Cyclic compounds and methods of use thereof

Abstract

This application relates to compounds of formula (I) as defined herein and pharmaceutically acceptable salts thereof, which are MALT1 inhibitors. This application also describes pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions to treat diseases such as cancer, autoimmune disorders, and inflammatory disorders. TIFF2023509886001065.tif2744

Description

[Technical Field]

[0001] Description of electronically submitted text files The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety, and a computer-readable format copy of the Sequence Listing (Filename: 17367-0076WO1.txt, Data Recorded: December 24, 2020, File Size:

number

[0002] This application relates to tricyclic and other polycyclic compounds that are useful for treating proliferative disorders such as cancer, as well as autoimmune and inflammatory disorders. [Background technology]

[0003] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is an intracellular protein involved in lymphocyte proliferation through upstream NF-κB signaling to regulate lymphocyte activation, survival, proliferation, and differentiation. Together with CARMA or CARD scaffolding proteins (e.g., CARD11 (also known as CARMA1, caspase recruitment domain family member 11), CARD14 (also known as CARMA2, caspase recruitment domain family member 14), CARD10 (also known as CARMA3, caspase recruitment domain family member 10), or CARD9 (caspase recruitment domain family member 9)) and BCL10 (B-cell CLL / lymphoma 10), MALT1 is one of three subunits of the CBM complex, which forms in response to cell surface antigen receptor activation. 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 scaffolding protein, recruiting NF-κB signaling proteins such as TRAF6, TAB (e.g., TAB1, TAB2, TAB3), TAK1, and NEMO-IKKα / β. Second, as a cysteine protease, MALT1 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, especially when NF-κB and related pathways are thought to play a key role. 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 highly aggressive ABC-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, Rokin-1, NIK, and LIMA la. 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.

[0005] In addition, several chromosomal translocations leading to the generation of constitutively active MALT1 have been identified in ABC-DLBCL, and the identification of the MALT1 fusion protein API2-MALT1 / IgH-MALT1, which leads to NF-κB activation independent 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, including hematological malignancies such as mantle cell lymphoma and chronic lymphocytic leukemia (CLL), lung adenocarcinoma, breast cancer, pancreatic cancer, and solid tumors such as glioblastoma. (See Jiang et al., Cancer Research 2011, 71, 2183-2192.) See also 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 diseases, such as psoriasis, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome, ulcerative colitis, and different types of allergic disorders caused by chronic inflammation. See Afofina et al., FEBS Journal 2015, DOI:10.1 111 / febs.13325. See also 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.Recently, findings have also suggested the importance of MALT1 in controlling regulatory T cell (Treg) function and homeostasis.Studies are underway to identify the potential of MALT1 inhibitors, either alone or in combination with immune checkpoint mechanisms, to treat patients with solid tumors. However, MALT1 inhibitors are not currently approved for therapeutic use. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Jaworski et al.,Cell Mol Life Science 2016,73,459-473 [Non-patent document 2] Juilland and Thome.Frontiers in Immunology 2018,9,1927 [Non-patent document 3] Rosebeck et al.,Science,2011,331,468-472 [Non-patent document 4] Ferch U,et al.,J Exp Med 2009,206,2313-2320 [Non-patent document 5] Hailfinger S,et al.,Proc Natl Acad Sci USA 2009,106,19946-19951 [Non-patent document 6] Rebeaud et al.,Nat Immunol 2008,9,272-281 [Non-Patent Document 7] Coornaert et al.,Nat Immunol 20008,9,263-271 [Non-patent document 8] Staal et al.,EMBO J 2011,30,1742-1752 [Non-Patent Document 9] Hailfinger et al.,PNAS 2011,108,14596-14601 [Non-Patent Document 10] Jeltsch et al.,Nat Immunol 2014,15,1079-1089 [Non-Patent Document 11] Uehata et al.,Cell 2013,153,1036-1049 [Non-Patent Document 12] Nie et al.,Nat Commun 2015,6,5908 [Non-Patent Document 13] Baens et al.,PLoS ONE 2014,9,e103774 [Non-Patent Document 14] Kasperkiewicz,et al.Scientific Reports 8.1(2018):1-10 Summary of the Invention [Means for solving the problem]

[0007] Thus, provided herein are compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, n, R 1 , R 2 , R 3 , m, R 4 , R 5 , R 6 , R A , R B , R C , R D , R E , and R F is as defined herein.

[0008] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0009] Also provided herein is a method for treating a CBM complex pathway-associated 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 as described herein.

[0010] Also provided is a method for treating cancer in a subject in need thereof, comprising: (a) Identifying cancers as CBM complex pathway-related cancers; 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 as described herein.

[0011] Also provided is a method for treating cancer in a subject in need thereof, comprising: Also provided are methods comprising administering to a subject identified as having a CBM complex pathway-associated cancer an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0012] Also provided is a method for treating MALT1-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a MALT1-associated cancer an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0013] Also provided is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or levels of the MALT1 gene, the MALT1 protease, or any of them; (b) administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0014] Also provided is a method for inhibiting metastasis in a subject having cancer in need of such treatment, comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0015] 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 as described herein.

[0016] Also provided is a method for treating a CBM complex pathway-associated disease or 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 as described herein.

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

[0018] Also provided is a method for treating a disease or disorder in a subject in need thereof, comprising: Also provided are methods comprising administering to a subject identified as having a CBM complex pathway-associated disease or disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

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

[0020] Also provided is a method for treating a MALT1-associated autoimmune disorder in a subject, comprising administering to a subject identified or diagnosed as having a MALT1-associated autoimmune disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0021] Also provided is a method for treating an autoimmune disorder in a subject in need thereof, comprising: (a) determining that the autoimmune disorder is associated with dysregulation of the expression or activity or levels of the MALT1 gene, the MALT1 protease, or any of them; (b) administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0022] Also provided is a method for treating a MALT1-associated autoimmune disorder in a subject, comprising administering to the subject determined to have a MALT1-associated autoimmune disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0023] Also provided is a method for treating an inflammatory 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 as described herein.

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

[0025] Also provided is a method for treating a MALT1-associated inflammatory disorder in a subject, comprising administering to a subject identified or diagnosed as having a MALT1-associated inflammatory disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0026] Also provided is a method for treating an inflammatory disorder in a subject in need thereof, comprising: (a) determining that the inflammatory disorder is associated with dysregulation of the expression or activity or levels of the MALT1 gene, the MALT1 protease, or any of them; (b) administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0027] Also provided is a method for treating a MALT1-associated inflammatory disorder in a subject, comprising administering to the subject determined to have a MALT1-associated inflammatory disorder an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0028] Also provided is a method for inhibiting CBM complex pathway activity in a mammalian cell, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0029] Also provided is a method for inhibiting MALT1 protease activity in a mammalian cell, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0030] Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a CBM complex pathway-related disease or disorder.

[0031] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of a CBM complex pathway-related disease or disorder.

[0032] Also provided are methods for treating an individual with a MALT1-associated cancer, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof before, during, or after administration of another anti-cancer agent (e.g., a first MALT1 inhibitor or another MALT1 inhibitor).

[0033] Also provided herein are processes for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0034] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof obtained by the process for preparing the compounds as defined herein.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Methods and materials are described herein for use in this disclosure; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are merely illustrative and are 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, shall control.

[0036] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0037] definition As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structures. Compounds herein that are identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0038] The term "tautomer" as used herein refers to a compound whose structure differs significantly in the arrangement of atoms, but which exists in easy and rapid equilibrium; the compounds provided herein may be depicted as different tautomers; it is understood that when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of the compound does not exclude any tautomer. Below are examples of tautomeric forms that are included: [ka]

[0039] It will be recognized that certain compounds provided herein may contain one or more asymmetric centers and therefore may be prepared and isolated in mixtures of isomers, such as racemic mixtures, or in enantiomerically pure form.

[0040] The term "halo" refers to one of the halogens, group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0041] The term "C1-C6 alkyl" refers to a linear 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 linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms.

[0042] The term "C1-C6 haloalkyl" refers to a hydrocarbon chain substituted with at least one independently selected halogen atom, such as fluorine, chlorine, bromine, and iodine, at each occurrence. The halogen atom can be located at any position on the hydrocarbon chain. Similarly, a C1-C3 haloalkyl group is a linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms substituted with at least one halogen atom. For example, C1-C3 haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloroethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 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, and trifluoropropyl.

[0043] The term "C1-C6 alkoxy" refers to a C1-C6 alkyl group attached to a molecule through an oxygen. It includes moieties such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy, where the alkyl portion can be linear or branched.

[0044] The term "C1-C6 haloalkoxy" refers to a C1-C6 alkyl group attached to a molecule through an oxygen atom, where at least one hydrogen atom of the alkyl group has been replaced with a halogen. This includes moieties where the alkyl portion can be linear or branched, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or trifluoropropoxy.

[0045] [ka] represents a single or double bond, as valence permits. For example, [ka]

[0046] As used herein, the term "cyano" refers to the -CN radical.

[0047] As used herein, the term "hydroxyl" refers to the --OH radical.

[0048] As used herein, the term "amino" refers to the group --NH.sub.2.

[0049] As used herein, the term "aryl" refers to a monocyclic or bicyclic group of 6 to 10 carbons in which at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl. In bicyclic ring systems in which only one ring is aromatic, the non-aromatic ring may be a cycloalkyl group, as defined herein.

[0050] As used herein, the term "heteroaryl" refers to a 5- to 10-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 with a heteroatom independently selected from N, O, and S. Heteroaryl groups include rings in which one or more groups are oxidized, such as a pyridone moiety. Non-limiting examples of heteroaryl groups include pyridine, pyrimidine, pyrrole, imidazole, and indole. In bicyclic ring systems in which only one ring is aromatic, the non-aromatic ring may be a cycloalkyl or heterocyclyl group, as defined herein.

[0051] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated 3-10 monocyclic or bicyclic hydrocarbon group, where bicyclic systems include fused, spiro (optionally referred to as "spirocycloalkyl" groups), and bridged ring systems. Non-limiting examples of cyclopropyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0052] The term "heterocyclyl" refers to a saturated or partially unsaturated 3- to 12-membered hydrocarbon monocyclic or bicyclic ring system that is not aromatic and has at least one heteroatom selected from N, O, and S in the ring. Bicyclic heterocyclyl groups include fused, spiro (optionally referred to as "spiroheterocyclyl" groups), and bridged ring systems. Heterocyclyl ring systems can include oxo substitution at one or more C, N, or S ring members. Heterocyclyl groups can be represented, for example, as "5- to 10-membered heterocyclyl groups," which are ring systems containing 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. For example, there can be one, two, or three, optionally one or two, heteroatoms. Heterocyclyl groups can be attached to the remainder of the molecule through any carbon atom or 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, isothiazolidine S,S-dioxide, and decahydronaphthalenyl.

[0053] As used herein, the term "geminal" refers to substituent atoms or groups attached to the same atom in a molecule.

[0054] As used herein, the term "vicinal" refers to substituent atoms or groups that are attached to adjacent atoms in a molecule. The stereochemical relationships between the substituent atoms or groups can be cis, trans, undefined, or unresolved.

[0055] As used herein, the term "oxo" refers to a "=O" group attached to a carbon atom.

[0056] As used herein, the symbols [ka] depicts the point of attachment of an atom or moiety to the indicated atom or group of the remainder of the molecule.

[0057] It is understood that the ring of the compound of formula (I), comprising atoms X, Y, and Z, does not contain more than two adjacent nitrogen atoms.

[0058] The compound of formula (I) includes its pharmaceutically acceptable salts. In addition, the compound of formula (I) also includes other salts of such compounds that are not necessarily pharmaceutically acceptable salts but may be useful as intermediates for preparing and / or purifying the compound of formula (I) and / or for separating the enantiomers of the compound of formula (I). Non-limiting examples of pharmaceutically acceptable salts of the compound of formula (I) include trifluoroacetic acid and hydrochloride salts.

[0059] It will be further recognized that the compounds of formula (I) or their salts may be isolated in the form of solvates, and therefore, any such solvates are included within the scope of the present disclosure. For example, the compounds of formula (I) and their salts can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0060] In some embodiments, the compounds of Formula (I) include the compounds of Examples 1-211, and stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (I) include the compounds of Examples 1-211, and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Examples 1-211 are in free base form. In some embodiments, the compounds of Examples 1-211 are in the form of pharmaceutically acceptable salts.

[0061] The term "pharmaceutically acceptable" indicates that a compound, or a salt thereof, or a composition thereof is chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or the subject being treated therewith.

[0062] A protecting group may be a temporary substituent that protects a potentially reactive functional group from undesired chemical transformations. The selection of the specific protecting group to be employed is well within the skill of one of ordinary skill in the art. Several considerations can determine the selection of a protecting group, including, but not limited to, the functional group being protected, other functionalities present in the molecule, the reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, the resistance of the functional group to the conditions required to remove the protecting group, and the reaction conditions for thermal decomposition of the compounds provided herein. The field of protecting group chemistry is reviewed in (Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed. Wiley: New York, 1991).

[0063] A nitrogen protecting group can be any temporary substituent that protects the amine moiety from undesired chemical transformations. Examples of the moiety formed when such a protecting group is attached to an amine include, but are not limited to, allylamine, benzylamine (e.g., benzylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and tritylamine), acetylamide, trichloroacetamide, trifluoroacetamide, pent-4-enamide, phthalimide, carbamates (e.g., methyl carbamate, t-butyl carbamate, benzyl carbamate, allyl carbamate, 2,2,2-trichloroethyl carbamate, and 9-fluorenylmethyl carbamate), imines, and sulfonamides (e.g., benzenesulfonamide, p-toluenesulfonamide, and p-nitrobenzenesulfonamide).

[0064] An oxygen protecting group can be any temporary substituent that protects a hydroxyl moiety from undesired chemical transformations. Examples of moieties formed when such a protecting group is attached to a hydroxyl include, but are not limited to, esters (e.g., acetyl, t-butylcarbonyl, and benzoyl), benzyls (e.g., benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, and trityl), carbonates (e.g., methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate, and benzyl carbonate), ketals, acetals, and ethers.

[0065] The compounds provided herein may also contain unnatural proportions of atomic isotopes in one or more of the atoms that constitute such compounds. That is, when an atom is specifically referred to in relation to a compound according to formula (I), it includes all isotopes and isotopic mixtures of that atom, whether naturally occurring or synthetically produced, in either natural abundance or isotopically enriched form. For example, unless otherwise specified, when hydrogen is referred to, it is 1 H, 2 H, 3 H, or mixtures thereof, and when carbon is mentioned, it is understood to refer to11 C. 12 C. 13 C. 14 C, or mixtures thereof, and when nitrogen is mentioned, it is understood to refer to 13 N, 14 N, 15 N, or mixtures thereof, and when oxygen is mentioned, it is understood to refer to 14 O. 15 O. 16 O. 17 O. 18 0, or mixtures thereof, and when fluoro is mentioned it is understood to refer to 18 F, 19 F, or mixtures thereof. For example, in deuterated alkyl and deuterated alkoxy groups, one or more hydrogen atoms are replaced with deuterium ( 2 H). Because some of the aforementioned isotopes are radioactive, the compounds provided herein also include compounds and mixtures thereof with one or more isotopes of one or more atoms, including radioactive compounds in which one or more non-radioactive atoms are replaced by one of the radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, for example, cancer therapeutic agents, research reagents, for example, assay reagents, and diagnostic agents, for example, in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0066] For illustrative purposes, general methods for preparing compounds, as well as key intermediates, are provided herein. For more detailed descriptions of the individual reaction steps, see the "Examples" section below. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compounds of the present invention. While specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0067] The ability of selected compounds to act as MALT1 inhibitors can be demonstrated by the biological assays described herein. 50 The values are shown in Table A.

[0068] The compounds of formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases and disorders that can be treated with MALT1 inhibitors, such as MALT1-associated cancers, including hematological cancers and solid tumors, MALT1-associated autoimmune disorders, and MALT1-associated inflammatory disorders.

[0069] As used herein, the term "treat" or "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, a decrease in the extent of the disease, a stable (i.e., not worsening) state of the disease, a delay or slowing of the progression of the disease, an improvement or alleviation of the condition (e.g., one or more symptoms of the disease), and remission (whether partial or total). "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment.

[0070] 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 is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented.

[0071] The term "pediatric subject" as used herein refers to a subject under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations, including neonates (birth to 1 month of age), infants (1 month to 2 years of age), children (2 to 12 years of age), and adolescents (12 to 21 years of age, up to but not including their 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is between birth and 28 days of age, between 29 days of age and less than 2 years of age, between 2 years and less than 12 years of age, or between 12 years of age and 21 years of age (up to but not including their 22nd birthday). In some embodiments, the pediatric subject is between birth and 28 days of age, between 29 days of age and under 1 year of age, between 1 month of age and under 4 months of age, between 3 months of age and under 7 months of age, between 6 months of age and under 1 year of age, between 1 year of age and under 2 years of age, between 2 years of age and under 3 years of age, between 2 years of age and under 7 years of age, between 3 years of age and under 5 years of age, between 5 years of age and under 10 years of age, between 6 years of age and under 13 years of age, between 10 years of age and under 15 years of age, or between 15 years of age and under 22 years of age.

[0072] In certain embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof are 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, in whole or in part, the onset, recurrence, or spread of a disease or condition as described herein, or a symptom thereof.

[0073] The term "regulatory authority" refers to a national agency that approves drugs for medical use in that country. For example, a non-limiting example of a regulatory authority is the United States Food and Drug Administration (FDA).

[0074] Signaling through the NF-κB pathway has been implicated in many cancers. See, e.g., 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, that bind to kB enhancer elements as various homo- and heterodimers and can induce transcription of several genes. Following 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)), CBM complexes form, likely through phosphorylation of CARD or CARMA proteins by protein kinase C (e.g., protein kinase C beta or protein kinase C theta) and recruitment of the BCL10-MALT1 complex. See, e.g., 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.

[0075] As described hereinabove, the CBM complex can function as a scaffolding protein in the activation of the NF-κB pathway. Once formed, the CBM complex can activate IKK complexes (e.g., IKKγ (also known as NEMO), IKKα, and IKKβ) presumably by ubiquitinating (e.g., K63-linked ubiquitination) MALT1, leading to the recruitment, ubiquitination (e.g., K63-linked ubiquitination), and degradation of IKKγ, thereby releasing IKKα and IKKβ to phosphorylate IκB, leading to the ubiquitination (e.g., K48-linked ubiquitination) and degradation of IκB, releasing NF-κB transcription factors (typically NF-κB1 subtype: p50-RelA and p50-cRel) into the nucleus. This cascade is presumably mediated by the ubiquitin ligase TRAF6 (tumor necrosis factor receptor (TNFR)-associated factor 6). The CBM complex can also influence NF-κB signaling through additional protein complexes, such as TAB1 / 2-TAK and the linear ubiquitin chain assembly complex (LUBAC). See, for example, Israel, 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 known as the JNK / AP-1 pathway), although less work has been done to explore this area. See, for example, Juilland, Front. Immunol. 9(2018):1927, and Wang, et al., Oncogenesis 6.7(2017):e365-e365.

[0076] In addition, MALT1 has cysteine protease activity. Non-limiting examples of substrates of wild-type MALT1 include BCL10, A20, CYLD, RelB, Regnase 1, Rokin-1, and HOIL1. In addition, API2-MALT1 (amino terminus of inhibitor of apoptosis 2, also known as cIAP2) fusion proteins have also been shown to cleave NIK and LIMA1α. BCL10 cleavage by MALT1 is thought to result in BCL10-independent activation of NF-κB. By cleaving A20 (TNF-alpha-induced protein 3), MALT1 may reduce negative regulation of the NF-κB pathway because A20 is a deubiquitinating enzyme that has been suggested to reduce MALT1 ubiquitination and thus the recruitment and activation of the IKK complex. By cleaving CYLD (CYLD lysine 63 deubiquitinase), a deubiquitinating enzyme, MALT1 is thought to increase signaling through the NF-κB and / or JNK pathways. Cleavage of RelB typically results in the alleviation of negative regulation of the NF-κB pathway, as RelB forms a transcriptionally inactive complex with RelA and c-Rel. Cleavage of HOIL1 (also known as RBCK1) is thought to alleviate negative regulation of NF-κB, as HOIL1 is thought to reduce linear ubiquitination. MALT1 can also be autoprocessed, which promotes signaling through the NF-κB pathway through a mechanism that is not fully understood. By cleaving NIK (NF-κB-inducing kinase), API2-MALT1 protease generates a C-terminal fragment of NIK that is resistant to proteasomal degradation, thereby increasing non-canonical NF-κB signaling. Cleavage of LIMA1α (LIM domain and actin-binding protein 1) reduces the tumor suppressor properties of this protein, while the remaining fragment is thought to be oncogenic and promotes cell proliferation, colony formation, and cell adhesion.Cleavage of Regnase 1 (Regulatory RNase 1, also known as MCPIP-1 or Zc3h12a) and Rokin-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 in 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 has also been implicated in oncogenic BCR signaling in ibrutinib-responsive cell lines and biopsy samples, which is regulated by a multiprotein supercomplex formed by MYD88, TLR9, and BCR (hereafter referred to as the My-T-BCR supercomplex). The My-T-BCR supercomplex colocalizes with mTOR on endolysosomes and drives pro-survival NF-κB and mTOR signaling. See Phelan et al., Nature 2018 Aug;560(7718):387-391.

[0077] Thus, MALT1 inhibition can provide beneficial effects in many types of disorders associated with abnormal signaling of the NF-κB or JNK pathways. For example, MALT1 inhibition can reduce flux through the NF-κB or JNK pathways due to one or more of the following: (1) Inactivation of tumor suppressor gene. Non-limiting examples of tumor suppressor gene that can be inactivated include BRCA1 and p53 (e.g., p53 H61L or I123T). For example, see 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. (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. (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. (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, Rokin-1, HOIL1, NIK, and LIMA1α. (5) Dysregulation of one or more components of the NF-κB pathway downstream of the CBM complex. Non-limiting examples of components of the NF-κB pathway downstream of the CBM complex include TRAF6, IKKα, IKKβ, IKKγ (also known as NEMO), IkBα, p50, p52, p65(RelA), RelB, and c-Rel. (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 AP-1 transcription factors (e.g., heterodimers of any of the c-Fos, c-Jun, ATF, or JDP families). (7) Dysregulation of one or more fusion proteins caused by chromosomal translocations of the MALT1 gene. Non-limiting examples include cIAP-MALT1 fusion proteins. (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.

[0078] The term "CBM complex pathway" as used herein includes genes, transcripts, and proteins in a signal transduction pathway that includes a CBM. For example, many aspects of the NF-κB pathway are part of the CBM complex pathway. The CBM complex pathway includes, for example, cell surface receptors (e.g., CD28, BCR, HER1, and HER2), signal transducers (e.g., protein kinase C beta or protein kinase C theta) between cell surface receptors and the CBM complex, 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, Rokin-1, These proteins can include components of the NF-κB pathway downstream of the CBM complex (e.g., TAK1, TRAF6, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65(RelA), or c-Rel), components of the JNK pathway downstream of the CBM complex (e.g., JNK1, JNK2, JNK3, or AP-1 transcription factors), or components of the My-T-BCR supercomplex (e.g., MYD88, TLR9, or mTOR).

[0079] As used herein, the term "CBM complex pathway-associated disease or disorder" refers to a disease or disorder associated with or characterized by dysregulation of the expression, activity, or levels of a gene in the CBM complex pathway, a protein in the CBM complex pathway, or any of (e.g., one or more) thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of a gene in the CBM complex pathway, a protein in the CBM complex pathway, or any of (e.g., one or more) thereof, as described herein. Non-limiting examples of CBM complex pathway-associated diseases or disorders include, for example, CBM-associated primary immunodeficiency, autoimmune disorders, multiple sclerosis, colitis, psoriasis, and cancer. See, e.g., 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-associated diseases or disorders include MALT1-associated diseases or disorders, such as MALT1-associated cancers, MALT1-associated autoimmune disorders, and MALT1-associated inflammatory disorders.

[0080] As used herein, the term "CBM complex pathway-associated autoimmune disorder" refers to an autoimmune disorder associated with or characterized by dysregulation of the expression, activity, or levels of a CBM complex pathway gene, a CBM complex pathway protein, or any (e.g., one or more) thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of a CBM complex pathway gene, a CBM complex pathway protein, or any (e.g., one or more) thereof described herein). Non-limiting examples of CBM complex pathway-associated autoimmune disorders are described herein.

[0081] As used herein, the term "CBM complex pathway-associated inflammatory disorder" refers to an inflammatory disorder associated with or having dysregulation of expression, activity, or levels of a CBM complex pathway gene, a CBM complex pathway protein, or any (e.g., one or more) thereof (e.g., any of the types of dysregulation of expression, activity, or levels of a CBM complex pathway gene, a CBM complex pathway protein, or any (e.g., one or more) thereof described herein). Non-limiting examples of CBM complex pathway-associated inflammatory disorders are described herein.

[0082] In some embodiments, the CBM complex pathway-associated disease or disorder is a CBM complex pathway cell surface receptor-associated cancer (e.g., CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, or HER2-associated cancer), a cancer associated with a signal transduction between a cell surface receptor and the CBM complex (e.g., protein kinase C beta (PKCβ)-associated cancer or protein kinase C theta (PKCθ)-associated cancer), a component of a CBM complex-associated cancer (e.g., MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, CARD10-associated cancer, CARD9-associated cancer, or BCL10-associated cancer), a MALT1 protease substrate-associated cancer (e.g., BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, RelB-associated cancer, Reg cancers associated with components 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); cancers associated with components 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); CBM complex pathway-related cancers, such as MYD88-related cancer, or a combination thereof.

[0083] As used herein, the term "CBM complex pathway-associated cancer" refers to a cancer that is associated with or has dysregulation of the expression, activity, or levels of a gene in the CBM complex pathway, a protein in the CBM complex pathway, or any of them (e.g., at the time of diagnosis or after developing resistance to a previous therapy), or is associated with or has dysregulation of the expression, activity, or levels of any (e.g., one or more) of them (e.g., any of the types of dysregulation of the expression, activity, or levels of a gene in the CBM complex pathway, a protein in the CBM complex pathway, or any of them, as described herein). Non-limiting examples of CBM complex pathway-associated cancers are described herein. In some embodiments, the CBM pathway-associated cancer is a CBM complex pathway cell surface receptor-associated cancer (e.g., CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, or HER2-associated cancer), a cancer associated with a signal transduction between a cell surface receptor and the CBM complex (e.g., protein kinase C beta (PKCβ)-associated cancer or protein kinase C theta (PKCθ)-associated cancer), a component of a CBM complex-associated cancer (e.g., MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, CARD10-associated cancer, CARD9-associated cancer, or BCL10-associated cancer), a MALT1 protease substrate-associated cancer (e.g., BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, Rel B-related cancer, Regnase 1-related cancer, Rokin-1-related cancer, HOIL1-related cancer, NIK-related cancer, or LIMA1α-related cancer), 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), 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.

[0084] In some embodiments, the dysregulation can be dysregulation that results in abnormal activation of a gene, protein, or any of its expression, activity, or level. 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 a protein product of an oncogene. In some embodiments, the dysregulation can be dysregulation that results in abnormal inactivation of a gene, protein, or any of its expression, activity, or level. 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, the dysregulation is dysregulation that results in increased signaling through the NF-κB or JNK signaling pathway, whether it is activation or inactivation.

[0085] The term "wild-type" refers to a nucleic acid (e.g., a MALT1 gene or MALT1 mRNA) or protein (e.g., a MALT1 protein) found in a subject who does not have (optionally, 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., a MALT1 gene, MALT1 mRNA, or MALT1 protein), or found in cells or tissues from a subject who does not have (optionally, does not have an increased risk of developing and / or is not suspected of having) a disease or disorder associated with the gene or protein (e.g., a MALT1-associated cancer, autoimmune disorder, or inflammatory disorder).

[0086] In some embodiments, the subject has been identified or diagnosed as having a cancer (CBM complex pathway-associated cancer) involving dysregulation of expression, activity, or levels of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). 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 expression, activity, or levels of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit) dysregulated expression, activity, or levels of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them. The subject may have a tumor that has (e.g., identified as such using a regulatory agency-approved, e.g., FDA-approved, assay or kit) dysregulated expression, activity, or levels of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them. 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-associated 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 clinical records indicating that the subject has dysregulated expression, activity, or levels of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has clinical records indicating that the subject has a tumor that is resistant to one or more previous therapies. In some embodiments, the subject has been identified or diagnosed with a cancer that is determined to be associated with dysregulated expression, activity, or levels of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (CBM complex pathway-associated cancer) based on histological examination.

[0087] In some embodiments, the subject has been identified or diagnosed as having an autoimmune disorder (e.g., a CBM complex pathway-associated autoimmune disorder) involving dysregulation of expression, activity, or levels of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., a CBM complex pathway-associated autoimmune disorder) (e.g., as determined using a regulatory-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of expression, activity, or levels of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved, e.g., FDA-approved assay or kit). In some embodiments, the subject is suspected of having a CBM complex pathway-associated autoimmune disorder. In some embodiments, the subject has clinical records indicating that the subject has dysregulation of expression, activity, or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with an autoimmune disorder (CBM complex pathway-associated autoimmune disorder) that is determined to be associated with dysregulation of expression, activity, or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them based on histological examination.

[0088] In some embodiments, the subject has been identified or diagnosed as having an inflammatory disorder (e.g., a CBM complex pathway-associated inflammatory disorder) involving dysregulation of expression, activity, or levels of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., a CBM complex pathway-associated inflammatory disorder) (e.g., as determined using a regulatory-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of expression, activity, or levels of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved, e.g., FDA-approved assay or kit). In some embodiments, the subject is suspected of having a CBM complex pathway-associated inflammatory disorder. In some embodiments, the subject has clinical records indicating that the subject has dysregulation of expression, activity, or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with an autoinflammatory disorder (CBM complex pathway-associated inflammatory disorder) determined to be associated with dysregulation of expression, activity, or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them based on histological examination.

[0089] As used herein, the term "CBM complex pathway cell surface receptor-associated cancer" refers to a cancer associated with or having dysregulation of expression or activity or levels of a gene, protein, or any (e.g., one or more) associated with a CBM complex pathway cell surface receptor. In some embodiments, the CBM complex pathway cell surface receptor-associated cancer is selected from the group consisting of CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, HER2-associated cancer, and combinations thereof.

[0090] As used herein, the term "*-related cancer" refers to a cancer that is associated with or has dysregulation of the expression or activity or level of a * gene, * protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression or activity or level of a * gene, * protein, or any of them described herein), where "*" 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, Regnase 1-associated cancer, LIMA1α-associated cancer, Rokin-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 a CD28-associated cancer. In some embodiments, the *associated cancer is a BCR-associated cancer. In some embodiments, the *associated cancer is a HER1-associated cancer. In some embodiments, the *associated cancer is a HER2-associated cancer. In some embodiments, the *associated cancer is a PKCβ-associated cancer. In some embodiments, the *associated cancer is a PKCθ-associated cancer. In some embodiments, the *associated cancer is a MALT1-associated cancer. In some embodiments, the *associated cancer is a CARD11-associated cancer. In some embodiments, the *associated cancer is a CARD14-associated cancer. In some embodiments, the *associated cancer is an A20-associated cancer. In some embodiments, the *associated cancer is a CYLD-associated cancer. In some embodiments, the *associated cancer is a RelB-associated cancer. In some embodiments, the *associated cancer is a HOIL1-associated cancer.In some embodiments, the * related cancer is a NIK-related cancer. In some embodiments, the * related cancer is a Regnase 1-related cancer. In some embodiments, the * related cancer is a LIMA1α-related cancer. In some embodiments, the * related cancer is a Rokin-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 cancer is an MKK7-related cancer and an 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 *associated cancer is a c-Rel-associated cancer. In some embodiments, the *associated cancer is a JNK1-associated cancer. In some embodiments, the *associated cancer is a JNK2-associated cancer. In some embodiments, the *associated cancer is a JNK3-associated cancer. In some embodiments, the *associated cancer is an AP-1 transcription factor-associated cancer. In some embodiments, the *associated cancer is a MYD88 transcription factor-associated cancer.

[0091] The phrase "dysregulated expression or activity or levels of a * gene, * protein, or any of them" (where * is a specific CBM complex pathway gene or protein described herein) refers to a genetic mutation (e.g., a chromosomal translocation resulting in expression of a fusion protein comprising a * domain and a fusion partner, a mutation in a * gene resulting in expression of a * protein with a deletion of at least one amino acid compared to the wild-type * protein, a mutation in a * gene resulting in expression of a * protein with one or more point mutations compared to the wild-type * protein, a mutation in a * gene resulting in expression of a * protein with an insertion of at least one amino acid compared to the wild-type * protein, a gene duplication resulting in increased levels of a * protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in increased levels of a * protein in a cell), an alternatively spliced version of a * mRNA resulting in a * protein with a deletion of at least one amino acid in the * protein compared to the wild-type * protein, or increased expression (e.g., increased levels) of a wild-type * protein in a mammalian cell due to aberrant 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 the * gene can result in overexpression of the * protein. For example, dysregulation of the expression or activity or levels of the * gene, the * protein, or any of them can be the result of a genetic or chromosomal translocation that results in expression of a fusion protein containing a first portion of * and a second portion of a partner protein (i.e., not *). In some examples, dysregulation of the expression or activity or levels of the * gene, the * protein, or any of them can be the result of a genetic translocation between one * gene and another non-* gene.In some embodiments, the *gene, *protein, or expression or activity or level of any thereof is selected from the group consisting of CD28, BCR, HER1, HER2, PKCβ, PKCθ, MALT1, CARD11, CARD14, A20, CYLD, RelB, HOIL1, NIK, Regnase 1, LIMA1α, Rokin-1, TRAF6, TAK1, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65, c-Rel, JNK1, JNK2, JNK3, MYD88, and AP-1 transcription factors. In some embodiments, the *gene or *protein is CD28. In some embodiments, the *gene or *protein is BCR. In some embodiments, the *gene or *protein is HER1. In some embodiments, the *gene or *protein is HER2. In some embodiments, the *gene or *protein is PKCβ. In some embodiments, the * gene or * protein is PKC theta. In some embodiments, the * gene or * protein is MALT1. In some embodiments, the * gene or * protein is CARD11. In some embodiments, the * gene or * protein is CARD14. In some embodiments, the * gene or * protein is A20. In some embodiments, the * gene or * protein is CYLD. In some embodiments, the * gene or * protein is RelB. In some embodiments, the * gene or * protein is HOIL1. In some embodiments, the * gene or * protein is NIK. In some embodiments, the * gene or * protein is Regnase 1. In some embodiments, the * gene or * protein is LIMA1α. In some embodiments, the * gene or * protein is Rokin-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 MYD88 transcription factor. In some embodiments, the * gene or * protein is AP-1 transcription factor.

[0092] In some embodiments, the dysregulation of the expression or activity or level of the * gene, * protein, or any of them can be a mutation in the * gene that encodes a * protein that is constitutively active or has increased activity compared to the protein encoded by a * gene that does not contain the mutation. In some embodiments, an increase in the copy number of the * gene can result in overexpression of the * protein. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is CD28. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is BCR. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is HER1. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is HER2. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is PKC beta. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is PKC theta. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is CARD14. In some embodiments, the * gene, * protein, or expression or activity or level of any of them is CARD9. In some embodiments, the * gene, * protein, or expression or activity or level of any of them is CARD10. In some embodiments, the * gene, * protein, or expression or activity or level of any of them is CARD11. In some embodiments, the * gene, * protein, or expression or activity or level of any of them is MALT1.

[0093] As another example, dysregulation of the expression or activity or level of the * gene, * protein, or any of them can be a mutation in the * gene that encodes a * protein that is constitutively inactive or has reduced activity compared to the protein encoded by the * gene that does not contain the mutation. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is A20. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is CYLD. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is RelB. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is HOIL1. In some embodiments, the expression or activity or level of the * gene, * protein, or any of them is NIK.

[0094] 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 the expression, activity, or level of a particular gene, a particular protein, or any of them (e.g., one or more) (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 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 the expression, activity, or level of a particular gene, a particular protein, or any of them (e.g., one or more) (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.

[0095] Exemplary sequences of the proteins described herein are shown below.

[0096] An exemplary sequence of human CD28 is shown below. SEQ ID NO: 1 (UniParc accession number UPI0000043F4D) MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIY FCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0097] 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.

[0098] An exemplary sequence of a human BCR is shown below. SEQ ID NO: 2 (UniParc accession number UPI000016A088)

[0099] 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.

[0100] An exemplary sequence of human HER1 is shown below. SEQ ID NO: 3 (UniParc accession number UPI000003E750)

[0101] Non-limiting examples of dysregulation 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.

[0102] An exemplary sequence of human HER2 is shown below. SEQ ID NO: 4 (UniParc accession number UPI000003F55F)

[0103] Non-limiting examples of dysregulation 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).

[0104] As used herein, the term "cancer associated with a signal transduction pathway between a cell surface receptor and a CBM complex" refers to a cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more) associated with a signal transduction pathway between a cell surface receptor and a CBM complex. In some embodiments, the cancer associated with a signal transduction pathway between a cell surface receptor and a CBM complex is selected from the group consisting of a PKCβ-associated cancer, a PCKθ-associated cancer, and combinations thereof. A cancer "associated with" a specific gene or protein described in this paragraph refers to a cancer associated with or having dysregulation of the expression, activity, or level of a specific gene, a specific protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression, activity, or level of a specific gene, a specific protein, or any of them described herein). Non-limiting examples of such cancers are described herein.

[0105] An exemplary sequence of human PKCβ is shown below. SEQ ID NO: 5 (UniParc accession number UPI000012DF67) MADPAAGPPPSEGEESTVRFARKGALRQKNVHEVKNHKFTARFKQPTFCSHCTDFIWGFGKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPASDDPRSKHKFKIHTYSSPTFCDHCGSLLYGLIHQGMKCDTCMMNVHKRCVMNVPSLCGTDHTERRGRIYIQAH IDRDVLIVLVRDAKNLVPMDPNGLSDPYVKLKLIPDPKSESKQKTKTIKCSLNPEWNETFRFQLKESDKDRRLSVEIWDWDLTSRNDFMGSLSFGISELQKASVDGWFKLLSQEEGEYFNPVVPEGSEANEELRQKFERAKISQGTKVPEEKTTNTVSKFDNNGNRD RMKLTDFNFLMVLGKGSFGKVMLSERKGTDELYAVKILKKDVVIQDDDVECTMVEKRVLALPGKPPFLTQLHSCFQTMDRLYFVMEYVNGGDLMYHIQQVGRFKEPHAVFYAAEIIAIGLFFLQSKGIIYRDLKLDNVMLDSEGHIKIADFGMCKENIWDGVTTKTFCG TPDYIAPEIIAYQPYGKSVDWWAFGVLLYEMLAGQAPFEGEDEDELFQSIMEHNVAYPKSMSKEAVAICKGLMTKHPGKRLGCGPEGERDIKEHAFFRYIDWEKLERKEIQPPYKPKARDKRDTSNFDKEFTRQPVELTPTDKLFIMNLDQNEFAGFSYTNPEFVINV

[0106] An exemplary sequence of human PKC theta is shown below. SEQ ID NO: 6 (UniParc accession number UPI000012DF74) MSPFLRIGLSNFDCGSCQSCQGEAVNPYCAVLVKEYVESENGQMYIQKKPTMYPPWDSTFDAHINKGRVMQIIVKGKNVDLISETTVELYSLAERCRKNNGKTEIWLELKPQGRMLMNARYFLEMSDTKDMNEFETEGFFALHQRRGAIKQAKVHHVKCHEFTATFFPQPTFCSVCHEFVWGLNKQGYQCRQCNAAIHKKCIDKVIAKCTGSAINSRETMFHKERFKIDMPHRFKVYNYKSPTFCEHCGTLLWGLARQGLKCDACGMNVHHRCQTKVANLCGINQKLMAEALAMIESTQQARCLRDTEQIFREGPVEIGLPPCSIKNEARPPPCLPTPGKREPQGISWESPLDEV DKMCHLPEPELNKERPSLQIKLKIEDFILHKMLGKGSFGKVFLAEFKKTNQFFAIKALKKDVVLMDDVECTMVEKRVLSLAWEHPFLTHMFCTFQTKENLFFVMEYLNGGDLMYHIQSCHKFDLSRATFYAAEIILGLQFLHSKGIVYRDLKLDNILLDKDGHIKIADFGMCKENMLGDAKTNTFCGTPDYIAPEILLGQKYNHSVDWWSFGVLLYEMLIGQSPFHGQDEELELFHSIRMDNPFYPRWLEKEAKDLLVKLFVREPEKRLGVRGDIRQHPLFREINWEELERKEIDPPFRPKVKSPFDCSNFDKEFLNEKPRLSFADRALINSMDQNMFRNFSFNMPGMERLIS

[0107] As used herein, the term "CBM complex-associated cancer component" refers to a cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more). In some embodiments, the CBM complex-associated cancer component is selected from the group consisting of MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, CARD10-associated cancer, CARD9-associated cancer, BCL10-associated cancer, and combinations thereof. In some embodiments, the CBM complex-associated cancer is selected from the group consisting of MALT1-associated cancer, CARD11-associated cancer, BCL10-associated cancer, and combinations thereof. 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 of them (e.g., one or more) (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.

[0108] As used herein, the term "MALT1-associated autoimmune disorder" refers to an autoimmune disorder associated with or characterized by dysregulation of the expression, activity, or levels of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any (e.g., one or more) of any of them (e.g., any of the types of dysregulation of the expression, activity, or levels of the MALT1 gene, MALT1 protease, MALT1 protease domain, or any of them described herein). Non-limiting examples of MALT1-associated autoimmune disorders are described herein.

[0109] As used herein, the term "MALT1-associated inflammatory disorder" refers to an inflammatory disorder associated with or dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any (e.g., one or more) thereof (e.g., any of the types of dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protease, MALT1 protease domain, or any of them described herein). Non-limiting examples of MALT1-associated inflammatory disorders are described herein.

[0110] As used herein, the term "MALT1-associated cancer" refers to cancer associated with or dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any of (e.g., one or more of) them (e.g., any of the types of dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protein, MALT1 protease domain, or any of (e.g., one or more of) them described herein). Non-limiting examples of MALT1-associated cancers are described herein.

[0111] The phrase "dysregulated expression or activity or levels of the MALT1 gene, MALT1 protein, or any of them" refers to a genetic mutation (e.g., a chromosomal translocation resulting in the expression of a fusion protein comprising a MALT1 domain and a fusion partner, a mutation in the MALT1 gene resulting in the expression of a MALT1 protein containing a deletion of at least one amino acid compared to the wild-type MALT1 protein, a mutation in the MALT1 gene resulting in the expression of a MALT1 protein with one or more point mutations compared to the wild-type MALT1 protein, a mutation in the MALT1 gene resulting in the expression of a MALT1 protein with an insertion of at least one amino acid compared to the wild-type MALT1 protein, a gene duplication resulting in an increased level of MALT1 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in an increased level of MALT1 protein in a cell), a MALT1 protein with a deletion of at least one amino acid in the MALT1 protein compared to the wild-type MALT1 protein, or a mutation in a MALT1 gene with a deletion of at least one amino acid in the MALT1 protein compared to the wild-type MALT1 protein. This refers to increased expression (e.g., increased levels) of wild-type MALT1 protein in mammalian cells due to alternatively spliced versions of mRNA or aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control, non-cancerous cells). As another example, dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protein, or any of them may be due to 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 a MALT1 gene that does not contain the mutation. As a further example, an increase in the copy number of the MALT1 gene may result in overexpression of the MALT1 protease. For example, dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protein, or any of them may be the result of a genetic or chromosomal translocation that results in the expression of a fusion protein containing a first portion of MALT1, including a functional protease domain, and a second portion of a partner protein (i.e., not MALT1).In some instances, dysregulation of the expression or activity or levels of the MALT1 gene, MALT1 protein, or any of them may be the result of a genetic translocation between one MALT1 gene and another non-MALT1 gene.

[0112] An exemplary sequence of human MALT1 is shown below. SEQ ID NO: 7 (UniParc accession number UPI000004D05E) MSLLGDPLQALPPSAAPTGPLLAPPAGATLNLREPLLRRLSELLDQAPEGRGWRRLAELAGSRGRLRLSCLDLEQCSLKVLEPEGSPSLCLLKLMGEKGCTVTELSDFLQAMEHTEVLQLLSPPGIKITVNPESKAVLAGQFVKLCCRATGHPFVQYQWFKMNKEIPNGNTSELIFNAVHVKDAGFYVCRVNNNFTFEFSQWSQL DVCDIPESFQRSVDGVSESKLQICVEPTSQKLMPGSTLVLQCVAVGSPIPHYQWFKNELPLTHETKKLYMVPYVDLEHQGTYWCHVYNDRDSQDSKKVEIIIG RTDEAVECTEDELNNLGHPDNKEQTTDQPLAKDKVALLIGNMNYREHPKLKAPLVDVYELTNLLRQLDFKVVSLLDLTEYEMRNAVDEFLLLLDKGVYGLLYY AGHGYENFGNSFMVPVDAPNPYRSENCLCVQNILKLMQEKETGLNVFLLDMCRKRNDYDDTIPILDALKVTANIVFGYATCQGAEAFEIQHSGLANGIFMKFL KDRLEDKKITVLLDEVAEDMGKCHLTKGKQALEIRSSLSEKRALTDPIQGTEYSAESLVRNLQWAKAHELPESMCLKFDCGVQIQLGFAAEFSNVMIIYTSI VYKPPEIIMCDAYVTDFPLDLDIDPKDANKGTPEETGSYLVSKDLPKHCLYTRLSSLQKLKEHLVFTVCLSYQYSGLEDTVEDKQEVNVGKPLIAKLDMHRGLGRKTCFQTCLMSNGPYQSSAATSGGAGHYHSLQDPFHGVYHSHPGNPSNVTPADSCHCSRTPDAFISSFAHHASCHFSRSNVPVETTDEIPFSFSDRLRISEK

[0113] Non-limiting examples of dysregulation of the MALT1 gene or MALT1 protein are shown in Table B1 below. [Table B1]

[0114] As used herein, the term "CARD11-associated autoimmune disorder" refers to an autoimmune disorder associated with or having dysregulation of the expression, activity or levels of the CARD11 gene, the CARD11 protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression, activity or levels of the CARD11 gene, the CARD11 protein, or any of them described herein).

[0115] As used herein, the term "CARD11-associated inflammatory disorder" refers to an inflammatory disorder associated with or having dysregulation of the expression, activity or levels of the CARD11 gene, CARD11 protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression, activity or levels of the CARD11 gene, CARD11 protein, or any of them described herein).

[0116] As used herein, the term "CARD11-associated cancer" refers to cancer that is associated with or has dysregulation of the expression or activity or level of the CARD11 gene, the CARD11 gene, the CARD11 protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression or activity or level of the CARD11 gene, the CARD11 protein, or any of them described herein).Non-limiting examples of CARD11-associated cancers are described herein.

[0117] The phrase "dysregulated expression or activity or levels of the CARD11 gene, CARD11 protein, or any of them" refers to a genetic mutation (e.g., a chromosomal translocation resulting in the expression of a fusion protein comprising a CARD11 domain and a fusion partner, a mutation in the CARD11 gene resulting in the expression of a CARD11 protein comprising a deletion of at least one amino acid compared to the wild-type CARD11 protein, a mutation in the CARD11 gene resulting in the expression of a CARD11 protein with one or more point mutations compared to the wild-type CARD11 protein, a mutation in the CARD11 gene resulting in the expression of a CARD11 protein with an insertion of at least one amino acid compared to the wild-type CARD11 protein, a gene duplication resulting in an increased level of CARD11 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in an increased level of CARD11 protein in a cell), a CARD11 protein resulting in a CARD11 protein with a deletion of at least one amino acid in the CARD11 protein compared to the wild-type CARD11 protein, This refers to increased expression (e.g., increased levels) of wild-type CARD11 protein in mammalian cells due to alternative splice versions of mRNA or aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them may 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 a CARD11 gene that does not contain a mutation. As a further example, an increase in the copy number of the CARD11 gene may result in overexpression of the CARD11 protein. For example, dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them may 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., not CARD11).In some examples, dysregulation of the CARD11 gene, the CARD11 protein, or the expression or activity or levels of any of them can be the result of a genetic translocation between one CARD11 gene and another non-CARD11 gene.

[0118] An exemplary sequence of human CARD11 is shown below. SEQ ID NO: 8 (UniParc accession number UPI00003FED38)

[0119] Non-limiting examples of dysregulation of the CARD11 gene or CARD11 protein are shown in Table B2 below. [Table B2]

[0120] As used herein, the term "CARD14-associated autoimmune disorder" refers to an autoimmune disorder associated with or having dysregulation of the CARD14 gene, the CARD14 protein, or any (e.g., one or more) expression, activity, or levels thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the CARD14 gene, the CARD14 protein, or any of them described herein).

[0121] As used herein, the term "CARD14-associated inflammatory disorder" refers to an inflammatory disorder associated with or having dysregulation of the CARD14 gene, CARD14 protein, or any (e.g., one or more) expression or activity or levels thereof (e.g., any of the types of dysregulation of the expression or activity or levels of the CARD14 gene, CARD14 protein, or any of them described herein).

[0122] As used herein, the term "CARD14-associated cancer" refers to a cancer that is associated with or has dysregulation of the CARD14 gene, the CARD14 protein, or any (e.g., one or more) expression, activity, or levels thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the CARD14 gene, the CARD14 protein, or any of them described herein).

[0123] An exemplary sequence of human CARD14 is shown below. SEQ ID NO: 9 (UniParc accession number UPI000013D81B)

[0124] As used herein, the term "CARD10-associated autoimmune disorder" refers to an autoimmune disorder associated with or having dysregulation of the CARD10 gene, CARD10 protein, or any (e.g., one or more) expression, activity, or levels thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the CARD10 gene, CARD10 protein, or any of them described herein).

[0125] As used herein, the term "CARD10-associated inflammatory disorder" refers to an inflammatory disorder associated with or having dysregulation of the CARD10 gene, CARD10 protein, or any (e.g., one or more) expression, activity, or levels thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the CARD10 gene, CARD10 protein, or any of them described herein).

[0126] As used herein, the term "CARD10-associated cancer" refers to a cancer that is associated with or has dysregulation of the CARD10 gene, CARD10 protein, or any (e.g., one or more) expression, activity, or levels thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the CARD10 gene, CARD10 protein, or any of them described herein).

[0127] The phrase "dysregulated expression or activity or levels of the CARD10 gene, CARD10 protein, or any of them" refers to a genetic mutation (e.g., a chromosomal translocation resulting in the expression of a fusion protein comprising a CARD10 domain and a fusion partner, a mutation in the CARD10 gene resulting in the expression of a CARD10 protein comprising a deletion of at least one amino acid compared to the wild-type CARD10 protein, a mutation in the CARD10 gene resulting in the expression of a CARD10 protein with one or more point mutations compared to the wild-type CARD10 protein, a mutation in the CARD10 gene resulting in the expression of a CARD10 protein with an insertion of at least one amino acid compared to the wild-type CARD10 protein, a gene duplication resulting in an increased level of CARD10 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in an increased level of CARD10 protein in a cell), a CARD10 protein with a deletion of at least one amino acid in the CARD10 protein compared to the wild-type CARD10 protein, This refers to increased expression (e.g., increased levels) of wild-type CARD10 protein in mammalian cells due to alternative splice versions of mRNA or aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them may 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 a CARD10 gene that does not contain a mutation. As a further example, an increase in the copy number of the CARD10 gene may result in overexpression of the CARD10 protein. For example, dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them may be the result of a genetic 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., not CARD10).In some instances, dysregulation of the CARD10 gene, CARD10 protein, or expression or activity or levels of any of them can be the result of a genetic translocation between one CARD10 gene and another non-CARD10 gene.

[0128] An exemplary sequence of human CARD10 is shown below. SEQ ID NO: 10 (UniParc accession number UPI0000044645)

[0129] As used herein, the term "CARD9-associated autoimmune disorder" refers to an autoimmune disorder associated with or having dysregulation of the CARD9 gene, CARD9 protein, or any (e.g., one or more) expression or activity or levels thereof (e.g., any of the types of dysregulation of the expression or activity or levels of the CARD9 gene, CARD9 protein, or any of them described herein).

[0130] As used herein, the term "CARD9-associated inflammatory disorder" refers to an inflammatory disorder associated with or having dysregulation of the CARD9 gene, CARD9 protein, or any (e.g., one or more) expression or activity or levels thereof (e.g., any of the types of dysregulation of the expression or activity or levels of the CARD9 gene, CARD9 protein, or any of them described herein).

[0131] As used herein, the term "CARD9-associated cancer" refers to a cancer that is associated with or has dysregulation of the CARD9 gene, CARD9 protein, or any (e.g., one or more) expression, activity, or levels thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the CARD9 gene, CARD9 protein, or any of them described herein).

[0132] The phrase "dysregulated expression or activity or levels of the CARD9 gene, CARD9 protein, or any of them" refers to a genetic mutation (e.g., a chromosomal translocation resulting in the expression of a fusion protein comprising a CARD9 domain and a fusion partner, a mutation in the CARD9 gene resulting in the expression of a CARD9 protein with a deletion of at least one amino acid compared to the wild-type CARD9 protein, a mutation in the CARD9 gene resulting in the expression of a CARD9 protein with one or more point mutations compared to the wild-type CARD9 protein, a mutation in the CARD9 gene resulting in the expression of a CARD9 protein with an insertion of at least one amino acid compared to the wild-type CARD9 protein, a gene duplication resulting in an increased level of the CARD9 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in an increased level of the CARD9 protein in a cell), a CARD9 protein with a deletion of at least one amino acid in the CARD9 protein compared to the wild-type CARD9 protein, This refers to increased expression (e.g., increased levels) of wild-type CARD9 protein in mammalian cells due to alternative splice versions of mRNA or aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulated expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them may 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 a CARD9 gene that does not contain a mutation. As a further example, an increase in the copy number of the CARD9 gene may result in overexpression of the CARD9 protein. For example, dysregulated expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them may be the result of a genetic 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., not CARD9).In some instances, dysregulation of the CARD9 gene, CARD9 protein, or expression or activity or levels of any of them can be the result of a genetic translocation between one CARD9 gene and another non-CARD9 gene.

[0133] An exemplary sequence of human CARD9 is shown below. SEQ ID NO: 11 (UniParc accession number UPI000013E4EB) MSDYENDDECWSVLEGFRVTLTSVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRKVGVLLDILQRTGHKGYVAFLESLELYYPQLYKKVTGKEPARVFSMIIDASGESGLTQLLMTEVMKLQKKVQDLT ALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECEAGSRELKRCKEENYDLAMRLAHQSEEKGAALMRNRDLQLEIDQLKHSLMKAEDDCKVERKHTLKLRHAMEQRPSQELLWELQQEKALLQARVQELEASV QEGKLDRSSPYIQVLEEDWRQALRDHQEQANTIFSLRKDLRQGEARRLRCMEEKEMFELQCLALRKDSKMYKDRIEAILLQMEEVAIERDQAIATREELHAQHARGLQEKDALRKQVRELGEKADELQLQVFQC EAQLLAVEGRLRRQQLETLVLSSDLEDGSPRRSQELSLPQDLEDTQLSDKGCLAGGGSPKQPFAALHQEQVLRNPHDAGLSSGEPPEKERRRLKESFENYRRKRALRKMQKGWRQGEEDRENTTGSDNTDTEGS

[0134] As used herein, the term "BCL10-associated autoimmune disorder" refers to an autoimmune disorder associated with or having dysregulation of the BCL10 gene, BCL10 protein, or any (e.g., one or more) expression or activity or levels thereof (e.g., any of the types of dysregulation of the expression or activity or levels of the BCL10 gene, BCL10 protein, or any of them described herein).

[0135] As used herein, the term "BCL10-associated inflammatory disorder" refers to an inflammatory disorder associated with or having dysregulation of the BCL10 gene, BCL10 protein, or any (e.g., one or more) expression or activity or levels thereof (e.g., any of the types of dysregulation of the expression or activity or levels of the BCL10 gene, BCL10 protein, or any of them described herein).

[0136] As used herein, the term "BCL10-associated cancer" refers to a cancer that is associated with or has dysregulation of the BCL10 gene, BCL10 protein, or any (e.g., one or more) expression or activity or levels thereof (e.g., any of the types of dysregulation of the expression or activity or levels of the BCL10 gene, BCL10 protein, or any of them described herein).

[0137] The phrase "dysregulated expression or activity or levels of the BCL10 gene, BCL10 protein, or any of them" refers to a genetic mutation (e.g., a chromosomal translocation resulting in expression of a fusion protein comprising a BCL10 domain and a fusion partner, a mutation in the BCL10 gene resulting in expression of a BCL10 protein with a deletion of at least one amino acid compared to the wild-type BCL10 protein, a mutation in the BCL10 gene resulting in expression of a BCL10 protein with one or more point mutations compared to the wild-type BCL10 protein, a mutation in the BCL10 gene resulting in expression of a BCL10 protein with an insertion of at least one amino acid compared to the wild-type BCL10 protein, a gene duplication resulting in increased levels of BCL10 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in increased levels of BCL10 protein in a cell), a BCL10 protein with a deletion of at least one amino acid in the BCL10 protein compared to the wild-type BCL10 protein, This refers to increased expression (e.g., increased levels) of wild-type BCL10 protein in mammalian cells due to alternative splice versions of mRNA or aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). For example, dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them may be the result of a genetic or chromosomal translocation that results in the expression of a fusion protein containing a first portion of BCL10 and a second portion of a partner protein (i.e., not BCL10). In some examples, dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them may be the result of a genetic translocation between one BCL10 gene and another non-BCL10 gene.

[0138] An exemplary sequence of human BCL10 is shown below. SEQ ID NO: 12 (UniParc accession number UPI000012682F) MEPTAPSLTEEDLTEVKKDALENLRVYLCEKIIAERHFDHLRAKKILSREDTEEISCRTSRKRAGKLLDYLQENPKGLDTLVESIRREKTQNFLIQKITDEVLKLRNIKLEHLKG LKCSSCEPFPDGATNNLSRSNSDESNFSEKLRASTVMYHPEGESSTTPFFSTNSSLNLPVLEVGRTENTIFSSTTLPRPGDPGAPLPPDLQLEEEGTCANSSEMFLPLRSRTVSRQ

[0139] Non-limiting examples of dysregulation of the BCL10 gene or BCL10 protein are shown in Table B3 below. [Table B3-1] [Table B3-2]

[0140] As used herein, the term "MALT1 protease substrate-associated 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) associated with a MALT1 protease substrate. In some embodiments, the MALT1 protease substrate-associated cancer is selected from the group consisting of BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, RelB-associated cancer, Regnase 1-associated cancer, Rokin-1-associated cancer, HOIL1-associated cancer, NIK-associated cancer, LIMA1α-associated cancer, and combinations thereof. In some embodiments, the MALT1 protease substrate-associated cancer is selected from the group consisting of BCL10-associated cancer, A20-associated cancer, CYLD-associated 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 of them (e.g., one or more) (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.

[0141] An exemplary sequence for human A20 is shown below. SEQ ID NO: 13 (UniParc accession number UPI000000D92D) MAEQVLPQALYLSNMRKAVKIRERTPEDIFKPTNGIIHHFKTMHRYTLEMFRTCQFCPQFREIIHKALIDRNIQATLESQKKLNWCREVRKLVALKTN GDGNCLMHATSQYMWGVQDTDLVLRKALFSTLKETDTRNFKFRWQLESLKSQEFVETGLCYDTRNWNDEWDNLIKMASTDTPMARSGLQYNSLEEIHIF VLCNILRRPIIVISDKMLRSLESGSNFAPLKVGGIYLPLHWPAQECYRYPIVLGYDSHHFVPLVTLKDSGPEIRAVPLVNRDRGRFEDLKVHFLTDPENEMKEKLLKEYLMVIEIPVQGWDHGTTHLINAAKLDEANLPKEINLVDDYFELVQHEYKKWQENSEQGRREGHAQNPMEPSVPQLSLMDVKCETPNCPFF MSVNTQPLCHECSERRQKNQNKLPKLNSKPGPEGLPGMALGASRGEAYEPLAWNPEESTGGPHSAPPTAPSPFLFSETTAMKCRSPGCPFTLNVQHNGFCERCHNARQLHASHAPDHTRHLDPGKCQACLQDVTRTFNGICSTCFKRTTAEASSSLSTSLPPSCHQRSKSDPSRLVRSPSPHSCHRAGNDAPAGCLS QAARTPGDRTGTSKCRKAGCVYFGTPENKGFCTLCFIEYRENKHFAAASGKVSPTASRFQNTIPCLGRECGTLGSTMFEGYCQKCFIEAQNQRFHEAKRTEEQLRSSQRRDVPRTTQSTSRPKCARASCKNILACRSEELCMECQHPNQRMGPGAHRGEPAPEDPPKQRCRAPACDHFGNAKCNGYCNECFQFKQMYG

[0142] Non-limiting examples of dysregulation of the A20 gene or A20 protein are shown in Table B4 below. [Table B4]

[0143] An exemplary sequence of human CYLD is shown below. SEQ ID NO: 14 (UniParc accession number UPI0000073A15) MSSGLWSQEKVTSPYWEERIFYLLLQECSVTDKQTQKLLKVPKGSIGQYIQDRSVGHSRIPSAKGKKNQIGLKILEQPHAVLFVDEKDVVEINEKFTELLLAITNCEERFSLFKNRNRLSKGLQIDVGCPVKVQLRSGEEKFPGVVRFRGPLLAERTVSGIFFGVELLEEGRGQGFTDGVYQGKQLFQCDEDCGVFVALDKLELIEDDDTALESDYAGPGDTMQVELPPLEINSRVSLKVGETIESGTVIFCDVLPGKESLGYFVGVDMDNPIGNWDGRFDGVQLCSFACVESTILLHINDIIPALSESVTQERRPPKLAFMSRGVGDKGSSSHNKPKATGSTSDPGNRNRSELFYTLNGSSVDSQPQSKSKNTWYIDEVAEDPAKSLTEISTDFDRSSPPLQPPPVNSLTTENRFHSLPFSLTKMPNTNGSIGHSPLSLSAQSVMEELNTAPVQESPPLAMPPGNSHGLEVGSLAEVKENPPFYGVIRWIGQPPGLNEVLAGLELEDECAGCTDGTFRGTRYFTCALKKALFVKLKSCRPDSRFASLQPVSNQIERCNSLAFGGYLSEVVEENTPPKMEKEGLEIMIGKKKGIQGHYNSCYLDSTLFCLFAFSSVLDTVLLRPKEKNDVEYYSETQELLRTEIVNPLRIYGYVCATKIMKLRKILEKVEAASGFTSEEKDPEEFLNILFHHILRVEPLLKIRSAGQKVQDCYFYQIFMEKNEKVGVPTIQQLLEWSFINSNLKFAEAPSCLIIQMPRFGKDFKLFKKIFPSLELNITDLLEDTPRQCRICGGLAMYECRECYDDPDISAGKIKQFCKTCNTQVHLHPKRLNHKYNPVSLPKDLPDWDWRHGCIPCQNMELFAVLCIETSHYVAFVKYGKDDSAWLFFDSMADRDGGQNGFNIPQVTPCPEVGEYLKMSLEDLHSLDSRRIQGCARRLLCDAYMCMYQSPTMSLYK

[0144] 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, JP, et al., Oncogene 29.50(2010):6522-6532, Williams, et al., Modern Pathology(2020):1-13, and Courtois and Gilmore. Oncogene 25.51(2006):6831-6843.

[0145] An exemplary sequence of human RelB is shown below. SEQ ID NO: 15 (UniParc accession number UPI00000012B7) MLRSGPASGPSVPTGRAMPSRRVARPPAAPELGALGSPDLSSLSLAVSRSTDELEIIDEYIKENGFGLDGGQPGPGEGLPRLVSRGAASLSTVTLGPVAPPATPPPWGCPLGRLVSPAPGPGPQPHLVITEQPKQRGMRFRYEC EGRSAGSILGESSTEASKTLPAIELRDCGGLREVEVTACLVWKDWPHRVHPHSLVGKDCTDGICRVRLRPHVSPRHSFNNLGIQCVRKKEIEAAIERKIQLGIDPYNAGSLKNHQEVDMNVVRICFQASYRDQQGQMRRMDPVLS EPVYDKKSTNTSELRICRINKESGPCTGGEELYLLCDKVQKEDISVVFSRASWEGRADFSQADVHRQIAIVFKTPPYEDLEIVEPVTVNVFLQRLTDGVCSEPLPFTYLPRDHDSYGVDKKRKRGMPDVLGELNSSDPHGIESKR RKKKPAILDHFLPNHGSGPFLPPSALLPDPDFFSGTVSLPGLEPPGGPDLLDDGFAYDPTAPTLFTMLDLLPAPPHASAVVCSGGAGAVVGETPGPEPLTLDSYQAPGPGDGGTASLVGSNMFPNHYREAAFGGGLLSPGPEAT

[0146] An exemplary sequence of human Regnase 1 is shown below. SEQ ID NO: 16 (UniParc accession number UPI000004D30E) MSGPCGEKPVLEASPTMSLWEFEDSHSRQGTPRPGQELAAEEASALELQMKVDFFRKLGYSSTEIHSVLQKLGVQADTNTVLGELVKHGTATERERQTSPDPCPQLPLVPRGGGTPKAPNLEPPLPEEEKEGSDLRPVVIDGSNVAMSH GNKEVFSCRGILLAVNWFLERGHTDITVFVPSWRKEQPRPDVPITDQHILRELEKKKILVFTPSRRVGGKRVVCYDDRFIVKLAYESDGIVVSNDTYRDLQGERQEWKRFIEERLLMYSFVNDKFMPPDDPLGRHGPSLDNFLRKKPLTL EHRKQPCPYGRKCTYGIKCRFFHPERPSCPQRSVADELRANALLSPPRAPSKDKNGRRPSPSSQSSSLLTESEQCSLDGKKLGAQASPGSRQEGLTQTYAPSGRSLAPSGGGSGSSFGPTDWLPQTLDSLPYVSQDCLDSGIGSLESQMSE LWGVRGGGPGEPGPPRAPYTGYSPYGSELPATAAFSAFGRAMGAGHFSVPADYPPAPPAFPPREYWSEPYPLPPPTSVLQEPPVQSPGAGRSPWGRAGSLAKEQASVYTKLCGVFPPHLVEAVMGRFPQLLDPQQLAAEILSYKSQHPSE

[0147] An exemplary sequence of human troponin-1 is shown below. SEQ ID NO: 17 (UniParc accession number UPI00001D7DA8)

[0148] An exemplary sequence of human HOIL1 is set forth below. SEQ ID NO: 17 (UniParc accession number UPI000006F045) MDEKTKKAEEMALSLTRAVAGGDEQVAMKCAIWLAEQRVPLSVQLKPEVSPTQDIRLWVSVEDAQMHTVTIWLTVRPDMTVASLKDMVFLDYGFPPVLQQWVIGQRLARDQETLHSHGVRQNGDSAY LYLLSARNTSLNPQELQRERQLRMLEDLGFKDLTLQPRGPLEPGPPKPGVPQEPGRGQPDAVPEPPPVGWQCPGCTFINKPTRPGCEMCCRARPEAYQVPASYQPDEEERARLAGEEEALRQYQQRKQ QQQEGNYLQHVQLDQRSLVLNTEPAECPVCYSVLAPGEAVVLRECLHTFCRECLQGTIRNSQEAEVSCPFIDNTYSCSGKLLEREIKALLTPEDYQRFLDLGISIAENRSAFSYHCKTPDCKGWCFF EDDVNEFTCPVCFHVNCLLCKAIHEQMNCKEYQEDLALRAQNDVAARQTTEMLKVMLQQGEAMRCPQCQIVVQKKDGCDWIRCTVCHTEICWVTKGPRWGPGGPGDTTSGGCRCRVNGIPCHPSCQNCH

[0149] An exemplary sequence of human NIK is shown below. SEQ ID NO: 18 (UniParc accession number UPI0000074220) MAVMEMACPGAPGSAVGQQKELPKAKEKTPPLGKKQSSVYKLEAVEKSPVFCGKWEILNDVITKGTAKEGSEAGPAAISIIAQAECENSQEFSPTFSERIFIAGSKQYSQSESLDQIPNNVAHATEGKMARVCWKGKRRSKARKKRKKKSSKSLAHAGVALAKPLPRTPEQESCTIPVQEDESPLGAPYVRNTPQFTKPLKEPGLGQLCFKQLGEGLRPALPRSELHKLISPLQCLNHVWKLHHPQDGGPLPLPTHPFPYSRLPHPFPFHPLQPWKPHPLESFLGKLACVDSQKPLPDPHLSKLACVDSPKPLPGPHLEPSCLSRGAHEKFSVEEYLVHALQGSVSSGQAHSLTSLAKTWAARGSRSREPSPKTEDNEGVLLTEKLKPVDYEYREEVHWATHQLRLGRGSFGEVHRMEDKQTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQLVKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVCLQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFFRGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNRALQQVGGLKSPWRGEYKEPRHPPPNQANYHQTLHAQPRELSPRAPGPRPAEETTGRAPKLQPPLPPEPPEPNKSPPLTLSKEESGMWEPLPLSSLEPAPARNPSSPERKATVPEQELQQLEIELFLNSLSQPFSLEEQEQILSCLSIDSLSLSDDSEKNPSKASQSSRDTLSSGVHSWSSQAEARSSSWNMVLARGRPTDTPSYFNGVKVQIQSLNGEHLHIREFHRVKVGDIATGISSQIPAAAFSLVTKDGQPVRYDMEVPDSGIDLQCTLAPDGSFAWSWRVKHGQLENRP

[0150] An exemplary sequence of human LIMA1α is shown below: SEQ ID NO: 19 (UniParc accession number UPI000002A906) MENCLGESRHEVEKSEISENTDASGKIEKYNVPLNRLKMMFEKGEPTQTKILRAQSRSASGRKISENSYSLDDLEIGPGQLSSSTFDSEKNESRRNLELPRLSETSIKDRMAKYQAAVSKQSSSTNYTNELKASGGEIKIHKMEQKENV PPGPEVCITHQEGEKISANENSLAVRSTPAEDDSRDSQVKSEVQQPVHPKPLSPDSRASSLSESSPPKAMKKFQAPARETCVECQKTVYPMERLLANQQVFHISCFRCSYCNNKLSLGTYASLHGRIYCKPHFNQLFKSKGNYDEGFGHR PHKDLWASKNENEEILERPAQLANARETPHSPGVEDAPIAKVGVLAASMEAKASSQQEKEDKPAETKKLRIAWPPPTELGSSGSALEEGIKMSKPKWPPEDEISKPEVPEDVDLDLKKLRRSSSLKERSRPFTVAASFQSTSVKSPKTVS PPIRKGWSMSEQSEESVGGRVAERKQVENAKASKKNGNVGKTTWQNKESKGETGKRSKEGHSLEMENENLVENGADSDEDDNSFLKQQSPQEPKSLNWSSFVDNTFAEEFTTQNQKSQDVELWEGEVVKELSVEEQIKRNRYYDEDEDEE

[0151] As used herein, the term "cancer associated with a component 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) thereof associated with a component of the NF-κB pathway downstream of the CBM complex. In some embodiments, the cancer associated with a component of the NF-κB pathway downstream of the CBM complex is selected from the group consisting of TAK1-associated cancer, TRAF6-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(RelA)-associated cancer, c-Rel-associated cancer, and combinations thereof. In some embodiments, the cancer associated with a component of the NF-κB pathway downstream of the CBM complex is an IKKγ-associated cancer. 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 of them (e.g., one or more) (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.

[0152] An exemplary sequence of human TAK1 is shown below. SEQ ID NO: 20 (UniParc accession number UPI000012EAD6) MSTASAASSSSSSSAGEMIEAPSQVLNFEEIDYKEIEVEEVVGRGAFGVVCKAKWRAKDVAIKQIESESERKAFIVELRQLSRVNHPNIVKLYGACLNPVCLVMEYAEGGSLYNVLHGAEPLPYYTAAHAMSWCLQCSQGVAYLHSMQPKA LIHRDLKPPNLLLVAGGTVLKICDFGTACDIQTHMTNNKGSAAWMAPEVFEGSNYSEKCDVFSWGIILWEVITRRKPFDEIGGPAFRIMWAVHNGTRPPLIKNLPKPIESLMTRCWSKDPSQRPSMEEIVKIMTHLMRYFPGADEPLQYPCQ YSDEGQSNSATSTGSFMDIASTNTSNKSDTNMEQVPATNDTIKRLESKLLKNQAKQQSESGRLSLGASRGSSVESLPPTSEGKRMSADMSEIEARIAATTAYSKPKRGHRKTASFGNILDVPEIVISGNGQPRRRSIQDLTVTGTEPGQVS SRSSSPSVRMITTSGPTSEKPTRSHPWTPDDSTDTNGSDNSIPMAYLTLDHQLQPLAPCPNSKESMAVFEQHCKMAQEYMKVQTEIALLLQRKQELVAELDQDEKDQQNTSRLVQEHKKLLDENKSLSTYYQQCKKQLEVIRSQQQKRQGTS

[0153] An exemplary sequence of human TRAF6 is shown below. SEQ ID NO: 21 (UniParc accession number UPI000000D924) MSLLNCENSCGSQSESDCCVAMASSCSAVTKDDSVGGTASTGNLSSSFMEEIQGYDVEFDPPLESKYECPICLMALREAVQTPCGHRFCKACIIKSIRDAGHKCPVDNEILLENQLFPDNFAKREILSL MVKCPNEGCLHKMELRHLEDHQAHCEFALMDCPQCQRPFQKFHINIHILKDCPRRQVSCDNCAASMAFEDKEIHDQNCPLANVICEYCNTILIREQMPNHYDLDCPTAPIPCTFSTFGCHEKMQRNHLARH LQENTQSHMRMLAQAVHSLSVIPDSGYISEVRNFQETIHQLEGRLVRQDHQIRELTAKMETQSMYVSELKRTIRTLEDKVAEIEAQQCNGIYIWKIGNFGMHLKCQEEEKPVVIHSPGFYTGKPGYKLCM RLHLQLPTAQRCANYISLFVHTMQGEYDSHLPWPFQGTIRLTILDQSEAPVRQNHEEIMDAKPELLAFQRPTIPRNPKGFGYVTFMHLEALRQRTFIKDDTLLVRCEVSTRFDMGSLRREGFQPRSTDAGV

[0154] An exemplary sequence of human TAB1 is shown below. SEQ ID NO: 22 (UniParc accession number UPI0000136861) MAAQRRSLLQSEQQPSWTDDLPLCHLSGVGSASNRSYSADGKGTESHPPEDSWLKFRSENNCFLYGVFNGYDGNRVTNFVAQRLSAELLLGQLNAEHAEADVRRVLLQAFDVVERSFLESIDDALA EKASLQSQLPEGVPQHQLPPQYQKILERLKTLEREISGGAMAVVAVLLNNKLYVANVGTNRALLCKSTVDGLQVTQLNVDHTTENEDELFRLSQLGLDAGKIKQVGIICGQESTRRIGDYKVKYGY TDIDLLSAAKSKPIIAEPEIHGAQPLDGVTGFLVLMSEGLYKALEAAHGPGQANQEIAAMIDTEFAKQTSLDAVAQAVVDRVKRIHSDTFASGGERARFCPRHEDMTLLVRNFGYPLGEMSQPTPS PAPAAGGRVYPVSVPYSSAQSTSKTSVTLSLVMPSQGQMVNGAHSASTLDEATPTLTNQSPTLTLQSTNTHTQSSSSSSDGGLFRSRPAHSLPPGEDGRVEPYVDFAEFYRLWSVDHGEQSVVTAP

[0155] An exemplary sequence of human TAB2 is shown below. SEQ ID NO: 23 (UniParc accession number UPI0000073C75) MAQGSHQIDFQVLHDLRQKFPEVPEVVVSRCMLQNNNNLDACCAVLSQESTRYLYGEGDLNFSDDSGISGLRNHMTSLNLDLQSQNIYHHGREGSRMNGSRTLTHSISDGQLQGGQSNSELFQQEPQTAPAQVPQGFNVFGMSSSGASNSAPHLGFHLGSKGTSSLSQQTPR FNPIMVTLAPNIQTGRNTPTSLHIHGVPPPVLNSPQGNSIYIRPYITTPGGTTRQTQQHSGWVSQFNPMNPQQVYQPSQPGPWTTCPASNPLSHTSSQQPNQQGHQTSHVYMPISSPTTSQPPTIHSSGSSQSSAHSQYNIQNISTGPRKNQIEIKLEPPQRNNSSKLRSSGP RTSSTSSSVNSQTLNRNQPTVYIAASPPNTDELMSRSQPKVYISANAATGDEQVMRNQPTLFISTNSGASAASRNMSGQVSMGPAFIHHHPPKSRAIGNNSATSPRVVVTQPNTKYTFKITVSPNKPPAVSPGVVSPTFELTNLLNHPDHYVETENIQHLTDPTLAHVDRISE TRKLSMGSDDAAYTQALLVHQKARMERLQRELEIQKKKLDKLKSEVNEMENNLTRRRLKRSNSISQIPSLEEMQQLRSCNRQLQIDIDCLTKEIDLFQARGPHFNPSAIHNFYDNIGFVGPVPPKPKDQRSIIKTPKTQDTEDDEGAQWNCTACTFLNHPALIRCEQCEMPRHF

[0156] An exemplary sequence of human TAB3 is shown below. SEQ ID NO: 24 (UniParc accession number UPI0000071648) MAQSSPQLDIQVLHDLRQRFPEIPEGVVSQCMLQNNNNLEACCRALSQESSKYLYMEYHSPDDNRMNRNRLLHINLGIHSPSSYHPGDGAQLNGGRTLVHSSSDGHIDPQHAAGKQLICLVQEPHSAPAVVAATPNYNPFFMNEQNRSAATPSQPPQQPSSMQTGMNPSAMQGPSPP PPPPSYMHIPRYSTNPITVTVSQNLPSGQTVPRALQILPQIPSNLYGSPGSIYIRQTSQSSSGRQTPQSTPWQSSPQGPVPHYSQRPLPVYPHQQNYQPSQYSPKQQQIPQSAYHSPPSQCPSPFSSPQHQVQPSQLGHIFMPPSPSTTPPHPYQQGPPSYQKQGSHSVAYLPYTAS SSLSK LEKEELERLKSEVNGMEHDLMQRRLRRVSCTTAIPTPEEMTRLRSMNRQLQINVDCTLKEVDLLQSRGNFDPKAMNNFYDNIEPGPVVPPKPSKKDSSDPCTIERKARRISVTSKVQADIHDTQAAAADEHRTGSTQSPRTQPRDEDYEGAPWNCDSCTFLNHPALNRCEQCEMPRYT

[0157] An exemplary sequence of human MKK7 is shown below. SEQ ID NO: 25 (UniParc accession number UPI000012F494) MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPTLQLPLANDGGSRSPSSESSPQHPTPPARPRHMLGLPSTLFTPRSMESIEIDQKLQEIMKQTG YLTIGGQRYQAEINDLENLGEMGSGTCGQVWKMRFRKTGHVIAVKQMRRSGNKEENKRILMDLDVVLKSHDCPYIVQCFGTFITNTDVFIAMELMGTCAEKLKKR MQGPIPERILGKMTVAIVKALYYLKEKHGVIHRDVKPSNILLDERGQIKLCDFGISGRLVDSKAKTRSAGCAAYMAPERIDPPDPTKPDYDIRADVWSLGISLVE LATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDCLTKDHRKRPKYNKLLEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR

[0158] An exemplary sequence of human IKKα is shown below. SEQ ID NO: 26 (UniParc accession number UPI000013D6C7) MERPPGLRPGAGGPWEMERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCHEIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTSFVGTLQ YLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPKCIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRCFVLMDHILNLKIVHILNMTSAKIISFLLPPDESLHSLQSRIERETGINTGSQELLSETGISLDPRKPASQCV LDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPIIQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKLEFFHKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYAEVGVIGYLEDQIMSLHAEIMELQKSPYGRRQGDLME SLEQRAIDLYKQLKHRPSDHSYSDSTEMVKIIVHTVQSQDRVLKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQSSARSLVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHLSTIIHEANEEQGNSMMNLDWSWLTE

[0159] An exemplary sequence of human IKKβ is shown below. SEQ ID NO: 27 (UniParc accession number UPI0000033729) MSWSPSLTTQTCGAWEMKERLGTGGFGNVIRWHNQETGEQIAIKQCRQELSPRNRERWCLEIQIMRRLTHPNVVAARDVPEGMQNLAPNDLPLLAMEYCQGGDLRKYLNQFENCCGLREGAILTLLSDIASALRYLHENRIIHRDLKPENIVLQQGEQRLIHKIIDLGYAKELDQGSLCTSFVGTLQYL APELLEQQKYTVTVDYWSFGTLAFECITGFRPFLPNWQPVQWHSKVRQKSEVDIVVSEDLNGTVKFSSSLPYPNNLNSVLAERLEKWLQLMLMWHPRQRGTDPTYGPNGCFKALDDILNLKLVHILNMMVTGTIHTYPVTEDESLQSLKARIQQDTGIPEEDQELLQEAGLALIPDKPATQCISDGKLNE GHTLDMDLVFLFDNSKITYETQISPRPQPESVSCILQEPKRNLAFFQLRKVWGQVWHSIQTLKEDCNRLQQGQRAAMMNLLRNNSCLSKMKNSMASMSQQLKAKLDFFKTSIQIDLEKYSEQTEFGITSDKLLLAWREMEQAVELCGRENEVKLLVERMMALQTDIVDLQRSPMGRKQGGTLDDLEEQA RELYRRLREKPRDQRTEGDSQEMVRLLLQAIQSFEKKVRVIYTQLSKTVVCKQKALELLPKVEEVVSLMNEDEKTVVRLQEKRQKELWNLLKIACSKVRGPVSGSPDSMNASRLSQPGQLMSQPSTASNSLPEPAKKSEELVAEAHNLCTLLENAIQDTVREQDQSFTALDWSWLQTEEEEHSCLEQAS

[0160] An exemplary sequence of human IKKγ is shown below. SEQ ID NO: 28 (UniParc accession number UPI0000000CC4) MNRHLWKSQLCEMVQPSGGPAADQDVLGEESPLGKPAMLHLPSEQGAPETLQRCLEENQELRDAIRQSNQILERCEELLHFQASQREEKEFLMCKFQEARKLV ERLGLEKLDLKRQKEQALREVEHLKRCQQQMAEDKASVKAQVTSLLGELQESQSRLEAATKECQALEGRARAASEQARQLESEREALQQQHSVQVDQLRMQGQSV EAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSERKRGMQLEDLKQQLQQAEEALVAKQEVIDKLKEEAEQHKIVMETVPVLKAQADIYKADFQA ERQAREKLAEKKELLQEQLEQLQREYSKLKASCQESARIEDMRKRHVEVSQAPLPPAPAYLSSPLALPSQRRSPPEEPPDFCCPKCQYQAPDMDTLQIHVMECIE

[0161] 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.

[0162] An exemplary sequence of human IkBα is shown below. SEQ ID NO: 29 (UniParc accession number UPI000004F0A9) MFQAAERPQEWAMEGPRDGLKKERLLDDRHDSGLDSMKDEEYEQMVKELQEIRLEPQEVPRGSEPWKQQLTEDGDSFLHLAIIHEEKALTMEVIRQVKGDLAFLNFQNNLQQTPLHLAVITNQPEIAEALLGAGCDPELRDFRGNTPLHLACEQGCLA SVGVLTQSCTTPHLHSILKATNYNGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVDLQNPDLVSLLLKCGADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQLTLENLQMLPESEDEESYDTESEFTEFTEDELPYDDCVFGGQRLTL

[0163] An exemplary sequence of human p105 that is processed into p50 is shown below. SEQ ID NO: 30 (UniParc accession number UPI000000D917) MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYVCEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCEDGICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQAEGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIYDSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDFSPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQRKRQKLMPNFSDFGGSGAGAGGGGMFGSGGGGTGSTGPGYSFPHYGFPTYGGITFHPGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGEVTLT YATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQDENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVEDLLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMMSNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGTTPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMATSWQVFDILNGKPYEPEFTSDDLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLGLGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQAHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQEGPLEGKI

[0164] An exemplary sequence of human p65 is shown below. SEQ ID NO: 31 (UniParc accession number UPI000013ED68) MDELFPLIFPAEPAQASGPYVEIIEQPKQRGMRFRYKCEGRSAGSIPGERSTDTTKTHPTIKINGYTGPGTVRISLVTKDPPHRPHPHELVGKDCRDGFYEAELCPDRCIHSFQNLGIQCVKKRDLEQAISQRIQTN NNPFQVPIEEQRGDYDLNAVRLCFQVTVRDPSGRPLRLPPVLSHPIFDNRAPNTAELKICRVNRNSGSCLGGDEIFLLCDKVQKEDIEVYFTGPGWEARGSFSQADVHRQVAIVFRTPPYADPSLQAPVRVSMQLRRP SDRELSEPMEFQYLPDTDDRHRIEEKRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAPQPYPFTSSLSTINYDEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQAPAPVPVL APGPPQAVAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDLASVDNSEFQQLLNQGIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNGLLSGDEDFSSIADMDFSALLSQISS

[0165] An exemplary sequence of human c-Rel is shown below. SEQ ID NO: 32 (UniParc accession number UPI000013367B) MASGAYNPYIEIIEQPRQRGMRFRYKCEGRSAGSIPGEHSTDNNRTYPSIQIMNYYGKGKVRITLVTKNDPYKPHPHDLVGKDCRDGYYEAEFGQERRPLFFQNLGIRCVKKKEVKEAIITRIKAGINPFNVPEKQLNDIEDCDLNVVRLCFQVFLPDEHGNLTTALPPVVSNPIYDNRAPNTAELRICRVNKNCGSVRGGDEIFLLCDKVQKDDIEVRFVLNDWEAKGIFSQADVHRQVAIVFKTPPYCKAITEPVTVKMQLRRPSDQEVSESMDFRYLPDEKDTYGNKAKKQKTTLLFQKLCQDHVETGFRHVDQDGLELLTSGDPPTLASQSAGITVNFPERPRPGLLGSIGEGRYFKKEPNLFSHDAVVREMPTGVSSQAESYYPSPGPISSGLSHHASMAPLPSSSWSSVAHPTPRSGNTNPLSSFSTRTLPSNSQGIPPFLRIPVGNDLNASNACIYNNADDIVGMEASSMPSADLYGISDPNMLSNCSVNMMTTSSDSMGETDNPRLLSMNLENPSCNSVLDPRDLRQLHQMSSSSMSAGANSNTTVFVSQSDAFEGSDFSCADNSMINESGPSNSTNPNSHGFVQDSQYSGIGSMQNEQLSDSFPYEFFQV

[0166] As used herein, the term "cancer associated with a component 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 (e.g., one or more) of a component of the JNK pathway downstream of the CBM complex. In some embodiments, the cancer associated with a component of the JNK pathway downstream of the CBM complex is selected from the group consisting of JNK1-associated cancer, JNK2-associated cancer, JNK3-associated cancer, MYD88 transcription factor-associated cancer, AP-1 transcription factor-associated cancer, and combinations thereof. A cancer "associated" with a specific gene or protein described in this paragraph refers to a cancer associated with or having dysregulation of the expression, activity, or level of a specific gene, specific protein, or any (e.g., one or more) ... protein, specific gene, specific protein, or any (e.g., one or more) of a specific protein, specific gene, specific protein, specific protein, specific protein, specific protein, specific protein, specific gene, specific protein, specific protein, specific protein, specific gene, specific protein, specific protein, specific protein, specific gene, specific protein, specific protein, specific gene, specific protein, specific protein, specific gene, specific protein, specific protein, specific gene, specific protein, specific protein, specific gene, specific protein, specific protein, specific gene, specific protein, specific protein, specific gene, specific protein, specific protein, specific gene, specific protein, specific protein, specific gene, specific protein, specific protein

[0167] An exemplary sequence of human JNK1 is shown below. SEQ ID NO: 33 (UniParc accession number UPI000012F17A) MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRPFQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYI VMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAPEVILGMGYKENVDLWSVGC IMGEMVCHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARDLLSKMLVIDASKRISVDEALQHPY INVWYDPSEEAEAPPPKIPDKQLDEREHTIEEWKELIYKEVMDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAAGPLGCCR

[0168] An exemplary sequence of human JNK2 is shown below. SEQ ID NO: 34 (UniParc accession number UPI000006E3AD) MSDSKCDSQFYSVQVADSTFTVLKRYQQLKPIGSGAQGIVCAAFDTVLGINVAVKKLSRPFQNQTHAKRAYRELVLLKCVNHKNIISLLNVFTPQKTLEEFQDVYL VMELMDANLCQVIHMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTACTNFMMTPYVVTRYYRAPEVILGMGYKENVDIWSVG CIMGELVKGCVIFQGTDHIDQWNKVIEQLGTPSAEFMKKLQPTVRNYVENRPKYPGIKFEELFPDWIFPSESERDKIKTSQARDLLSKMLVIDPDKRISVDEALRH PYITVWYDPAEAEAPPPQIYDAQLEEREHAIEEWKELIYKEVMDWEERSKNGVVKDQPSDAAVSSNATPSQSSSINDISSMSTEQTLASDTDSSLDASTGPLEGCR

[0169] An exemplary sequence of human JNK3 is shown below. SEQ ID NO: 35 (UniParc accession number UPI0000049042) MSLHFLYYCSEPTLDVKIAFCQGFDKQVDVSYIAKHYNMSKSKVDNQFYSVEVGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAVLDRNVAIKKLSRPFQNQTHAKRAYRELVLMK CVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAP EVILGMGYKENVDIWSVGCIMGEMVRHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRNYVENRPKYAGLTFPKLFPDSLFPADSEHNKLKASQARDLLSKMLVIDPAKRI SVDDALQHPYINVWYDPAEVEAPPPQIYDKQLDEREHTIEEWKELIYKEVMNSEEKTKNGVVKGQPSPSGAAVNSSESLPPSSSVNDISSMSTDQTLASDTDSSLEASAGPLGCCR

[0170] Compounds of formula (I) Provided herein are compounds of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, each [ka] is a single or double bond, X is N or C; Y is N or C; Z is N or CR 5 and when one of X and Y is N, the other of X and Y is C; n is 1, 2, or 3; R 1 is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR A R B or C1-C3 alkyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl and C1-C3 alkoxy; R 2 is hydrogen, amino, or halogen; R 2A is hydrogen, halogen, or C1-C6 alkyl; Each R 3 are independently selected from halogen, hydroxyl, cyano, C3-C6 cycloalkyl, -NR A R B , 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano, or two R 3 together with the carbon atoms to which they are attached form an oxo group or a C3-C8 cycloalkyl; m is 0, 1, 2, or 3; R 4 is phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is R 6 and optionally substituted with 1 to 3 substituents independently selected from R 5 is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR C R D or C1-C3 alkyl, Each R 6 is halogen, cyano, hydroxyl, -CO2H, -N(S=O)(C1-C3 alkyl)2, -S(=O) p(C1-C3 alkyl), -NR E R F , -(C=O)NR E R F , amino, hydroxyl, or -(C=O)NR E R F C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, optionally substituted with 1 to 3 independently selected R X 5-6 membered heteroaryl optionally substituted with -NR E R F , C1-C3 alkyl optionally substituted with 1 to 2 substituents independently selected from C1-C3 alkoxy, and C3-C6 cycloalkyl, C3-C6 cycloalkyl optionally substituted with hydroxyl, and -(Q) optionally substituted with 1 to 3 independently selected C1-C3 alkyl. q -3- to 8-membered heterocyclyl; p is 1 or 2; Q is —O— or —NH—; q is 0 or 1, Each R X is halogen, cyano, hydroxyl, amino, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or hydroxyl, C1-C3 alkoxy, and -NR G R H C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from R A , R B , R C , R D are independently hydrogen, C1-C3 alkyl Is it , or R A and R B , Or is R C and R D teeth together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl; R E , R F , RG , and R H are independently hydrogen, C1-C3 alkyl, Or is C3-C6 cycloalkyl Is it , or R E and R F , Or is R G and R H teeth together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy.

[0171] In some embodiments, each [ka] is a single or double bond, X is N or C; Y is N or C; Z is N or CR 5 and when one of X and Y is N, the other of X and Y is C; n is 1, 2, or 3; R 1 is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR A R B or C1-C3 alkyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl and C1-C3 alkoxy; R 2 is hydrogen or halogen, R 2A is hydrogen, Each R 3 are independently halogen, hydroxyl, C-C cycloalkyl, C-C alkoxy, C-C haloalkoxy, C-C haloalkyl, or C-C alkyl optionally substituted with C-C alkoxy, or two R3 together with the carbon atoms to which they are attached form an oxo group or a C3-C8 cycloalkyl; m is 0, 1, 2, or 3; R 4 is phenyl, 5- to 6-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is R 6 and optionally substituted with 1 to 3 substituents independently selected from R 5 is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR C R D or C1-C3 alkyl, Each R 6 is halogen, cyano, -COH, -NR E R F , -(C=O)NR E R F , C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, hydroxyl, -NR E R F or 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl optionally substituted with C1-C3 alkoxy, and 3-8 membered heterocyclyl; R A , R B , R C , R D are independently hydrogen, C1-C3 alkyl Is it , or R A and R B , Or is R C and R D teeth together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl; R E and R F are independently hydrogen, C1-C3 alkyl Is it , or R E and R F teethtogether with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy.

[0172] In some embodiments, the five-membered nitrogen-containing ring formed in part by X and Y is a heteroaromatic ring.

[0173] In some embodiments, X is C and Y is C.

[0174] In some embodiments, X is N and Y is C.

[0175] In some embodiments, X is C and Y is N.

[0176] In some embodiments, Z is N. In some embodiments, Z is CR 5 is.

[0177] In some embodiments, X is C, Y is C, and Z is CR 5 In some embodiments, X is N, Y is C, and Z is CR 5 In some embodiments, X is C, Y is N, and Z is CR 5 In some embodiments, X is C, Y is C, and Z is N. In some embodiments, X is N, Y is C, and Z is N. In some embodiments, X is C, Y is N, and Z is N.

[0178] In some embodiments, R 1 is hydrogen.

[0179] In some embodiments, R 1 is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NR A R Bor C1-C3 alkyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl and C1-C3 alkoxy.

[0180] In some embodiments, R 1 is halogen or cyano. In some embodiments, R 1 is chloro or cyano. In some embodiments, R 1 is a halogen. For example, R 1 is fluoro. For example, R 1 is chloro. In some embodiments, R 1 is cyano. In some embodiments, R 1 is a hydroxyl.

[0181] In some embodiments, R 1 is C1-C3 alkoxy. In some embodiments, R 1 is methoxy or ethoxy.

[0182] In some embodiments, R 1 is C1-C3 haloalkoxy. In some embodiments, R 1 is trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

[0183] In some embodiments, R 1 is C1-C3 haloalkyl. In some embodiments, R 1 is trifluoromethyl or 2,2,2-trifluoroethyl.

[0184] In some embodiments, R 1 is -NR A R B In some embodiments, R A and R B is independently hydrogen or C1-C3 alkyl. In certain embodiments, R A and R B is hydrogen and R Aand R B and the other is C1-C3 alkyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is methyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is ethyl. In certain embodiments, R A and R B are both hydrogen. In certain embodiments, R A and R B are both C1-C3 alkyl. In some embodiments, R A and R B and R are both methyl. A and R B is methyl, and R A and R B The other of R is ethyl. A and R B Both are ethyl.

[0185] In some embodiments, R A and R B together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. A and R B together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl. A and R B together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl. A and R B together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl.

[0186] In some embodiments, R 1is C1-C3 alkyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl and C1-C3 alkoxy. In certain embodiments, R 1 is C1-C3 alkyl optionally substituted with one substituent selected from hydroxyl and C1-C3 alkoxy. In certain of these embodiments, R 1 is methyl optionally substituted with one substituent selected from hydroxyl and C1-C3 alkoxy. In certain embodiments, R 1 is ethyl optionally substituted with one substituent selected from hydroxyl and C1-C3 alkoxy. In certain embodiments, R 1 is C1-C3 alkyl optionally substituted with hydroxyl. In certain embodiments, R 1 is C-C alkyl optionally substituted with C-C alkoxy (e.g., methoxy). In some embodiments, R 1 is hydroxymethyl or methoxyethyl.

[0187] In some embodiments, R 1 is unsubstituted C1-C3 alkyl (e.g., methyl or ethyl).

[0188] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen. For example, R 2 is fluoro. For example, R 2 is chloro. In some embodiments, R 2 is an amino.

[0189] In some embodiments, R 2A is hydrogen. In some embodiments, R 2A is a halogen, for example, R 2A is fluoro or chloro. In some embodiments, R 2A is a C1-C6 alkyl such as those described herein.

[0190] 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.

[0191] 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.

[0192] In some embodiments, each R 3 is independently halogen, cyano, C-C cycloalkyl, C-C alkyl optionally substituted with C-C alkoxy or cyano, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy. In some embodiments, each R 3 is independently C-C cycloalkyl, C-C alkyl optionally substituted with C-C alkoxy or cyano, C-C haloalkyl, C-C alkoxy, or C-C haloalkoxy. 3 is independently unsubstituted C-C alkyl or C-C haloalkyl. In some embodiments, each R 3is independently cyclopropyl, methyl optionally substituted with methoxy, trifluoromethyl, methoxy, or trifluoromethoxy. 3 is independently cyclopropyl, methyl, methoxymethyl, or trifluoromethyl. In some embodiments, each R 3 is independently hydroxyl, C-C cycloalkyl, C-C alkyl optionally substituted with C-C alkoxy, or C-C haloalkyl. 3 is independently hydroxyl, cyclopropyl, methyl optionally substituted with methoxy, or trifluoromethyl.

[0193] In some embodiments, each R 3 are independently hydroxyl, cyano, -NR A R B , 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano, or C1-C3 haloalkyl. 3 is independently hydroxyl, C-C cycloalkyl, C-C alkyl substituted with C-C alkoxy, or C-C haloalkyl. 3 is independently hydroxyl, cyano, C3-C6 cycloalkyl, C1-C3 alkyl, or C1-C3 haloalkyl.

[0194] In some embodiments, each R 3 are independently halogen. For example, R 3 is fluoro or chloro. In some embodiments, each R 3 is independently hydroxyl.

[0195] In some embodiments, each R 3is independently C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl.

[0196] In some embodiments, each R 3 is independently hydroxyl.

[0197] In some embodiments, each R 3 are independently cyano.

[0198] In some embodiments, each R 3 is independently C-C cycloalkyl. In some embodiments, each R 3 is independently C-C cycloalkyl. In some embodiments, each R 3 is independently cyclopropyl. In some embodiments, each R 3 is independently C-C cycloalkyl, and m is 1 or 2. In some embodiments, when m is 2, one R 3 is C3-C6 cycloalkyl, and the other R 3 is not a C3-C6 cycloalkyl.

[0199] In some embodiments, each R 3 are independently -NR A R B In some embodiments, each R 3 are independently -NR A R B and m is 1 or 2. In some embodiments, when m is 2, one R 3 is -NR A R B and the other R 3 is -NR A R B isn't it.

[0200] In some embodiments, each R 3is independently a 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl. In some embodiments, each R 3 are independently 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl, and m is 1 or 2. In some embodiments, when m is 2, one R 3 is a 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl, and the other R 3 is not a 5- to 6-membered heteroaryl. 3 is independently a 5-6 membered heteroaryl substituted with C1-C3 alkyl. In some embodiments, each R 3 is independently a 5-6 membered heteroaryl substituted with C1-C3 alkyl, and m is 1 or 2. In some embodiments, when m is 2, one R 3 is a 5-6 membered heteroaryl substituted with C1-C3 alkyl, and the other R 3 is not a 5- to 6-membered heteroaryl. 3 is independently 5-6 membered heteroaryl. In some embodiments, each R 3 is independently a 5- to 6-membered heteroaryl, and m is 1 or 2. In some embodiments, when m is 2, one R 3 is a 5- to 6-membered heteroaryl, and the other R 3 is not a 5- to 6-membered heteroaryl.

[0201] In some embodiments, each R 3 is independently C-C alkyl optionally substituted with C-C alkoxy or cyano. In some embodiments, each R 3 are independently C1-C3 alkyl. For example, R 3 is methyl or ethyl. In some embodiments, each R 3 is independently a C-C alkyl substituted with a C-C alkoxy, such as methoxy, ethoxy, n-propoxy, or isopropoxy. 3is methoxymethyl or methoxyethyl. In some embodiments, each R 3 is independently cyanomethyl, or C-C alkyl substituted with cyano, such as 1- or 2-cyanoethyl. In some embodiments, each R 3 are independently C1-C3 alkoxy. For example, R 3 is methoxy or ethoxy. In some embodiments, each R 3 are 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.

[0202] In some embodiments, m is 1 and R 3 is C-C alkyl optionally substituted with C-C alkoxy or cyano. In some embodiments, m is 2 and each R 3 is independently C-C alkyl optionally substituted with C-C alkoxy or cyano. In some embodiments, m is 1 and R 3 is C1-C3 alkyl. In some embodiments, m is 2 and each R 3 is independently C1-C3 alkyl. In some embodiments, m is 1 and R 3 is C1-C3 alkyl substituted with C1-C3 alkoxy. In some embodiments, m is 2 and each R 3 is independently a C1-C3 alkyl substituted with a C1-C3 alkoxy. In some embodiments, m is 1 and R 3 is a C1-C3 alkyl substituted with cyano. In some embodiments, m is 2 and each R 3 is independently a C1-C3 alkyl substituted with cyano.

[0203] In some embodiments, m is 2 and each R 3 is independently C1-C3 alkyl optionally substituted with C1-C3 alkoxy, and R 3 groups are geminal C1-C3 alkyl groups optionally substituted with C1-C3 alkoxy. In some embodiments, each R 3 is independently C1-C3 alkyl optionally substituted with C1-C3 alkoxy. In some embodiments, one R 3 The group is methyl or methoxymethyl.

[0204] In some embodiments, each R 3 is independently C-C alkoxy. In some embodiments, each R 3 is independently C1-C3 alkoxy and m is 1 or 2. In some embodiments, when m is 2, one R 3 is C1-C3 alkoxy, and the other R 3 is not C1-C3 alkoxy. In certain of these embodiments, the C1-C3 alkoxy is methoxy.

[0205] In some embodiments, each R 3 is independently C-C haloalkoxy. In some embodiments, each R 3 is independently C1-C3 haloalkoxy and m is 1 or 2. In some embodiments, when m is 2, one R 3 is C1-C3 haloalkoxy, and the other R 3 is not C1-C3 haloalkoxy. In certain of these embodiments, the C1-C3 haloalkoxy is trifluoromethoxy.

[0206] In some embodiments, each R 3 is independently C-C haloalkyl. In some embodiments, each R 3 is independently C1-C3 haloalkyl and m is 1 or 2. In some embodiments, when m is 2, one R3 is C1-C3 haloalkyl, and the other R 3 is not C1-C3 haloalkyl. In certain of these embodiments, C1-C3 haloalkyl is trifluoromethyl.

[0207] In some embodiments, m is 2 and R 3 In some embodiments, m is 2 and each R 3 is independently C1-C3 haloalkyl. In some embodiments, R 3 In some embodiments, m is 2 and one R 3 is C1-C3 alkoxy or C1-C3 alkyl substituted with cyano, and the other R 3 is C1-C3 haloalkyl. In some embodiments, m is 2 and one R 3 is C1-C3 alkoxy or C1-C3 alkyl substituted with cyano, and the other R 3 is C1-C3 haloalkyl. In some embodiments, m is 2 and one R 3 is C1-C3 alkyl, and the other R 3 is C1-C3 haloalkyl. In some embodiments, R 3 Groups are geminal C1-C3 alkyl (optionally substituted with C1-C3 alkoxy or cyano) and C1-C3 haloalkyl groups. In some embodiments, R 3 Groups are geminal C1-C3 alkyl (substituted with C1-C3 alkoxy or cyano) and C1-C3 haloalkyl groups. In some embodiments, R 3 In some embodiments, m is 2 and one R 3 is C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano, and the other R 3 is C-C cycloalkyl. In some embodiments, m is 2 and one R3 is C1-C3 alkyl substituted with C1-C3 alkoxy, and the other R 3 is C-C cycloalkyl. In some embodiments, m is 2 and one R 3 is a C1-C3 alkyl substituted with cyano, and the other R 3 is C-C cycloalkyl. In some embodiments, m is 2 and one R 3 is C1-C3 alkyl, and the other R 3 is C-C cycloalkyl. In some embodiments, R 3 Groups are geminal C1-C3 alkyl (optionally substituted with C1-C3 alkoxy or cyano) and C3-C6 cycloalkyl groups. In some embodiments, R 3 Groups are geminal C1-C3 alkyl (substituted with C1-C3 alkoxy or cyano) and C3-C6 cycloalkyl groups. In some embodiments, R 3 In some embodiments, m is 2 and one R 3 is C1-C3 haloalkyl, and the other R 3 is C-C cycloalkyl. In some embodiments, R 3 The groups are geminal C1-C3 haloalkyl and C3-C6 cycloalkyl groups.

[0208] In some embodiments, m is 1 and R 3 is methyl, methoxymethyl, trifluoromethyl, or cyclopropyl. In some embodiments, m is 2 and each R 3 In some embodiments, m is 2 and each R 3 In some embodiments, m is 2 and one R 3 is methyl, and the other R 3 In some embodiments, m is 2 and one R 3 is cyclopropyl, and the other R 3is methoxy.

[0209] In some embodiments, m is 1 and each R 3 In some embodiments, m is 2 and each R 3 In some embodiments, m is 2 and each R 3 is methyl and R 3 In some embodiments, each R 3 In some embodiments, m is 1 and R 3 In some embodiments, m is 2 and one R 3 In some embodiments, m is 2 and one R 3 In some embodiments, m is 2 and each R 3 is methyl and R 3 In some embodiments, m is 2 and R 3 The groups are geminal methyl and methoxymethyl groups.

[0210] In some embodiments, m is 2 and R 3 In some embodiments, m is 2 and each R 3 is trifluoromethyl. In some embodiments, R 3 In some embodiments, m is 2 and one R 3 is C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano, and the other R 3 In some embodiments, m is 2 and one R 3 is C1-C3 alkyl substituted with C1-C3 alkoxy, and the other R 3 In some embodiments, m is 2 and one R 3 is C1-C3 alkyl, and the other R 3In some embodiments, m is 2 and one R 3 is methyl, and the other R 3 In some embodiments, m is 2 and one R 3 is methoxymethyl, and the other R 3 is trifluoromethyl. In some embodiments, R 3 Groups are geminal methyl and trifluoromethyl groups. In some embodiments, R 3 In some embodiments, m is 2 and one R 3 is methyl, and the other R 3 In some embodiments, m is 2 and one R 3 is methoxymethyl, and the other R 3 is cyclopropyl. In some embodiments, R 3 Groups are geminal methyl and cyclopropyl groups. In some embodiments, R 3 In some embodiments, m is 2 and one R 3 is trifluoromethyl, and the other R 3 is cyclopropyl. In some embodiments, R 3 The groups are geminal trifluoromethyl and cyclopropyl groups.

[0211] In some embodiments, m is 2 and two R 3 together with the carbon atoms to which they are attached form an oxo group. In some embodiments, m is 2 and two R 3 together form a C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

[0212] In some embodiments, R 4is phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is selected from 1 to 2 independently selected R 6 In some embodiments, R 4 is phenyl, 5- to 6-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is selected from 1 to 2 independently selected R 6 In some embodiments, R 4 is phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is composed of two to three independently selected R 6 In some embodiments, R 4 is phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is selected from 1 to 3 independently selected R 6 In some embodiments, R 4 is phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is one independently selected R 6 In some embodiments, R 4 is phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is selected from two independently selected R 6 In some embodiments, R 4 is phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is selected from three independently selected R 6 In some embodiments, R 4is phenyl, 5- to 6-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is composed of two to three independently selected R 6 In some embodiments, R 4 is phenyl, 5- to 6-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is selected from 1 to 3 independently selected R 6 In some embodiments, R 4 is phenyl, 5- to 6-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is one independently selected R 6 In some embodiments, R 4 is phenyl, 5- to 6-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is selected from two independently selected R 6 In some embodiments, R 4 is phenyl, 5- to 6-membered heteroaryl, 3- to 10-membered heterocyclyl, or C-C cycloalkyl, and each R 4 The group is selected from three independently selected R 6 is optionally substituted with

[0213] In some embodiments, R 4 is phenyl or 5-membered heteroaryl, and each R 4 The group is R 6 In some embodiments, R 4 is phenyl or 6-membered heteroaryl, and each R 4 The group is R 6 In some embodiments, R 4 is naphthyl or 9-10 membered heteroaryl, and each R 4 The group is R6 is optionally substituted with 1 to 3 substituents independently selected from:

[0214] In some embodiments, R 4 is phenyl, 5-membered heteroaryl, or cyclopentyl, and each R 4 The group is R 6 In some embodiments, R 4 is phenyl, 6-membered heteroaryl, cyclopentyl, or cyclohexyl, and each R 4 The group is R 6 is optionally substituted with 1 to 3 substituents independently selected from:

[0215] In some embodiments, R 4 is one to three independently selected R 6 In certain embodiments, R 4 is one R 6 In certain embodiments, R 4 are two independently selected R 6 In certain embodiments, R 4 are three independently selected R 6 is phenyl optionally substituted with

[0216] In some embodiments, R 4 is unsubstituted phenyl.

[0217] In some embodiments, R 4 is R 6 In certain embodiments, R 4 is R 6 In certain embodiments, R 4 are two independently selected R 6 In some embodiments, R 4are three independently selected R 6 is a phenyl substituted with

[0218] In some embodiments, R 4 is one to three independently selected R 6 In some embodiments, R 4 is one to three independently selected R 6 and naphthyl substituted with .

[0219] In some embodiments, R 4 is unsubstituted naphthyl.

[0220] In some embodiments, R 4 is R 6 In some embodiments, R is a 5-6 membered heteroaryl optionally substituted with 1-3 (e.g., 2) substituents independently selected from 4 is one to three (e.g., two) independently selected R 6 In some embodiments, R is a 6-membered heteroaryl optionally substituted with 4 is one to three (e.g., two) independently selected R 6 In some embodiments, R is a 9-10 membered heteroaryl optionally substituted with 4 is one to three (e.g., two) independently selected R 6 In some embodiments, R 4 is one to three (e.g., two) independently selected R 6 is a 10-membered heteroaryl optionally substituted with

[0221] In some embodiments, R 4 is an unsubstituted 5-6 membered heteroaryl. In some embodiments, R 4 is an unsubstituted 9-10 membered heteroaryl.

[0222] In some embodiments, R 4 is R6 In some embodiments, R is a 5- to 6-membered heteroaryl substituted with 1 to 3 substituents independently selected from 4 is R 6 is a 9- to 10-membered heteroaryl substituted with 1 to 3 substituents independently selected from:

[0223] In some embodiments, the 5- to 6-membered heteroaryl is 3-pyridyl, 4-pyridyl, or 4-pyridazinyl. 4 The 5-6 membered heteroaryl is 3-pyridyl or 4-pyridyl. In some embodiments, R 4 The 5-6 membered heteroaryl is pyridonyl.

[0224] In some embodiments, R 4 is R 6 In some embodiments, R is a 3- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from 4 is R 6 In some embodiments, R is a 6- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from 4 is R 6 In some embodiments, R is a 3- to 10-membered heterocyclyl substituted with 1 to 3 substituents independently selected from 4 is R 6 In some embodiments, R is a 6- to 10-membered heterocyclyl substituted with 1 to 3 substituents independently selected from 4 is R 6 In some embodiments, R is a 3- to 10-membered heterocyclyl substituted with 1 to 2 substituents independently selected from 4 is R 6 In some embodiments, R is a 6- to 10-membered heterocyclyl substituted with 1 to 2 substituents independently selected from 4 is a 3- to 10-membered heterocyclyl. In some embodiments, R 4 is a 6- to 10-membered heterocyclyl. In some embodiments, R 4is one to two independently selected R 6 In some embodiments, R is morpholino optionally substituted with 4 is one to two independently selected R 6 In some embodiments, R is tetrahydropyranyl optionally substituted with 4 is one to two independently selected R 6 1-oxaspiro[4.5]decane optionally substituted with

[0225] In some embodiments, R 4 is one to three independently selected R 6 In certain embodiments, R 4 is one R 6 In certain embodiments, R 4 are two independently selected R 6 In certain embodiments, R 4 are three independently selected R 6 is a C3-C8 cycloalkyl optionally substituted with

[0226] In some embodiments, R 4 is an unsubstituted C3-C8 cycloalkyl.

[0227] In some embodiments, R 4 is one to three independently selected R 6 In certain embodiments, R 4 is one R 6 In certain embodiments, R 4 are two independently selected R 6 In certain embodiments, R 4 are three independently selected R 6 is a C3-C8 cycloalkyl substituted with

[0228] In some embodiments, R 6 At least one of R is halogen. 6 At least one of R is fluoro. 6 At least one of R is chloro. 6 In some embodiments, one of R 6 In some embodiments, one of R 6 In some embodiments, one of R 6 In some embodiments, two of R 6 In some embodiments, two of R 6 In some embodiments, two of R 6 In some embodiments, three of R 6 In some embodiments, three of R 6 In some embodiments, three of R 6 At least one of R is cyano. 6 At least one of R is hydroxyl. 6 At least one of the is -CO2H.

[0229] In some embodiments, R 6 At least one of R is -N=(S=O)(C1-C3 alkyl). For example, R 6 At least one of the groups is -N=(S=O)(methyl)2.

[0230] In some embodiments, R 6 At least one of the following is -S(=O) p (C1-C3 alkyl) (e.g., -S(=O) p (methyl)). In some embodiments, R6 At least one of R is -S(=O)(C1-C3 alkyl) (e.g., -S(=O)(methyl)). 6 At least one of is -S(=O)2(C1-C3 alkyl) (e.g., -S(=O)2(methyl)).

[0231] In some embodiments, p is 1. In some embodiments, p is 2.

[0232] In some embodiments, R 6 At least one of the is -NR E R F In some embodiments, R 6 At least one of the groups is —(C═O)NR E R F is.

[0233] In some embodiments, R 6 at least one of is amino, hydroxyl, or —(C═O)NR E R Fで In some embodiments, R is an optionally substituted C1-C3 alkoxy. 6 At least one of R is unsubstituted C-C alkoxy. 6 at least one of is amino, hydroxyl, or —(C═O)NR E R F In some embodiments, R is C1-C3 alkoxy substituted with 6 At least one of R is C-C alkoxy substituted with amino. 6 At least one of R is C-C alkoxy substituted with hydroxyl. 6 At least one of the groups is —(C═O)NR E R F and C1-C3 alkoxy substituted with

[0234] In certain embodiments, R6 At least one of is methoxy or ethoxy.

[0235] In some embodiments, R E and R F is independently hydrogen or C1-C3 alkyl. In certain embodiments, R E and R F is hydrogen and R E and R F and the other is C1-C3 alkyl. In some embodiments, R E and R F is hydrogen and R E and R F and the other is methyl. In some embodiments, R E and R F is hydrogen and R E and R F and the other is ethyl. In certain embodiments, R E and R F are both hydrogen. In certain embodiments, R E and R F are both C1-C3 alkyl. In some embodiments, R E and R F and R are both methyl. E and R F is methyl, and R E and R F The other of R is ethyl. E and R F and R are both ethyl. E and R F is independently hydrogen or C-C cycloalkyl. In some embodiments, R E and R F is independently hydrogen or cyclopropyl. In some embodiments, R E and R F is hydrogen and R E and R FThe other is cyclopropyl.

[0236] In some embodiments, R E and R F together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy. E and R F together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl optionally substituted with C-C alkyl or C-C alkoxy. E and R F together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl optionally substituted with C-C alkyl or C-C alkoxy. E and R F together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl optionally substituted with C-C alkyl or C-C alkoxy. E and R F together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl substituted with C1-C3 alkyl or C1-C3 alkoxy. E and R F together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl substituted with C1-C3 alkyl. E and R F together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl substituted with C1-C3 alkoxy. E and R F together with the nitrogen atom to which they are attached form an unsubstituted 4- to 6-membered heterocyclyl.

[0237] In some embodiments, R6 At least one of R is C-C haloalkyl. 6 At least one of R is trifluoromethyl, difluoromethyl, or 2,2,2-trifluoroethyl. 6 At least one of R is trifluoromethyl or 2,2,2-trifluoroethyl. 6 At least one of is difluoromethyl.

[0238] In some embodiments, R 6 At least one of R is C-C haloalkoxy. 6 In some embodiments, at least one of R 6 At least one of is difluoromethoxy.

[0239] In some embodiments, R 6 At least one of the X In some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 6 At least one of the X In some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 6 At least one of the R X In some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 6 At least one of the groups is selected from one or three independently selected R X In some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 6 At least one of the X In some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 6 At least one of the two independently selected R XIn some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 6 At least one of the three independently selected R X In some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 6 at least one of is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, or hydroxyl or -NR E R F In some embodiments, R is a 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl optionally substituted with 6 is hydroxyl or -NR E R F In some embodiments, R is a 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl optionally substituted with 6 at least one of is halogen, C1-C3 haloalkyl, or hydroxyl or -NR E R F In some embodiments, R is a 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl optionally substituted with 6 is hydroxyl or -NR E R F In some embodiments, R is a 5-6 membered heteroaryl substituted with C1-C3 alkyl substituted with 6 is a 5-6 membered heteroaryl substituted with hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, propan-2-ol, or propan-2-amine.

[0240] In certain embodiments, R 6 at least one of the groups is selected from 1 to 3 (e.g., 1 to 2, 2 to 3, 1, 2, or 3) independently selected R X In certain embodiments, R 6At least one of R is a 5-membered heteroaryl optionally substituted with halogen, cyano, hydroxyl, C-C alkoxy, C-C haloalkoxy, C-C alkyl, amino, or C-C haloalkyl. 6 at least one of is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, or hydroxyl or -NR E R F In some embodiments, R is a 6-membered heteroaryl optionally substituted with C-C alkyl optionally substituted with 6 is a 5-membered heteroaryl substituted with hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, propan-2-ol, or propan-2-amine. 6 is a 6-membered heteroaryl substituted with hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, propan-2-ol, or propan-2-amine.

[0241] In some embodiments, R 6 At least one of R is an unsubstituted 5- to 6-membered heteroaryl. 6 At least one of is 1,2,3-triazol-2-yl.

[0242] In some embodiments, each R X is cyano, hydroxyl, C1-C3 alkoxy, or hydroxyl, C1-C3 alkoxy, and -NR G R H In some embodiments, each R X is hydroxyl, or hydroxyl, C1-C3 alkoxy, and -NR G R HIn some embodiments, each R X is independently selected from hydroxyl or C1-C2 alkyl optionally substituted with 1-3 (e.g., 1-2) substituents independently selected from hydroxyl, methoxy, and dimethylamino. In some embodiments, each R X is hydroxyl, or hydroxyl, C1-C3 alkoxy, and -NR G R H and C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from:

[0243] In some embodiments, R G and R H is independently hydrogen or C1-C3 alkyl. In certain embodiments, R G and R H is hydrogen and R G and R H and the other is C1-C3 alkyl. In some embodiments, R G and R H is hydrogen and R G and R H and the other is methyl. In some embodiments, R G and R H is hydrogen and R G and R H and the other is ethyl. In certain embodiments, R G and R H are both hydrogen. In certain embodiments, R G and R H are both C1-C3 alkyl. In some embodiments, R G and R H and R are both methyl. G and R H is methyl, and R G and R H The other of R is ethyl.G and R H and R are both ethyl. G and R H is independently hydrogen or C-C cycloalkyl. In some embodiments, R G and R H is independently hydrogen or cyclopropyl. In some embodiments, R G and R H is hydrogen and R G and R H The other is cyclopropyl.

[0244] In some embodiments, R G and R H together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy. G and R H together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl optionally substituted with C-C alkyl or C-C alkoxy. G and R H together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl optionally substituted with C-C alkyl or C-C alkoxy. G and R H together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl optionally substituted with C-C alkyl or C-C alkoxy. G and R H together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl substituted with C1-C3 alkyl or C1-C3 alkoxy. G and R Htogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl substituted with C1-C3 alkyl. G and R H together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl substituted with C1-C3 alkoxy. G and R H together with the nitrogen atom to which they are attached form an unsubstituted 4- to 6-membered heterocyclyl.

[0245] In some embodiments, R 6 At least one of the groups is hydroxyl, -NR E R F , C1-C3 alkyl optionally substituted with 1-2 substituents independently selected from C1-C3 alkoxy, and C3-C6 cycloalkyl. 6 At least one of is a C3-C6 cycloalkyl optionally substituted with hydroxyl.

[0246] In some embodiments, R 6 At least one of the groups is hydroxyl, -NR E R F or C1-C3 alkyl optionally substituted with C1-C3 alkoxy. In certain embodiments, R 6 At least one of the groups is hydroxyl, -NR E R F or methyl optionally substituted with C1-C3 alkoxy. In some embodiments, R 6 At least one of R is hydroxymethyl, 2-aminoethyl, or methoxyethyl. 6 At least one of the groups is hydroxyl, -NR E R F or ethyl optionally substituted with C1-C3 alkoxy.

[0247] In some embodiments, R E and R F together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy. E and R F together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl. E and R F together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl. In some embodiments, R E and R F together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl. In some embodiments, R E and R F together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl substituted with C1-C3 alkyl or C1-C3 alkoxy. E and R F together with the nitrogen atom to which they are attached form an unsubstituted 4- to 6-membered heterocyclyl.

[0248] In some embodiments, R 6 at least one of which is optionally substituted with 1 to 3 independently selected C1-C3 alkyl; q -3- to 8-membered heterocyclyl. In some embodiments, R 6 At least one of R is -O-3- to 8-membered heterocyclyl optionally substituted with 1-3 independently selected C-C alkyl. 6 At least one of R is -NH-3-8 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C3 alkyl. 6 is -(Q) q -3- to 8-membered heterocyclyl. In some embodiments, R 6is substituted with 1 to 3 independently selected C1-C3 alkyl groups, -(Q) q -3- to 8-membered heterocyclyl. In some embodiments, R 6 is -(Q) substituted with C1-C3 alkyl q -3- to 8-membered heterocyclyl. In some embodiments, R 6 is substituted with two independently selected C1-C3 alkyls -(Q) q -3- to 8-membered heterocyclyl. In some embodiments, R 6 is substituted with three independently selected C1-C3 alkyl groups -(Q) q -3 to 8-membered heterocyclyl.

[0249] In some embodiments, q is 0. In some embodiments, q is 1.

[0250] In some embodiments, Q is -O-. In some embodiments, Q is -NH-.

[0251] In some embodiments, R 6 At least one of R is a 3- to 8-membered heterocyclyl. 6 At least one of R is a 3-membered heterocyclyl. 6 At least one of R is a 4-membered heterocyclyl. 6 At least one of R is a 5-membered heterocyclyl. 6 At least one of R is a 5-membered heterocyclyl containing one heteroatom ring member selected from O, S, and NH. 6 At least one of R is tetrahydrofuranyl (e.g., 2-tetrahydrofuranyl). 6 At least one of R is a 6-membered heterocyclyl. 6 At least one of R is a 7-membered heterocyclyl. 6At least one of is an 8-membered heterocyclyl.

[0252] In some embodiments, R 4 are two R 6 pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, or imidazolyl, substituted by one R 6 is triazolyl, imidazolyl, oxazolyl, pyrazolyl, or pyrrolidinyl, and the other R 6 is methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. In some embodiments, R 4 are two R 6 pyridyl, pyrimidinyl, or pyrazinyl substituted with one R 6 is triazolyl, imidazolyl, oxazolyl, pyrazolyl, or pyrrolidinyl, and the other R 6 is methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. In some embodiments, R 4 are two R 6 pyridyl substituted with one R 6 is triazolyl, imidazolyl, or oxazolyl, and the other R 6 is methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. In some embodiments, R 4 are two R 6 pyridyl or phenyl, substituted with one R 6 is triazolyl or pyrazolyl optionally substituted with hydroxymethyl, methyl, hydroxyl, hydroxyethyl, cyano, or methoxy, and the other R 6 is methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, chloro, or cyano.

[0253] In some embodiments, R 4 is one to three independently selected R 6 and 3-pyridyl or 4-pyridyl substituted with

[0254] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0255] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0256] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0257] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0258] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0259] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0260] In some embodiments, R 4 but [ka] When R 6 is selected from the group consisting of cyano, halogen, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0261] In some embodiments, R 4 but [ka] When R 6 is selected from the group consisting of cyano, halogen, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0262] In some embodiments, R 4 but [ka] When R 6 is selected from the group consisting of cyano, chloro, difluoromethyl, trifluoromethyl, and methoxy. For example, R 4 but [ka] When R 6 is chloro or trifluoromethyl (eg, chloro).

[0263] In some embodiments, R 4 teeth [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0264] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0265] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0266] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R 6B is cyano, amino, or hydroxyl or -NR E R F 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl optionally substituted with ; -(C=O)NR E R F ; C1-C3 alkoxy ; C1-C3 haloalkyl ; C1-C3 haloalkoxy ; Cyano ; and C1-C3 alkyl.

[0267] In some embodiments, R 4 teeth, [ka] and R 6A is selected from the group consisting of cyano, halogen, unsubstituted C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R 6B is cyano, hydroxyl, -N=(S=O)(C1-C3 alkyl)2, C1-C3 alkoxy, hydroxyl, C1-C3 alkoxy, and -NR G R H mosquito C1-C3 alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 aryl, C1-C3 aryl, C1-C3 alkyl ... ; -(C=O)NR E R F ; C1-C3 alkoxy ; C1-C3 haloalkyl ; C1-C3 haloalkoxy ; Cyano ; C1-C3 alkyl ; and -(Q) optionally substituted with 1 to 3 independently selected C1-C3 alkyl. q - selected from the group consisting of 3- to 8-membered heterocyclyl.

[0268] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, trifluoromethyl; R 6Bare 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 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-5-yl, pyrrolidone - and n-methyl-1-yl, thiazol-2-yl, isothiazolidine-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, -(C=O)N(CH3), -(C=O)NHCH3, methoxy, ethoxy, difluoromethoxy, methyl, cyano.

[0269] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, trifluoromethyl; R 6Bare 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 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-5-yl, pyrrolidone - and cyano.

[0270] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl; R 6Bare 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-hydroxymethyl-1,2,3-triazol-2-yl, 4-(1,2-dihydroxyethyl)-1,2,3-triazol-2-yl, 4-(1-hydroxyethyl)-1,2,3-triazol-2-yl, 4-methoxymethyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-methoxy-1,2,3-triazol-2-yl, 4-amino-1,2,3-triazol-2-yl, 4-dimethylaminomethyl-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-on-2-yl, tetrazol-5-yl, 2-methyl-tetrazol-5-yl, 1-methyl-tetrazol-5-yl, imidazol-1-yl, pyrazol-1-yl, 5-cyano-pyrazol-1-yl, 1-methyl-imidazol-3-yl, 1-methyl-5-amino-imidazol-3-yl, 3-methylimidazol-2-on-1-yl, 1-methyl-pyrazol-3-yl, 1-methyl-pyrazol-5-yl, pyrro - and n-methyl-1-yl, thiazol-2-yl, isothiazolidine-2-yl-1,1-dioxide, pyrrolidin-2-one-1-yl, oxazol-2-yl, oxadiazol-2-yl, 2-amino-pyrimidin-4-yl, 2-tetrahydrofuranyl, -(C=O)4-methylpiperazin-1-yl, -(C=O)N(CH3), -(C=O)NHCH3, -N=(S=O)(methyl), methoxy, ethoxy, difluoromethoxy, methyl, cyano.

[0271] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, chloro, and trifluoromethyl; R 6B is selected from the group consisting of 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, and 1,2,4-triazol-4-one-2-yl.

[0272] In some embodiments, R 4 but [ka] When R 6A is chloro, R 6B is selected from the group consisting of 1,2,3-triazol-2-yl, 1,2,3-triazol-1-yl, and 1,2,4-triazol-4-one-2-yl.

[0273] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0274] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0275] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0276] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R 6B is a 5-6 membered heteroaryl optionally substituted with cyano, C1-C3 alkyl, or amino ; -(C=O)NR E R F ; C1-C3 alkoxy ; C1-C3 haloalkyl ; C1-C3 haloalkoxy ; Cyano ; and C1-C3 alkyl; R 6C is optionally substituted with cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and 1 to 3 independently selected C1-C3 alkyl; q - selected from the group consisting of 3- to 8-membered heterocyclyl.

[0277] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, trifluoromethyl; R 6B are 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 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-5-yl, pyrrolidone - -1-yl, -2-thiazol-1-yl, -3-thiazol-2-yl, -4-thiazol-2-yl, -5-thiazolidin-2-yl-1,1-dioxide, -6-thiazolidin-2-yl-1,1-dioxide, -7-thiazolidin-2-yl-1,1-dioxide, -8-thiazolidin-2-yl, -1-thiazol-1-yl, -2-thiazol-2-yl, -3-thiazolidin-2-yl-1,1-dioxide, -8-thiazolidin-2-yl-1,1-dioxide, -1-thiazol-1-yl, -1-thiazol-1-yl, -2-thiazol-2-yl, -3-thiazol-2-yl, -4-thiazol-1-yl, -1-thiazol-1-yl, -2-thiazol-1-yl, -3-thiazol-2-yl, -4-thiazol-1-yl, -1-thiazol-1-yl, -2-thiazol-1-yl, -3-thiazol-1-yl, -4 ... R 6C is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, methyl, trifluoromethyl, and pyrrolidin-3-yloxy.

[0278] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, chloro, and trifluoromethyl; R 6B is selected from the group consisting of methoxy, 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, and 1,2,4-triazol-4-one-2-yl; R 6C is selected from the group consisting of cyano, chloro, methyl, trifluoromethyl, and pyrrolidin-3-yloxy.

[0279] In some embodiments, R 4 but [ka] When R 6A is chloro, R 6B is selected from the group consisting of methoxy, 1,2,3-triazol-2-yl, and 1,2,4-triazol-4-one-2-yl; R 6C is selected from the group consisting of cyano, chloro, methyl, trifluoromethyl, and pyrrolidin-3-yloxy.

[0280] In some embodiments, R 4 but [ka] When R 6Ais selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R 6B is a 5-6 membered heteroaryl optionally substituted with cyano, C1-C3 alkyl, or amino ; -(C=O)NR E R F ; C1-C3 alkoxy ; C1-C3 haloalkyl ; C1-C3 haloalkoxy ; Cyano ; and C1-C3 alkyl; R 6C is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl.

[0281] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, trifluoromethyl; R 6Bare 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 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-5-yl, pyrrolidone - -1-yl, -2-thiazol-1-yl, -3-thiazol-2-yl, -4-thiazol-2-yl, -5-thiazolidin-2-yl-1,1-dioxide, -6-thiazolidin-2-yl-1,1-dioxide, -7-thiazolidin-2-yl-1,1-dioxide, -8-thiazolidin-2-yl, -1-thiazol-1-yl, -2-thiazol-2-yl, -3-thiazolidin-2-yl-1,1-dioxide, -8-thiazolidin-2-yl-1,1-dioxide, -1-thiazol-1-yl, -1-thiazol-1-yl, -2-thiazol-2-yl, -3-thiazol-2-yl, -4-thiazol-1-yl, -1-thiazol-1-yl, -2-thiazol-1-yl, -3-thiazol-2-yl, -4-thiazol-1-yl, -1-thiazol-1-yl, -2-thiazol-1-yl, -3-thiazol-1-yl, -4 ... R 6C is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, methyl, and trifluoromethyl.

[0282] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, chloro, and trifluoromethyl; R 6Bis selected from the group consisting of 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, and 1,2,4-triazol-4-one-2-yl; R 6C is selected from the group consisting of cyano, chloro, methyl, and trifluoromethyl.

[0283] In some embodiments, R 4 but [ka] When R 6A is chloro, R 6B is selected from the group consisting of 1,2,3-triazol-2-yl and 1,2,4-triazol-4-one-2-yl; R 6C is selected from the group consisting of cyano, chloro, methyl, and trifluoromethyl.

[0284] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0285] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R 6B is selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl.

[0286] In some embodiments, R 4 but [ka] When R 6A is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, trifluoromethyl; R 6B is selected from the group consisting of methyl, ethyl, difluoromethyl, and trifluoromethyl.

[0287] In some embodiments, R 4 but [ka] When R 6A is chloro, R 6B is selected from the group consisting of trifluoromethyl and difluoromethyl.

[0288] In some embodiments, R 5 is hydrogen.

[0289] In some embodiments, R 5 is a halogen. For example, R 5 is fluoro. For example, R 5 is chloro. In some embodiments, R 5 is cyano. In some embodiments, R 5 is a hydroxyl.

[0290] In some embodiments, R 5 is C1-C3 alkoxy. In some embodiments, R 5 is methoxy or ethoxy.

[0291] In some embodiments, R 5 is C1-C3 haloalkoxy. In some embodiments, R 5 is trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

[0292] In some embodiments, R 5 is C1-C3 haloalkyl. In some embodiments, R 5 is trifluoromethyl or 2,2,2-trifluoroethyl.

[0293] In some embodiments, R 5 is -NR C R D In some embodiments, R C and R D is independently hydrogen or C1-C3 alkyl. In certain embodiments, R C and R D is hydrogen and R C and R D and the other is C1-C3 alkyl. In some embodiments, R C and R D is hydrogen and R C and R D and the other is methyl. In some embodiments, R C and R D is hydrogen and R C and R D and the other is ethyl. In certain embodiments, R C and R D are both hydrogen. In certain embodiments, R C and R D are both C1-C3 alkyl. In some embodiments, RC and R D and R are both methyl. C and R D is methyl, and R C and R D The other of R is ethyl. C and R D Both are ethyl.

[0294] In some embodiments, R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. C and R D together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl. C and R D together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl. C and R D together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl.

[0295] In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl or ethyl.

[0296] In some embodiments, X is N, Y is C, Z is N, R 1 is a halogen, R 2 is hydrogen, R 2A is hydrogen, m is 2 and R 3 is independently unsubstituted C1-C3 alkyl or C1-C3 haloalkoxy; n is 1, R 4 is C1-C3 haloalkyl and 1 to 3 independently selected R X and 5- to 6-membered heteroaryl optionally substituted with 1 to 2 substituents independently selected from 5- to 6-membered heteroaryl optionally substituted with .

[0297] In some embodiments, R 1 is chloro or fluoro.

[0298] In some embodiments, R 2 is hydrogen.

[0299] In some embodiments, R 2A is hydrogen.

[0300] In some embodiments, each R 3 In some embodiments, one R 3 is an unsubstituted C1-C3 alkyl, and the other R 3 is C1-C3 haloalkoxy. In some embodiments, one R 3 is methyl, and the other R 3 is trifluoromethyl.

[0301] In some embodiments, R 4 is an unsubstituted 6-membered heteroaryl. In some embodiments, R 4 is 1,2,3-triazolyl.

[0302] In some embodiments, the compound of Formula (I) is a compound of Formula (II): [ka] During the ceremony, n is 1 or 2, R 1 is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR AR B or C1-C3 alkyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl and C1-C3 alkoxy; R 3A is halogen, hydroxyl, cyano, C3-C6 cycloalkyl, -NR A R B , a 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano; R 3B is halogen, hydroxyl, cyano, C3-C6 cycloalkyl, -NR A R B , a 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano; Or, R 3A and R 3B together with the carbon atoms to which they are attached form an oxo group or a C3-C8 cycloalkyl; Each R 6 is halogen, cyano, hydroxyl, -CO2H, -N(S=O)(C1-C3 alkyl)2, -S(=O) p (C1-C3 alkyl), -NR E R F , -(C=O)NR E R F , amino, hydroxyl, or -(C=O)NR E R F C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, optionally substituted with 1 to 3 independently selected R X 5-6 membered heteroaryl optionally substituted with -NR E R F, C1-C3 alkyl optionally substituted with 1 to 2 substituents independently selected from C1-C3 alkoxy, and C3-C6 cycloalkyl, C3-C6 cycloalkyl optionally substituted with hydroxyl, and -(Q) optionally substituted with 1 to 3 independently selected C1-C3 alkyl. q -3- to 8-membered heterocyclyl; p is 1 or 2; Q is —O— or —NH—; q is 0 or 1, Each R X is halogen, cyano, hydroxyl, amino, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or hydroxyl, C1-C3 alkoxy, and -NR G R H C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from R A and R B are independently hydrogen, C1-C3 alkyl Is it , or R A and R B teeth together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl; R E , R F , R G , and R H are independently hydrogen, C1-C3 alkyl, Or is C3-C6 cycloalkyl Is it , or R E and R F , Or is R G and R H teeth together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy.

[0303] In some embodiments of Formula (II), n is 1, R 1 is hydrogen, halogen, or cyano; R 3A and R 3B one of R is halogen, hydroxyl, cyano, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano; 3A and R 3B the other is C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano; Each R 6 is halogen, cyano, hydroxyl, -CO2H, -N=(S=O)(C1-C3 alkyl)2, -S(=O) p (C1-C3 alkyl), -NR E R F , -(C=O)NR E R F , amino, hydroxyl, or -(C=O)NR E R F C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, optionally substituted with 1 to 3 independently selected R X 5-6 membered heteroaryl optionally substituted with -NR E R F , C1-C3 alkyl optionally substituted with 1 to 2 substituents independently selected from C1-C3 alkoxy, and C3-C6 cycloalkyl, and C3-C6 cycloalkyl optionally substituted with hydroxyl; p is 1 or 2; Each R X is halogen, cyano, hydroxyl, amino, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or hydroxyl, C1-C3 alkoxy, and -NR G R H C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from R E , R F , R G , and R H are independently hydrogen, C1-C3 alkyl, Or is C3-C6 cycloalkyl Is it , or R E and R F , Or is R G and R H teeth together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy.

[0304] In some embodiments of Formula (II), n is 2, R 1 is hydrogen, halogen, or cyano; R 3A and R 3B one of R is halogen, hydroxyl, cyano, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano; 3A and R 3B the other is C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano; Each R 6 is halogen, cyano, hydroxyl, -CO2H, -N=(S=O)(C1-C3 alkyl)2, -S(=O) p (C1-C3 alkyl), -NR E R F , -(C=O)NR E R F , amino, hydroxyl, or -(C=O)NR E R F C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, optionally substituted with 1 to 3 independently selected RX 5-6 membered heteroaryl optionally substituted with -NR E R F , C1-C3 alkyl optionally substituted with 1 to 2 substituents independently selected from C1-C3 alkoxy, and C3-C6 cycloalkyl, and C3-C6 cycloalkyl optionally substituted with hydroxyl; p is 1 or 2; Each R X is halogen, cyano, hydroxyl, amino, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or hydroxyl, C1-C3 alkoxy, and -NR G R H C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from R E , R F , R G , and R H are independently hydrogen, C1-C3 alkyl, Or is C3-C6 cycloalkyl Is it , or R E and R F , Or is R G and R H teeth together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy.

[0305] In some embodiments, the compound is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. Unless otherwise indicated, (1) the stereochemical configuration of each stereocenter and / or adjacent CIP configuration shown with a dash and wedge bond designation is considered relative, and (2) any stereocenter whose valency is filled with a bond not depicted using a dash and wedge is a mixture of the stereochemical configurations at that stereocenter. For example, compounds 3 and 4 are enantiomers, but it is not yet known which is the (R) enantiomer and which is the (S) enantiomer. In another example, compounds 33 and 34 are diastereomers in which the absolute configuration of the stereocenter attached to the trifluoromethyl is known, but the stereocenter at the tetrahydrofuryl group is relative (i.e., the tetrahydrofuryl stereocenter in one of compounds 33 and 34 has the (R) configuration, and the tetrahydrofuryl stereocenter in the other of compounds 33 and 34 has the (S) configuration). [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

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

[0306] Preparation process Provided herein is a process for preparing a compound of formula (I) (e.g., any compound described herein), comprising: Compounds of formula (IA) [ka] of, R 4 -NH2, forming a compound of formula (I):

[0307] In some embodiments, the compound of formula (IA) is 4 Reacting with —NH produces a compound of formula (IA) and R 4 one of the —NH2 groups is reacted with a carbonyl equivalent to form an intermediate, which is then reacted with a compound of formula (IA) and R 4In some of these embodiments, the compound of formula (IA) is reacted with an intermediate R 4 Reacting with -NH2 gives R 4 In any of the foregoing embodiments, the "carbonyl equivalent" may be a compound of formula (IA) and / or R 4 It refers to a reagent that replaces the NH group in —NH with a carbonyl moiety. Non-limiting examples of carbonyl equivalents include triphosgene and bis(trichloromethyl)carbonate.

[0308] In some embodiments, the compound of formula (IA) is 4 Reacting with —NH produces a compound of formula (IA) and R 4 one of —NH with a carbonyl equivalent selected from triphosgene and bis(trichloromethyl) carbonate to form an intermediate, which is then reacted with a compound of formula (IA) and R 4 In some of these embodiments, the compound of formula (IA) is reacted with an intermediate R 4 Reacting with -NH2 gives R 4 The method comprises reacting —NH with a carbonyl equivalent selected from triphosgene and bis(trichloromethyl) carbonate to form an intermediate, and then reacting a compound of Formula (IA) with the intermediate. In some embodiments, the carbonyl equivalent is triphosgene. In some embodiments, the carbonyl equivalent is bis(trichloromethyl) carbonate.

[0309] Provided herein is a process for preparing a compound of formula (I) (e.g., any compound described herein), comprising: Compounds of formula (IA) [ka] of, R 4 -C(O)OH, forming a compound of formula (I):

[0310] In some embodiments, the compound of formula (IA) is 4 Reacting with —C(O)OH can provide an intermediate (e.g., R 4 -C(O)N3) to form R 4 -C(O)OH is reacted with diphenylphosphoryl azide and then (e.g., a second intermediate (e.g., R 4 in the presence of a compound of formula (IA) to form a compound of formula (I).

[0311] In some embodiments, the compound of formula (IA) is a compound of formula (IAN): [ka] .

[0312] In some embodiments, when the compound of formula (IA) is a compound of formula (IAN), the process comprises reacting a compound of formula (IANi) [ka] reacting with a compound of formula (IAN-ii), [ka] further comprising forming a compound of formula (IAN).

[0313] In certain embodiments, reacting a compound of Formula (IANi) with a compound of Formula (IAN-ii) is carried out in the presence of an acid, such as an organic acid or an inorganic acid. In some embodiments, the acid is hydrochloric acid or acetic acid.

[0314] In some embodiments, the compound of formula (IA) is a compound of formula (IAM): [ka] .

[0315] In some embodiments, when the compound of formula (IA) is a compound of formula (IAM), the process comprises reacting a compound of formula (IANi): [ka] forming a compound of formula (IAM):

[0316] In some of these embodiments, the compound of Formula (IAMi) is reacted with an iron salt, a silane, a peroxide, and an acid to form a compound of Formula (IAM). In some embodiments, the iron salt is ferric (Z)-4-oxopent-2-en-2-oleate. In some embodiments, the silane is phenylsilane. In some embodiments, the peroxide is 2-tert-butylperoxy-2-methyl-propane. In some embodiments, the acid is 2,2,2-trifluoroacetic acid.

[0317] Treatment method Some embodiments provide a method of treating an autoimmune disorder (e.g., a MALT1-associated autoimmune disorder) in a subject in need of such treatment, 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).

[0318] Some embodiments provide a method of treating an inflammatory disorder (e.g., a MALT1-associated inflammatory disorder) in a subject in need of such treatment, 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).

[0319] Some embodiments provide a method of treating cancer (e.g., a MALT1-associated cancer) in a subject in need of such treatment, 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 of treating a MALT1-associated cancer in a subject in need of such treatment, comprising: a) detecting dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or 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 expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them comprises one or more fusion proteins.

[0320] In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-associated 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 neoplasm, lung adenocarcinoma, bronchiolopulmonary cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer,carcinoma), breast tumor, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-associated cancer) is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adolescent cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinomatous tumor, cancer of unknown primary, cardiac tumor, cervical cancer, childhood cancer, or chordoma. , chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal cancer, gastrointestinal stromal tumor (GIST), Germ cell tumors, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, breast neoplasms, head and neck neoplasms, CNS tumors, primary CNS tumors, cardiac cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, Kaposi's 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 cell carcinoma, midline duct carcinoma, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, neoplasm by site, neoplasm, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, lung neoplasm, lung cancer, lung neoplasm, respiratory tract neoplasm, bronchogenic carcinoma, bronchial neoplasm, oral cancer, oral cavity cancercancer), lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, cancer of the paranasal sinuses and nasal cavity, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasms, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon neoplasms, renal cell carcinoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell cervical cancer, gastric cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0321] 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 a MALT1-associated cancer) is, for example, leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CML), and chronic myelomonocytic leukemia (CLL). The hematological cancer is selected from the group consisting of AML, chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorders (MPDs), and multiple myeloma (MM). Additional examples of hematological cancers include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer (e.g., a hematological cancer that is a MALT1-associated cancer) is AML or CMML.

[0322] In some embodiments, the cancer is glioblastoma, chronic myeloid leukemia, myeloid leukemia, or non-Hodgkin's lymphoma.

[0323] In some embodiments, cancer (e.g., MALT1-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are MALT1-associated cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal carcinoma, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, neuroblastoma, and melanoma. See, for example, Jiang et al., Cancer Research 2011,71,2183-2192. See also, Pan et al., Mol Cancer Res 2016,14,93-102, and Penas et al., Blood 2010,115,2214-2219.

[0324] In some embodiments, the subject is a human.

[0325] The compound of formula (I) and its pharmaceutically acceptable salts are also useful for treating MALT1-associated cancer. The compound of formula (I) and its pharmaceutically acceptable salts are also useful for treating MALT1-associated autoimmune disorders. The compound of formula (I) and its pharmaceutically acceptable salts are also useful for treating MALT1-associated inflammatory diseases.

[0326] Accordingly, also provided herein is a method for treating a subject diagnosed or identified as having a MALT1-associated cancer, e.g., any of the exemplary MALT1-associated cancers disclosed herein, 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 as defined herein.

[0327] In some embodiments of any of the methods provided herein, the compound of Formula (I) is selected from Examples 1-211.

[0328] Dysregulation of the expression, activity, or level of MALT1 protease, MALT1 gene, or any of them (e.g., one or more) can contribute to tumorigenesis. For example, a fusion protein can have increased protease activity compared to wild-type MALT1 protein, increased expression (e.g., increased level) of wild-type MALT1 protease in mammalian cells (e.g., compared to control non-cancerous cells) can result from aberrant cell signaling and / or dysregulated autocrine / paracrine signaling, and MALT1 mRNA splice variants can also result in dysregulation of MALT1.

[0329] In some aspects, provided herein are methods for treating 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. Also provided herein are methods for treating a CBM complex pathway-associated cancer (such as any of those disclosed herein) 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. Also provided are methods for treating cancer in a subject in need thereof, comprising (a) identifying the cancer as a CBM complex pathway-associated cancer, and (b) administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0330] Identifying a cancer in a subject as a CBM complex pathway-associated cancer can be performed by any suitable method. In some embodiments, identifying a cancer in a subject as a CBM complex pathway-associated cancer includes performing an assay to detect dysregulation of expression, activity, or levels of a CBM complex pathway-associated gene, a CBM complex pathway-associated protease protein, or any of them in a sample from the subject. In some embodiments, the method further includes obtaining a sample (e.g., a biopsy sample) from the subject. The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0331] Also provided herein is a method for treating 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, to the subject, the subject being identified as having the CBM complex pathway.

[0332] Also provided herein are methods for treating MALT1-associated cancer in a subject identified or diagnosed with MALT1-associated cancer, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein are methods for treating cancer in a subject in need thereof, comprising (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the MALT1 gene, MALT1 protease, or any of them, and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0333] Determining that a cancer is associated with dysregulation of the MALT1 gene, MALT1 protease, or expression, activity, or level of any of them can be performed using any suitable method. In some embodiments, determining that a cancer in a subject is a MALT1-associated cancer includes performing an assay to detect dysregulation in the expression, activity, or level of the MALT1 gene, MALT1 protease protein, or any of them in a sample from the subject. In some embodiments, the method further includes obtaining a sample (e.g., a biopsy sample) from the subject. The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0334] As described herein, the CBM complex pathway-associated cancer can be any suitable CBM complex pathway-associated cancer (such as any of those described herein). In some embodiments, the CBM complex pathway-associated cancer is selected from the group consisting of a CBM complex pathway cell surface receptor-associated cancer, a cancer associated with a signal transduction between a cell surface receptor and the CBM complex, a component of a CBM complex-associated cancer, a MALT1 protease substrate-associated cancer, a disease or disorder associated with a component of the NF-κB pathway downstream of the CBM complex, a cancer associated with a component of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, the CBM complex pathway cell surface receptor-associated cancer is selected from the group consisting of a CD28-associated cancer, a BCR-associated cancer, a HER1-associated cancer, a HER2-associated cancer, and combinations thereof. In some embodiments, the cancer associated with a signal transduction between a cell surface receptor and the CBM complex is a protein kinase C beta (PKCβ)-associated cancer, a protein kinase C theta (PKCθ)-associated cancer, or a combination thereof. In some embodiments, the component of the CBM complex-associated cancer is selected from the group consisting of MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, CARD10-associated cancer, CARD9-associated cancer, BCL10-associated cancer, and combinations thereof. In some embodiments, the component of the CBM complex-associated cancer is selected from the group consisting of MALT1-associated cancer, CARD11-associated cancer, BCL10-associated cancer, and combinations thereof. See, e.g., Tables B1, B2, and B3 for exemplary examples of dysregulation of MALT1, CARD11, and BCL10. In some embodiments, the MALT1 protease substrate-associated cancer is selected from the group consisting of BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, RelB-associated cancer, Regnase 1-associated cancer, Rokin-1-associated cancer, HOIL1-associated cancer, NIK-associated cancer, LIMA1α-associated cancer, and combinations thereof. In some embodiments, the MALT1 protease substrate-associated cancer is selected from the group consisting of BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, and combinations thereof.See, e.g., Tables B3 and B4 for exemplary dysregulation of BCL10 and A20. In some embodiments, the cancer associated with a component of the NF-κB pathway downstream of the CBM complex is selected from the group consisting of 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, c-Rel-related cancer, and combinations thereof. In some embodiments, the cancer associated with a component of the NF-κB pathway downstream of the CBM complex is IKKγ-related cancer. In some embodiments, the cancer associated with a component of the JNK pathway downstream of the CBM complex is selected from the group consisting of JNK1-related cancer, JNK2-related cancer, JNK3-related cancer, MYD88 transcription factor-related cancer, AP-1 transcription factor-related cancer, and combinations thereof.

[0335] In some embodiments, the CBM complex pathway-associated cancer is a MALT1-associated cancer. The MALT1-associated cancer may have any suitable dysregulation, such as any of those described herein. In some embodiments, the MALT1-associated cancer comprises an IAP2-MALT1 fusion. In some embodiments, the MALT1-associated cancer comprises an IGH-MALT1 fusion.

[0336] Also provided herein are methods for 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, 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-associated autoimmune disorder in a subject identified or diagnosed as having a MALT1-associated autoimmune disorder, 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 an autoimmune disorder in a subject in need thereof, comprising (a) determining that the autoimmune disorder is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them, and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating an inflammatory disorder in a subject determined to have a MALT1-associated autoimmune disorder, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. Additionally, provided herein is a method for treating an inflammatory 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. In some cases, provided herein is a method for treating an MALT1-associated inflammatory disorder in a subject in need thereof, comprising administering to a subject identified or diagnosed with a MALT1-associated inflammatory disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating an inflammatory disorder in a subject in need thereof, comprising (a) determining that the inflammatory disorder is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them, and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.Also provided herein is a method for treating a MALT1-associated inflammatory disorder in a subject, comprising administering to the subject determined to have a MALT1-associated inflammatory disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0337] Additionally, provided herein is a method for treating a CBM complex pathway-associated disease or 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. Also provided herein is a method for treating a disease or disorder in a subject in need thereof, comprising (a) identifying cancer as a CBM complex pathway-associated disease or disorder, and (b) administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Additionally, provided herein is a method for treating a disease or 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, to a subject identified as having a CBM complex pathway-associated disease or disorder.

[0338] The CBM complex pathway-associated disease or disorder can be any suitable CBM complex pathway-associated disease or disorder, such as any of those described herein. In some embodiments, the CBM complex pathway-associated disease or disorder is an autoimmune disease. In some embodiments, the CBM complex pathway-associated disease or disorder is an inflammatory disease. In some embodiments, the CBM complex pathway-associated cancer is selected from the group consisting of a CBM complex cell surface receptor-associated cancer, a disease or disorder associated with a signal transduction entity between a cell surface receptor and the CBM complex, a component of a CBM complex-associated cancer, a MALT1 protease substrate-associated 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-associated disease or disorder is a MALT1-associated disease or disorder.

[0339] In some cases, a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be useful for inhibiting a cellular process, such as inhibiting cell proliferation. Accordingly, provided herein is a method for inhibiting mammalian cell proliferation, comprising contacting a mammalian cell 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 a mammalian cell, comprising contacting a mammalian cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for inhibiting MALT1 protease activity in a mammalian cell, comprising contacting a mammalian cell 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 cell can be any suitable cell. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian CBM complex pathway-associated cancer cell. In some embodiments, the mammalian cancer cell is a mammalian MALT1-associated cancer cell. In some embodiments, the mammalian cell has a dysregulated expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them. In some embodiments, the dysregulated expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0340] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, may also be useful in the manufacture of a medicament. 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-associated disease or disorder. The CBM complex pathway-associated disease or disorder can be any suitable CBM complex pathway-associated disease or disorder, such as those described herein. In some embodiments, the CBM complex pathway-associated disease or disorder is selected from the group consisting of a CBM complex pathway cell surface receptor-associated cancer, a disease or disorder associated with a signal transduction entity between a cell surface receptor and the CBM complex, a component of a CBM complex-associated cancer, a MALT1 protease substrate-associated 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-associated disease or disorder is a CBM complex pathway-associated autoimmune disorder. In some embodiments, the CBM complex pathway-associated disease or disorder is a CBM complex pathway-associated inflammatory disorder. In some embodiments, the CBM complex pathway-associated disease or disorder is a CBM complex pathway-associated cancer. In some embodiments, the CBM complex pathway-associated disease or disorder is a MALT1-associated disease or disorder. In some embodiments, the MALT1-associated disease or disorder comprises dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them. In some embodiments, the dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0341] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood-brain barrier and inhibiting MALT1 protease in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in an effective amount. For example, treating a subject with cancer (e.g., a MALT1-associated cancer, such as a MALT1-associated brain or CNS cancer) can include administering (e.g., orally administering) a compound to the subject. In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors. For example, the compounds can be used in the treatment of one or more gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglioma, ependymoma, and mixed glioma, meningioma, medulloblastoma, ganglioglioma, schwannoma (neurinoma), and craniopharyngioma (see, e.g., the tumors listed in Louis, DNet 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 previously been treated with another anti-cancer agent, e.g., another protease inhibitor (e.g., a compound that is not a compound of Formula (I)). In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the subject has previously been treated with another anti-cancer agent, e.g., another protease inhibitor (e.g., a compound that is not a compound of Formula (I)).

[0342] In some embodiments of any of the methods or uses described herein, assays used to determine whether a subject has dysregulated expression, activity, or levels of a gene (e.g., the MALT1 gene), or a protein (e.g., the MALT1 protein), or any of them, using a sample from the subject, may 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, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assays can utilize other detection methods known in the art for detecting dysregulated expression, activity, or levels of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them. In some embodiments, the sample is a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a MALT1-associated cancer, a subject with one or more symptoms of a MALT1-associated cancer, and / or a subject at high risk of developing a MALT1-associated cancer.

[0343] In some embodiments, dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a MALT1 protein (e.g., the MALT1 protein), or any of them can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid-phase biopsy). Liquid biopsy methods can be used to detect gross tumor burden and / or dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a MALT1 protein (e.g., the MALT1 protein), or any of them. Liquid biopsies can be performed on a biological sample relatively easily obtained from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect gross tumor burden and / or dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a MALT1 protein (e.g., the MALT1 protein), or any of them. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them at an earlier stage than traditional methods. In some embodiments, biological samples used in liquid biopsy can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using highly 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 the expression, activity, or levels of a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or any of them.

[0344] In some embodiments, ctDNA derived from a single gene can be detected using liquid biopsy. In some embodiments, multiple genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more genes, or any number between these numbers) can be detected using 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 the expression or activity or level of a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or any of them). Liquid biopsies can be used to detect dysregulation of expression, activity, or levels of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them, including, but not limited to, point mutations or single nucleotide variants (SNVs), copy number variants (CNVs), gene fusions (e.g., translocations or rearrangements), insertions, deletions, or any combination thereof. In some embodiments, liquid biopsies can be used to detect germline mutations. In some embodiments, liquid biopsies can be used to detect somatic mutations. In some embodiments, liquid biopsies can be used to detect primary genetic mutations (e.g., primary mutations or primary fusions associated with the early development of a disease, e.g., cancer). In some embodiments, dysregulation of expression, activity, or levels of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them identified using 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 expression or activity or levels of a gene (e.g., MALT1 gene), protein (e.g., MALT1 protein), or any of the genes described herein can be detected using liquid biopsy.In some embodiments, genetic mutations identified via liquid biopsy can be used to identify a subject as a candidate for a particular treatment. For example, detection of dysregulation of the expression, activity, or level of a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or any of them in a subject can indicate that the subject will respond to treatment comprising administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0345] Liquid biopsies can be performed multiple times during the course of diagnosis, monitoring, and / or treatment to determine one or more clinically relevant parameters, including, but not limited to, disease progression and / or treatment effectiveness. 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 course of diagnosis, monitoring, and / or treatment. In some embodiments, the first time point can be a time point before the subject is diagnosed 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 a disease (e.g., the second time point can be used to diagnose the subject with a disease). In some embodiments, the first time point can be a time point before the subject is diagnosed 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 the subject has been monitored. In some embodiments, the first time point can be a time point after the subject is diagnosed with a disease, and then a treatment is administered to the subject, and the second time point can be a time point after the treatment is administered.In such cases, the second time point can be used to evaluate the effectiveness of the treatment (for example, when the genetic mutation detected at the first time point is reduced in abundance or cannot be detected).In some embodiments, the treatment administered to the subject can include a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the effectiveness of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by assessing the allele frequency of a gene (e.g., the MALT1 gene) in cfDNA obtained from a subject at different time points, for example, 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 the 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 at least one dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject between the first time point and the second time point.For example, a reduction in the allele frequency (AF) of a dysregulated gene (e.g., MALT1 gene) in cfDNA obtained from the subject at a second time point compared to the allele frequency (AF) of the gene (e.g., MALT1 gene) in cfDNA obtained from the subject at a first time point (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% to about Approximately 70% reduction, 1% reduction to approximately 65% reduction, 1% reduction to approximately 60% reduction, 1% reduction to approximately 55% reduction, 1% reduction to approximately 50% reduction, 1% reduction to approximately 45% reduction, 1% reduction to approximately 40% reduction, 1% reduction to approximately 35% reduction, 1% reduction to approximately 30% reduction, 1% reduction to approximately 25% reduction, 1% reduction to approximately 20% reduction, 1% reduction to approximately 15% reduction, 1% reduction to approximately 10% reduction, 1% to approximately 5% reduction, approximately 5% to approximately 99% reduction, approximately 10% to 99% reduction, 15% to 99% reduction, 20% to 99% reduction, 25% to 99% reduction, 30% to 99% reduction, 35% to 99% reduction, 40% to 99% reduction, 45% to 99% reduction, 50% to 99% reduction, 55% to 99% reduction, 60% to 99% reduction, 65% to 99% reduction, 70% to 99% reduction, 75% to 95% reduction, 80% to 99% reduction, 90% to 99% reduction A reduction of AF of about 99%, about 95% to about 99%, about 5% to about 10%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 50%, about 35% to about 55%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, or about 65% to about 85% indicates that the compound of Formula (I) or a pharmaceutically acceptable salt thereof was effective in the subject. In some embodiments, AF is reduced such that levels are below the detection limit of the instrument.Alternatively, an increase in the dysregulated allele frequency (AF) of a gene (e.g., the MALT1 gene) in cfDNA obtained from the subject at a second time point compared to the dysregulated allele frequency (AF) 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 is not effective in the subject. Some embodiments of these methods can further include administering an additional dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject for whom the compound of Formula (I) or a pharmaceutically acceptable salt thereof is determined to be effective. Some embodiments of these methods can further include administering a different treatment (e.g., a treatment that does not include administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof as monotherapy) to the subject for whom the compound of Formula (I) or a pharmaceutically acceptable salt thereof is determined to be ineffective.

[0347] In some examples of these methods, the time difference between the first time point and the second time point is between about 1 day and about 1 year, about 1 day and about 11 months, about 1 day and about 10 months, about 1 day and about 9 months, about 1 day and about 8 months, about 1 day and about 7 months, about 1 day and about 6 months, about 1 day and about 5 months, about 1 day and about 4 months, about 1 day and about 3 months, about 1 day and about 10 weeks, about 1 day and about 2 months, about 1 day and about 6 weeks, about 1 day and about 1 month, about 1 day and about 25 days, about 1 day and about 20 days, about 1 day and about 15 days, about 1 day and about 10 days, about 1 day and about 5 days, about 2 days and about 1 year, about 5 days and about 1 year, about 10 days and about 1 year, about 15 days and about 1 year, about 20 days and about 1 year, about 25 days and about 1 year, about 25 days and about 1 year, about 25 days and about 1 year, about 25 days and about 1 year, about 25 days and about 1 year, about 25 days and about 1 year, about 25 days and about 1 year, about 25 days and about 1 year, about 25 days and about 1 month ... It may be about 1 year, about 1 month to about 1 year, about 6 weeks to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year, about 4 months to about 1 year, about 5 months to about 1 year, about 6 months to about 1 year, about 7 months to about 1 year, about 8 months to about 1 year, about 9 months to about 1 year, about 10 months to about 1 year, about 11 months to about 1 year, about 1 day to about 7 days, about 1 day to about 14 days, about 5 days to about 10 days, about 5 days to about 20 days, about 10 to about 20 days, about 15 days to about 1 month, about 15 days to about 2 months, about 1 week to about 1 month, about 2 weeks to about 1 month, about 1 month to about 3 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 8 months, or about 7 months to about 9 months. In some embodiments of these methods, the subject can be previously identified as having a cancer with a dysregulated gene (e.g., any of the exemplary dysregulated genes described herein) (e.g., the MALT1 gene). In some embodiments of these methods, the subject may have previously been identified as having any of the types of cancer described herein. In some embodiments of these methods, the subject may have one or more metastases (e.g., one or more brain metastases).

[0348] In some of the above embodiments, cfDNA comprises ctDNA such as MALT1-associated ctDNA.For example, cfDNA is ctDNA such as MALT1-associated ctDNA.In some embodiments, at least a portion of cfDNA is determined to be MALT1-associated ctDNA, for example, the sequencing and / or quantification of total cfDNA determines that it has MALT1 fusion and / or MALT1 overexpression.

[0349] In the field of medical oncology, it is common practice to use a combination of different types of treatment to treat each subject with cancer.In medical oncology, in addition to the compositions provided herein, other components of such combined treatment or therapy can be, for example, surgery, radiotherapy, and other chemotherapeutic agents such as protease inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies.

[0350] For example, the surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, may also be useful as adjuncts in cancer treatment, i.e., they may 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, compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be used prior to the administration of additional therapeutic agents or therapies. For example, a subject in need thereof may be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time, followed by at least partial tumor resection. In some embodiments, treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to at least partial tumor resection. In some embodiments, a subject in need thereof may be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time, followed by one or more radiation therapy sessions. In some embodiments, treatment with one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) prior to one or more radiation therapies.

[0351] In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent), 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 a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a previous therapy (e.g., administration of a chemotherapeutic agent, 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 a cancer (e.g., a locally advanced or metastatic tumor) for which no standard therapy exists. In some embodiments, the subject is MALT1-protease inhibitor naive. For example, the subject is naive to treatment with a selective MALT1-protease inhibitor. In some embodiments, the subject is not MALT1-protease inhibitor naive.

[0352] 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., a chemotherapeutic agent or an immunomodulatory agent). The additional therapy or therapeutic agent can be any suitable additional therapy or therapeutic agent, such as any of those described herein.

[0353] Non-limiting examples of additional therapeutic agents include other MALT1-targeted therapies (i.e., first or second MALT1 protease inhibitors, e.g., JNJ-67856633 or CTX-177), other protease inhibitors, kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapies such as BTK or EGFR inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways (e.g., venetoclax or obataclax), cytotoxic chemotherapy, angiogenesis-targeted therapies, immune-targeted agents (including antibody and cell-based immunotherapies, and antibody-drug conjugates), and radiation therapy.

[0354] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate doses. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially as separate doses in any order.

[0355] In some embodiments, the other MALT1-targeted therapeutic 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) 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 25 nM, less than about 10 nM, or less than about 1 nM, as measured in an assay as described herein. 50 In some embodiments, the MALT1 protease inhibitor can exhibit an inhibitory activity against MALT1 protease (IC) 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 an assay as provided herein. 50 ) can be shown.

[0356] Non-limiting examples of protease-targeted therapeutics (e.g., first MALT1 inhibitors or second MALT1 inhibitors) include JNJ-67856633 and CTX-177.

[0357] Non-limiting examples of multikinase 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-nicotinamide methanesulfonate), 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-dihydro benzimidazol-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), fostamantinib (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)), ilolasertib (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 (AMG 706) (N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide), nintedanib (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methyoxycarbonyl-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 (Tolquinib) (2-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indol-5-ol), Quizartinib (1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazol-2-yl)phenyl)urea), Regorafenib (BAY 73-4506, stivarga) (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate), RXDX-105 (CEP-32496, agerafenib) (1-(3-((6,7-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)methylidene]-1,3-dihydro-2H-indol-2-one), sitravatinib (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 (BAY 43-9006) (4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide), vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine), vatalanib (PTK787, PTK / ZK, ZK222584) (N-(4-chlorophenoxy) 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]- methyl)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)methyl)- (N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazole)-3-yl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide), PD173955 (6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanilanilino)pyrido[2,3-d]pyrimidin-7-one), PP2 (4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine), PZ-1 (N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazole)-3-yl)-3H-pyrazole), -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-carbaldehyde), 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), Withaferin 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)indoline-2-yl), BPR1J373 (5-phenylthiazol-2-ylamine-pyriminide 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-methylbenzamido d), 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 the structure)), ITRI-305 (D0N5TB, DIB003599), BLU-667 ((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6 -((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589, NMS-E668, TAS0286 / HM05, TPX0046, and N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide.

[0358] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeted therapeutics include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, 1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Go 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'-b-ipyridine]-2'-yl)piperidin-4-ol.

[0359] In some embodiments, the additional therapeutic agent is a BRAF inhibitor.Non-limiting examples of BRAF inhibitor 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 inhibitor are known in the art.

[0360] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portolaza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0361] 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 baricitinib, bricitinib, or bricitinib. Gatinib, capmatinib, danusertib, ibrutinib, mirciclib, quercetin, regorafenib, ruxolitinib, semaxanib, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF Other kinase inhibitors include 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).

[0362] In some embodiments, the additional therapeutic agent is a BTK inhibitor. Non-limiting examples of BTK inhibitors include ibrutinib, acalabrutinib, and zanubrutinib.

[0363] 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.

[0364] 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.

[0365] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include everolimus, temsirolimus, and ridaforolimus.

[0366] In some embodiments, the additional therapeutic agent is an HDAC inhibitor. Non-limiting examples of HDAC inhibitors include vorinostat, romidepsin, belinstat, chidamide, panobinostat, CXD101, and abexinostat.

[0367] 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.

[0368] 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.

[0369] In some embodiments, the additional therapeutic agent is an angiogenesis-targeted therapeutic agent. Non-limiting examples of angiogenesis-targeted therapies include lenalidomide, enzastaurin, aflibercept, and bevacizumab.

[0370] In some embodiments, the additional therapy or therapeutic agent can include a histidyl-tRNA synthetase (HRS) polypeptide or an expressible nucleotide encoding an HRS polypeptide.

[0371] The term "immunotherapy" refers to an agent that modulates the immune system. In some embodiments, immunotherapy can increase the expression and / or activity of a regulator of the immune system. In some embodiments, immunotherapy can decrease the expression and / or activity of a regulator of the immune system. In some embodiments, immunotherapy can recruit and / or enhance the activity of recruiting immune cells.

[0372] In some embodiments, the immunotherapy is a cellular immunotherapy (e.g., adoptive T cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015, Provenge™, Plosker (2011) Drugs 71(1):101-108). In some embodiments, the cellular immunotherapy comprises cells expressing a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is a CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymria). In some embodiments, the CAR-T cell therapy is axicabtagene cilorucel (Yescarta). In some embodiments, the CAR-T cell therapy is brexucabtagene autorucel (Tecartus). In some embodiments, the CAR-T cell therapy is lermacabutagen autorucel. In some embodiments, the CAR-T cell therapy is ALLO-501.

[0373] In some embodiments, the immunotherapy is an antibody therapy (e.g., a monoclonal antibody, a conjugated antibody, or a bispecific antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®), rituximab with human hyaluronidase (Rituxan®), or a combination of these. Hycela™), edrecolomab (Panorex), daratumab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dilutidine-2-phosphate dehydrogenase (DHT), rifampin (RI ... Mab (Unituxin®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza™), sirmutuzumab (U C-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), rituximab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), lenzilumab, avelumab, spartalizumab, pembrolizumab, utomilumab, ublituximab, blinatumumab, ganitumab, urelumab, pidilizumab, amatuximab, mosunetuzumab (BTCT4465A), CD20-TCB, RO7082859, XmAb13676, glofitamab, CD20-TDB, odronextamab (REGN1979), IGM-2323, BTCT4465A, AMG-562, or TTI-621.

[0374] 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®), adotrastuzumab emtansine (TDM-1, Kadcyla®), mirvetuximab soravtansine (IMGN853), anetumab ravtansine, polatuzumab vedotin, loncastuximab tesirin (ADCT-402), kamidanlumab tesirin (ADCT-301), or naratuximab emtansine (Debio 1562).

[0375] In some embodiments, the immunotherapy includes blinatumomab (AMG103, Blincyto®) or midostaurin (Ridapt).

[0376] In some embodiments, the immunotherapy comprises a toxin, hi some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

[0377] 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®).

[0378] 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™).

[0379] 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).

[0380] In some embodiments, the immunotherapy is Bacillus Calmette-Guerin (BCG) therapy.

[0381] In some embodiments, the immunotherapy is oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene laherparepvec (T-VEC, Imlygic®).

[0382] 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®, Gardasil 9®, 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, sipuleucel-T (APC8024, Neuvenge™), GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlisimut-L (Hepko-V5), DCVAX®, SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac, or viagenpumatucel-L (HS-110).

[0383] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is neripepimut-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).

[0384] In some embodiments, the immune targeting agent is selected from aldesleukin, interferon alpha-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

[0385] 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.

[0386] In some embodiments, the additional therapeutic agent is GSK-3368715, PF-06821497, selalasertib, AZD6738, BI-894999, MAK-683, AZD-6738, taminadenant, TAK-981, MIK-665, or dambatirsen.

[0387] Additional kinase inhibitors include those described, for example, in U.S. Pat. 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, and 9,273,051; U.S. Publication No. 2015 / 0018336; WO 2007 / 002325; WO 2007 / 002433; WO 2008 / 080001; WO 2008 / 079906; WO 2008 / 079903; WO 2008 / 079904; 909, WO2008 / 080015, WO2009 / 007748, WO2009 / 012283, WO2009 / 143018, WO2009 / 143024, WO2009 / 014637, 2009 / 152083, WO2010 / 111527, WO2012 / 109075, WO2014 / 194127, WO2015 / 112806, WO2007 / 110344, WO2009 / 071480, WO2009 / 118411, WO2010 / 031816, WO2010 / 145998, WO2011 / 092120, W O2012 / 101032, WO2012 / 139930, WO2012 / 143248, WO2012 / 152763, WO2013 / 014039, WO2013 / 102059, WO2013 / 050448, WO2013 / 050446, WO2014 / 01 9908, WO2014 / 072220, WO2014 / 184069, WO2016 / 075224, WO2016 / 081450, WO2016 / 022569, WO2016 / 011141, WO2016 / 011144, WO2016 / 011147, WO20 15 / 191667, WO2012 / 101029, WO2012 / 113774, WO2015 / 191666, WO2015 / 161277, WO2015 / 161274, WO2015 / 108992, WO2015 / 061572, WO2015 / 058129, WO2015 / 057873, WO2015 / 017528, WO / 2015 / 017533, WO2014 / 160521, and WO2014 / 011900, each of which is incorporated herein by reference in its entirety.

[0388] In some embodiments, the subject has previously received one or more standard of care therapies for lymphoma, ie, polatuzumab vedotin, selinexor, axicabtagene ciloreucel (Yescarta), tisagenlecleucel (Kymriah), bendamustine in combination with rituximab and polatuzumab vedotin, tafasitamab in combination with lenalidomide, or rituximab with human hyaluronidase (Rituxan Hycela).

[0389] In some embodiments, the subject is concurrently receiving standard of care therapy for lymphoma, ie, polatuzumab vedotin, selinexor, axicabtagene ciloreucel (Yescarta), tisagenlecleucel (Kymriah), bendamustine in combination with rituximab and polatuzumab vedotin, tafasitamab in combination with lenalidomide, or rituximab with human hyaluronidase (Rituxan Hycela).

[0390] Although the genetic basis of tumorigenesis may vary among different cancer types, 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 adhesive changes, and produce enzymes that can degrade extracellular matrix components. This leads to detachment of tumor cells from the original tumor, invasion into the circulation through newly formed vasculature, and migration and extravasation of tumor cells at favorable distant sites where they can colonize.

[0391] Therefore, the present invention also provides a method for inhibiting, preventing, or assisting in the prevention of cancer metastasis or reducing symptoms in a subject who needs it, comprising administering to the subject an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition.Such method can be used in the treatment of one or more of the cancers described herein.For example, see US Publication No. 2013 / 0029925, International Publication No. WO2014 / 083567 and US Patent No. 8,568,998. See, 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-associated 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, as described herein. For example, a first or second MALT1 protease inhibitor.

[0392] The term "metastasis" is a term known in the art and refers to the formation of additional tumors (e.g., solid tumors) at sites distant from a subject's primary tumor, wherein the additional tumors contain the same or similar cancer cells as the primary tumor.

[0393] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject with MALT1-associated cancer, comprising selecting, identifying, or diagnosing the subject as having MALT1-associated cancer and administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject with MALT1-associated cancer, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. The reduced risk of developing metastasis or additional metastases in a subject with MALT1-associated cancer can be compared to the risk of developing metastasis or additional metastases in the subject before treatment, or compared to a subject or population of subjects with a similar or identical MALT1-associated cancer that has not been treated or has received a different treatment.

[0394] The phrase "risk of developing metastases" refers to the risk that a subject with a primary tumor will develop additional tumors (e.g., solid tumors) at sites distant from the subject's primary tumor over a period of time, where the additional tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing metastases in a subject with cancer are described herein.

[0395] The phrase "risk of developing additional metastases" refers to the risk that a subject who has a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors contain the same or similar cancer cells as the primary tumor) will develop one or more additional tumors distant from the primary tumor, where the additional tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0396] Some embodiments described herein provide a method for treating an autoimmune disorder (e.g., a MALT1-associated autoimmune disorder), such as rheumatoid arthritis, multiple sclerosis, and SLE, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0397] Some embodiments described herein provide a method of treating an inflammatory disorder (e.g., a MALT1-associated autoimmune disorder), such as chronic graft-versus-host disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0398] Also provided is a method for inhibiting MALT1 protease activity in a mammalian cell, comprising contacting the mammalian cell 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 comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell with MALT1 protease activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell.

[0399] Also provided is a method for inhibiting MALT1 protease activity in a mammalian cell, comprising contacting the mammalian cell 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 comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a mammal having mammalian cells with MALT1 protease activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell. In some embodiments, the mammalian cell is a gastrointestinal mammalian cell.

[0400] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" a MALT1 protease with a compound provided herein includes administering a compound provided herein to a subject, such as a human, having MALT1 protease activity, as well as introducing a compound provided herein into a sample containing, for example, mammalian cells or a purified preparation containing MALT1 protease activity.

[0401] Also provided herein are methods for inhibiting the proliferation of mammalian cells in vitro or in vivo, comprising 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.

[0402] As defined herein, a "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) 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 50 nM, less than 25 nM, less than about 10 nM, or less than about 1 nM, as measured in an assay as described herein. 50 In some embodiments, the MALT1 protease inhibitor can exhibit an inhibitory activity against MALT1 protease (IC) 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 an assay as provided herein. 50 ) can be shown.

[0403] As used herein, a "first MALT1 protease inhibitor" or "first MALT1 inhibitor" refers to a MALT1 protease inhibitor as defined herein, but does not include a compound of Formula (I) as defined herein or a pharmaceutically acceptable salt thereof. As used herein, a "second MALT1 protease inhibitor" or "second MALT1 inhibitor" refers to a MALT1 protease inhibitor as defined herein, but does not include a compound of Formula (I) as defined herein or a pharmaceutically acceptable salt thereof. When both a first and a second MALT1 inhibitor are present in the methods provided herein, the first and second MALT1 protease inhibitors are different.

[0404] Exemplary first and second MALT1 protease inhibitors are described herein. In some embodiments, the first or second MALT1 protease inhibitor may be, for example, JNJ-67856633 or CTX-177.

[0405] The phrase "effective amount" refers to an amount sufficient, when administered to a subject in need of such treatment, to (i) treat a MALT1-associated disease or disorder (such as a MALT1-associated cancer), (ii) reduce, 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. The amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof that would correspond to such an amount, will vary depending on factors such as the particular compound, the condition and its severity, and the identity (e.g., body weight) of the subject requiring treatment, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0406] When employed as a pharmaceutical, the compounds of formula (I), including their pharmaceutically acceptable salts, can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal, by inhalation or insufflation of powders or aerosols, including by nebulizer), oral, or parenteral. Oral administration can include dosages formulated for once-daily or twice-daily (BID) administration. 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 a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like may be necessary or desirable.

[0407] Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable excipients. 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 an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, a sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In some embodiments, the pharmaceutical 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 capsule.

[0408] Further provided herein is a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by 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 variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0409] Suitable pharmaceutically acceptable carriers are well known in the art, and 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 Royal College of Pharmacists.

[0410] 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.

[0411] When preparing compositions in oral dosage form, any common pharmaceutical medium can be used.Therefore, 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, and the like; for solid oral preparations such as powders, capsules, and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.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, and the like.Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Solid oral preparations can also be coated with substances such as sugars to modify the primary absorption site, or enteric coated. For parenteral administration, the carrier is usually composed of sterile water, and other ingredients can be added to increase solubility or preservation. Injection suspensions or solutions can also be prepared using aqueous carriers with suitable additives. The pharmaceutical compositions herein will contain the amount of active ingredient necessary to deliver an effective dose as described herein per dosage unit, for example, tablet, capsule, powder, injection, teaspoon, and the like.

[0412] Compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human and other subjects, each unit containing a predetermined quantity of the active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0413] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of active ingredient. One of skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of active ingredient.

[0414] In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of active ingredient. One of skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of active ingredient.

[0415] In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of active ingredient. One of skill in the art will understand that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

[0416] The daily dosage of a compound of formula (I) or a pharmaceutically acceptable salt thereof can vary over a wide range, from 1.0 to 10,000 mg or more per adult per day, 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 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 body weight to about 1000 mg / kg body weight per day, or any range therein. Preferably, the range is about 0.5 to about 500 mg / kg body weight per day, or any range therein. More preferably, it is about 1.0 to about 250 mg / kg body weight per day, or any range therein. More preferably, it is about 0.1 to about 100 mg / kg body weight per day, or any range therein. In one example, the range can be about 0.1 to about 50.0 mg / kg 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 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 body weight per day, or any amount or range therein. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered in a dosing regimen of 1 to 4 times per day, or in a single daily dose.

[0417] Active compound can be effective in a wide range of dosage, and generally administered in a pharmaceutically effective amount.The optimal dosage to be administered can be easily determined by those skilled in the art.Therefore, it should be understood that the amount of compound actually administered will usually be determined by a doctor and will vary according to relevant circumstances, including administration method, the actual compound to be administered, the strength of the preparation, the condition to be treated and the progression of the disease.In addition, factors related to the specific subject being treated, including subject's response, age, weight, diet, administration time and the severity of subject's symptoms, will result in the need to adjust dosage.

[0418] In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, 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.

[0419] Those skilled in the art will recognize that both in vivo and in vitro tests using suitable, known, and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0420] Those skilled in the art will further recognize that human clinical trials, including first-in-human dose-ranging and efficacy studies in healthy subjects and / or subjects afflicted with a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0421] Provided herein is a pharmaceutical kit useful for treating 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 a kit can further comprise, if desired, one or more of various conventional pharmaceutical kit components, such as a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.Instructions, either as an insert or label, indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing components, can also be included in the kit. [Example]

[0422] material and method The compounds provided herein, including the salts thereof, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0423] The reactions for preparing the compounds provided herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0424] Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1 stEd.,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).

[0425] Moisture- or air-sensitive reactions were carried out under nitrogen or argon using anhydrous solvents and reagents. Reaction progress was determined either by analytical thin-layer chromatography (TLC), typically performed using Sanpont pre-coated TLC plates, silica gel GF-254, 0.25 mm layer thickness, or by liquid chromatography-mass spectrometry (LC-MS).

[0426] The analytical LC-MS system used typically consisted of a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode, using a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS 2020 MS detector. The column was typically a HALO a C18 30*5.0 mm, 2.7 μm column. Mobile phase A was water containing 0.05% TFA, and mobile phase B was acetonitrile containing 0.05% TFA. The gradient was from 5% mobile phase B to 100% in 2.0 min, held for 0.7 min, then returned to 5% mobile phase B over 0.05 min and maintained for 0.25 min. 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. The PDA (SPD-M20A) detection range was 190-400 nm. The MS detector was configured with electrospray ionization as the ionization source. The acquisition mode was scan, the nebulization gas flow rate was 1.5 L / min, the drying gas flow rate was 15 L / min, the detector voltage was adjusted to ±0.2 kV, the DL temperature was 250 °C, the heating block temperature was 250 °C, and the scan range was 90.00-900.00 m / z. The ELSD (Alltech 3300) detector parameters were drift tube temperature: 60 ±5 °C, N2 flow rate: 1.8 ±0.2 L / min. The mobile phase gradient was optimized for each compound.

[0427] The GC-MS system was typically run using a Shimadzu GCMS-QP2010 Ultra with an FID and MS detector. The MS detector in acquisition mode was: Start time: 2.00 min, End time: 9.00 min, ACQ mode: scan, Event time: 0.30 s, Scan rate: 2000, Start m / z: 50.00, End m / z: 550.00, Ion source temperature: 200.00 °C, Interface temperature: 250.00 °C, Solvent cut time: 2.00 min.

[0428] Preparative HPLC purification was typically performed using a Waters Auto Purification System (2545-2767) with a 2489 UV detector. The column was a Waters C18, 19 x 150 mm, 5 μm. The mobile phase consisted of a mixture of acetonitrile (5-95%) in water containing 0.1% FA. The flow rate was maintained at 25 mL / min, the injection volume was 1200 μL, and two UV detector channels, 254 nm and 220 nm, were used. The mobile phase gradient was optimized for each compound.

[0429] Chiral analytical chromatography was performed on one of the following columns (Daicel Chemical Industries, Ltd.): 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.), and CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) in 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 the indicated proportions of either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as the isocratic solvent system.

[0430] Reactions performed using microwave irradiation were typically carried out using an initiator manufactured by Biotage. Concentration of solutions was performed on a rotary evaporator under reduced pressure. Flash column chromatography was typically performed using a Biotage chromatography system (Dyax Corp.) on silica gel (40-60 μM, 60 Å pore size) in pre-packed cartridges of the sizes indicated. 1H NMR spectra were obtained on a 400 MHz spectrometer in DMSO-d6 solution unless otherwise noted. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as the internal reference in DMSO-d6 solutions, and the residual CH3OH peak or TMS was used as the internal reference in CD3OD solutions. Coupling constants (J) are reported in hertz (Hz). Chiral analytical chromatography was performed on one of the following columns (250 × 4.6 mm) (Daicel Chemical Industries, Ltd.) using the indicated proportions of either ethanol in hexane (%Et / Hex) or isopropanol in heptane (%IPA / Hep) as the isocratic solvent system. Chiral preparative chromatography was performed using the desired isocratic solvent system identified in chiral analytical chromatography 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.), and Chiralcellulose SB, SC, and SA columns (YMC Co., Ltd.) in different column sizes (250 × 20 mm, 250 × 30 mm, and 250 × 50 mm).

[0431] Abbreviations used herein are: -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), ethyl acetate (EtOAc), diethyl ether (ether or Et2O), petroleum ether (PE), grams (g), hours (h or hr), 2-propanol (IPA), mass spectrum (ms or MS), microliters (μL), milligrams (mg), milliliters (mL), millimole (mmol), minutes (min), methyl t-butyl ether (MTBE), (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), retention time (R t ), room temperature (rt or RT), saturated aqueous sodium chloride (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), dichloromethane (DCM), dimethylacetamide (DMA or DMAC), dimethyl sulfoxide (DMSO), toluene (tol), 1,3-bis(diphenylphosphino)propane (DPPP), acetic acid (HOAc), 3-chloroperoxybenzoic acid (m-CPBA), methyl (Me), methanol (MeOH), chloroximide-dioxo-chromium, pyridin-1-ium (PCC), N-bromosuccinamide (NBS), thin layer chromatography (TLC).

[0432] Below are representative procedures for the preparation of compounds used in the following examples or compounds that may be substituted for the compounds used in the following examples that may not be commercially available.

[0433] Method A1 [ka] Step 1: 3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine [ka] In a 500 mL flask, 2,3-dichloro-5-nitropyridine (22.8 g, 118.2 mmol, 1.0 equiv.), CHCN (250 mL), 2H-1,2,3-triazole (9.0 g, 130.0 mmol, 1.1 equiv.), and KCO (21.2 g, 153.6 mmol, 1.3 equiv.) were placed. The resulting mixture was stirred at 40 °C for 15 h. The mixture was allowed to cool to 25 °C. The mixture was poured into 300 mL of EtOAc. The organic layer was washed with HO (2 × 300 mL) and brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. To the residue, CHCl (50 mL) was added. The resulting mixture was filtered. The filter cake was washed with CH2Cl2 (2 x 10 mL) and dried to give 3-chloro-5-nitro-2-(1,2,3-triazol-2-yl)pyridine (6.8 g, 26% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 8.39 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.33 (s, 2). LC-MS: m / z 226 [M+H] + It was.

[0434] Step 2: 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine [ka] In a 1.0 L flask, 3-chloro-5-nitro-2-(1,2,3-triazol-2-yl)pyridine (6.6 g, 29.3 mmol, 1.0 equiv) and EtOH (200 mL) were placed. HCl (50 mL) was added at 0 °C. Then, SnCl dihydrate (33.0 g, 146.3 mmol, 5.0 equiv) was added portionwise at 0 °C. The resulting mixture was stirred at 25 °C for 15 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in water (300 mL). The mixture was basified to pH 9 with 3 N NaOH. The resulting mixture was extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 5-chloro-6-(1,2,3-triazol-2-yl)pyridin-3-amine (5.4 g, 94% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ: 8.05 (s, 2H), 7.83 (d, J = 2.5 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H), 6.19 (s, 2H). LC-MS: m / z 196 [M+H] + It was.

[0435] Method B1 [ka] Example 1: 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxamide Step 1: 3,3-dimethylbutane-1,2,4-triol [ka] In a 2.0 L three-neck flask were placed pantolactone (26.0 g, 199.8 mmol, 1.0 equiv) and MeOH (800 mL). NaBH (18.9 g, 499.5 mmol, 2.5 equiv) was added portionwise at 0 °C. The resulting mixture was stirred at 25 °C for 4 h. The mixture was acidified to pH 7 with 1 N HCl. The resulting mixture was concentrated under reduced pressure. MeOH (200 mL) was added, and the solid was filtered off. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column and eluted with CHCl / MeOH (10:1) to give 3,3-dimethylbutane-1,2,4-triol (21.0 g, 78% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) 、 δ: 4.36 (s, 3H), 3.70-3.30 (m, 5H), 0.87-0.83 (m, 6H).

[0436] Step 2: 3-hydroxy-2,2-dimethylbutane-1,4-diyl dimethanesulfonate [ka] In a 500 mL three-neck flask, 3,3-dimethylbutane-1,2,4-triol (21.0 g, 156.5 mmol, 1.0 equiv) and pyridine (150 mL) were placed. Methanesulfonyl chloride (35.9 g, 312.9 mmol, 2.0 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 18 h. The mixture was poured into DCM (200 mL). The mixture was acidified to pH 2 with 2 N HCl. The resulting mixture was extracted with CHCl (3 × 300 mL). The combined organic layers were dried over NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with CH2Cl2 / MeOH (25:1) to give 2-hydroxy-4-(methanesulfonyloxy)-3,3-dimethylbutyl methanesulfonate (17.4 g, 38% yield) as a red oil. 1H NMR (400 MHz, CDCl) δ: 4.35–4.31 (m, 1H), 4.19–4.11 (m, 2H), 3.88 (d, J = 9.4 Hz, 1H), 3.81–3.78 (m, 1H), 3.05 (s, 3H), 3.02 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H). LC-MS: m / z 291 (M+H). + It was.

[0437] Step 3: 1-benzyl-4,4-dimethylpyrrolidin-3-ol [ka] Into a 150 mL pressure tank reactor were placed 2-hydroxy-4-(methanesulfonyloxy)-3,3-dimethylbutyl methanesulfonate (15.0 g, 51.6 mmol, 1.0 equiv), EtOH (70 mL), and benzylamine (16.6 g, 154.9 mmol, 3.0 equiv). The resulting mixture was stirred at 120 °C for 18 h. The mixture was cooled to 25 °C and concentrated under vacuum. EtO (500 mL) was added, and the solid was filtered off. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column and eluted with CHCl / MeOH (30:1) to give 1-benzyl-4,4-dimethylpyrrolidin-3-ol (5.5 g, 52% yield) as a red oil. 1 H NMR (400 MHz, CDCl) δ: 7.32–7.22 (m, 5H), 3.75–3.73 (m, 1H), 3.62 (s, 2H), 2.95–2.91 (m, 1H), 2.59–2.52 (m, 2H), 2.31–2.24 (m, 2H), 1.06 (s, 6H). LC-MS: m / z 206 (M+H). + It was.

[0438] Step 4: 4,4-Dimethylpyrrolidin-3-ol Hydrochloride [ka] In a 500 mL flask were placed 1-benzyl-4,4-dimethylpyrrolidin-3-ol (5.6 g, 27.4 mmol, 1.0 equiv.), EtOH (140 mL), 1 N HCl (30 mL), and Pd / C (500 mg). The resulting mixture was stirred under a hydrogen atmosphere at 25° C. for 18 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give 4,4-dimethylpyrrolidin-3-ol hydrochloride (4.0 g, 96% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 3.79-3.77 (m, 1H), 3.47-3.35 (m, 1H), 3.00-2.86 (m, 3H), 1.00 (s, 3H), 0.97 (s, 3H). LC-MS: m / z 116 (M+H). + It was.

[0439] Step 5: tert-Butyl 4-hydroxy-3,3-dimethylpyrrolidine-1-carboxylate [ka] In a 500 mL flask were placed 4,4-dimethylpyrrolidin-3-ol hydrochloride (4.0 g, 26.3 mmol, 1.0 equiv), THF (100 mL), (Boc)O (8.6 g, 39.5 mmol, 1.5 equiv), and TEA (13.4 g, 131.9 mmol, 5.0 equiv). The resulting mixture was stirred at 25 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column and eluted with CHCl / MeOH (20:1) to give tert-butyl 4-hydroxy-3,3-dimethylpyrrolidine-1-carboxylate (5.5 g, 96% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl) δ: 3.94–3.79 (m, 1H), 3.74–3.64 (m, 1H), 3.34–3.06 (m, 3H), 1.46 (s, 9H), 1.07 (s, 3H), 1.02 (s, 3H). LC-MS: m / z 216 (M+H). + It was.

[0440] Step 6: tert-Butyl 3,3-dimethyl-4-oxopyrrolidine-1-carboxylate [ka] In a 250 mL flask were placed tert-butyl 4-hydroxy-3,3-dimethylpyrrolidine-1-carboxylate (5.0 g, 23.2 mmol, 1.0 equiv.), ACN (60 mL), N-methylmorpholine N-oxide (3.5 g, 30.2 mmol, 1.3 equiv.), and TPAP (408 mg, 1.2 mmol, 0.05 equiv.). The resulting mixture was stirred at 25 °C for 1.5 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with PE / EtOAc (8:1) to give tert-butyl 3,3-dimethyl-4-oxopyrrolidine-1-carboxylate (3.4 g, 68% yield) as a colorless oil. 1 H NMR (300 MHz, DMSO-d6) δ: 3.80 (s, 2H), 3.45 (s, 2H), 1.43 (s, 9H), 1.06 (s, 6H). LC-MS: m / z 214 (M+H) + It was.

[0441] Step 7: tert-Butyl (E)-2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopyrrolidine-1-carboxylate [ka] In a 250 mL flask were placed tert-butyl 3,3-dimethyl-4-oxo-pyrrolidine-1-carboxylate (3.4 g, 15.9 mmol) and DMF-DMA (35 mL). The mixture was stirred at 105 °C for 5 h. The reaction mixture was cooled to 20 °C and concentrated under vacuum to give tert-butyl (E)-2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopyrrolidine-1-carboxylate (4.3 g, crude) as a yellow oil. LC-MS: m / z 269 (M+H) + It was.

[0442] Step 8: 2-Chloro-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine [ka] A mixture of tert-butyl (2E)-2-(dimethylaminomethylene)-4,4-dimethyl-3-oxo-pyrrolidine-1-carboxylate (4.2 g, 15.6 mmol), 5-chloro-1H-pyrazol-3-amine (1.8 g, 15.6 mmol), EtOH (45 mL), and HCl (4 N, 22.5 mL) was divided equally into three 40 mL vials. The vials were stirred at 80 °C for 1.5 h. The reaction mixtures were cooled to 25 °C, combined, and concentrated in vacuo. To the residue was added aqueous NaHCO (50 mL), and the resulting mixture was extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over NaSO, and concentrated in vacuo. The residue was applied onto a silica gel column and eluted with MeOH / DCM (1 / 20) to give 2-chloro-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine (300 mg, 9% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl) δ: 8.22 (s, 1H), 6.60 (s, 1H), 3.52 (s, 2H), 1.66 (s, 6H). LC-MS: m / z 223 (M+H). + It was.

[0443] Step 9: 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxamide [ka] In a 40 mL vial were placed 5-chloro-6-(triazol-2-yl)pyridin-3-amine (Step 2 of Method A1, 179 mg, 0.9 mmol), THF (10 mL), triphosgene (113 mg, 0.4 mmol), and N,N-diethylethanamine (100 mg, 1.0 mmol). The mixture was stirred at 25° C. for 0.5 h. The formed solid was filtered off, and 2-chloro-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine (170 mg, 0.8 mmol) and N,N-diethylethanamine (313 mg, 3.1 mmol) were added to the filtrate. The mixture was stirred at 25° C. for 15 h. The reaction mixture was concentrated in vacuo. The residue was applied to a silica gel column and eluted with MeOH / DCM (1 / 30) to give 160 mg of crude product as a yellow solid. The crude product was purified by preparative HPLC. The collected fractions were lyophilized to give 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxamide (22.2 mg, 6% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ:9.50(s, 1H), 9.28(s, 1H), 8.78(d, J=2.0Hz, 1H), 8. 54 (d, J=2.4Hz, 1H), 8.18 (s, 2H), 6.94 (s, 1H), 4.19 (s, 2H), 1.69 (s, 6H). LC-MS:m / z 444(M+H) + It was.

[0444] Method C1 [ka] Example 2: 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxamide Step 1: (E)-(((3,3,3-trifluoroprop-1-en-1-yl)oxy)methyl)benzene [ka] Into a 150 mL pressure tank reactor were added phenylmethanol (37.3 g, 344.8 mmol), HO (6.2 g, 344.8 mmol), and potassium hydroxide (19.4 g, 344.8 mmol). (E)-1-chloro-3,3,3-trifluoro-prop-1-ene (22.5 g, 172.4 mmol) was added at −20° C. The mixture was stirred at 22° C. for 1 hour and then at 70° C. for an additional 12.0 hours. The mixture was cooled to 25° C. The solid was filtered off. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc / hexane (1 / 25) to give (E)-(((3,3,3-trifluoroprop-1-en-1-yl)oxy)methyl)benzene (11.5 g, 29% yield) as a colorless liquid. 1 H NMR (300 MHz, CDCl), δ: 7.49–7.35 (m, 5H), 7.22–7.13 (m, 1H), 5.19–5.04 (m, 1H), 4.86 (s, 2H).

[0445] Step 2: 1-benzyl-3-(benzyloxy)-4-(trifluoromethyl)pyrrolidine [ka] In a 250 mL three-neck flask, (E)-(((3,3,3-trifluoroprop-1-en-1-yl)oxy)methyl)benzene (8.9 g, 44.1 mmol) and N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (15.7 g, 66.2 mmol) were placed, followed by the dropwise addition of 2,2,2-trifluoroacetic acid (503 mg, 4.4 mmol) at 0 °C. The mixture was stirred at 25 °C for 5 h and poured into 150 mL of NaHCO (aq). The resulting solution was extracted with 3 × 150 mL of EtOAc. The organic layers were combined, dried, and concentrated in vacuo. The residue was applied onto a silica gel column and eluted with EtOAc / hexane (1 / 20) to give 1-benzyl-3-benzyloxy-4-(trifluoromethyl)pyrrolidine (5.0 g, 30% yield) as a colorless liquid. LC-MS: m / z 336 (M+H) + It was.

[0446] Step 3: tert-Butyl 3-hydroxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate [ka] A 250 mL flask was charged with 1-benzyl-3-benzyloxy-4-(trifluoromethyl)pyrrolidine (5.0 g, 14.9 mmol), MeOH (60 mL), (Boc)O (3.6 g, 16.4 mmol), and Pd(OH) / C (3.0 g). The flask was evacuated and flushed with nitrogen three times, followed by a hydrogen flush. The mixture was stirred under a hydrogen atmosphere (balloon) at 25 °C for 15 h. The solids were filtered off. The filtrate was concentrated in vacuo. The residue was applied to a silica gel column and eluted with EtOAc / hexane (1 / 3) to give tert-butyl 3-hydroxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate (3.7 g, 77% yield) as a colorless oil. 1H NMR (300 MHz, CDCl) δ: 4.60–4.53 (m, 1H), 3.90–3.65 (m, 2H), 3.57–3.30 (m, 2H), 2.97–2.90 (m, 1H), 2.70–2.45 (m, 1H), 1.48 (s, 9H). LC-MS: m / z 256 (M+H). + It was.

[0447] Step 4: tert-Butyl 3-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate [ka] In a 250 mL flask were placed tert-butyl 3-hydroxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate (2.2 g, 8.4 mmol), DCM (50 mL), pyridinium chlorochromate (PCC) (7.26 g, 33.7 mmol), and silica gel (2.0 g). The mixture was stirred at 40 °C for 48 h. The solids were filtered off. The filtrate was concentrated under vacuum. The residue was applied to a silica gel column and eluted with EtOAc / hexane (1 / 10) to give tert-butyl 3-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (560 mg, 24% yield) as a colorless oil. 1 H NMR (300 MHz, CDCl) δ: 4.20-4.09 (m, 1H), 3.97-3.75 (m, 3H), 3.45-3.30 (m, 1H), 1.51 (s, 9H). LC-MS: m / z 254 (M+H). + It was.

[0448] Step 5: tert-Butyl (E)-2-((dimethylamino)methylene)-3-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate [ka] In a 100 mL flask, tert-butyl 3-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (560 mg, 2.2 mmol) and DMF-DMA (6 mL) were placed. The mixture was stirred at 35 °C for 1 hour. The mixture was concentrated in vacuo to give tert-butyl (2E)-2-(dimethylaminomethylene)-3-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (682 mg, crude) as a yellow oil. LC-MS: m / z 309 (M+H) + It was.

[0449] Step 6: tert-Butyl 2-chloro-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxylate [ka] Into a 100 mL flask were placed tert-butyl 3-oxo-4-(trifluoromethyl)pyrrolidine-1-carboxylate (682 mg, 2.7 mmol), 3-chloro-1H-pyrazol-5-amine (316 mg, 2.7 mmol), toluene (10 mL), and AcOH (1 mL). The mixture was stirred at 95 °C for 15 h. The reaction mixture was cooled to 25 °C and concentrated in vacuo. Then, 20 mL of NaHCO (aq) was added. The resulting solution was extracted with 3 × 20 mL of EtOAc. The organic layers were combined, dried, and concentrated in vacuo. The residue was applied onto a silica gel column and eluted with EtOAc / hexane (1 / 20) to give tert-butyl 2-chloro-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxylate (200 mg, 18% yield) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ: 8.83–8.79 (m, 1H), 7.06 (s, 1H), 4.37–4.20 (m, 2H), 4.07–3.99 (m, 1H), 1.47 (s, 9H). LC-MS: m / z 363 (M+H). +It wa...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 980】 During the ceremony, each 【Chemistry 981】 is a single or double bond, X is N or C; Y is N or C; Z is N or CR ５ and when one of X and Y is N, the other of X and Y is C; n is 1, 2, or 3; R １ is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —NR Ａ R Ｂ or C1-C3 alkyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl and C1-C3 alkoxy; R ２ is hydrogen, amino, or halogen; R ２Ａ is hydrogen, halogen, or C1-C6 alkyl; Each R ３ are independently halogen, hydroxyl, cyano, C3-C6 cycloalkyl, —NR Ａ R Ｂ , 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl, C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl, or two R ３ together with the carbon atom to which they are attached form an oxo group or a C3-C8 cycloalkyl; m is 0, 1, 2, or 3; R ４ is phenyl, naphthyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, or C3-C8 cycloalkyl, and each R ４ The group is R ６ optionally substituted with 1 to 3 substituents independently selected from R ５ is hydrogen, halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —NR Ｃ R Ｄ or C1-C3 alkyl; Each R ６ is a halogen, cyano, hydroxyl, -CO ２ H, —N(S═O)(C1-C3 alkyl) ２ , -S(=O) ｐ (C1-C3 alkyl), —NR Ｅ R Ｆ , —(C═O)NR Ｅ R Ｆ , amino, hydroxyl, or —(C═O)NR Ｅ R Ｆ C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, optionally substituted with 1 to 3 independently selected R Ｘ 5-6 membered heteroaryl optionally substituted with -NR Ｅ R Ｆ , C1-C3 alkyl optionally substituted with 1 to 2 substituents independently selected from C1-C3 alkoxy, and C3-C6 cycloalkyl, C3-C6 cycloalkyl optionally substituted with hydroxyl, and -(Q) optionally substituted with 1 to 3 independently selected C1-C3 alkyl. ｑ - independently selected from 3- to 8-membered heterocyclyl; p is 1 or 2; Q is —O— or —NH—; q is 0 or 1; Each R Ｘ is halogen, cyano, hydroxyl, amino, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or hydroxyl, C1-C3 alkoxy, and —NR Ｇ R Ｈ C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from R Ａ , R Ｂ , R Ｃ , R Ｄ are independently hydrogen, C1-C3 alkyl, or R Ａ and R Ｂ , or R Ｃ and R Ｄ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; R Ｅ , R Ｆ , R Ｇ , and R Ｈ are independently hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl, or R Ｅ and R Ｆ , or R Ｇ and R Ｈ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with C1-C3 alkyl or C1-C3 alkoxy.

2. 2. The compound of claim 1, wherein X is N, Y is C, and Z is N.

3. R １ 3. The compound of claim 1 or 2, wherein is hydrogen.

4. R １ is halogen, -NR Ａ R Ｂ 3. The compound of claim 1 or 2, wherein the aryl group is aryl, cyano, or hydroxyl.

5. R １ The compound of any one of claims 1 to 2 and 4, wherein is fluoro or chloro.

6. R １ is C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl and C1-C3 alkoxy.

7. R ２ The compound according to any one of claims 1 to 6, wherein is hydrogen.

8. R ２ The compound of any one of claims 1 to 6, wherein is halogen or amino.

9. R ２Ａ The compound according to any one of claims 1 to 8, wherein is hydrogen.

10. R ２Ａ The compound of any one of claims 1 to 8, wherein is halogen or C1-C6 alkyl.

11. The compound according to any one of claims 1 to 10, wherein n is 1.

12. The compound according to any one of claims 1 to 11, wherein m is 1.

13. The compound according to any one of claims 1 to 11, wherein m is 2.

14. The compound according to any one of claims 1 to 11, wherein m is 3.

15. Each R ３ is independently halogen, cyano, C3-C6 cycloalkyl, C1-C3 alkyl optionally substituted with C1-C3 alkoxy or cyano, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy.

16. Each R ３ The compound of any one of claims 1 to 15, wherein is independently cyclopropyl, methyl optionally substituted with methoxy, trifluoromethyl, methoxy, or trifluoromethoxy.

17. m is 2, and each R ３ is methyl; or m is 2 and each R ３ is trifluoromethyl; or m is 2 and one R ３ is methyl, and the other R ３ is trifluoromethyl; or m is 2 and one R ３ is methoxymethyl, and the other R ３ is trifluoromethyl; or m is 2 and one R ３ is methyl, and the other R ３ is cyclopropyl; or m is 2 and one R ３ is methoxymethyl, and the other R ３ is cyclopropyl; or m is 2 and one R ３ is trifluoromethyl, and the other R ３ is cyclopropyl; or m is 2 and one R ３ is methyl, and the other R ３ is methoxy; or m is 2 and one R ３ is cyclopropyl, and the other R ３ The compound of any one of claims 1 to 11, wherein is methoxy.

18. R ３ The compound of any one of claims 1 to 11, 13, and 17, wherein the group is geminal.

19. R ４ is one to three independently selected R ６ or phenyl optionally substituted with 1 to 3 independently selected R ６ 19. The compound of any one of claims 1 to 18, wherein the compound is a 5-6 membered heteroaryl optionally substituted with

20. R ６ is halogen, cyano, hydroxy, or —CO ２ 20. The compound of claim 1, wherein R is H.

21. R ６ 21. The compound of claim 20, wherein one of is chloro.

22. R ６ One of the groups is -NR Ｅ R Ｆ , —(C═O)NR Ｅ R Ｆ , —N═(S═O)(C1-C3 alkyl) ２ or -S(=O) ｐ (C1-C3 alkyl).

23. R ６ one of which is C1-C3 haloalkyl, C1-C3 haloalkoxy, or amino, hydroxyl, or —(C═O)NR Ｅ R Ｆ 20. The compound of any one of claims 1 to 19, wherein the compound is C1-C3 alkoxy optionally substituted with

24. R ６ one of which is selected from 1 to 3 independently selected R Ｘ 20. The compound of any one of claims 1 to 19, wherein the compound is a 5-6 membered heteroaryl optionally substituted with

25. R ６ 25. The compound of any one of claims 1 to 19 and 24, wherein one of is unsubstituted 5-6 membered heteroaryl.

26. R ６ One of the groups is hydroxyl, -NR Ｅ R Ｆ , C1-C3 alkyl optionally substituted with 1 to 2 substituents independently selected from C1-C3 alkoxy, and C3-C6 cycloalkyl; C3-C6 cycloalkyl optionally substituted with hydroxyl; or -(Q) optionally substituted with 1 to 3 independently selected C1-C3 alkyl. ｑ The compound of any one of claims 1 to 19, which is a 3- to 8-membered heterocyclyl.

27. R ４ but, 【Hua982】 and the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

28. R ６ is selected from the group consisting of cyano, halogen, C1-C3 haloalkyl, and C1-C3 alkoxy; or R ６ is selected from the group consisting of cyano, chloro, difluoromethyl, trifluoromethyl, and methoxy; or R ６Ａ is selected from the group consisting of cyano, halogen, unsubstituted C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R ６Ｂ is cyano, hydroxyl, -N=(S=O)(C1-C3 alkyl) ２ , C1-C3 alkoxy, hydroxyl, C1-C3 alkoxy, and —NR Ｇ R Ｈ C1-C3 alkyl optionally substituted with 1 to 2 substituents independently selected from, or a 5- to 6-membered heteroaryl optionally substituted with amino; —(C═O)NR Ｅ R Ｆ ; C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 haloalkoxy; cyano; C1-C3 alkyl; and -(Q) optionally substituted with 1 to 3 independently selected C1-C3 alkyl. ｑ - selected from the group consisting of 3- to 8-membered heterocyclyl; or R ６Ａ is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl; R ６Ｂ 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-hydroxymethyl-1,2,3-triazol-2-yl, 4-(1,2-dihydroxyethyl)-1,2,3-triazol-2-yl, 4-(1-hydroxyethyl)-1,2,3-triazol-2-yl, 4-methoxymethyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-methoxy-1,2,3-triazol-2-yl, 4-amino-1,2,3-triazol-2-yl, 4-dimethylaminomethyl-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, pyrazol-1-yl, 5-cyano-pyrazol-1-yl, 1-methyl-imidazol-3-yl, 1-methyl-5-amino-imidazol-3-yl, 3-methylimidazole -2-one-1-yl, 1-methyl-pyrazol-3-yl, 1-methyl-pyrazol-5-yl, pyrrol-1-yl, thiazol-2-yl, isothiazolidine-2-yl-1,1-dioxide, pyrrolidin-2-one-1-yl, oxazol-2-yl, oxadiazol-2-yl, 2-amino-pyrimidin-4-yl, 2-tetrahydrofuranyl, -(C=O)4-methylpiperazin-1-yl, -(C=O)N(CH ３ ) ２ , -(C=O)NHCH ３ , -N=(S=O)(methyl) ２ , methoxy, ethoxy, difluoromethoxy, methyl, cyano; or R ６Ａ is selected from the group consisting of cyano, chloro, and trifluoromethyl; R ６Ｂ is selected from the group consisting of 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, and 1,2,4-triazol-4-one-2-yl; or R ６Ａ is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R ６Ｂ is a 5-6 membered heteroaryl optionally substituted with cyano, C1-C3 alkyl, or amino; —(C═O)NR Ｅ R Ｆ C1-C3 alkoxy; C1-C3 haloalkyl; C1-C3 haloalkoxy; cyano; and C1-C3 alkyl; R ６Ｃ is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; or R ６Ａ is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, and trifluoromethyl; R ６Ｂ However, 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-on-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-5-yl, pyrrol-1-yl, thiazol-2-yl, isothiazolidine-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, -(C=O)N(CH ３ ) ２ , -(C=O)NHCH ３ , methoxy, ethoxy, difluoromethoxy, methyl, cyano; R ６Ｃ is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, methyl, and trifluoromethyl; or R ６Ａ is selected from the group consisting of cyano, chloro, and trifluoromethyl; R ６Ｂ is selected from the group consisting of 1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-2-yl, 4-methyl-1,2,3-triazol-1-yl, 4-amino-1,2,3-triazol-2-yl, 5-cyano-1,2,3-triazol-1-yl, 1,2,3-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 5-amino-1,2,4-triazol-1-yl, 1-methyl-5-amino-1,2,4-triazol-3-yl, and 1,2,4-triazol-4-one-2-yl; R ６Ｃ 28. The compound of claim 27, wherein is selected from the group consisting of cyano, chloro, methyl, and trifluoromethyl.

29. R ５ The compound of any one of claims 1 and 3 to 28, wherein is hydrogen.

30. R ５ is halogen, cyano, hydroxyl, or —NR Ｃ R Ｄ 29. The compound of any one of claims 1 and 3 to 28, wherein

31. R ５ 29. The compound of any one of claims 1 and 3-28, wherein is C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, or C1-C3 alkyl.

32. The compound is 【Hua995】 【Hua996】 【Hua997】 【Hua998】 【999】 【1000】 【Chemistry 1001】 【Chemistry 1002】 【Chemistry 1003】 【Chemistry 1004】 【Chemistry 1005】 【Chemistry 1006】 【Chemistry 1007】 【Chemistry 1008】 【Chemistry 1009】 【Chemistry 1010】 【Chemistry 1011】 【Chemistry 1012】 【Chemistry 1013】 【Chemistry 1014】 【Chemistry 1015】 【Chemistry 1016】 【Chemistry 1017】 【Chemistry 1018】 【Chemistry 1019】 10. The compound of claim 1, which is selected from the group consisting of:

33. The compound of claim 32, 【Chemistry 1020】 or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33, 【Chemistry 1021】 33. The compound of claim 1 or 32, which is: or a pharmaceutically acceptable salt thereof.

35. [Chemical 1022] (S)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxamide or a pharmaceutically acceptable salt thereof. [Request 36] [Chemical 1023] (R)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxamide or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

38. A composition comprising the compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37, for treating cancer in a subject in need thereof.

39. The composition or pharmaceutical composition described in claim 38, wherein the cancer is leukemia or lymphoma.

40. The composition or pharmaceutical composition described in claim 38 or 39, wherein the cancer is non-Hodgkin's lymphoma.

41. A composition or pharmaceutical composition described in any one of claims 38 to 40, wherein the cancer is selected from diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), macroglobulinemia, extranodal marginal zone lymphoma, nodal marginal zone lymphoma, splenic marginal zone lymphoma, primary central nervous system lymphoma, and T-cell lymphoma.

42. 42. The composition or pharmaceutical composition of any one of claims 38 to 41, wherein the composition or pharmaceutical composition is administered to the subject in combination with an additional therapy or therapeutic agent, wherein the additional therapy or therapeutic agent is selected from radiation therapy, cytotoxic chemotherapy, protease-targeted therapy, kinase-targeted therapy, apoptosis modulators, signal transduction inhibitors, immune-targeted therapy, and angiogenesis-targeted therapy.

43. A composition comprising a compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 37, for treating an autoimmune disorder in a subject in need thereof.

44. The composition or pharmaceutical composition of claim 43, wherein the autoimmune disorder is selected from rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus (SLE).

45. A composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37, for treating an inflammatory disorder in a subject in need thereof.

46. The composition or pharmaceutical composition of claim 45, wherein the inflammatory disorder is chronic graft-versus-host disease (cGVHD), psoriasis, or ulcerative colitis.

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