1 is halogen or cyano. In some embodiments, R 1 is chloro or cyano. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 1 is fluoro or chloro. In some embodiments, R 1 is fluoro. In some embodiments, R 1is chloro. In some embodiments, R 1 is cyano. In some embodiments, R 1 is hydroxyl.

[0190] In some embodiments, R 1 is C1-C3 alkoxy. In some embodiments, R 1 is methoxy or ethoxy.

[0191] In some embodiments, R 1 is C1-C3 haloalkoxy. In some embodiments, R 1 is trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

[0192] In some embodiments, R 1 is C1-C3 haloalkyl. In some embodiments, R 1 is difluoromethyl, trifluoromethyl, or 2,2,2-trifluoroethyl.

[0193] In some embodiments, R 1 is C1-C3 alkyl optionally substituted by 1 to 3 substituents selected from hydroxyl and C1-C3 alkoxy.

[0194] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluorine. In some embodiments, R 2 is chloro. In some embodiments, R 2 is amino. In some embodiments, R 2 is C1-C3 alkyl such as methyl.

[0195] 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.

[0196] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0, 2, or 3. In some embodiments, m is 0, 1, or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 0 or 2. In some embodiments, m is 0 or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0197] In some embodiments, each R 3 is independently deuterium, a halogen, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy.

[0198] In some embodiments, each R 3 is independently a halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, each R 3 is independently hydroxyl.

[0199] In some embodiments, each R 3is independently C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl.

[0200] In some embodiments, each R 3 is independently C1-C3 alkyl. For example, R 3 is methyl or ethyl. In some embodiments, each R 3 is independently C1-C3 alkoxy. For example, R 3 is methoxy or ethoxy. In some embodiments, each R 3 is independently C1-C3 haloalkoxy. For example, R 3 is trifluoromethoxy, difluoromethoxy, or fluoromethoxy. In some embodiments, each R 3 is independently C1-C3 haloalkyl. For example, each R 3 is trifluoromethyl, or 2,2,2-trifluoroethyl.

[0201] In some embodiments, m is 1, and R 3 is methyl or trifluoromethyl.

[0202] In some embodiments, R 4 is optionally substituted 5- or 6-membered heteroaryl independently selected from 1 to 3 substituents each selected from R 7 .

[0203] In some embodiments, R 4 is optionally substituted 6-membered heteroaryl independently selected from 1 to 3 substituents each selected from R 7 .

[0204] In some embodiments, R 4 is optionally substituted 5-membered heteroaryl independently selected from 1 to 3 substituents each selected from R 7 .

[0205] In some embodiments, R 4 is 4H-pyrazolyl, 3H-pyrazolyl, or thiazolyl optionally substituted with 1 to 3 substituents each independently selected from R 7 .

[0206] In some embodiments, R 4 is unsubstituted. For example, R 4 is unsubstituted 4H-pyrazolyl, 3H-pyrazolyl, or thiazolyl.

[0207] In some embodiments, R 4 is 5- or 6-membered heteroaryl substituted with 1 to 3 substituents each independently selected from R 7 . In other embodiments, R 4 is 5- or 6-membered heteroaryl substituted with 1 substituent selected from R 7 .

[0208] In some embodiments, each R 7 is independently selected from the group consisting of C1-C3 haloalkyl, C1-C3 alkyl, and cycloalkyl. In some embodiments, R 7 is methyl, ethyl, cyclopropyl, or difluoromethyl.

[0209] In some embodiments, each R 7 is independently selected from the group consisting of C1-C3 alkyl optionally substituted with 1 cyclopropyl.

[0210] In some embodiments, each R 7 is independently selected from the group consisting of C3-C7 cycloalkyl optionally substituted with 1 C1-C3 alkyl. In some embodiments, the C3-C7 alkyl is cyclopropyl.

[0211] In some embodiments, R 4 is as follows.

Chemical formula

[0212] In some embodiments, R 4 is as follows.

Chemical formula

[0213] In some embodiments, R 4 is as follows.

Chemical formula

[0214] In some embodiments, R 4 is as follows.

Chemical formula

[0215] In some embodiments, R 4 is as follows.

Chemical formula

[0216] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

[0217] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

[0218] In some embodiments, R 5 is phenyl or 5- to 6-membered heteroaryl, and each R 5The group is optionally substituted by one or two independently selected R 8 . In some embodiments, R 5 is phenyl or 5- to 6-membered heteroaryl, and each R 5 group is optionally substituted by two or three independently selected R 8 . In some embodiments, R 5 is phenyl or 5- to 6-membered heteroaryl, and each R 5 group is optionally substituted by one to three independently selected R 8 . In some embodiments, R 5 is phenyl or 5- to 6-membered heteroaryl, and each R 5 group is optionally substituted by one R 8 . In some embodiments, R 5 is phenyl or 5- to 6-membered heteroaryl, and each R 8 group is optionally substituted by two independently selected R 8 . In some embodiments, R 5 is phenyl or 5- to 6-membered heteroaryl, and each R 5 group is optionally substituted by three independently selected R 8 .

[0219] In some embodiments, R 5 is phenyl or 5-membered heteroaryl, and each R 5 group is optionally substituted by one to three substituents independently selected from R 8 . In some embodiments, R 5 is phenyl or 6-membered heteroaryl, and each R 5 group is optionally substituted by one to three substituents independently selected from R 8 .

[0220] In some embodiments, R 5 is phenyl optionally substituted by one to three independently selected R 8 . In certain embodiments, R5 is phenyl optionally substituted by one R 8 . In certain embodiments, R 5 is phenyl optionally substituted by two independently selected R 8 . In certain embodiments, R 5 is phenyl optionally substituted by three independently selected R 8 .

[0221] In some embodiments, R 5 is unsubstituted phenyl.

[0222] In some embodiments, R 5 is 5- to 6-membered heteroaryl optionally substituted by one to three (e.g., two) substituents independently selected from R 8 . In some embodiments, R 5 is 6-membered heteroaryl optionally substituted by one to three (e.g., two) substituents independently selected from R 8 .

[0223] In some embodiments, R 5 is unsubstituted 5- to 6-membered heteroaryl.

[0224] In some embodiments, R 5 is 5- to 6-membered heteroaryl substituted by one to three substituents independently selected from R 8 .

[0225] In some embodiments, R 5 is unsubstituted 5- to 6-membered heteroaryl. In some embodiments, at least one of R 8 is halogen. In some embodiments, at least one of R 8 is fluoro. In some embodiments, at least one of R 8 is chloro. In some embodiments, R 8One of them is a halogen. In some embodiments, R 8 One of them is fluoro. In some embodiments, R 8 One of them is chloro. In some embodiments, R 8 Two of them are halogens. In some embodiments, R 8 Two of them are fluoro. In some embodiments, R 8 Two of them are chloro. In some embodiments, R 8 Three of them are halogens. In some embodiments, R 8 Three of them are fluoro. In some embodiments, R 8 Three of them are chloro. In some embodiments, R 8 At least one of them is cyano. In some embodiments, R 8 At least one of them is amino.

[0226] In some embodiments, R 8 At least one of them is C1-C3 alkoxy. In some embodiments, R 8 At least one of them is methoxy or ethoxy.

[0227] In some embodiments, R 8 At least one of them is C1-C3 haloalkyl optionally substituted by hydroxyl. In some embodiments, R 8 At least one of them is unsubstituted C1-C3 haloalkyl. In some embodiments, R 8 At least one of them is C1-C3 haloalkyl substituted by hydroxyl. In some embodiments, R 8 At least one of them is trifluoromethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl. In some embodiments, R 8 At least one of them is 1-hydroxy-2,2-difluoroethyl.

[0228] In some embodiments, R 8 at least one of which is C1-C3 haloalkoxy. In some embodiments, R 8 at least one of which is trifluoromethoxy.

[0229] In some embodiments, R 8 at least one of which is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl optionally substituted by hydroxyl or -NR E R F optionally substituted by C1-C3 alkyl optionally substituted by R 8 In some embodiments, R E at least one of which is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxyl or -NR F optionally substituted by C1-C3 alkyl optionally substituted by R 8 is hydroxyl or -NR E R F optionally substituted by C1-C3 alkyl optionally substituted by R 8 In some embodiments, R E at least one of which is halogen, C1-C3 haloalkyl, or 5-6 membered heteroaryl optionally substituted by hydroxyl or -NR F optionally substituted by C1-C3 alkyl optionally substituted by R 8 is hydroxyl or -NR E R F substituted by C1-C3 alkyl substituted by R 8is a 5- to 6-membered heteroaryl substituted with hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, propan-2-ol, or propan-2-amine. In some embodiments, R 8 is at least one of a 5- to 6-membered heteroaryl optionally substituted with a 4- to 6-membered heterocyclyl.

[0230] In some embodiments, R 5 is pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, or imidazolyl, each of which is substituted with two R 8 , one of R 8 is triazolyl, imidazolyl, oxazolyl, pyrazolyl, or pyrrolidinyl, and the other R 8 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. In some embodiments, R 5 is pyridyl, pyrimidinyl, or pyrazinyl, each of which is substituted with two R 8 , one of R 8 is triazolyl, imidazolyl, oxazolyl, pyrazolyl, or pyrrolidinyl, and the other R 8 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. In some embodiments, R 5 is pyridyl substituted with two R 8 , one of R 8 is triazolyl, imidazolyl, or oxazolyl, and the other R 8 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano.

[0231] In some embodiments, R 5 is 3-pyridyl or 4-pyridyl substituted with 1 to 3 independently selected R 8 .

[0232] In some embodiments, R 5 is pyridyl substituted with two R 8is replaced, and one R 8 is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, and trifluoromethyl, and the other R8 is 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, imidazol-1-yl, 1-methyl-imidazol-3-yl, 1-methyl-5-amino-imidazol-3-yl, 3-methylimidazol-2-one-1-yl, 1-methyl-pyrazol-3-yl, 1-methyl-pyrazol-4-yl, 1-methyl-pyrazol-5-yl, pyrrol-1-yl, thiazol-2-yl, isothiazolidin-2-yl-1,1-dioxide, pyrrolidin-2-one-1-yl, oxazol-2-yl, oxadiazol-2-yl, 2-amino-pyrimidin-4-yl, -(C=O)4-methylpiperazin-1-yl, 2-oxoazetidin-1-yl, azetidin-1-yl, -(C=O)N(CH3)2, (C=O)NHCH3, -(C=O)NHCH2CH 3、 -(C=O)NHcyclopropyl, -(C=O)(3,3-difluoroazetidin-1-y), 2-hydroxypropan-2-yl, 1-hydroxyethyl, dimethyl(oxo)-λ 6 -sulfanilidene, methoxy, ethoxy, difluoromethoxy, methyl, cyano is selected from the group consisting of.

[0233] In some embodiments, R 5 is as follows.

Chemical formula

[0234] In some embodiments, R 5 is as follows. [Chemical formula]

[0235] In some embodiments, R 5 is as follows. [Chemical formula]

[0236] In some embodiments, R 5 is as follows. [Chemical formula]

[0237] In some embodiments, R 5 is as follows. [Chemical formula]

[0238] In some embodiments, R 5 is as follows. [Chemical formula]

[0239] In some embodiments, R X is hydrogen. In some embodiments, R X is a halogen. In some embodiments, R X is fluoro. In some embodiments, R X is chloro.

[0240] In some embodiments, R A , R B , R C , R D , RE and R F is, independently, hydrogen or C1-C3 alkyl.

[0241] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

[0242] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

[0243] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

[0244] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

[0245] Preparation process In the present specification, there is provided a process for preparing a compound of formula (I) (for example, any compound described in the present specification), reacting a compound of formula (Ih) with

Chemical formula

[0246] In some embodiments, reacting a compound of formula (Ih) with R 5 -NH2 (for example, 5-chloro-6-(triazolyl)pyridin-3-amine) is carried out in the presence of POCl3 and pyridine.

[0247] In some embodiments, reacting a compound of formula (Ih) with R 5 -NH2 is carried out in the presence of N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate (TCFH).

[0248] In some embodiments, reacting a compound of formula (Ih) with R5 Reacting with -NH2 is carried out in the presence of N-methylimidazole (NMI).

[0249] In some embodiments, the compound of formula (Ih) is prepared from a compound of formula (Ih-N):

Chemical formula

[0250] In some embodiments (when the compound of formula (Ih) is prepared from a compound of formula (Ih-N)), the process comprises reacting a compound of formula (Ih-N-i) with

Chemical formula

Chemical formula

[0251] In certain embodiments, reacting the compound of formula (Ih-N-i) with the compound of formula (Ih-N-ii) is carried out in the presence of an acid.

[0252] In some of these embodiments, the acid is selected from the group consisting of hydrochloric acid and acetic acid.

[0253] As used herein, a process for preparing a compound of formula (I) (e.g., any compound described herein), wherein a compound of formula (Ij) is

Chemical formula

[0254] In some embodiments, reacting the compound of formula (Ij) with R 5 -Hal is carried out in the presence of a catalyst and a ligand.

[0255] In some embodiments (when reacting the compound of formula (Ij) with R 5 -Hal is carried out in the presence of a catalyst and a ligand), the catalyst is tris(dibenzylideneacetone)dipalladium(0).

[0256] In some embodiments (when reacting the compound of formula (Ij) with R 5 -Hal is carried out in the presence of a catalyst and a ligand), the ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0257] In some embodiments, the compound of formula (Ij) is prepared from the compound of formula (Ih-N):

Chemical formula

[0258] In some embodiments, the process comprises reacting a compound of formula (Ih-N-i) with

Chemical formula

Chemical formula

[0259] In some embodiments, reacting the compound of formula (Ih-N-i) with the compound of formula (Ih-N-ii) is carried out in the presence of an acid.

[0260] In some embodiments (when reacting the compound of formula (Ih-N-i) with the compound of formula (Ih-N-ii) is carried out in the presence of an acid), the acid is selected from the group consisting of hydrochloric acid and acetic acid.

[0261] Treatment method Some embodiments provide a method of treating an autoimmune disorder in a subject in need thereof (e.g., a MALT1-related autoimmune disorder), 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 disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE).

[0262] Some embodiments provide a method of treating an inflammatory disorder in a subject in need thereof (e.g., a MALT1-related inflammatory disorder), 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 disorder is chronic graft-versus-host disease (cGVHD).

[0263] Some embodiments provide a method of treating cancer in a subject in need thereof (e.g., a MALT1-related cancer), 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. For example, provided herein is a method for treating a MALT1-related cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the MALT1 gene, MALT1 protease, or the expression or activity or level of any of them in a sample from the subject; and b) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the MALT1 gene, MALT1 protease, or the expression or activity or level of any of them comprises one or more fusion proteins.

[0264] 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 cancer, medullary thyroid cancer (e.g., sporadic medullary thyroid cancer or hereditary medullary thyroid cancer), differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland neoplasm, lung adenocarcinoma, bronchioloalveolar carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, breast tumor, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or head and neck cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adolescence, adrenocortical cancer, anal cancer, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, canceroid tumor, cancer of unknown primary origin, cardiac tumor, head and neck cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenousleukemia, chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, site-specific neoplasms, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct cancer, non-invasive ductal carcinoma of the breast, embryonal tumors, endometrial cancer, epithelioma, esophageal cancer, nasal neuroblastoma, Ewing sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic diseases, glioma, hairy cell tumors, hairy cell leukemia, head and neck cancer, thoracic neoplasms, head and neck neoplasms, CNS tumors, primary CNS tumors, cardiac cancer, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline duct cancer, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma, fungating polyps, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, site-specific neoplasms, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal and paranasal cavity cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung neoplasms, lung cancer, lung neoplasms, respiratory tract neoplasms, bronchogenic cancer, bronchial neoplasms, oralselected from the group consisting of cancer, oral cancer, lip cancer, oro-pharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon neoplasm, renal cell cancer, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell cancer, squamous cell neck cancer, stomach cancer, T cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell cancer of the renal pelvis, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

[0265] In some embodiments, the cancer is a blood cancer such as leukemia or lymphoma. In some embodiments, the blood cancer (e.g., a blood cancer that is MALT1-related cancer) is selected from the group consisting of leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also called Hodgkin lymphoma), and myeloma, e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia, AML, acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, CML, chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prelymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), and multiple myeloma (MM). Additional examples of blood cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the blood cancer (e.g., a blood cancer that is MALT1-related cancer) is AML or CMML.

[0266] In some embodiments, the cancer is glioblastoma, chronic myelogenous leukemia, myeloid leukemia, or non-Hodgkin lymphoma.

[0267] In some embodiments, the cancer is non-Hodgkin lymphoma. In other embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In other embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In other embodiments, the cancer is mantle cell lymphoma (MCL). In other embodiments, the cancer is marginal zone lymphoma (MZL). In other embodiments, the cancer is chronic lymphocytic leukemia (CLL). In other embodiments, the cancer is a mature B-cell tumor.

[0268] In some embodiments, the cancer is T-cell acute lymphoblastic leukemia.

[0269] 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 cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell cancer, neuroblastoma, and melanoma. See, for example, Jiang et al., Cancer Research 2011, 71, 2183-2192. Also see Pan et al., Mol Cancer Res 2016, 14, 93-102, and Penas et al., Blood 2010, 115, 2214-2219.

[0270] In some embodiments, the subject is human.

[0271] The compounds of formula (I) and their pharmaceutically acceptable salts are also useful for treating MALT1-related cancers. The compounds of formula (I) and their pharmaceutically acceptable salts are also useful for treating MALT1-related autoimmune disorders. The compounds of formula (I) and their pharmaceutically acceptable salts are also useful for treating MALT1-related inflammatory diseases.

[0272] Accordingly, provided herein is a method for treating a subject diagnosed or identified as having a MALT1-related cancer, such as any of the exemplary MALT1-related cancers 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.

[0273] In some embodiments of any of the methods provided herein, the compound of formula (I) is selected from Examples 1-196.

[0274] Dysregulation of MALT1 protease, the MALT1 gene, or the expression or activity or level of any (e.g., one or more) of them can contribute to tumorigenesis. For example, the fusion protein can have increased protease activity compared to the wild-type MALT1 protein, and increased expression (e.g., increased levels) of wild-type MALT1 protease in mammalian cells can result from abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells), and MALT1 mRNA splice variants can also result in dysregulation of MALT1.

[0275] In some embodiments, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a CBM complex pathway-related cancer (such as any of those disclosed herein) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method for treating cancer in a subject in need thereof, 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.

[0276] Identifying the cancer in the subject as a CBM complex pathway-related cancer can be carried out by any suitable method. In some embodiments, the step of identifying the cancer in the subject as a CBM complex pathway-related cancer comprises performing an assay to detect dysregulation in the expression or activity or level of a CBM complex pathway-related gene, a CBM complex pathway-related protease protein, or any of them in a sample from the subject. In some embodiments, the method further comprises 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, and fluorescence in situ hybridization (FISH).

[0277] Also provided herein is a method for treating cancer in a subject in need thereof, 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 cancer.

[0278] Also provided herein is a method of treating MALT1-related cancer in a subject, the method comprising administering to a subject identified or diagnosed as having MALT1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising: (a) determining that the cancer is associated with a dysregulation of the MALT1 gene, MALT1 protease, or the expression, activity, or level of any of them; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0279] Determining that the cancer is associated with a dysregulation of the MALT1 gene, MALT1 protease, or the expression, activity, or level of any of them can be carried out using any suitable method. In some embodiments, the step of determining that the cancer in the subject is MALT1-related cancer comprises performing an assay for detecting a dysregulation in the MALT1 gene, MALT1 protease protein, or the expression, activity, or level of any of them in a sample from the subject. In some embodiments, the method further comprises 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, and fluorescence in situ hybridization (FISH).

[0280] As described herein, the CBM complex pathway-related cancer can be any suitable CBM complex pathway-related cancer (such as any of those described herein). In some embodiments, the CBM complex pathway-related cancer is selected from the group consisting of CBM complex pathway cell surface receptor-related cancer, cancer associated with a signal transducer between a cell surface receptor and the CBM complex, a constituent of the CBM complex-related cancer, MALT1 protease substrate-related cancer, cancer associated with a constituent of the NF-κB pathway downstream of the CBM complex, cancer associated with a constituent of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, the CBM complex pathway cell surface receptor-related cancer is selected from the group consisting of CD28-related cancer, BCR-related cancer, HER1-related cancer, HER2-related cancer, and combinations thereof. In some embodiments, the cancer associated with a signal transducer between a cell surface receptor and the CBM complex is protein kinase C beta (PKCβ)-related cancer, protein kinase C theta (PCKθ)-related cancer, or a combination thereof. In some embodiments, the constituent of the CBM complex-related cancer is selected from the group consisting of MALT1-related cancer, CARD11-related cancer, CARD14-related cancer, CARD10-related cancer, CARD9-related cancer, BCL10-related cancer, and combinations thereof. In some embodiments, the constituent of the CBM complex-related cancer is selected from the group consisting of MALT1-related cancer, CARD11-related cancer, BCL10-related cancer, and combinations thereof. See Tables B1, B2, and B3 for exemplary dysregulations in MALT1, CARD11, and BCL10, for example. In some embodiments, the MALT1 protease substrate-related cancer is selected from the group consisting of BCL10-related cancer, A20-related cancer, CYLD-related cancer, RelB-related cancer, Legumain-1-related cancer, Rockin-1-related cancer, HOIL1-related cancer, NIK-related cancer, LIMA1α-related cancer, and combinations thereof. In some embodiments, the MALT1 protease substrate-related cancer is selected from the group consisting of BCL10-related cancer, A20-related cancer, CYLD-related cancer, and combinations thereof.For example, see Tables B3 and B4 for exemplary deregulation in BCL10 and A20. 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-associated 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-associated cancers, JNK2-associated cancers, JNK3-associated cancers, MYD88 transcription factor-associated cancers, AP-1 transcription factor-associated cancers, and combinations thereof.

[0281] In some embodiments, CBM complex pathway-associated cancers are MALT1-associated cancers. MALT1-associated cancers can have any suitable deregulation, such as any of those described herein. In some embodiments, MALT1-associated cancers include an IAP2-MALT1 fusion. In some embodiments, MALT1-associated cancers include an IGH-MALT1 fusion.

[0282] Also provided herein are methods of treating CBM complex pathway-related diseases or disorders, autoimmune disorders, and inflammatory disorders. Accordingly, provided herein is a method for treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a MALT1-related autoimmune disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a MALT1-related autoimmune disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some cases, provided herein is a method for treating an autoimmune disorder in a subject in need thereof, the method comprising: (a) determining that the autoimmune disorder is associated with a dysregulation of the MALT1 gene, MALT1 protease, or the expression, activity, or level of any of them; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a MALT1-related autoimmune disorder in a subject, the method comprising administering to a subject determined to have a MALT1-related autoimmune disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In addition, provided herein is a method for treating an inflammatory disorder in a subject in need thereof, 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, provided herein is a method for treating a MALT1-related inflammatory disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a MALT1-related inflammatory disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.A method for treating an inflammatory disorder in a subject in need thereof, the method comprising: (a) determining that the inflammatory disorder is associated with dysregulation of the MALT1 gene, MALT1 protease, or the expression, activity, or level of any of them; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a MALT1-related inflammatory disorder in a subject, the method comprising administering to a subject determined to have a MALT1-related inflammatory disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0283] Additionally, provided herein is a method for treating a CBM complex pathway-related disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method for treating a disease or disorder in a subject in need thereof, the method comprising: (a) identifying cancer as a CBM complex pathway-related disease or disorder; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Further provided herein is a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to a subject identified as having a CBM complex pathway-related disease or disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0284] CBM complex pathway-related diseases or disorders can be any suitable CBM complex pathway-related diseases or disorders, such as any of those described herein. In some embodiments, the CBM complex pathway-related disease or disorder is an autoimmune disease. In some embodiments, the CBM complex pathway-related disease or disorder is an inflammatory disease. In some embodiments, the CBM complex pathway-related cancer is selected from the group consisting of CBM complex pathway cell surface receptor-related cancer, diseases or disorders related to signal transducers between cell surface receptors and the CBM complex, components of CBM complex-related cancer, MALT1 protease substrate-related cancer, diseases or disorders related to components of the NF-κB pathway downstream of the CBM complex, diseases or disorders 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 disorder is a MALT1-related disease or disorder.

[0285] In some cases, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful for inhibiting cellular processes such as inhibiting cell proliferation. Accordingly, provided herein is a method for inhibiting the proliferation of mammalian cells, the method comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is 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. Also provided herein is 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 contacting occurs in vivo. In some embodiments, the contacting 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-related cancer cells. In some embodiments, the mammalian cancer cells are mammalian MALT1-related cancer cells. In some embodiments, the mammalian cells have deregulation of the expression or activity or level of the MALT1 gene, the MALT1 protease protein, or any of them. In some embodiments, the deregulation of the expression or 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.

[0286] The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be useful in the manufacture of medicaments. Accordingly, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a CBM complex pathway-related disease or disorder. The CBM complex pathway-related disease or disorder can be any suitable CBM complex pathway-related disease or disorder such as those described herein. In some embodiments, the CBM complex pathway-related disease or disorder is selected from the group consisting of CBM complex pathway cell surface receptor-related cancer, a disease or disorder associated with a signal transducer between a cell surface receptor and the CBM complex, a component of a CBM complex-related cancer, MALT1 protease substrate-related cancer, a disease or disorder associated with a component of the NF-κB pathway downstream of the CBM complex, a disease or disorder associated with a component of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, the CBM complex pathway-related disease or disorder is a CBM complex pathway-related autoimmune disorder. In some embodiments, the CBM complex pathway-related disease or disorder is a CBM complex pathway-related inflammatory disorder. In some embodiments, the CBM complex pathway-related disease or disorder is a CBM complex pathway-related cancer. In some embodiments, the CBM complex pathway-related disease or disorder is a MALT1-related disease or disorder. In some embodiments, the MALT1-related disease or disorder comprises dysregulation of the MALT1 gene, the MALT1 protease protein, or the expression or activity or level of any of them. In some embodiments, the dysregulation of the MALT1 gene, the MALT1 protease protein, or the expression or activity or level of any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0287] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) penetration. Such compounds are capable of crossing the blood-brain barrier and inhibiting MALT1 protease within 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, the treatment of a subject having cancer (e.g., MALT1-related cancer such as MALT1-related brain or CNS cancer) can include administration of the compound to the subject (e.g., oral administration). In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors. For example, the compound can be used in the treatment of one or more of gliomas (e.g., glioblastoma multiforme, also known as glioblastoma, astrocytoma, oligodendroglioma, ependymoma, and mixed glioma), meningioma, medulloblastoma, ganglioglioma, schwannoma (neurilemmoma), and craniopharyngioma (see, e.g., the tumors listed in Louis, D. N. 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 anti-cancer agent, e.g., another protease inhibitor (e.g., a compound other than a compound 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 anti-cancer agent, e.g., another protease inhibitor (e.g., a compound other than a compound of formula (I)).

[0288] In some embodiments of any of the methods or uses described herein, an assay used to determine whether a subject has a dysregulation of a gene (e.g., the MALT1 gene), or a protein (e.g., the MALT1 protein), or the expression or activity or level of any of them using a sample from the subject can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH 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 antigen-binding fragment thereof. The assay can utilize other detection methods known in the art to detect a dysregulation of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or the expression or activity or level of any of them. In some embodiments, the sample is a biological sample or a 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 having one or more symptoms of MALT1-related cancer, and / or a subject at high risk of developing MALT1-related cancer).

[0289] In some embodiments, dysregulation of a gene (e.g., the MALT1 gene), the MALT1 protein (e.g., the MALT1 protein), or the expression or activity or level of any of them can be identified using a liquid biopsy (also variously referred to as a fluid biopsy or a liquid-phase biopsy). Liquid biopsy methods can be used to detect the total tumor burden and / or dysregulation of a gene (e.g., the MALT1 gene), the MALT1 protein (e.g., the MALT1 protein), or the expression or activity or level of any of them. Liquid biopsies can be performed on biological samples relatively easily obtained from a subject (e.g., via simple blood collection), and are generally less invasive than conventional methods used to detect the total tumor burden and / or dysregulation of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or the expression or activity or level of any of them. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or the expression or activity or level of any of them at an earlier stage than conventional methods. In some embodiments, the biological samples used in liquid biopsies can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph fluid, cyst fluid, feces, ascites, and combinations thereof. In some embodiments, liquid biopsies can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or the expression or activity or level of any of them.

[0290] In some embodiments, ctDNA derived from a single gene can be detected using a liquid biopsy. In some embodiments, 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, or any number of genes between these numbers) can be detected using a liquid biopsy. In some embodiments, ctDNA derived from multiple genes can be detected using any of a variety of commercially available test panels (e.g., commercially available test panels designed to detect dysregulation of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or the expression or activity or level of any of them). A liquid biopsy can be used to detect dysregulation of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or the expression or activity or level of 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, a liquid biopsy can be used to detect germline mutations. In some embodiments, a liquid biopsy can be used to detect somatic mutations. In some embodiments, a liquid biopsy can be used to detect primary gene mutations (e.g., primary mutations or primary fusions associated with the initial onset of a disease, e.g., cancer). In some embodiments, the dysregulation of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or the expression or activity or level of any of them identified using a liquid biopsy is also present in cancer cells present in a subject (e.g., in a tumor). In some embodiments, any of the types of dysregulation of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or the expression or activity or level of any of them described herein can be detected using a liquid biopsy.In some embodiments, genetic mutations identified via a liquid biopsy can be used to identify a subject as a candidate for a particular treatment. For example, detection of a dysregulation in the expression or activity or level of a gene (e.g., the MALT1 gene), protein (e.g., the MALT1 protein), or any of them in a subject can indicate that the subject will respond to a treatment comprising administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0291] A liquid biopsy can be performed multiple times during the diagnostic, monitoring, and / or treatment processes 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, and a second liquid biopsy can be performed at a second time point during the diagnostic, monitoring, and / or treatment processes. In some embodiments, the first time point can be a time point before diagnosing the subject with a disease (e.g., when the subject is healthy), and the second time point can be a time point after the subject has developed the disease (e.g., the second time point can be used to diagnose the subject with the disease). In some embodiments, the first time point can be a time point before diagnosing the subject with a disease (e.g., when the subject is healthy), after which the subject is monitored, 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 diagnosing the subject with a disease, after which treatment is administered to the subject, and the second time point can be a time point after the treatment has been administered, and in such cases, the second time point can be used to evaluate the efficacy of the treatment (e.g., if the amount of the detected genetic mutation(s) at the first time point is reduced or undetectable). In some embodiments, the treatment administered to the subject can comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0292] In some embodiments, the efficacy of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by assessing the allelic frequency of dysregulation of a gene (e.g., the MALT1 gene) in cfDNA obtained from a subject at different time points, e.g., cfDNA obtained from the subject at a first time point and cfDNA obtained from the subject at a second time point, and at least one dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject between the first time point and the second time point. Some embodiments of these methods can further include administering to the subject at least one dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof between the first time point and the second time point.For example, the reduction (e.g., 1% to about 99% reduction, 1% to about 95% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% reduction, 1% to about 75% reduction, 1% reduction to about 70% reduction, 1% reduction to about 65% reduction, 1% reduction to about 60% reduction, 1% reduction to about 55% reduction, 1% reduction to about 50% reduction, 1% reduction to about 45% reduction, 1% reduction to about 40% reduction, 1% reduction to about 35% reduction, 1% reduction to about 30% reduction, 1% reduction to about 25% reduction, 1% reduction to about 20% reduction, 1% reduction to about 15% reduction, 1% reduction to about 10% reduction, 1% to about 5% reduction, about 5% to about 99% reduction, about 10% to about 99% reduction, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% reduction, about 40% to about 99% reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% reduction, about 65% to about 99% reduction, about 70% to about 99% reduction, about 75% to about 95% reduction, about 80% to about 99% reduction, about 90% reduction to about 99% reduction, about 95% to about 99% reduction, about 5% to about 10% reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction, about 35% to about 55% reduction, about 40% to about 60% reduction, about 50% reduction to about 75% reduction, about 60% reduction to about 80% reduction, or about 65% to about 85% reduction) in the allele frequency (AF) of dysregulation of a gene (e.g., the MALT1 gene) in cfDNA obtained from a subject at a second time point compared to the AF of dysregulation of the gene (e.g., the MALT1 gene) in cfDNA obtained from the subject at a first time point indicates that the compound of formula (I) or a pharmaceutically acceptable salt thereof was effective in the subject. In some embodiments, the AF is reduced such that the level is below the detection limit of the instrument. Alternatively, an increase in the allele frequency (AF) of dysregulation of a gene (e.g., the MALT1 gene) in cfDNA obtained from a subject at a second time point compared to the AF of dysregulation of the gene (e.g., the MALT1 gene) in cfDNA obtained from the subject at a first time point indicates that the compound of formula (I) or a pharmaceutically acceptable salt thereof was not effective in the subject.Some embodiments of these methods can further include administering an additional dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject determined to be responsive to the compound of formula (I) or a pharmaceutically acceptable salt thereof. Some embodiments of these methods can further include administering a different treatment (e.g., a treatment that does not include administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as monotherapy) to a subject determined to be non-responsive to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0293] In some examples of these methods, the time difference between the first time point and the second time point is from about 1 day to about 1 year, from about 1 day to about 11 months, from about 1 day to about 10 months, from about 1 day to about 9 months, from about 1 day to about 8 months, from about 1 day to about 7 months, from about 1 day to about 6 months, from about 1 day to about 5 months, from about 1 day to about 4 months, from about 1 day to about 3 months, from about 1 day to about 10 weeks, from about 1 day to about 2 months, from about 1 day to about 6 weeks, from about 1 day to about 1 month, from about 1 day to about 25 days, from about 1 day to about 20 days, from about 1 day to about 15 days, from about 1 day to about 10 days, from about 1 day to about 5 days, from about 2 days to about 1 year, from about 5 days to about 1 year, from about 10 days to about 1 year, from about 15 days to about 1 year, from about 20 days to about 1 year, from about 25 days to about 1 year, from about 1 month to about 1 year, from about 6 weeks to about 1 year, from about 2 months to about 1 year, from about 3 months to about 1 year, from about 4 months to about 1 year, from about 5 months to about 1 year, from about 6 months to about 1 year, from about 7 months to about 1 year, from about 8 months to about 1 year, from about 9 months to about 1 year, from about 10 months to about 1 year, from about 11 months to about 1 year, from about 1 day to about 7 days, from about 1 day to about 14 days, from about 5 days to about 10 days, from about 5 days to about 20 days, from about 10 days to about 20 days, from about 15 days to about 1 month, from about 15 days to about 2 months, from about 1 week to about 1 month, from about 2 weeks to about 1 month, from about 1 month to about 3 months, from about 3 months to about 6 months, from about 4 months to about 6 months, from about 5 months to about 8 months, or from about 7 months to about 9 months. In some embodiments of these methods, the subject may have been previously identified as having a cancer having a dysregulated gene (e.g., any of the examples of dysregulated genes described herein) (e.g., the MALT1 gene). In some embodiments of these methods, the subject may have been previously diagnosed as having any of the cancer types described herein. In some embodiments of these methods, the subject may have one or more metastases (e.g., one or more brain metastases).

[0294] In some of the above embodiments, the cfDNA includes ctDNA such as MALT1-related ctDNA. For example, the cfDNA is ctDNA such as MALT1-related ctDNA. In some embodiments, at least some portions of the cfDNA are determined to be MALT1-related ctDNA, e.g., the sequencing and / or quantified amount of the total cfDNA is determined to have MALT1 fusion and / or overexpression of MALT1.

[0295] The genetic basis of tumor formation can vary between different cancer types, but the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During the metastatic cascade, cancer cells lose growth inhibitory responses, undergo changes in adhesion, and produce enzymes that can degrade components of the extracellular matrix. This leads to the detachment of tumor cells from the primary tumor, invasion into the circulation through the newly formed vasculature, movement, and extravasation of tumor cells at favorable distant sites where they can form colonies.

[0296] Accordingly, provided herein is also a method for doing so in a subject in need of inhibiting, preventing, assisting in preventing, or reducing the symptoms of cancer metastasis, 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 for the treatment of one or more of the cancers described herein. See, for example, U.S. Publication No. 2013 / 0029925, International Publication No. 2014 / 083567, and U.S. Patent No. 8,568,998. See also, for example, Hezam K et al., Rev Neurosci 2018 Jan 26;29:93 - 98, Gao L,et al.,Pancreas 2015 Jan;44:134 - 143, Ding K et al.,J Biol Chem 2014 Jun 6;289:16057 - 71, and Amit M et al.,Oncogene 2017 Jun 8;36:3232 - 3239. In some embodiments, the cancer is a MALT1 - related cancer. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent described herein. For example, a first or second MALT1 protease inhibitor.

[0297] The term "metastasis" is a term known in the art and means the formation of additional tumors (e.g., solid tumors) at sites distant from a primary tumor in a subject, where the additional tumors contain cancer cells that are the same as or similar to those of the primary tumor.

[0298] A method for reducing the risk of developing metastases or additional metastases in a subject having a MALT1-related cancer, the method comprising selecting, identifying, or diagnosing a subject as having a MALT1-related cancer and administering to the subject so selected, identified, or diagnosed as having a MALT1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method for reducing the risk of developing metastases or additional metastases in a subject having a MALT1-related cancer, the method comprising administering to a subject having a MALT1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in the risk of developing metastases or additional metastases in a subject having a MALT1-related cancer is compared to the risk of developing metastases or additional metastases in the subject prior to treatment or to a subject or population of subjects having a similar or the same MALT1-related cancer who have not been treated or have received a different treatment.

[0299] The phrase "risk of developing metastases" means the risk that a subject having a primary tumor will develop additional tumors (e.g., solid tumors) at sites remote from the primary tumor in the subject over a period of time, the additional tumors containing cancer cells that are the same as or similar to the primary tumor. Methods for reducing the risk of developing metastases in a subject having cancer are described herein.

[0300] The phrase "risk of developing additional metastases" means the risk that a subject having a primary tumor and one or more additional tumors at sites remote from the primary tumor (wherein the one or more additional tumors contain cancer cells that are the same as or similar to the primary tumor) will develop one or more further tumors at sites remote from the primary tumor, the further tumors containing cancer cells that are the same as or similar to the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0301] Some embodiments described herein are methods of treating autoimmune disorders (e.g., MALT1-related autoimmune disorders) such as rheumatoid arthritis, multiple sclerosis, and SLE, and include administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0302] Some embodiments described herein are methods of treating inflammatory disorders (e.g., MALT1-related autoimmune disorders) such as chronic graft-versus-host disease, and include administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0303] Also provided are methods for inhibiting MALT1 protease activity in mammalian cells, which include contacting mammalian cells with a compound of formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method includes administering to a subject having mammalian cells with MALT1 protease activity an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. 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-related mammalian cancer cells.

[0304] A method for inhibiting MALT1 protease activity in mammalian mammalian cells, which comprises contacting the mammalian cells with a compound of formula (I) is also provided. In some embodiments, contacting is in vitro. In some embodiments, contacting is in vivo. In some embodiments, contacting is in vivo and the method comprises administering to a mammal having mammalian cells with MALT1 protease activity an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. 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-related mammalian cancer cells. In some embodiments, the mammalian cells are gastrointestinal mammalian cells.

[0305] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro or in vivo system. For example, "contacting" MALT1 protease with a compound provided herein includes administering the compound provided herein to a subject such as a human having MALT1 protease, and introducing the compound provided herein into a sample containing mammalian cells or a purified preparation containing MALT1 protease, for example.

[0306] Also provided herein is a method for inhibiting the proliferation of mammalian cells in vitro or in vivo, which comprises contacting the 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.

[0307] As used herein, "MALT1 protease inhibitor" includes any compound that exhibits MALT1 inhibitory activity. In some embodiments, the MALT1 protease inhibitor is selective for MALT1 protease. Exemplary MALT1 protease inhibitors have an inhibitory activity (IC 50 ) against 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 as measured in the assays described herein. In some embodiments, the MALT1 protease inhibitor has an inhibitory activity (IC 50 ) against MALT1 protease of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in the assays provided herein.

[0308] As used herein, "first MALT1 protease inhibitor" or "first MALT1 inhibitor" is a MALT1 protease inhibitor as defined herein, but does not include a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein. As used herein, "second MALT1 protease inhibitor" or "second MALT1 inhibitor" is a MALT1 protease inhibitor as defined herein, but does not include a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein. If both a first and a second MALT1 inhibitor are present in the methods provided herein, the first and second MALT1 protease inhibitors are different.

[0309] Exemplary first and second MALT1 protease inhibitors are described herein. In some embodiments, the first or second MALT1 protease inhibitor can be, for example, JNJ-67856633 or CTX-177 (ONO-7018).

[0310] The term "effective amount" is sufficient to (i) treat a MALT1-related disease or disorder (such as a MALT1-related cancer), (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein when administered to a subject in need of such treatment. The amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof that would correspond to such amount, will vary depending on factors such as the particular compound, disease state and its severity, the individuality of the subject in need of treatment (e.g., weight), etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0311] Another embodiment features a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0312] Another embodiment features a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting MALT1 in a subject.

[0313] Another embodiment features a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating cancer, an autoimmune disorder or an inflammatory disorder.

[0314] Other embodiments provide a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating an autoimmune disorder (such as a MALT1-related autoimmune disorder) in a subject. In some embodiments, the autoimmune disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE).

[0315] Some embodiments provide a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating an inflammatory disorder (e.g., a MALT1-related inflammatory disorder) in a subject. In some embodiments, the inflammatory disorder is chronic graft-versus-host disease (cGVHD).

[0316] Some embodiments provide a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating cancer (e.g., a MALT1-related cancer) in a subject. In some embodiments, the dysregulation of the MALT1 gene, MALT1 protease, or the expression or activity or level of any of them involves one or more fusion proteins.

[0317] Accordingly, provided herein is also a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject diagnosed or identified as having a MALT1-related cancer, e.g., any of the exemplary MALT1-related cancers disclosed herein.

[0318] Also provided herein is a pharmaceutically acceptable salt of a compound of formula (I), or a pharmaceutical composition thereof, for use in a method of treating diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL) or mature B-cell tumors.

[0319] Also provided herein is a pharmaceutically acceptable salt of a compound of formula (I), or a pharmaceutical composition thereof, for use in a method of treating T-cell acute lymphoblastic leukemia.

[0320] Also provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a CBM complex pathway-related cancer (such as any of those disclosed herein) in a subject.

[0321] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating cancer in a subject identified as having a CBM complex pathway-related cancer.

[0322] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating MALT1-related cancer in a subject.

[0323] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating a CBM complex pathway-related disease or disorder, an autoimmune disorder, and an inflammatory disorder in a subject.

[0324] Accordingly, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating an autoimmune disorder in a subject. Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating a MALT1-related autoimmune disorder in a subject. Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating a MALT1-related autoimmune disorder in a subject.

[0325] In addition, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating an inflammatory disorder in a subject. In some cases, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating a MALT1-related inflammatory disorder in a subject identified or diagnosed as having a MALT1-related inflammatory disorder. Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating a MALT1-related inflammatory disorder in a subject determined to have a MALT1-related inflammatory disorder.

[0326] Additionally, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating a CBM complex pathway-related disease or disorder in a subject. In addition, provided herein are compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in a method of treating a disease or disorder in a subject identified as having a CBM complex pathway-related disease or disorder.

[0327] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of inhibiting the proliferation of mammalian cells. Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of inhibiting CBM complex pathway activity in mammalian cells. Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of inhibiting MALT1 protease activity in mammalian cells. 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-related cancer cells. In some embodiments, the mammalian cancer cells are mammalian MALT1-related cancer cells. In some embodiments, the mammalian cells have a dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease protein, or any combination thereof. In some embodiments, the dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease protein, or any combination thereof is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0328] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of inhibiting, preventing, assisting in the prevention of, or reducing the symptoms of cancer metastasis in a subject. Such methods can be used in the treatment of one or more of the cancers described herein. See, for example, U.S. Publication No. 2013 / 0029925, International Publication No. 2014 / 083567, and U.S. Patent No. 8,568,998. See also, for example, Hezam K et al., Rev Neurosci 2018 Jan 26;29:93-98, Gao L,et al.,Pancreas 2015 Jan;44:134-143, Ding K et al.,J Biol Chem 2014 Jun 6;289:16057-71, and Amit M et al.,Oncogene 2017 Jun 8;36:3232-3239. In some embodiments, the cancer is a MALT1-related cancer. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent described herein. For example, a first or second MALT1 protease inhibitor.

[0329] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of reducing the risk of developing metastases or additional metastases in a subject having a MALT1-related cancer. The reduction in the risk of developing metastases or additional metastases in a subject having a MALT1-related cancer can be compared to the risk of developing metastases or additional metastases in the subject prior to treatment, or to a subject or population of subjects having a similar or the same MALT1-related cancer who have not been treated or who have received a different treatment.

[0330] Some embodiments described herein provide compounds of formula (I), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in a method of treating autoimmune disorders (e.g., MALT1-related autoimmune disorders) such as rheumatoid arthritis, multiple sclerosis, and SLE in a subject.

[0331] Some embodiments described herein provide a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating an inflammatory disorder (e.g., MALT1-related autoimmune disorder), such as chronic graft-versus-host disease, in a subject.

[0332] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting MALT1 protease activity in mammalian 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 any cancer described herein. In some embodiments, the mammalian cancer cells are MALT1-related mammalian cancer cells.

[0333] Also provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting the proliferation of mammalian cells.

[0334] In another aspect, the invention features a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method in which a subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or after treatment with an effective amount of the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

[0335] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0336] In another aspect, the invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in inhibiting MALT1 in a subject.

[0337] In yet another aspect, the present invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment of cancer, autoimmune disorders, or inflammatory disorders in a subject.

[0338] Some embodiments provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of an autoimmune disorder (e.g., a MALT1-related autoimmune disorder) in a subject. In some embodiments, the autoimmune disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE).

[0339] Some embodiments provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of an inflammatory disorder (e.g., a MALT1-related inflammatory disorder) in a subject. In some embodiments, the inflammatory disorder is chronic graft-versus-host disease (cGVHD).

[0340] Some embodiments provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of cancer (e.g., a MALT1-related cancer) in a subject. In some embodiments, the dysregulation of the MALT1 gene, MALT1 protease, or the expression or activity or level of any of them involves one or more fusion proteins.

[0341] Accordingly, provided herein is also the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of a subject diagnosed or identified as having a MALT1-related cancer, e.g., any of the exemplary MALT1-related cancers disclosed herein.

[0342] Accordingly, provided herein is also the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of a subject having diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), or a mature B-cell tumor.

[0343] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt of a pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of a subject having T-cell acute lymphoblastic leukemia.

[0344] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of CBM complex pathway-related cancer (such as any of those disclosed herein) in a subject.

[0345] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of cancer in a subject identified as having CBM complex pathway-related cancer.

[0346] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of MALT1-related cancer in a subject.

[0347] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of CBM complex pathway-related diseases or disorders, autoimmune disorders, and inflammatory disorders in a subject. Accordingly, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of autoimmune disorders in a subject. Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of MALT1-related autoimmune disorders in a subject. Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of MALT1-related autoimmune disorders in a subject. In addition, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of inflammatory disorders in a subject. In some cases, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of MALT1-related inflammatory disorders in a subject identified or diagnosed as having a MALT1-related inflammatory disorder. Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of MALT1-related inflammatory disorders in a subject determined to have a MALT1-related inflammatory disorder.

[0348] Additionally, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of CBM complex pathway-related diseases or disorders in a subject. In addition, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder in a subject identified as having a CBM complex pathway-related disease or disorder.

[0349] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting mammalian cell proliferation. Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting CBM complex pathway activity in mammalian cells. Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting MALT1 protease activity in mammalian cells. 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-related cancer cells. In some embodiments, the mammalian cancer cells are mammalian MALT1-related cancer cells. In some embodiments, the mammalian cells have dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease protein, or any of them. In some embodiments, the dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease protein, or any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0350] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting, preventing, assisting in preventing, or alleviating the symptoms of metastasis of cancer in a subject. In some embodiments, the cancer is MALT1-related cancer. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent described herein. For example, a first or second MALT1 protease inhibitor.

[0351] Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in reducing the risk of developing metastases or additional metastases in a subject having a MALT1-related cancer. The reduction in the risk of developing metastases or additional metastases in a subject having a MALT1-related cancer can be compared to the risk of developing metastases or additional metastases in the subject prior to treatment, or to a subject or population of subjects having a similar or the same MALT1-related cancer who have not been treated or have received a different treatment.

[0352] Some embodiments described herein provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of autoimmune disorders (e.g., MALT1-related autoimmune disorders) such as rheumatoid arthritis, multiple sclerosis, and SLE in a subject.

[0353] Some embodiments described herein provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of inflammatory disorders (e.g., MALT1-related autoimmune disorders), such as chronic graft-versus-host disease, in a subject.

[0354] Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting MALT1 protease activity in mammalian 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 any cancer described herein. In some embodiments, the mammalian cancer cells are MALT1-related mammalian cancer cells.

[0355] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting mammalian cell proliferation.

[0356] In yet another aspect, the present invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound or pharmaceutical composition.

[0357] In the field of medical oncology, it is common practice to use combinations of different forms of treatment to treat each subject having cancer. In medical oncology, in addition to the compositions provided herein, other components of such conjoint treatment or therapy can be, for example, surgery, radiation therapy, and chemotherapeutic agents such as other protease inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies.

[0358] For example, the surgery can be open surgery or minimally invasive surgery. Thus, the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be useful as adjuvants for cancer treatment, i.e., they can be used in combination with one or more additional therapies or therapeutic agents, such as chemotherapeutic agents that function by the same or different mechanisms of action. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof can be used prior to the administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof over a period of time and then can undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size (e.g., tumor mass) of the tumor prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof over a period of time under one or more rounds of radiotherapy. In some embodiments, treatment with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size (e.g., tumor mass) of the tumor prior to one or more rounds of radiotherapy.

[0359] In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumors) that is refractory or intolerant to standard therapies (e.g., administration of chemotherapeutic agents) such as a first MALT1 inhibitor, a kinase inhibitor, immunotherapy, cell or gene therapy, or radiation (e.g., radioactive iodine). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumors) that is refractory or intolerant to previous therapies (e.g., administration of chemotherapeutic agents such as a first MALT1 inhibitor or another protease inhibitor, immunotherapy, cell or gene therapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumors) that has not received standard therapy. In some embodiments, the subject is naïve to MALT1-protease inhibitors. For example, the subject is naïve to treatment with a selective MALT1-protease inhibitor. In some embodiments, the subject is not naïve to MALT1-protease inhibitors.

[0360] In some embodiments of any of the methods described herein, the 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 additional therapies or therapeutic agents (e.g., chemotherapeutic agents or immunomodulatory agents). The additional therapy or therapeutic agent can be any suitable additional therapy or therapeutic agent, such as any of those described herein.

[0361] Non-limiting examples of additional therapeutic agents include other MALT1-targeted therapeutic agents (i.e., first or second MALT1 protease inhibitors, e.g., JNJ-67856633 or CTX-177 (ONO-7018)), other protease inhibitors, kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents such as BTK or EGFR inhibitors), signaling pathway inhibitors, checkpoint inhibitors, modulators of the apoptotic pathway (e.g., venetoclax or obatoclax), cytotoxic chemotherapy, angiogenesis-targeted therapy, immunotargeting agents (including antibody and cell-based immunotherapies, and antibody-drug conjugates), and radiation therapy.

[0362] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent are administered sequentially as separate dosages in any order.

[0363] In some embodiments, the other MALT1-targeted therapeutic agent is another protease inhibitor that exhibits MALT1 inhibitory activity. In some embodiments, the other MALT1-targeted therapeutic inhibitor is selective for MALT1 protease. Exemplary MALT1 protease inhibitors have an inhibitory activity (IC 50 ) against 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 as measured in the assays described herein. In some embodiments, the MALT1 protease inhibitor has an inhibitory activity (IC 50 ) against MALT1 protease of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in the assays provided herein.

[0364] Non-limiting examples of protease-targeted therapeutic agents (e.g., a first MALT1 inhibitor or a second MALT1 inhibitor) include JNJ-67856633 and CTX-177 (ONO-7018).

[0365] 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-carbonitrile); amuvatinib (MP470, HPK56) (N-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide); apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-picolyl)amino-3-nicotinamidomethanesulfonate); cabozantinib (Cometriq XL-184) (N-(4-((6,7-dimethoxyquinolin-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-ylidene]quinolin-2-one); famitinib (5-[2-(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one); fedratinib (SAR302503, TG101348) (N-(2-methyl-2-propanyl)-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-quinolyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); fostamatinib (R788) (2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphonooxy)methyl]-, sodium salt (1:2));Irolacertib (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-quinolinecarboxamide); Motesanib (AMG706) (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-methylpiperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenylmethylene]-6-methoxycarbonyl-2-indolinone); 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 (Torquinib) (2-[4-Amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indol-5-ol); Crizotinib (1-(5-(tert-Butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)urea); Regorafenib (BAY73-4506, 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-Dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea); Semaxanib (SU5416) ((3Z)-3-[(3,5-Dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one);Citrambinib (MGCD516, MG516) (N-(3-Fluoro-4-{[2-(5-{[(2-Methoxyethyl)amino]methyl}-2-pyridinyl)thieno[3,2-b]pyridin-7-yl]oxy}phenyl)-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide); Sorafenib (BAY43-9006) (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); Batalanib (PTK787, PTK / ZK, ZK222584) (N-(4-Chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-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-propan-2-ylpyrazolo[3,4-d]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)thiazol-2-yl)urea); CLM3 (1-Phenethyl-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); EBI-907 (N-(2-Chloro-3-(1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]isoquinolin-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-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one); PP2 (4-Amino-5-(4-chlorophenyl)-7-(dimethyl ethyl)pyrazolo[3,4-d]pyrimidine); PZ-1 (N-(5-(tert-Butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide); RPI-1 (1,3-Dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one; (3E)-3-[(4-hydroxyphenyl)methylidene]-5,6-dimethoxy-1H-indol-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]benzeneacetonitrile); SPP86 (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); SU4984 (4-[4-[(E)-(2-oxo-1H-indol-3-ylidene)methyl]phenyl]piperazine-1-carboxaldehyde); Sunitinib (SU11248) (N-(2-Diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)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);Vitafellin A ((4β,5β,6β,22R)-4,27-dihydroxy-5,6:22,26-diepoxyergosta-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)indolin-2-one); BPR1J373 (5-phenylthiazol-2-ylamine-pyrimidinide derivative); 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 (cyclobenzaprine hydrochloride); XMD15-44 (N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide (generated from 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 are mentioned.;

[0366] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) target therapeutic agents include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, l-((3S,4R)-4-(3-fluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Goe 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-pyrrol-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)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-[2,4’-bipyridin]-2’-yl)piperidin-4-ol are included.

[0367] In some embodiments, the 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). Additional examples of BRAF inhibitors are known in the art.

[0368] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors can include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0369] In some embodiments, the additional therapeutic agent is a Ras-Raf-MEK-ERK pathway inhibitor (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib), a PI3K-Akt-mTOR-S6K pathway inhibitor (e.g., everolimus, rapamycin, perifosine, temsirolimus), and other kinase inhibitors such as baricitinib, brigatinib, capmatinib, danusertib, ibrutinib, milciclib, quercetin, regorafenib, ruxolitinib, semaxanib, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736 ((R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H pyrrolo[4,3,2-ef][2,3]benzodiazepin-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).

[0370] In some embodiments, the additional therapeutic agent is a BTK inhibitor. Non-limiting examples of BTK inhibitors include ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib, and NX-2127.

[0371] In some embodiments, the additional therapeutic agent is a Bcl-2 inhibitor. Non-limiting examples of Bcl-2 inhibitors include venetoclax, navitoclax, oblimersen, obatoclax, and AT-101.

[0372] 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.

[0373] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include everolimus, temsirolimus, and ridaforolimus.

[0374] 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.

[0375] In some embodiments, the 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.

[0376] In some embodiments, the additional therapeutic agent is a cytotoxic chemotherapeutic agent. Non-limiting examples of cytotoxic chemotherapeutic agents include arsenic trioxide, bleomycin, bendamustine, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

[0377] In some embodiments, the additional therapeutic agent is an angiogenesis target therapeutic agent. Non-limiting examples of angiogenesis target therapies include lenalidomide, enzastaurin, aflibercept, and bevacizumab.

[0378] In some embodiments, the additional therapy or therapeutic agent can include a histidyl tRNA synthetase (HRS) polypeptide or an expressible nucleotide encoding the HRS polypeptide.

[0379] The term "immunotherapy" refers to an agent that modulates the immune system. In some embodiments, immunotherapy can increase the expression and / or activity of regulators of the immune system. In some embodiments, immunotherapy can decrease the expression and / or activity of regulators of the immune system. In some embodiments, immunotherapy can mobilize and / or enhance the activity of immune cells.

[0380] In some embodiments, the immunotherapy is 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™, Plosker (2011) Drugs 71(1):101-108). In some embodiments, the cellular immunotherapy comprises cells that express a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah). In some embodiments, the CAR-T cell therapy is axicabtagene ciloleucel (Yescarta). In some embodiments, the CAR-T cell therapy is brexucabtagene autoleucel (Tecartus). In some embodiments, the CAR-T cell therapy is relmacabtagene autoleucel. In some embodiments, the CAR-T cell therapy is ALLO-501.

[0381] In some embodiments, the immunotherapy is an antibody therapy (e.g., monoclonal antibody, conjugate antibody, or bispecific antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®), rituximab with human hyaluronidase (Rituxan Hycela™), edrecolomab (Panorex), daratumumab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutuximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza™), siltuximab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), lenzilumab, avelumab, spartalizumab, pembrolizumab, utomilumab, ublituximab, blinatumomab, ganitumab, urelumab, pidilizumab, amatuximab, mosunetuzumab (BTCT4465A), CD20-TCB, RO7082859, XmAb13676, glofitamab, CD20-TDB, odronextamab (REGN1979), IGM-2323, BTCT4465A, AMG-562, or TTI-621.

[0382] In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM-1, Kadcyla®), mirvetuximab soravtansine (IMGN853), anetumab ravtansine, polatuzumab vedotin, loncastuximab tesirine (ADCT-402), camidanlumab tesirine (ADCT-301), or naratuximab emtansine (Debio1562).

[0383] In some embodiments, the immunotherapy comprises blinatumomab (AMG103, Blincyto®) or midostaurin (Rydapt).

[0384] In some embodiments, the immunotherapy comprises a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

[0385] In some embodiments, the immunotherapy is cytokine therapy. In some embodiments, the 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, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNα therapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapy is filgrastim (Neupogen®).

[0386] In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the 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 (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®), or durvalumab (Imfinzi™).

[0387] 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 Vaccin Immunother 10(11):3146-52, and Kubler et al. (2015) J. Immunother Cancer 3:26).

[0388] In some embodiments, the immunotherapy is Bacillus Calmette-Guerin (BCG) therapy.

[0389] In some embodiments, the immunotherapy is oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC, Imlygic®).

[0390] In some embodiments, the immunotherapy is a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is Gardasil®, Gardasil9®, or Cervarix®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®, Recombivax HB®, or GI-13020 (Tarmogen®). In some embodiments, the cancer vaccine is Twinrix® or Pediarix®. In some embodiments, the cancer vaccine is BiovaxID®, Oncophage®, GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®, Rindopepimut®, CimaVax-EGF, lapuleucel-T (APC8024, Neuvenge™), GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlisimut-L (Hepko-V5), DCVAX®, SCIB1, BMT, CTN1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac, or viagenpumatucel-L (HS-110).

[0391] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is nelipeptimut-S (E75) (NeuVax™), IMA901, or SurVaxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic personalized neoantigen vaccine (see, e.g., 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 mammaglobin-A DNA vaccine (see, e.g., Kim et al. (2016) OncoImmunology 5(2):e1069940).

[0392] In some embodiments, the immunotargeting agent is selected from aldesleukin, interferon alpha-2b, ipilimumab, ranibizumab, nivolumab, prednisone, and sipuleucel-T.

[0393] In some embodiments, the additional therapy is radiation therapy. Non-limiting examples of radiation therapy include radioactive iodide therapy, external beam radiation, and radium-223 therapy.

[0394] In some embodiments, the additional therapeutic agent is GSK-3368715, PF-06821497, selarasertib, AZD6738, BI-894999, MAK-683, AZD-6738, tamidinadenant, TAK-981, MIK-665, or danvatirsen.

[0395] As additional kinase inhibitors, 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,No. 051, U.S. Patent Publication No. 2015 / 0018336, International Publication Nos. 2007 / 002325, 2007 / 002433, 2008 / 080001, 2008 / 079906, 2008 / 079903, 2008 / 079909, 2008 / 080015, 2009 / 007748, 2009 / 012283, 2009 / 143018, 2009 / 143024, 2009 / 014637, 2009 / 152083, 2010 / 111527, 2012 / 109075, 2014 / 194127, 2015 / 112806, 2007 / 110344, 2009 / 071480, 2009 / 118411, 2010 / 031816, 2010 / 145998, 2011 / 092120, 2012 / 101032, 2012 / 139930, 2012 / 143248, 2012 / 152763, 2013 / 014039, 2013 / 102059, 2013 / 050448, 2013 / 050446, 2014 / 019908, 2014 / 072220, 2014 / 184069, 2016 / 075224, 2016 / 081450, 2016 / 022569, 2016 / 011141, 2016 / 011144, 2016 / 011147, 2015 / 191667, 2012 / 101029, 2012 / 113774, 2015 / 191666, 2015 / 161277, 2015 / 161274, 2015 / 108992, 2015 / 061572, 2015 / 058129, 2015 / 057873, 2015 / 017528, 2015 / 017533, 2014 / 160521, and 2014 / 011900 are included, and each of them is incorporated herein by reference in its entirety.,

[0396] 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 polatuzumab vedotin, selinexor, axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), rituximab, bendamustine in combination with polatuzumab vedotin, tafasitamab in combination with lenalidomide, or rituximab with hyaluronidase (Rituxan Hycela).

[0397] In some embodiments, the subject is concurrently receiving standard of care therapy for lymphoma. In some embodiments, the standard of care therapy is polatuzumab vedotin, selinexor, axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), rituximab, bendamustine in combination with polatuzumab vedotin, tafasitamab in combination with lenalidomide, or rituximab with hyaluronidase (Rituxan Hycela).

[0398] Pharmaceutical composition When used as a drug, the compounds of formula (I), including 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 art and can be administered by various routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be local (including transdermal, epidermal, ocular, and mucosal including nasal, vaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal by inhalation or insufflation of powder or aerosol including by nebulizer), oral, or parenteral. Oral administration can include dosage forms formulated for once-daily or twice-daily (BID) dosing. Parenteral administration includes intravenous, intraarterial, 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, for example, by continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickening agents, etc. may be required or desirable.

[0399] In the present invention, there is also provided a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients as an active ingredient. For example, a pharmaceutical composition prepared using a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with the excipient, diluted by the excipient, or enclosed in such a carrier in the form of, for example, capsules, sachets, paper, or other containers. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of, for example, tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, containing up to 10% by weight of the active compound, soft 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 a tablet or a capsule.

[0400] There is further provided herein a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by intimately mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0401] 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 Codex.

[0402] Methods of formulating pharmaceutical compositions are 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 and published by Marcel Dekker, Inc.

[0403] When preparing the composition in an oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc., and for solid oral preparations such as powders, capsules, and tablets, suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, 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 preparations may also be coated with substances such as sugar or enteric-coated to regulate the main absorption site. For parenteral administration, the carrier is usually composed of sterile water, and other components may be added to increase solubility or preservability. Injectable suspensions or solutions may also be prepared using an aqueous carrier together with appropriate additives. The pharmaceutical compositions herein will contain, per dosage unit, e.g., per tablet, capsule, powder, injection, teaspoonful, etc., the amount of the active ingredient necessary to deliver the effective dosage described herein.

[0404] The composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated in unit dosage form, and each dosage contains from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human and other subjects, each unit containing a predetermined quantity of the active substance (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0405] In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of an active ingredient. Those skilled in the art will understand that this embodies a compound or composition containing from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, or from about 45 mg to about 50 mg of an active ingredient.

[0406] In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of an active ingredient. Those skilled in the art will understand that this embodies a compound or composition containing from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 350 mg to about 400 mg, or from about 450 mg to about 500 mg of an active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of an active ingredient.

[0407] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of an active ingredient. Those skilled in the art will understand that this embodies a compound or composition containing from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1,000 mg of an active ingredient.

[0408] The daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof can vary widely, from 1.0 to 10,000 mg or more per day per adult, or any range therein. For oral administration, the composition is preferably provided in the form of tablets 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 milligrams of the active ingredient for symptomatic adjustment of the dosage to the subject being treated. An effective amount of the drug is usually supplied at a dosage level of about 0.1 mg / kg to about 1000 mg / kg of body weight per day, or any range therein. Preferably, the range is about 0.5 to about 500 mg / kg of body weight per day, or any range therein. More preferably, it is about 1.0 to about 250 mg / kg of body weight per day, or any range therein. More preferably, it is about 0.1 to about 100 mg / kg of body weight per day, or any range therein. In one example, the range can be about 0.1 to about 50.0 mg / kg of body weight per day, or any amount or range therein. In another example, the range can be about 0.1 to about 15.0 mg / kg of body weight per day, or any range therein. In yet another example, the range can be about 0.5 to about 7.5 mg / kg of body weight per day, or any amount or range therein. The pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered in a regimen of 1 to 4 times a day, or in a single daily dose.

[0409] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. The optimal dosage to be administered can be readily determined by one of ordinary skill in the art. Thus, it will be understood that the amount of the compound actually administered will usually be determined by a physician and will vary according to the relevant circumstances, including the method of administration, the actual compound being administered, the strength of the preparation, the condition being treated, and the progression of the disease state. In addition, factors related to the particular subject being treated, including the subject's response, age, weight, diet, time of administration, and severity of the subject's symptoms, will give rise to the need to adjust the dosage.

[0410] In some embodiments, the compounds provided herein can be administered in an amount in the range of about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein can be administered in an amount of 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, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg.

[0411] One of ordinary skill in the art will recognize that both in vivo and in vitro tests using suitable, known, and generally accepted cell and / or animal models can predict the ability of a test compound to treat or prevent a given disorder.

[0412] One of ordinary skill in the art will further recognize that human clinical trials, including human first-in-dose range and efficacy studies in healthy and / or subjects suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0413] Provided herein is a pharmaceutical kit useful for the treatment of MALT1-related diseases or disorders such as cancer, comprising one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. Such kits can further comprise one or more of various conventional pharmaceutical kit components, such as containers with one or more pharmaceutically acceptable carriers, additional containers, etc., if desired, for example, as will be readily apparent to one of ordinary skill in the art. Instructions indicating the amount of the administered components, guidelines for administration, and / or guidelines for mixing the components can also be included in the kit, either as an insert or a label.

[0414] Additional embodiments Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

Chemical formula

[0415] Embodiment 2. The compound according to Embodiment 1, wherein X is N and Y is C.

[0416] Embodiment 3. The compound according to Embodiment 1 or 2, wherein Z is N.

[0417] Embodiment 4. The compound according to any one of Embodiments 1 to 3, wherein R X is hydrogen.

[0418] Embodiment 5. The compound according to any one of Embodiments 1 to 4, wherein Q is -CH2-.

[0419] Embodiment 6. The compound according to any one of Embodiments 1 to 5, wherein R 1 is hydrogen.

[0420] Embodiment 7. The compound according to any one of Embodiments 1 to 5, wherein R 1 is halogen.

[0421] Embodiment 8. The compound according to any one of Embodiments 1 to 7, wherein R 2 is hydrogen.

[0422] Embodiment 9. The compound according to any one of Embodiments 1 to 7, wherein R 2 is halogen.

[0423] Embodiment 10. The compound according to any one of Embodiments 1 to 9, wherein n is 1.

[0424] Compound according to any one of Embodiments 1 to 10, wherein m is 1.

[0425] Embodiment 12. Each R 3 is independently deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy, and is a compound according to any one of Embodiments 1 to 11.

[0426] Embodiment 13. m is 1, and R 3 is methyl or trifluoromethyl, and is a compound according to any one of Embodiments 1 to 12.

[0427] Embodiment 14. R 4 is a 5- to 6-membered heteroaryl optionally substituted by 1 to 3 substituents each independently selected from R 7 and is a compound according to any one of Embodiments 1 to 13.

[0428] Embodiment 15. R 4 is a 6-membered heteroaryl optionally substituted by 1 to 3 substituents each independently selected from R 7 and is a compound according to any one of Embodiments 1 to 13.

[0429] Embodiment 16. R 4 is a 5-membered heteroaryl optionally substituted by 1 to 3 substituents each independently selected from R 7 and is a compound according to any one of Embodiments 1 to 13.

[0430] Embodiment 17. R 4 is 4H-pyrazolyl, 3H-pyrazolyl, or thiazolyl optionally substituted by 1 to 3 substituents each independently selected from R 7 and is a compound according to any one of Embodiments 1 to 13.

[0431] Embodiment 18. R 4The compound according to any one of Embodiments 1 to 13, which is unsubstituted.

[0432] Embodiment 19. Each R 7 The compound according to any one of Embodiments 1 to 13, wherein each R is independently selected from the group consisting of C1-C3 haloalkyl, C1-C3 alkyl, and cycloalkyl.

[0433] Embodiment 20. R 5 is a 5- to 9-membered heteroaryl optionally substituted by 1 to 3 independently selected Rs 8 The compound according to any one of Embodiments 1 to 19.

[0434] Embodiment 21. R 5 is a 5- to 6-membered heteroaryl substituted by 1 to 3 independently selected Rs 8 The compound according to any one of Embodiments 1 to 19.

[0435] Embodiment 22. R 5 is 3-pyridyl or 4-pyridyl optionally substituted by 1 to 3 independently selected Rs 8 The compound according to any one of Embodiments 1 to 21.

[0436] Embodiment 23. At least one of the Rs 8 is halogen. The compound according to any one of Embodiments 1 to 21.

[0437] Embodiment 24. At least one of the Rs 8 is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxyl or -NR E R F is a 5- to 6-membered heteroaryl optionally substituted by C1-C3 alkyl, amino, or C1-C3 haloalkyl optionally substituted by Rs

[0438] Embodiment 25. R 8at least one of which is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxyl or -NR E R F optionally substituted by C1-C3 alkyl optionally substituted by C1-C3 alkyl, amino, or C1-C3 haloalkyl, a 5-membered heteroaryl, a compound according to any one of embodiments 1 to 21.

[0439] Embodiment 26. A compound according to any one of embodiments 1 to 25, which is a compound according to formula (Ib), or a pharmaceutically acceptable salt thereof.

Chemical formula

[0440] Embodiment 27. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.

[0441] Embodiment 28. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 27.

[0442] Embodiment 29. The method according to embodiment 28, wherein the cancer is a MALT1-related cancer.

[0443] Embodiment 30. The method according to embodiment 28 or 29, wherein the cancer is lymphoma.

[0444] Embodiment 31. The method according to embodiment 30, wherein the lymphoma is non-Hodgkin lymphoma, DLBCL, refractory DLBCL, the (ABC) subtype of DLBCL, mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL).

[0445] Embodiment 32. The method according to embodiment 28 or 29, wherein the cancer is leukemia.

[0446] Embodiment 33. The method according to embodiment 32, wherein the leukemia is chronic lymphocytic leukemia (CLL).

[0447] Embodiment 34. The method according to embodiment 28 or 29, wherein the cancer is a solid tumor.

[0448] Embodiment 35. A method for treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 27.

[0449] Embodiment 36. The method according to embodiment 35, wherein the autoimmune disorder is chronic graft-versus-host disease.

[0450] Embodiment 37. The method according to any one of embodiments 30 to 36, further comprising administering an additional therapy or therapeutic agent to the subject.

Examples

[0451] Materials and Methods The compounds provided herein, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0452] The reactions for preparing the compounds provided herein can be carried out in a suitable solvent that can be readily selected by one of ordinary skill in the art of organic synthesis. The suitable solvent can be at a temperature at which the reaction is carried out, for example, a temperature in the range from the freezing temperature to the boiling temperature of the solvent, and can be substantially non-reactive with the starting materials (reactants), intermediates, or products. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, the solvent suitable for the particular reaction step can be selected by one of ordinary skill in the art.

[0453] The preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th Ed., Wiley-Interscience Publication, 2001, and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297(1997).

[0454] Reactions sensitive to moisture or air were carried out under nitrogen or argon using anhydrous solvents and reagents. The progress of the reaction was usually determined by either analytical thin-layer chromatography (TLC) using Sanpont pre-coated TLC plates, silica gel GF-254, layer thickness 0.25 mm, or liquid chromatography-mass spectrometry (LC-MS).

[0455] Typically, the analytical LC-MS system used was composed of a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode using a 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA detector, and LCMS 2020 MS detector. The column was usually HALO a C18 30*5.0mm, 2.7μm. Mobile phase A was water containing 0.05% TFA, and mobile phase B was acetonitrile containing 0.05% TFA. The gradient was 5% mobile phase B to 100% in 2.0 minutes, held for 0.7 minutes, then returned to 5% mobile phase B over 0.05 minutes and maintained for 0.25 minutes. The column oven (CTO-20AC) was operated at a temperature of 40.0°C. The flow rate was 1.5 mL / min, and the injection volume was 1 μl. Detection by PDA (SPD-M20A) was in the range of 190 - 400 nm. The MS detector was configured with electrospray ionization as the ionizable source, acquisition mode: scan, spray gas flow rate: 1.5 L / min, drying gas flow rate: 15 L / min, detector voltage: tuning voltage ±0.2 kv, DL temperature: 250°C, heating block temperature: 250°C, scan range: 90.00 - 900.00 m / z. ELSD (Alltech 3300) detector parameters: drift tube temperature: 60 ± 5°C, N2 flow rate: 1.8 ± 0.2 L / min. The mobile phase gradient was optimized for each compound.

[0456] The GC-MS system was usually performed using a Shimadzu GCMS-QP2010 Ultra with an FID and an MS detector. MS detector acquisition mode: start time: 2.00 minutes, end time: 9.00 minutes, ACQ mode: scan, event time: 0.30 seconds, scan speed: 2000, start m / z: 50.00, end m / z: 550.00, ion source temperature: 200.00°C, interface temperature: 250.00°C, solvent cut time: 2.00 minutes.

[0457] Fractional HPLC purification was usually carried out using a Waters Auto purification system (2545 - 2767) with a 2489 UV detector. The column was a Waters C18, 19×150 mm, 5 μm. The mobile phase was composed 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 at 254 nm and 220 nm. The mobile phase gradient was optimized for each individual compound.

[0458] 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 columns (Daicel Chemical Industries, Ltd.), (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc.), CHIRAL cellulose-SB, SC, SA columns (YMC Co., Ltd.) with different column sizes (50×4.6 mm, 100×4.6 mm, 150×4.6 mm, 250×4.6 mm, 50×3.0 mm, 100×3.0 mm) using either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) at the described percentages as an isocratic solvent system.

[0459] The reactions carried out using microwave irradiation were usually performed using an Initiator manufactured by Biotage. The concentration of the solution was carried out on a rotary evaporator under reduced pressure. Flash column chromatography was usually carried out using a Biotage flash chromatography apparatus (Dyax Corp.) on silica gel (40 - 60 μM, 60 Å pore size) in a pre-packed cartridge of the described size. Unless otherwise stated, 11H NMR spectra were acquired on a 400 MHz spectrometer in DMSO-d6 solution. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in DMSO-d6 solution, and the residual CH3OH peak or TMS was used as an internal reference in CD3OD solution. Coupling constants (J) were reported in Hertz (Hz). Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250×4.6 mm) (Daicel Chemical Industries, Ltd.) using either ethanol in hexane (%Et / Hex) or isopropanol in heptane (%IPA / Hep) as an isocratic solvent system described in percentage. Chiral preparative chromatography was performed on one of Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.), (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc.), CHIRAL cellulose-SB, SC, SA columns (YMC Co., Ltd.) at different column sizes (250×20 mm, 250×30 mm, 250×50 mm) using the desired isocratic solvent system identified on chiral analytical chromatography.

[0460] The abbreviations used in this specification 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 (ether or Et2O), PE (PE), gram(s) (g), hour(s) (h or hr), 2-propanol (IPA), mass spectrum (ms or MS), microliter(s) (μL), milligram(s) (mg), milliliter(s) (mL), millimole(s) (mmol), minute(s) (min), methyl t-butyl ether (MTBE), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), retention time (R t ), rt (rt or RT), saturated aqueous sodium chloride solution (brine), trifluoroacetic acid (TFA), tetrahydrofuran (THF), flash chromatography (FC), liquid chromatography (LC), liquid chromatography-mass spectrometry (LCMS or LC-MS), supercritical fluid chromatography (SFC), t-butyloxycarbonyl (Boc or BOC), diethylaminosulfur trifluoride (DAST), DCM (DCM), dimethylacetamide (DMA, DMAC), dimethyl sulfoxide (DMSO), 1,3-bis(diphenylphosphino)propane (DPPP), acetic acid (HOAc), 3-chloroperbenzoic acid (m-CPBA), methyl (Me), methanol (MeOH), N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate (TCFH), N-methylimidazole (NMI), N-bromosuccinimide (NBS), thin layer chromatography (TLC).

[0461] The following are representative procedures for the preparation of compounds used in the following examples, or compounds that may be substituted for compounds used in the following examples that may not be commercially available.

[0462] Method A1 [Chem.] Examples 1, 2: (6S,8R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide, (6R,8S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide Example 3: (cis)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide The relative and absolute stereochemistry of each example was not determined.

[0463] Step 1: 2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-ol A solution of 4-iodo-1-methyl-pyrazole (48 g, 231.8 mmol) in Et2O (2L) was added with n-butyllithium (14.8 g, 231.8 mmol, 2.5 M in hexane) at -78 °C. The reaction mixture was stirred at -78 °C for 30 minutes under nitrogen. To the above mixture were added 6-oxabicyclo[3.1.0]hexane (15 g, 178.3 mmol) and boron trifluoride diethyl etherate (32.9 g, 231.8 mmol). The reaction mixture was stirred at -78 °C for 30 minutes under nitrogen. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (500 mL). The obtained mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with DCM / MeOH (10:1) to obtain the title compound (8 g, yield 21%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.37 (s, 1H), 7.24 (s, 1H), 3.99 - 4.07 (m, 1H), 3.87 (s, 3H), 2.79 - 2.88 (m, 1H), 2.00 - 2.21 (m, 2H), 1.56 - 1.92 (m, 4H). LC-MS: m / z 167 [M+H] + .

[0464] Step 2: 2-(1-Methyl-1H-pyrazol-4-yl)cyclopentan-1-one To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-ol (5 g, 30 mmol) in ethyl acetate (250 mL) was added IBX (27.4 g, 45.1 mmol, purity 46%). The obtained mixture was stirred at 80 °C for 16 hours. The mixture was cooled to 25 °C. The reaction was quenched with saturated aqueous NaHSO3 solution (200 mL). The obtained mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (1.6 g, yield 32%) as a yellow oil. LC-MS: m / z 165 [M+H] + .

[0465] Step 3: 2-Methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one (A1-3) To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one (3.9 g, 23.7 mmol) in t-BuOH (60 mL) was added potassium 2-methylpropane-2-olate (2.9 g, 26.1 mmol) portionwise at 25 °C. The resulting mixture was stirred at 40 °C for 0.5 h. Iodomethane (3.4 g, 23.7 mmol) was added dropwise at 40 °C and the resulting mixture was stirred at 40 °C for 2 h. The reaction was quenched with water (200 mL) and the mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with THF / PE (1:1) to afford the title compound (A1-3, 3.9 g, 82% yield) as a yellow oil. LC-MS: m / z 179 [M+H] + .

[0466] Step 4: 5-((Dimethylamino)methylene)-2-methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one (A1-4) A solution of 2-methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one (5.5 g, 30.8 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (70 mL) was stirred at 100 °C for 24 h. The mixture was cooled to 25 °C and then concentrated under reduced pressure to afford the crude title compound (A1-4, 5.5 g) as a red oil. LC-MS: m / z 234 [M+H] + .

[0467] Step 5: 2-Fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine To a stirred solution of 5-((dimethylamino)methylene)-2-methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one (2 g, 8.5 mmol) in toluene (20 mL) was added 3-fluoro-1H-pyrazol-5-amine (1 g, 10.3 mmol) and AcOH (2 mL). The resulting mixture was stirred at 110 °C for 16 h. The mixture was cooled to 25 °C. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with EtOAc / PE (1:1) to afford the title compound (2 g, yield 60%) as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.63 (s, 1H), 7.39 (s, 1H), 6.47 (d, J = 5.1 Hz, 1H), 3.75 (s, 3H), 2.97 - 3.21 (m, 2H), 2.39 - 2.57 (m, 1H), 2.28 - 2.32 (m, 1H), 1.88 (s, 3H). LC-MS: m / z 272 [M+H] + .

[0468] Step 6: 2-Fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile To a stirred solution of 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (2 g, 7.4 mmol) in toluene (80 mL) were added (4R)-4-benzyl-2-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methylethyl]-4,5-dihydrooxazole (641 mg, 1.8 mmol), copper acetoxyl (181 mg, 1.5 mmol), N-fluorobenzenesulfonimide (3.4 g, 11.1 mmol) and TMSCN (3.7 g, 36.9 mmol). The reaction was stirred at 25 °C for 16 h under nitrogen. The solvent was removed under reduced pressure and the residue was applied onto a silica gel column and eluted with EtOAc / PE (1:1) to give the crude product. The crude product was further purified by preparative HPLC to give the title compound (100 mg, yield 4%) as a yellow oil. LC-MS (ES, m / z): 297 [M+H] + .

[0469] Step 7: 2-Fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (A1-7) A solution of 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (130 mg, 0.44 mmol) in AcOH (2 mL) and HCl (12 M, 2 mL) was stirred at 100 °C for 2 h. The mixture was cooled to 25 °C. The mixture was concentrated under reduced pressure and the residue was diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (A1-7, 130 mg, yield 90%) as a yellow oil. LC-MS: m / z 316 [M+H] + .

[0470] Step 8: Example 3 and trans-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide To a stirred solution of 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (165 mg, 523 μmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (123 mg, 628 μmol) in ACN (10 mL) were added TCFH (587 mg, 2.1 mmol) and NMI (215 mg, 2.6 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with DCM / MeOH (10:1) to give the crude product. The crude product was further purified by preparative HPLC to give Example 3 (cis racemic mixture, 80 mg, yield 29%) as a white solid and a racemic mixture of trans-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (120 mg, yield 44%) as a white solid.

[0471] Example 3: 11H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.71 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.18 (s, 2H), 7.62 (s, 1H), 7.35 (s, 1H), 6.55 (d, J = 5.1 Hz, 1H), 4.51 - 4.56 (m, 1H), 3.76 (s, 3H), 2.68 - 2.84 (m, 2H), 1.88 (s, 3H). LC-MS: m / z 493 [M+H] + .

[0472] Step 9: Separation of enantiomers to obtain Example 1 and Example 2 120 mg of trans-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART cellulose-SA, 2 * 25 cm, 5 μm, mobile phase A: Hex(0.1% FA)--HPLC, mobile phase B: IPA--HPLC, flow rate: 20 mL / min, isocratic: 50% B in 25 min, wavelength: 220 / 254 nm, RT1 (min): 10.008, RT2 (min): 19.257, sample solvent: EtOH--HPLC, injection volume: 1.5 mL, number of runs: 3). The first eluted isomer was concentrated and lyophilized to obtain Example 1 (40.7 mg, yield 33%) as a white solid. The second eluted isomer was concentrated and lyophilized to obtain Example 2 (33.9 mg, yield 28%) as a white solid.

[0473] Example 1: 11H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.67 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.18 (s, 2H), 7.65 (s, 1H), 7.43 (s, 1H), 6.58 (d, J = 5.1 Hz, 1H), 4.54 (t, J = 8.4 Hz, 1H), 3.76 (s, 3H), 2.85 - 2.98 (m, 1H), 2.50 - 2.56 (m, 1H), 1.97 (s, 3H). LC-MS: m / z 493 [M+H] + .

[0474] Example 2: 1 1H NMR (300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.67 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.18 (s, 2H), 7.65 (s, 1H), 7.43 (s, 1H), 6.58 (d, J = 5.1 Hz, 1H), 4.54 (t, J = 8.4 Hz, 1H), 3.76 (s, 3H), 2.85 - 2.98 (m, 1H), 2.50 - 2.56 (m, 1H), 1.97 (s, 3H). LC-MS: m / z 493 [M+H] + .

[0475] Method A2 [Chemical formula] Examples 4, 5: (6R,8S)-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide, (6S,8R)-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide Examples 6 and 7: (6R,8R)-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide, (6S,8S)-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide The relative and absolute stereochemistry of each example was not determined.

[0476] Step 1: trans-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and cis-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide Similar to step 8 of method A1, using 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (A1-7, 128 mg, 405.9 μmol) and 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (93 mg, 405.9 μmol), a racemic mixture of the title compound: trans isomer as a white solid (65 mg, yield 30%), LC-MS: m / z 527 [M+H] + , cis-isomer as a white solid (60 mg, yield 28%), LC-MS: m / z 527 [M+H] +was obtained.

[0477] Step 2: Separation of enantiomers to obtain Example 4 and Example 5 65 mg of trans-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART amylose-SA, 2 * 25 cm, 5 μm, mobile phase A: Hex(0.1% FA)--HPLC, mobile phase B: IPA--HPLC, flow rate: 20 mL / min, isocratic: 50% B in 20 min, wavelength: 220 / 254 nm, RT1 (min): 7.514, RT2 (min): 19.166, sample solvent: EtOH--HPLC, injection volume: 2 mL, number of runs: 2). The first eluted isomer was concentrated and lyophilized to obtain Example 4 (17 mg, yield 26%) as a white solid. The second eluted isomer was concentrated and lyophilized to obtain Example 5 (24.6 mg, yield 37%) as a white solid.

[0478] Example 4: 1 H NMR (300 MHz, DMSO-d6) δ: 11.21 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.69 (s, 1H), 8.20 (s, 2H), 7.65 (s, 1H), 7.42 (s, 1H), 6.58 (d, J = 4.8 Hz, 1H), 4.53 - 4.58 (m, 1H), 3.76 (s, 3H), 2.88 - 2.99 (m, 1H), 2.51 - 2.58 (m, 1H), 1.97 (s, 3H). LC-MS: m / z 527 [M + H] + .

[0479] Example 5: 11H NMR (300 MHz, DMSO-d6) δ: 11.21 (s, 1H), 9.02 (d, J = 2.1 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.69 (s, 1H), 8.20 (s, 2H), 7.65 (s, 1H), 7.43 (s, 1H), 6.58 (d, J = 4.8 Hz, 1H), 4.53 - 4.58 (m, 1H), 3.76 (s, 3H), 2.88 - 2.95 (m, 1H), 2.50 - 2.58 (m, 1H), 1.97 (s, 3H). LC-MS: m / z 527 [M+H] + .

[0480] Step 3: Separation of enantiomers to obtain Example 6 and Example 7 60 mg of cis-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART amylose-SA, 2 * 25 cm, 5 μm, mobile phase A: Hex(0.1% FA)--HPLC, mobile phase B: EtOH--HPLC, flow rate: 20 mL / min, isocratic: 25% B in 13 min, wavelength: 220 / 254 nm, RT1 (min): 8.968, RT2 (min): 11.575, sample solvent: EtOH--HPLC, injection volume: 0.5 mL, number of runs: 8). The first eluted isomer was concentrated and lyophilized to obtain Example 6 (23 mg, yield 38%) as a white solid. The second eluted isomer was concentrated and lyophilized to obtain Example 7 (24.6 mg, yield 41%) as a white solid.

[0481] Example 6: 11H NMR (300 MHz, DMSO-d6) δ: 11.20 (s, 1H), 9.03 (d, J = 2.1 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.72 (s, 1H), 8.19 (s, 2H), 7.62 (s, 1H), 7.35 (s, 1H), 6.55 (d, J = 4.8 Hz, 1H), 4.54 - 4.57 (m, 1H), 3.74 (s, 3H), 2.69 - 2.88 (m, 2H), 1.87 (s, 3H). LC-MS: m / z 527 [M+H] + .

[0482] Example 7: 1 1H NMR (300 MHz, DMSO-d6) δ: 11.21 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.72 (s, 1H), 8.19 (s, 2H), 7.62 (s, 1H), 7.34 (s, 1H), 6.55 (d, J = 5.1 Hz, 1H), 4.54 - 4.57 (m, 1H), 3.75 (s, 3H), 2.69 - 2.88 (m, 2H), 1.87 (s, 3H). LC-MS: m / z 527 [M+H] + .

[0483] Method A3

Chemical formula

[0484] Step 1: 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine To a stirred solution of 5-((dimethylamino)methylene)-2-methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one (A1-4, 2.2 g, 9.43 mmol) in toluene (15 mL) was added 3-chloro-1H-pyrazol-5-amine (1.3 g, 11.3 mmol) and AcOH (1.5 mL). The resulting mixture was stirred at 110 °C for 24 h. The mixture was cooled to 25 °C. The reaction mixture was concentrated under reduced pressure and the residue was applied onto a silica gel column and eluted with EtOAc / PE (10:1) to give 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (1.5 g, 44% yield) as a pale yellow solid. LC-MS: m / z 288 [M+H] + .

[0485] Step 2: 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile To a stirred solution of 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (1.1 g, 3.82 mmol) in toluene (40 mL) were added (4R)-4-benzyl-2-[(1R)-1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methylethyl]-4,5-dihydrooxazole (1.4 g, 3.8 mmol), cupric acetate (94 mg, 764 μmol), N-fluorobenzenesulfonimide (1.8 g, 5.7 mmol), and TMSCN (1.9 g, 19.1 mmol). The reaction was stirred at 25 °C for 24 h under nitrogen. The solvent was removed under reduced pressure. The residue was diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with EtOAc / PE (1:1) to give the crude product, which was further purified by HPLC to afford the title compound (240 mg, yield 17%) as a yellow oil. LC-MS (ES, m / z): 313 [M+H] + .

[0486] Step 3: 2-Chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (A3-3) Similar to Step 7 of Method A1, using 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (240 mg, 0.77 mmol), the title compound was obtained as a yellow oil (A3-3, 235 mg, yield 94%). LC-MS: m / z 332 [M+H] + .

[0487] Step 4: trans-2-Chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide, and cis-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide Similar to Step 8 of Method A1, using 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (120 mg, 362 μmol) and 5-chloro-6-(triazol-2-yl)pyridin-3-amine (141 mg, 723 μmol), stirred at 25 °C for 24 hours to obtain a racemic mixture of the title compounds: trans isomer as a white solid (25 mg, yield 13%), LC-MS: m / z 509 [M+H] + , cis-isomer as a white solid (15 mg, yield 8%), LC-MS: m / z 509 [M+H] + was obtained.

[0488] Step 5: Separation of enantiomers to obtain Example 8 and Example 9 25 mg of trans-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRALPAK IF, 2 * 25 cm, 5 μm, mobile phase A: Hex(0.1% FA)--HPLC, mobile phase B: EtOH--HPLC, flow rate: 20 mL / min, gradient: isocratic 50% mobile phase B, wavelength: 220 / 254 nm, RT1 (min): 13.764, RT2 (min): 19.041, sample solvent: EtOH--HPLC, injection volume: 2 mL, number of runs: 2). The second eluted isomer was concentrated and lyophilized to obtain Example 8 (8.9 mg, yield 43%) as a white solid. The first eluted isomer was concentrated and lyophilized to obtain Example 9 (8.4 mg, yield 40%) as a white solid.

[0489] Example 8: 1 H NMR(300 MHz, DMSO-d6) δ 11.10(s, 1H), 8.72(d, J = 2.1 Hz, 1H), 8.68(s, 1H), 8.61(d, J = 2.1 Hz, 1H), 8.18(s, 2H), 7.63(s, 1H), 7.41(s, 1H), 6.96(s, 1H), 4.51 - 4.57(m, 1H), 3.76(s, 3H), 2.86 - 2.93(m, 1H), 2.50 - 2.51(m, 1H), 1.99(s, 3H). LC-MS: m / z 509[M + H] + .

[0490] Example 9: 1 H NMR(300 MHz, DMSO-d6) δ 11.10(s, 1H), 8.72(d, J = 2.1 Hz, 1H), 8.68(s, 1H), 8.61(d, J = 2.1 Hz, 1H), 8.18(s, 2H), 7.63(s, 1H), 7.41(s, 1H), 6.96(s, 1H), 4.50 - 4.54(m, 1H), 3.76(s, 3H), 2.86 - 2.93(m, 1H), 2.50 - 2.51(m, 1H), 1.99(s, 3H). LC-MS: m / z 509[M + H] + .

[0491] Step 6: Separation of enantiomers to obtain Example 10 and Example 11 15 mg of cis-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRALPAK IF, 2 * 25 cm, 5 μm, mobile phase A: Hex(0.1% FA)--HPLC, mobile phase B: EtOH--HPLC, flow rate: 20 mL / min, gradient: isocratic 50% mobile phase B, wavelength: 220 / 254 nm, RT1 (min): 14.519, RT2 (min): 26.523, sample solvent: EtOH--HPLC, injection volume: 2 mL, number of runs: 2). The first eluted isomer was concentrated and lyophilized to obtain Example 10 (2.4 mg, yield 15%) as a white solid. The second eluted isomer was concentrated and lyophilized to obtain Example 11 (1.7 mg, yield 11%) as a white solid.

[0492] Example 10: 1 H NMR(300MHz,DMSO-d6) δ 11.09(s,1H),8.70-8.72(m,2H),8.57(d,J=2.4Hz,1H),8.17(s,2H),7.61(s,1H),7.34(s,1H),6.94(s,1H),4.51-4.56(m,1H),3.75(s,3H),2.66-2.88(m,2H),1.89(s,3H).LC-MS:m / z 509[M+H] + .

[0493] Example 11: 11H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.70 - 8.72 (m, 2H), 8.57 (d, J = 2...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 101】 During the ceremony, each 【Chemical Engineering 102】 However, it is either a single bond or a double bond. Q is -CH ２ -, O, or NH, X is N or C, Y is either N or C, Z is N or CR ６ And, If one of X and Y is N, then the other of X and Y is C. n is 1, 2, or 3, R Ｘ However, it is hydrogen or halogen, R １ However, hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR Ａ R Ｂ , or a C1-C3 alkyl group optionally substituted with one to three substituents selected from hydroxyl and C1-C3 alkoxy, R ２ However, it is hydrogen, halogen, amino, or C1-C3 alkyl, Each R ３ However, independently, these are deuterium, halogen, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl. m is 0, 1, 2, or 3, R ４ is a 5- to 10-membered heteroaryl optionally substituted by 1 to 3 substituents each independently selected from ７ R, R ５ However, each R is phenyl or a 5-9 member heteroaryl, ５ The base is R ８ It is optionally substituted by one to three substituents that are independently selected from the original molecule. R ６ However, hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR Ｃ R Ｄ , and C1-C3 alkyl, Each R ７ However, independently, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, oxetanyl, -NR Ｃ R Ｄ Selected from the group consisting of C1-C3 alkyl groups optionally substituted with one cyclopropyl group, and C3-C7 cycloalkyl groups optionally substituted with one C1-C3 alkyl group, Each R ８ However, independently, halogen; cyano; amino; -N=(S=O)(C1-C3 alkyl) ２ ; -S (=O) ｐ (C1-C3 alkyl); 1-imino-1-lambda ６ -thietanyl 1-oxide, -(C=O)NR Ｅ R Ｆ ; C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4-6 member heterocyclyl, or hydroxyl or -NR Ｅ R Ｆ Optionally substituted 5-6 member heteroaryls with C1-C3 alkyl groups; hydroxyl, -NR Ｅ R Ｆ , or selected from C1-C4 alkyl groups optionally substituted with C1-C3 alkoxy groups; 3-8 member heterocyclyl groups; and C3-C6 cycloalkoxy groups, p is 1 or 2, R Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ , and R Ｆ However, independently, they are 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 A compound, or a pharmaceutically acceptable salt thereof, wherein these atoms, together with the nitrogen atom to which they are bonded, form a 4-6 membered heterocycline optionally substituted with one or two halogens.

2. The compound according to claim 1, wherein X is N and Y is C.

3. The compound according to claim 1, wherein Z is N.

4. R Ｘ The compound according to claim 1, wherein the compound is hydrogen.

5. Q is -CH ２ - The compound according to claim 1.

6. R １ The compound according to claim 1, wherein the compound is a halogen.

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

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

9. The compound according to claim 1, wherein m is 1.

10. Each R ３ The compound according to claim 1, wherein independently, it is a halogen, a C3-C6 cycloalkyl, a C1-C3 alkyl, a C1-C3 haloalkyl, a C1-C3 alkoxy, or a C1-C3 haloalkoxy.

11. m is 1, R ３ The compound according to claim 1, wherein the compound is methyl or trifluoromethyl.

12. The compound according to claim 1, which is a compound of formula (Ic), or a pharmaceutically acceptable salt thereof. 【Chemistry 103】

13. R ４ However, R ７ The compound according to claim 1, which is a 5-6 member heteroaryl compound optionally substituted with 1-3 substituents independently selected from each of the above.

14. R ４ However, R ７ The compound according to claim 1, which is a six-membered heteroaryl compound optionally substituted with one to three substituents independently selected from each of the above.

15. R ４ However, R ７ The compound according to claim 1, which is a five-membered heteroaryl compound optionally substituted with one to three substituents independently selected from each of the above.

16. R ４ However, R ７ The compound according to claim 1, which is a 4H-pyrazolyl, 3H-pyrazolyl, triazolyl, or thiazolyl compound optionally substituted with one to three substituents independently selected from each of the above.

17. Each R ７ The compound according to claim 1, which is independently selected from the group consisting of a C1-C3 haloalkyl group, a C1-C3 alkyl group optionally substituted with one cyclopropyl group, and a C3-C7 cycloalkyl group optionally substituted with one C1-C3 alkyl group.

18. R ４ but, 【Chemical 104】 The compound according to claim 1.

19. R ４ but, 【Chemistry 105】 The compound according to claim 1.

20. R ４ but, 【Chemistry 106】 The compound according to claim 1.

21. R ４ but, 【Chemistry 107】 The compound according to claim 1.

22. R ４ but, 【Chemistry 108】 The compound according to claim 1.

23. R ５ However, 1 to 3 independently selected R ８ The compound according to claim 1, wherein the phenyl is optionally substituted by the phenyl compound.

24. R ５ However, 1 to 3 independently selected R ８ The compound according to claim 1, which is a 5- to 9-membered heteroaryl optionally substituted by [the specified agent].

25. R ５ However, 1 to 3 independently selected R ８ The compound according to claim 1, which is a 5-6 member heteroaryl substituted with [the specified compound].

26. R ５ However, 1 to 3 independently selected R ８ The compound according to claim 1, wherein it is 3-pyridyl or 4-pyridyl optionally substituted by the above.

27. R ８ The compound according to claim 1, wherein at least one of them is a halogen.

28. R ８ At least one of these is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxyl, or -NR Ｅ R Ｆ The compound according to claim 1, wherein it is a 5-6 member heteroaryl optionally substituted with a C1-C3 alkyl, amino, or C1-C3 haloalkyl optionally substituted by the above.

29. R ８ At least one of these is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxyl, or -NR Ｅ R Ｆ The compound according to claim 1, wherein it is a five-membered heteroaryl optionally substituted with a C1-C3 alkyl, amino, or C1-C3 haloalkyl group optionally substituted by the above.

30. R ５ but, 【Chemistry 109】 The compound according to claim 1.

31. R ５ but, 【Chemical 110】 The compound according to claim 1.

32. R ５ but, 【Chemistry 111】 The compound according to claim 1.

33. R ５ but, 【Chemistry 112】 The compound according to claim 1.

34. R ５ but, 【Chemistry 113】 The compound according to claim 1.

35. The compound according to claim 1, which is a compound of formula (Id), or a pharmaceutically acceptable salt thereof. 【Chemical 114】

36. A compound according to claim 1, which is a compound of formula (Ie), or a pharmaceutically acceptable salt thereof. 【Chemical 115】

37. A compound according to claim 1, which is a compound of formula (If), or a pharmaceutically acceptable salt thereof. 【Chemistry 116】

38. The compound according to claim 1, which is a compound of formula (Ig), or a pharmaceutically acceptable salt thereof. 【Chemistry 117】

39. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from Table 1.

40. A pharmaceutical composition comprising, in combination with one or more pharmaceutically acceptable excipients, a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

41. A composition or pharmaceutical composition for treating cancer in a subject, wherein the composition comprises a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprises a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients.

42. The composition or pharmaceutical composition according to claim 41, wherein the cancer is MALT1-related cancer.

43. The composition or pharmaceutical composition according to claim 41, wherein the cancer is lymphoma.

44. The composition or pharmaceutical composition according to claim 43, wherein the lymphoma is non-Hodgkin lymphoma, DLBCL, refractory DLBCL, DLBCL (ABC) subtype, mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL).

45. The composition or pharmaceutical composition according to claim 41, wherein the cancer is leukemia.

46. The composition or pharmaceutical composition according to claim 45, wherein the leukemia is chronic lymphocytic leukemia (CLL).

47. The composition or pharmaceutical composition according to claim 41, wherein the cancer is a solid tumor.

48. A composition or pharmaceutical composition for treating an autoimmune disorder in a subject, wherein the composition comprises a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprises a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients.

49. The composition or pharmaceutical composition according to claim 48, wherein the autoimmune disorder is chronic graft-versus-host disease.

50. The composition or pharmaceutical composition according to claim 41, characterized in that the composition or pharmaceutical composition is administered to the subject in combination with an additional therapy or therapeutic agent.

51. The composition or pharmaceutical composition according to claim 48, characterized in that the composition or pharmaceutical composition is administered to the subject in combination with an additional therapy or therapeutic agent.

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