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

Abstract

This application relates to compounds of formula (I) as defined herein, and pharma- ceutically acceptable salts thereof. This application also describes pharmaceutical compositions comprising the compounds of formula (I), and pharma- ceutically acceptable salts thereof, and methods of using the compounds and compositions to treat diseases such as cancer, autoimmune disorders, and inflammatory disorders. Also provided 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

Description

[Technical Field]

[0001] This application relates to tricyclic and other polycyclic compounds that are useful for treating cancer and proliferative disorders such as autoimmune and inflammatory disorders. [Background technology]

[0002] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is an intracellular protein involved in lymphocyte proliferation through upstream signaling of NF-κB 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 is formed 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.

[0003] 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, roquin-1, NIK, and LIMA 1a. See Rebeaud et al., Nat Immunol 2008, 9, 272-281. See also Coornaert et al., Nat Immunol 20008,9,263-271; Staal et al., EMBO J 2011,30,1742-1752; Hailfinger et al., PNAS 2011,108,14596-14601; Jeltsch et al., Nat Immunol 2014,15,1079-1089; Uehata et al., Cell 2013,153,1036-1049; Nie et al., Nat Commun 2015,6,5908; and Baens et al., PLoS ONE 2014,9,e103774. One general profile of MALT1 substrates is described in Kasperkiewicz, et al. Scientific Reports 8.1(2018):1-10. Additionally, several chromosomal translocations leading to the 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 highlights 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), as well as solid tumors such as lung adenocarcinoma, breast cancer, pancreatic cancer, and 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 disorders, such as psoriasis, multiple sclerosis, rheumatoid arthritis, Sjögren'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. Recent findings also suggest 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]

[0004] [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

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[0005] Thus, as used herein, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, Q, n, R X , R 1 , R 2 , R 3 , m, and R 4 is as defined herein.

[0006] In some embodiments, the compound of Formula (I) has the structure: [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, Q, n, R 1 , R 2 , R 3 , m, and R 4 is as defined herein.

[0007] 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.

[0008] Also provided 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 described herein.

[0009] 1. A method 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, or a pharmaceutical composition described herein.

[0010] 1. 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 described herein.

[0011] 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 described herein.

[0012] 1. A method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the MALT1 gene, the MALT1 protease, or the expression or activity or levels of 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 described herein.

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

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

[0015] Also provided is a method for treating a CBM complex pathway-associated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0016] 1. A method for treating a disease or disorder in a subject in need thereof, comprising: (a) identifying the disease or disorder as a CBM complex pathway-associated 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 described herein.

[0017] 1. 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 described herein.

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

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

[0020] 1. 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 MALT1 gene, the MALT1 protease, or the expression or activity or levels of 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 described herein.

[0021] Also provided is a method for treating a MALT1-associated autoimmune disorder in a subject, comprising administering to a 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 described herein.

[0022] 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 described herein.

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

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

[0025] 1. 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 MALT1 gene, the MALT1 protease, or the expression or activity or levels of 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 described herein.

[0026] Also provided is a method for treating a MALT1-associated inflammatory disorder in a subject, comprising administering to a 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 described herein.

[0027] 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.

[0028] 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.

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

[0030] 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-associated disease or disorder.

[0031] 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).

[0032] Also provided herein are processes for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0033] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof obtained by the process for preparing the compounds defined herein.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

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

[0036] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. A compound identified herein by name or structure as one particular tautomeric form is intended to include other tautomeric forms unless otherwise specified.

[0037] The term "tautomer," as used herein, refers to compounds that differ significantly in structure in the arrangement of atoms, but exist in easy and rapid equilibrium; the compounds provided herein may be represented as different tautomers; it should be understood that, where a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of a compound does not exclude any tautomer. Below is an example of a tautomeric form that is included: [ka]

[0038] It will be understood 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.

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

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

[0041] The term "C1-C6 haloalkyl" refers to a hydrocarbon chain substituted with at least one independently selected halogen atom, such as fluorine, chlorine, bromine, and iodine, at each occurrence. The halogen atom may be present at any position on the hydrocarbon chain. Similarly, a C1-C3 haloalkyl group is a straight 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.

[0042] The term "C1-C6 alkoxy" refers to a C1-C6 alkyl group attached to a molecule through an oxygen. It includes moieties where the alkyl portion can be straight or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0043] The term "C1-C6 haloalkoxy" refers to a C1-C6 alkyl group attached to the molecule through an oxygen and in which at least one hydrogen atom of the alkyl group is replaced by a halogen. This includes moieties in which the alkyl portion can be straight or branched, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or trifluoropropoxy.

[0044] [ka] represents a single or double bond, valence is allowed. For example, [ka]

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

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

[0047] As used herein, the term "amino" refers to the group --NH.sub.2.

[0048] As used herein, the term "aryl" refers to a 6-10 all-carbon monocyclic or bicyclic group 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.

[0049] 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 by a heteroatom independently selected from N, O, and S. Heteroaryl groups include rings in which one or more atoms are oxidized (e.g., carbon, nitrogen, and sulfur), 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.

[0050] As used herein, the term "cycloalkoxy" refers to a saturated or partially unsaturated 3-10 monocyclic or bicyclic hydrocarbon group connected through an oxy (i.e., -O-) ring, where bicyclic systems include fused, spiro (optionally referred to as "spirocycloalkyl" groups), and bridged ring systems. Non-limiting examples of cycloalkoxy groups include cyclopropoxy, cyclohexoxy, spiro[2.3]hexoxy, and bicyclo[1.1.1]pentoxy.

[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 cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0052] The term "heterocyclyl" refers to a non-aromatic, saturated or partially unsaturated 3- to 12-membered hydrocarbon monocyclic or bicyclic ring system having at least one heteroatom in the ring selected from N, O, and S. 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 may be referred to, for example, as "5- to 10-membered heterocyclyl groups," which are ring systems containing 5, 6, 7, 8, 9, or 10 atoms, with at least one atom being a heteroatom. For example, there may be 1, 2, or 3 heteroatoms, optionally 1 or 2. 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 that are 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 an "=O" group attached to a carbon atom.

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

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

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

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

[0060] In some embodiments, the compounds of Formula (I) include the compounds of Examples 1-203, and stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (I) include the compounds of Examples 1-203, and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Examples 1-203 are in free base form. In some embodiments, the compounds of Examples 1-203 are in the form of a pharmaceutically acceptable salt.

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

[0062] Protecting groups may be temporary substituents that protect potentially reactive functional groups from undesired chemical transformations. The selection of the specific protecting group to be used 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 to be protected, other functionalities present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, functional group resistance to conditions required to remove the protecting group, and reaction conditions for thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed (Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed. Wiley: New York, 1991).

[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, carbamate (e.g., methylcarbamate, t-butylcarbamate, benzylcarbamate, allylcarbamate, 2,2,2-trichloroethylcarbamate, and 9-fluorenylmethylcarbamate), imine, and sulfonamide (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, and 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 connection with 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, the atom is 1 H, 2 H, 3H, or mixtures thereof, and when carbon is mentioned, the atom is 11 C. 12 C. 13 C. 14 C, or mixtures thereof, and when nitrogen is mentioned, the atom 13 N, 14 N, 15 N, or mixtures thereof, and when oxygen is mentioned, the atom is 14 O. 15 O. 16 O. 17 O. 18 O, or mixtures thereof, and when fluoro is mentioned, the atom is 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 Some of the aforementioned isotopes are radioactive, and therefore the compounds provided herein also include compounds with one or more isotopes of one or more atoms, including radioactive compounds, and mixtures thereof, in which one or more non-radioactive atoms are replaced by one of their radioactively enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0066] For illustrative purposes, general methods for preparing compounds and key intermediates are provided herein. For more detailed descriptions of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. While specific starting materials and reagents are shown 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 Tables A and B.

[0068] The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful for treating diseases and disorders that can be treated by MALT1 inhibitors, such as MALT1-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 curative 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 stabilization of the disease state (i.e., does not worsen), a delay or slowing of disease progression, an improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete). "Treatment" can also mean prolonging survival as 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 the disease or disorder being 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), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 21 years, including but not limited to, 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 old, between 29 days old and under 2 years old, between 2 years old and under 12 years old, or between 12 years old and 21 years old (including but not including the 22nd birthday). In some embodiments, the pediatric subject is between birth and 28 days old, between 29 days old and under 1 year old, between 1 month old and under 4 months old, between 3 months old and under 7 months old, between 6 months old and under 1 year old, between 1 year old and under 2 years old, between 2 years old and under 3 years old, between 2 years old and under 7 years old, between 3 years old and under 5 years old, between 5 years old and under 10 years old, between 6 years old and under 13 years old, between 10 years old and under 15 years old, or between 15 years old and under 22 years old.

[0072] In certain embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof are useful for preventing diseases and disorders defined herein (e.g., autoimmune disorders, inflammatory disorders, and cancer). The term "preventing," as used herein, means preventing the onset, recurrence, or spread, in whole or in part, of a disease or condition described herein, or a symptom thereof.

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

[0074] Signaling through the NF-κB pathway is involved 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 recruitment of protein kinase C (e.g., protein kinase C beta or protein kinase C theta) and 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), likely through ubiquitination (e.g., K63-linked ubiquitination) of 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 and the release of NF-κB transcription factors (typically the NF-κB1 subtype: p50-RelA and p50-cRel) into the nucleus. This cascade is likely mediated by the ubiquitin ligase TRAF6 (tumor necrosis factor receptor (TNFR)-associated factor 6). The CBM complex can also 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 research has been conducted 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 possesses cysteine ​​protease activity. Non-limiting examples of substrates of wild-type MALT1 include BCL10, A20, CYLD, RelB, Regnase 1, Rokin-1, and HOIL1. Additionally, 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 NF-κB activation. 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, therefore, 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 because 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 because 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 have oncogenic properties and promote 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 stabilization of mRNAs, including those for 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, e.g., 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, inhibition of MALT1 can provide beneficial effects in many types of disorders associated with abnormal signaling in the NF-κB or JNK pathways. For example, inhibition of MALT1 can reduce flux through the NF-κB or JNK pathways resulting from one or more of the following: (1) Inactivation of tumor suppressor genes. Non-limiting examples of tumor suppressor genes that can be inactivated include BRCA1 and p53 (e.g., p53 H61L or I123T). See, for example, Sau, et al. Cell Stem Cell 19.1 (2016): 52-65; Xia, et al. Cancer Immunol. Res. 2.9 (2014): 823-830; Johansson, et al. Oncotarget 7.38 (2016): 62627. (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 the MALT1 protease (e.g., wild-type MALT1 protease or dysregulated MALT1 protease). Non-limiting examples of substrates of the 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] As used herein, the term "CBM complex pathway" includes genes, transcripts, and proteins within 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 between cell surface receptors and the CBM complex (e.g., protein kinase C beta or protein kinase C theta), components of the CBM complex (e.g., MALT1, CARD11, CARD14, CARD10, CARD9, or BCL10), substrates of the MALT1 protease (e.g., BCL10, A20, CYLD, RelB, Regnus1, Rokin-1), and the like. 1, HOIL1, NIK, and LIMA1α), components of the NF-κB pathway downstream of the CBM complex (e.g., TAK1, TRAF6, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65(RelA), or c-Rel), components of the JNK pathway downstream of the CBM complex (e.g., JNK1, JNK2, JNK3, or AP-1 transcription 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 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] The term "CBM complex pathway-associated autoimmune disorder," as used herein, refers to an autoimmune 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 autoimmune disorders are described herein.

[0081] The term "CBM complex pathway-associated inflammatory disorder," as used herein, 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 transducer 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), or a cancer associated with a CBM complex pathway cell surface receptor-associated cancer (e.g., CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, or HER2-associated cancer). cancers associated with components of the NF-κB pathway downstream of the CBM complex (e.g., TAK1-related cancers, TRAF6-related cancers, TAB1-related cancers, TAB2-related cancers, TAB3-related cancers, MKK7-related cancers, IKKα-related cancers, IKKβ-related cancers, IKKγ-related cancers, IkBα-related cancers, p50-related cancers, p65(RelA)-related cancers, or c-Rel-related cancers); cancers associated with components of the JNK pathway downstream of the CBM complex (e.g., JNK1-related cancers, JNK2-related cancers, JNK3-related cancers, or AP-1 transcription factor-related cancers); CBM complex pathway-related cancers, such as MYD88-related cancers, or combinations thereof.

[0083] The term "CBM complex pathway-associated cancer," as used herein, 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 (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 them described herein) (e.g., at the time of diagnosis or after developing resistance to a previous therapy). Non-limiting examples of CBM complex pathway-associated cancers are described herein. In some embodiments, a 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 transducer between a cell surface receptor and the CBM complex (e.g., protein kinase C beta (PKCβ)-associated cancer or protein kinase C theta (PKCβ)-associated cancer). θ)-related cancers, components of CBM complex-related cancers (e.g., MALT1-related cancers, CARD11-related cancers, CARD14-related cancers, CARD10-related cancers, CARD9-related cancers, or BCL10-related cancers), MALT1 protease substrate-related cancers (e.g., BCL10-related cancers, A20-related cancers, CYLD-related cancers, RelB-related cancers, Regnase 1-related cancers, Rokin 1-related cancers, HOIL1-related cancers, NIK-related cancers, or LIMA1α-related cancers), and components of the NF-κB pathway downstream of the CBM complex The cancer may be a cancer associated with a component of the JNK pathway downstream of the CBM complex (e.g., a TAK1-related cancer, a TRAF6-related cancer, a TAB1-related cancer, a TAB2-related cancer, a TAB3-related cancer, an MKK7-related cancer, an IKKα-related cancer, an IKKβ-related cancer, an IKKγ-related cancer, an IkBα-related cancer, a p50-related cancer, a p65(RelA)-related cancer, or a c-Rel-related cancer), a cancer associated with a component of the JNK pathway downstream of the CBM complex (e.g., a JNK1-related cancer, a JNK2-related cancer, a JNK3-related cancer, or an AP-1 transcription factor-related cancer), or a combination thereof.

[0084] In some embodiments, the dysregulation can be a dysregulation that results in aberrant activation of a gene, protein, or any of its expression, activity, or levels. Activation can be through any suitable mechanism, including, but not limited to, gene amplification, activating mutations, activating translocations, transcriptional activation, epigenetic changes, and / or overexpression of the protein product of an oncogene. In some embodiments, the dysregulation can be a dysregulation that results in aberrant inactivation of a gene, protein, or any of its expression, activity, or levels. 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 a 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" describes 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 (and, where appropriate, 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 (and, where appropriate, 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 with a cancer (CBM complex pathway-associated cancer) 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., 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 prior 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., 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 agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or dysregulated expression, activity, or levels of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or dysregulated expression, activity, or levels of any of them (e.g., identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). 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 a tumor with dysregulated 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 (and 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 determined to be associated with dysregulated 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 (a 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 (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 agency-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 agency-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 a tumor with 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 (and, 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, based on histological examination, as having an autoimmune disorder (CBM complex pathway-associated autoimmune disorder) determined to be associated with 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.

[0088] In some embodiments, the subject has been identified or diagnosed as having an inflammatory disorder (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 agency-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 agency-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 a tumor with 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 (and, 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, based on histological examination, as having an inflammatory disorder (CBM complex pathway-associated inflammatory disorder) determined to be associated with 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.

[0089] The term "CBM complex pathway cell surface receptor-associated cancer," as used herein, 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 "associated cancer" means * gene, * dysregulation of the expression or activity or levels of any (e.g., one or more) of a protein (e.g., a protein described herein) * gene, * In some embodiments, "*" refers to a cancer associated with or having dysregulation of a CBM complex pathway gene or protein, or any type of dysregulation of the expression or activity or level of any of them, and "*" refers to a specific CBM complex pathway gene or protein as described herein. * 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 PKC theta-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 associated cancer is a NIK-associated cancer. * In some embodiments, the associated cancer is a Regnes 1-associated cancer. * In some embodiments, the associated cancer is a LIMA1α-associated cancer. * In some embodiments, the associated cancer is a rokin-1 associated cancer. * In some embodiments, the associated cancer is a TRAF6-associated cancer. * In some embodiments, the associated cancer is a TAK1-associated cancer. * In some embodiments, the associated cancer is a TAB1-associated cancer. * In some embodiments, the associated cancer is a TAB2-associated cancer. * In some embodiments, the associated cancer is a TAB3-associated cancer. * In some embodiments, the associated cancers are MKK7-associated cancers and IKKα-associated cancers. * In some embodiments, the associated cancer is an IKKβ-associated cancer.* In some embodiments, the associated cancer is an IKKγ-associated cancer. * In some embodiments, the associated cancer is an IkBα-associated cancer. * In some embodiments, the associated cancer is a p50-associated cancer. * In some embodiments, the associated cancer is a p65-associated 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. * The associated cancer is MYD88 transcription factor-associated cancer.

[0091] " * gene, * proteins, or dysregulation of the expression or activity or levels of any of them" ( * is a particular CBM complex pathway gene or protein described herein) refers to a genetic mutation (e.g., * chromosomal translocation resulting in expression of a fusion protein comprising the domain and the fusion partner, wild type * Contains at least one amino acid deletion compared to the protein * leading to protein expression * Mutation in gene, wild type * with one or more point mutations compared to the protein * leading to protein expression * Mutation in gene, wild type * with at least one inserted amino acid compared to the protein * leading to protein expression * Mutations in genes, cells * Gene duplication, which leads to increased levels of a protein, or *Mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in increased levels of a protein, wild-type * Compared to protein * The protein has at least one amino acid deletion * Providing protein * alternatively spliced ​​versions of mRNA or wild-type in mammalian cells due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells) * It refers to an increase in the expression (e.g., an increase in the level) of a protein. * Increased copy number of a gene * This can result in overexpression of the protein. For example, * gene, * Dysregulation of the expression or activity or levels of any of the proteins or any of them * and a partner protein (i.e., * This may be the result of a genetic or chromosomal translocation that results in the expression of a fusion protein containing a second moiety (which is not a * gene, * Dysregulation of the expression or activity or levels of a protein, or any of them, can result in * Genes and other non- * In some embodiments, the gene may be the result of a genetic translocation with a gene. * gene, * The protein, or the 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. * Genes or *The protein is CD28. * Genes or * The protein is BCR. * Genes or * The protein is HER1. In some embodiments, * Genes or * In some embodiments, the protein is HER2. * Genes or * The protein is PKCβ. In some embodiments, * Genes or * The protein is PKC theta. * Genes or * The protein is MALT1. * Genes or * The protein is CARD11. * Genes or * The protein is CARD14. * Genes or * In some embodiments, the protein is A20. * Genes or * In some embodiments, the protein is CYLD. * Genes or * In some embodiments, the protein is RelB. * Genes or * In some embodiments, the protein is HOIL1. * Genes or * In some embodiments, the protein is NIK. * Genes or * The protein is Regnase 1. In some embodiments, * Genes or * In some embodiments, the protein is LIMA1α. * Genes or * In some embodiments, the protein is roquin-1. * Genes or *In some embodiments, the protein is TRAF6. * Genes or * In some embodiments, the protein is TAK1. * Genes or * In some embodiments, the protein is TAB1. * Genes or * In some embodiments, the protein is TAB2. * Genes or * In some embodiments, the protein is TAB3. * Genes or * In some embodiments, the protein is MKK7. * Genes or * In some embodiments, the protein is IKKα. * Genes or * In some embodiments, the protein is IKKβ. * Genes or * In some embodiments, the protein is IKKγ. * Genes or * In some embodiments, the protein is IkBα. * Genes or * The protein is p50. In some embodiments, * Genes or * The protein is p65. In some embodiments, * Genes or * The protein is c-Rel. * Genes or * In some embodiments, the protein is JNK1. * Genes or * In some embodiments, the protein is JNK2. * Genes or * In some embodiments, the protein is JNK3. * Genes or * The protein is a MYD88 transcription factor. * Genes or *The protein is the AP-1 transcription factor.

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

[0093] As another example, * gene, * Dysregulation of the expression or activity or levels of a protein or any of them does not include mutations * encodes a protein that is constitutively inactive or has reduced activity compared to the protein encoded by the gene, * In some embodiments, the mutation may be in a gene. * gene, * In some embodiments, the protein, or the expression or activity or level of any of them, is A20. * gene, * In some embodiments, the protein, or the expression or activity or level of any of them, is CYLD. * gene, * In some embodiments, the protein, or the expression or activity or level of any of them, is RelB. * gene, * In some embodiments, the protein, or the expression or activity or level of any of them, is HOIL1. * gene, * The protein, or the expression or activity or level of 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 for 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 for 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] The term "cancer associated with a signal transducer between a cell surface receptor and a CBM complex," as used herein, 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 signal transducer between a cell surface receptor and a CBM complex. In some embodiments, the cancer associated with a signal transducer between a cell surface receptor and a CBM complex is selected from the group consisting of 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 (e.g., one or more) ... protein, described herein. Non-limiting examples of such cancers are described herein.

[0105] An exemplary sequence for 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] The term "CBM complex-associated cancer component," as used herein, refers to a cancer associated with or having dysregulation of the expression, activity, or levels of a gene, protein, or any (e.g., one or more) thereof associated with a component of the CBM complex. 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 levels of a particular gene, a particular 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 particular gene, a particular protein, or any (e.g., one or more) thereof described herein). Non-limiting examples of such cancers are described herein.

[0108] The term "MALT1-associated autoimmune disorder," as used herein, 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] The term "MALT1-associated inflammatory disorder," as used herein, refers to an inflammatory disorder associated with or involving 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 inflammatory disorders are described herein.

[0110] The term "MALT1-associated cancer," as used herein, refers to cancer associated with or having dysregulation 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 expression, activity, or levels thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the MALT1 gene, MALT1 protein, MALT1 protease domain, or any 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 the MALT1 protease domain and a fusion partner, a mutation in the MALT1 gene resulting in the expression of a MALT1 protein with at least one amino acid deletion 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 at least one inserted 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 resulting in a MALT1 protein with at least one amino acid deletion 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 can be a mutation in the MALT1 gene that encodes a MALT1 protein that is constitutively active or has increased activity compared to the protein encoded by a MALT1 gene that does not contain the mutation. As a further example, an increase in the copy number of the MALT1 gene can result in overexpression of the MALT1 protease. For example, dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protein, or any of them can 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., that is not MALT1).In some instances, dysregulation of the MALT1 gene, MALT1 protein, or expression or activity or levels of 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] The term "CARD11-associated autoimmune disorder," as used herein, 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] The term "CARD11-associated inflammatory disorder," as used herein, refers to an inflammatory 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).

[0116] The term "CARD11-associated cancer," as used herein, refers to a cancer that is associated with or has dysregulation of the expression, activity, or level 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 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 expression of a fusion protein comprising a CARD11 domain and a fusion partner, a mutation in the CARD11 gene resulting in expression of a CARD11 protein with at least one amino acid deletion compared to the wild-type CARD11 protein, a mutation in the CARD11 gene resulting in 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 expression of a CARD11 protein with at least one inserted amino acid compared to the wild-type CARD11 protein, a gene duplication resulting in increased levels of CARD11 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in increased levels of CARD11 protein in a cell), a CARD11 protein resulting in a CARD11 protein with at least one amino acid deletion 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 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 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 a protein encoded by a CARD11 gene that does not contain the 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, dysregulated expression, activity, or levels of the CARD11 gene, CARD11 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 CARD11 and a second portion of a partner protein (i.e., that is not CARD11).In some instances, 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] The term "CARD14-associated autoimmune disorder," as used herein, refers to an autoimmune disorder associated with or having dysregulation of the expression, activity, or levels of the CARD14 gene, the CARD14 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 CARD14 gene, the CARD14 protein, or any of them described herein).

[0121] The term "CARD14-associated inflammatory disorder," as used herein, refers to an inflammatory disorder associated with or having dysregulation of the expression, activity, or levels of the CARD14 gene, the CARD14 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 CARD14 gene, the CARD14 protein, or any of them described herein).

[0122] The term "CARD14-associated cancer," as used herein, refers to a cancer that is associated with or has dysregulation of the expression, activity, or levels of the CARD14 gene, the CARD14 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 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] The term "CARD10-associated autoimmune disorder," as used herein, refers to an autoimmune disorder associated with or having dysregulation of the expression, activity, or levels of the CARD10 gene, the CARD10 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 CARD10 gene, the CARD10 protein, or any of them described herein).

[0125] The term "CARD10-associated inflammatory disorder," as used herein, refers to an inflammatory disorder associated with or having dysregulation of the expression, activity, or levels of the CARD10 gene, CARD10 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 CARD10 gene, CARD10 protein, or any of them described herein).

[0126] The term "CARD10-associated cancer," as used herein, refers to a cancer that is associated with or has dysregulation of the expression, activity, or levels of the CARD10 gene, CARD10 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 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 expression of a fusion protein comprising a CARD10 domain and a fusion partner, a mutation in the CARD10 gene resulting in expression of a CARD10 protein with at least one amino acid deletion compared to the wild-type CARD10 protein, a mutation in the CARD10 gene resulting in 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 expression of a CARD10 protein with at least one inserted amino acid compared to the wild-type CARD10 protein, a gene duplication resulting in increased levels of CARD10 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in increased levels of CARD10 protein in a cell), a CARD10 protein resulting in a CARD10 protein with at least one amino acid deletion 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 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, dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them can be a mutation in the CARD10 gene that encodes a CARD10 protein that is constitutively active or has increased activity compared to a protein encoded by a CARD10 gene that does not contain the mutation. As a further example, an increase in the copy number of the CARD10 gene can result in overexpression of the CARD10 protein. For example, dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them can 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., that is 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] The term "CARD9-associated autoimmune disorder," as used herein, refers to an autoimmune disorder that is associated with or has dysregulation of the expression, activity, or levels of the CARD9 gene, CARD9 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 CARD9 gene, CARD9 protein, or any of them described herein).

[0130] The term "CARD9-associated inflammatory disorder," as used herein, refers to an inflammatory disorder associated with or having dysregulation of the expression, activity, or levels of the CARD9 gene, CARD9 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 CARD9 gene, CARD9 protein, or any of them described herein).

[0131] The term "CARD9-associated cancer," as used herein, refers to a cancer that is associated with or has dysregulation of the expression, activity, or levels of the CARD9 gene, CARD9 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 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 expression of a fusion protein comprising a CARD9 domain and a fusion partner, a mutation in the CARD9 gene resulting in expression of a CARD9 protein with at least one amino acid deletion compared to the wild-type CARD9 protein, a mutation in the CARD9 gene resulting in 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 expression of a CARD9 protein with at least one inserted amino acid compared to the wild-type CARD9 protein, a gene duplication resulting in increased levels of the CARD9 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in increased levels of the CARD9 protein in a cell), a CARD9 protein with at least one amino acid deletion 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 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 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 a protein encoded by a CARD9 gene that does not contain the 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 levels 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., that is 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] The term "BCL10-associated autoimmune disorder," as used herein, refers to an autoimmune disorder that is associated with or has dysregulation of the expression, activity, or levels of the BCL10 gene, the BCL10 protein, or any (e.g., one or more) thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the BCL10 gene, the BCL10 protein, or any (e.g., one or more) thereof described herein).

[0135] The term "BCL10-associated inflammatory disorder," as used herein, refers to an inflammatory disorder associated with or having dysregulation of the expression, activity, or levels of the BCL10 gene, BCL10 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 BCL10 gene, BCL10 protein, or any of them described herein).

[0136] The term "BCL10-associated cancer," as used herein, refers to a cancer that is associated with or has dysregulation of the expression, activity, or levels of the BCL10 gene, the BCL10 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 BCL10 gene, the 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 that results in the expression of a fusion protein comprising a BCL10 domain and a fusion partner, a mutation in the BCL10 gene that results in the expression of a BCL10 protein with at least one amino acid deletion compared to the wild-type BCL10 protein, a mutation in the BCL10 gene that results in the expression of a BCL10 protein with one or more point mutations compared to the wild-type BCL10 protein, a mutation in the BCL10 gene that results in the expression of a BCL10 protein with at least one inserted amino acid compared to the wild-type BCL10 protein, a gene duplication that results in an increased level of BCL10 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of BCL10 protein in a cell), a BCL10 protein that results in a BCL10 protein with at least one amino acid deletion 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 alternatively spliced ​​versions of mRNA, or aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control, non-cancerous cells). For example, dysregulated expression, activity, or levels of the BCL10 gene, BCL10 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 BCL10 and a second portion of a partner protein (i.e., that is not BCL10). In some examples, dysregulated expression, activity, or levels of the BCL10 gene, BCL10 protein, or any of them can be the result of a genetic translocation between one BCL10 gene and another, non-BCL10 gene.

[0138] An exemplary sequence for 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]

[0140] The term "MALT1 protease substrate-associated cancer," as used herein, refers to a cancer associated with or having dysregulation of the expression, activity, or levels of a gene, protein, or any (e.g., one or more) thereof 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, Regnace-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 levels of the particular gene, particular 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 particular gene, 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 Regnus 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) SEQ ID NO: 17 (UniParc accession number UPI000006F045) MDEKTKKAEEMALSLTRAVAGGDEQVAMKCAIWLAEQRVPLSVQLKPEVSPTQDIRLWVSVEDAQMHTVTIWLTVRPDMTVASLKDMVFLDYGFPPVLQQWVIGQRLARDQETLHSHGVRQNGDSAY LYLLSARNTSLNPQELQRERQLRMLEDLGFKDLTLQPRGPLEPGPPKPGVPQEPGRGQPDAVPEPPPVGWQCPGCTFINKPTRPGCEMCCRARPEAYQVPASYQPDEEERARLAGEEEALRQYQQRKQ QQQEGNYLQHVQLDQRSLVLNTEPAECPVCYSVLAPGEAVVLRECLHTFCRECLQGTIRNSQEAEVSCPFIDNTYSCSGKLLEREIKALLTPEDYQRFLDLGISIAENRSAFSYHCKTPDCKGWCFF EDDVNEFTCPVCFHVNCLLCKAIHEQMNCKEYQEDLALRAQNDVAARQTTEMLKVMLQQGEAMRCPQCQIVVQKKDGCDWIRCTVCHTEICWVTKGPRWGPGGPGDTTSGGCRCRVNGIPCHPSCQNCH

[0148] An exemplary sequence for human NIK is shown below: SEQ ID NO: 18 (UniParc accession number UPI0000074220) MAVMEMACPGAPGSAVGQQKELPKAKEKTPPLGKKQSSVYKLEAVEKSPVFCGKWEILNDVITKGTAKEGSEAGPAAISIIAQAECENSQEFSPTFSERIFIAGSKQYSQSESLDQIPNNVAHATEGKMARVCWKGKRRSKARKKRKKKSSKSLAHAGVALAKPLPRTPEQESCTIPVQEDESPLGAPYVRNTPQFTKPLKEPGLGQLCFKQLGEGLRPALPRSELHKLISPLQCLNHVWKLHHPQDGGPLPLPTHPFPYSRLPHPFPFHPLQPWKPHPLESFLGKLACVDSQKPLPDPHLSKLACVDSPKPLPGPHLEPSCLSRGAHEKFSVEEYLVHALQGSVSSGQAHSLTSLAKTWAARGSRSREPSPKTEDNEGVLLTEKLKPVDYEYREEVHWATHQLRLGRGSFGEVHRMEDKQTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQLVKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVCLQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFFRGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNRALQQVGGLKSPWRGEYKEPRHPPPNQANYHQTLHAQPRELSPRAPGPRPAEETTGRAPKLQPPLPPEPPEPNKSPPLTLSKEESGMWEPLPLSSLEPAPARNPSSPERKATVPEQELQQLEIELFLNSLSQPFSLEEQEQILSCLSIDSLSLSDDSEKNPSKASQSSRDTLSSGVHSWSSQAEARSSSWNMVLARGRPTDTPSYFNGVKVQIQSLNGEHLHIREFHRVKVGDIATGISSQIPAAAFSLVTKDGQPVRYDMEVPDSGIDLQCTLAPDGSFAWSWRVKHGQLENRP

[0149] An exemplary sequence of human LIMA1α is shown below: SEQ ID NO: 19 (UniParc accession number UPI000002A906) MENCLGESRHEVEKSEISENTDASGKIEKYNVPLNRLKMMFEKGEPTQTKILRAQSRSASGRKISENSYSLDDLEIGPGQLSSSTFDSEKNESRRNLELPRLSETSIKDRMAKYQAAVSKQSSSTNYTNELKASGGEIKIHKMEQKENV PPGPEVCITHQEGEKISANENSLAVRSTPAEDDSRDSQVKSEVQQPVHPKPLSPDSRASSLSESSPPKAMKKFQAPARETCVECQKTVYPMERLLANQQVFHISCFRCSYCNNKLSLGTYASLHGRIYCKPHFNQLFKSKGNYDEGFGHR PHKDLWASKNENEEILERPAQLANARETPHSPGVEDAPIAKVGVLAASMEAKASSQQEKEDKPAETKKLRIAWPPPTELGSSGSALEEGIKMSKPKWPPEDEISKPEVPEDVDLDLKKLRRSSSLKERSRPFTVAASFQSTSVKSPKTVS PPIRKGWSMSEQSEESVGGRVAERKQVENAKASKKNGNVGKTTWQNKESKGETGKRSKEGHSLEMENENLVENGADSDEDDNSFLKQQSPQEPKSLNWSSFVDNTFAEEFTTQNQKSQDVELWEGEVVKELSVEEQIKRNRYYDEDEDEE

[0150] The term "cancer associated with a component of the NF-κB pathway downstream of the CBM complex," as used herein, refers to a cancer associated with or having dysregulation of the expression, activity, or levels of a gene, protein, or any (e.g., one or more) 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 levels of the particular gene, particular 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 particular gene, particular protein, or any of them described herein). Non-limiting examples of such cancers are described herein.

[0151] An exemplary sequence of human TAK1 is shown below. SEQ ID NO: 20 (UniParc accession number UPI000012EAD6) MSTASAASSSSSSSAGEMIEAPSQVLNFEEIDYKEIEVEEVVGRGAFGVVCKAKWRAKDVAIKQIESESERKAFIVELRQLSRVNHPNIVKLYGACLNPVCLVMEYAEGGSLYNVLHGAEPLPYYTAAHAMSWCLQCSQGVAYLHSMQPKA LIHRDLKPPNLLLVAGGTVLKICDFGTACDIQTHMTNNKGSAAWMAPEVFEGSNYSEKCDVFSWGIILWEVITRRKPFDEIGGPAFRIMWAVHNGTRPPLIKNLPKPIESLMTRCWSKDPSQRPSMEEIVKIMTHLMRYFPGADEPLQYPCQ YSDEGQSNSATSTGSFMDIASTNTSNKSDTNMEQVPATNDTIKRLESKLLKNQAKQQSESGRLSLGASRGSSVESLPPTSEGKRMSADMSEIEARIAATTAYSKPKRGHRKTASFGNILDVPEIVISGNGQPRRRSIQDLTVTGTEPGQVS SRSSSPSVRMITTSGPTSEKPTRSHPWTPDDSTDTNGSDNSIPMAYLTLDHQLQPLAPCPNSKESMAVFEQHCKMAQEYMKVQTEIALLLQRKQELVAELDQDEKDQQNTSRLVQEHKKLLDENKSLSTYYQQCKKQLEVIRSQQQKRQGTS

[0152] An exemplary sequence for human TRAF6 is shown below. SEQ ID NO: 21 (UniParc accession number UPI000000D924) MSLLNCENSCGSQSESDCCVAMASSCSAVTKDDSVGGTASTGNLSSSFMEEIQGYDVEFDPPLESKYECPICLMALREAVQTPCGHRFCKACIIKSIRDAGHKCPVDNEILLENQLFPDNFAKREILSL MVKCPNEGCLHKMELRHLEDHQAHCEFALMDCPQCQRPFQKFHINIHILKDCPRRQVSCDNCAASMAFEDKEIHDQNCPLANVICEYCNTILIREQMPNHYDLDCPTAPIPCTFSTFGCHEKMQRNHLARH LQENTQSHMRMLAQAVHSLSVIPDSGYISEVRNFQETIHQLEGRLVRQDHQIRELTAKMETQSMYVSELKRTIRTLEDKVAEIEAQQCNGIYIWKIGNFGMHLKCQEEEKPVVIHSPGFYTGKPGYKLCM RLHLQLPTAQRCANYISLFVHTMQGEYDSHLPWPFQGTIRLTILDQSEAPVRQNHEEIMDAKPELLAFQRPTIPRNPKGFGYVTFMHLEALRQRTFIKDDTLLVRCEVSTRFDMGSLRREGFQPRSTDAGV

[0153] An exemplary sequence of human TAB1 is shown below: SEQ ID NO: 22 (UniParc accession number UPI0000136861) MAAQRRSLLQSEQQPSWTDDLPLCHLSGVGSASNRSYSADGKGTESHPPEDSWLKFRSENNCFLYGVFNGYDGNRVTNFVAQRLSAELLLGQLNAEHAEADVRRVLLQAFDVVERSFLESIDDALA EKASLQSQLPEGVPQHQLPPQYQKILERLKTLEREISGGAMAVVAVLLNNKLYVANVGTNRALLCKSTVDGLQVTQLNVDHTTENEDELFRLSQLGLDAGKIKQVGIICGQESTRRIGDYKVKYGY TDIDLLSAAKSKPIIAEPEIHGAQPLDGVTGFLVLMSEGLYKALEAAHGPGQANQEIAAMIDTEFAKQTSLDAVAQAVVDRVKRIHSDTFASGGERARFCPRHEDMTLLVRNFGYPLGEMSQPTPS PAPAAGGRVYPVSVPYSSAQSTSKTSVTLSLVMPSQGQMVNGAHSASTLDEATPTLTNQSPTLTLQSTNTHTQSSSSSSDGGLFRSRPAHSLPPGEDGRVEPYVDFAEFYRLWSVDHGEQSVVTAP

[0154] An exemplary sequence for human TAB2 is shown below: SEQ ID NO: 23 (UniParc accession number UPI0000073C75) MAQGSHQIDFQVLHDLRQKFPEVPEVVVSRCMLQNNNNLDACCAVLSQESTRYLYGEGDLNFSDDSGISGLRNHMTSLNLDLQSQNIYHHGREGSRMNGSRTLTHSISDGQLQGGQSNSELFQQEPQTAPAQVPQGFNVFGMSSSGASNSAPHLGFHLGSKGTSSLSQQTPR FNPIMVTLAPNIQTGRNTPTSLHIHGVPPPVLNSPQGNSIYIRPYITTPGGTTRQTQQHSGWVSQFNPMNPQQVYQPSQPGPWTTCPASNPLSHTSSQQPNQQGHQTSHVYMPISSPTTSQPPTIHSSGSSQSSAHSQYNIQNISTGPRKNQIEIKLEPPQRNNSSKLRSSGP RTSSTSSSVNSQTLNRNQPTVYIAASPPNTDELMSRSQPKVYISANAATGDEQVMRNQPTLFISTNSGASAASRNMSGQVSMGPAFIHHHPPKSRAIGNNSATSPRVVVTQPNTKYTFKITVSPNKPPAVSPGVVSPTFELTNLLNHPDHYVETENIQHLTDPTLAHVDRISE TRKLSMGSDDAAYTQALLVHQKARMERLQRELEIQKKKLDKLKSEVNEMENNLTRRRLKRSNSISQIPSLEEMQQLRSCNRQLQIDIDCLTKEIDLFQARGPHFNPSAIHNFYDNIGFVGPVPPKPKDQRSIIKTPKTQDTEDDEGAQWNCTACTFLNHPALIRCEQCEMPRHF

[0155] An exemplary sequence for human TAB3 is shown below. SEQ ID NO: 24 (UniParc accession number UPI0000071648) MAQSSPQLDIQVLHDLRQRFPEIPEGVVSQCMLQNNNNLEACCRALSQESSKYLYMEYHSPDDNRMNRNRLLHINLGIHSPSSYHPGDGAQLNGGRTLVHSSSDGHIDPQHAAGKQLICLVQEPHSAPAVVAATPNYNPFFMNEQNRSAATPSQPPQQPSSMQTGMNPSAMQGPSPP PPPPSYMHIPRYSTNPITVTVSQNLPSGQTVPRALQILPQIPSNLYGSPGSIYIRQTSQSSSGRQTPQSTPWQSSPQGPVPHYSQRPLPVYPHQQNYQPSQYSPKQQQIPQSAYHSPPSQCPSPFSSPQHQVQPSQLGHIFMPPSPSTTPPHPYQQGPPSYQKQGSHSVAYLPYTAS SSLSK LEKEELERLKSEVNGMEHDLMQRRLRRVSCTTAIPTPEEMTRLRSMNRQLQINVDCTLKEVDLLQSRGNFDPKAMNNFYDNIEPGPVVPPKPSKKDSSDPCTIERKARRISVTSKVQADIHDTQAAAADEHRTGSTQSPRTQPRDEDYEGAPWNCDSCTFLNHPALNRCEQCEMPRYT

[0156] An exemplary sequence of human MKK7 is shown below. SEQ ID NO: 25 (UniParc accession number UPI000012F494) MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPTLQLPLANDGGSRSPSSESSPQHPTPPARPRHMLGLPSTLFTPRSMESIEIDQKLQEIMKQTG YLTIGGQRYQAEINDLENLGEMGSGTCGQVWKMRFRKTGHVIAVKQMRRSGNKEENKRILMDLDVVLKSHDCPYIVQCFGTFITNTDVFIAMELMGTCAEKLKKR MQGPIPERILGKMTVAIVKALYYLKEKHGVIHRDVKPSNILLDERGQIKLCDFGISGRLVDSKAKTRSAGCAAYMAPERIDPPDPTKPDYDIRADVWSLGISLVE LATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDCLTKDHRKRPKYNKLLEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR

[0157] An exemplary sequence of human IKKα is shown below. SEQ ID NO: 26 (UniParc accession number UPI000013D6C7) MERPPGLRPGAGGPWEMERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCHEIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTSFVGTLQ YLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPKCIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRCFVLMDHILNLKIVHILNMTSAKIISFLLPPDESLHSLQSRIERETGINTGSQELLSETGISLDPRKPASQCV LDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPIIQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKLEFFHKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYAEVGVIGYLEDQIMSLHAEIMELQKSPYGRRQGDLME SLEQRAIDLYKQLKHRPSDHSYSDSTEMVKIIVHTVQSQDRVLKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQSSARSLVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHLSTIIHEANEEQGNSMMNLDWSWLTE

[0158] An exemplary sequence of human IKKβ is shown below. SEQ ID NO: 27 (UniParc accession number UPI0000033729) MSWSPSLTTQTCGAWEMKERLGTGGFGNVIRWHNQETGEQIAIKQCRQELSPRNRERWCLEIQIMRRLTHPNVVAARDVPEGMQNLAPNDLPLLAMEYCQGGDLRKYLNQFENCCGLREGAILTLLSDIASALRYLHENRIIHRDLKPENIVLQQGEQRLIHKIIDLGYAKELDQGSLCTSFVGTLQYL APELLEQQKYTVTVDYWSFGTLAFECITGFRPFLPNWQPVQWHSKVRQKSEVDIVVSEDLNGTVKFSSSLPYPNNLNSVLAERLEKWLQLMLMWHPRQRGTDPTYGPNGCFKALDDILNLKLVHILNMMVTGTIHTYPVTEDESLQSLKARIQQDTGIPEEDQELLQEAGLALIPDKPATQCISDGKLNE GHTLDMDLVFLFDNSKITYETQISPRPQPESVSCILQEPKRNLAFFQLRKVWGQVWHSIQTLKEDCNRLQQGQRAAMMNLLRNNSCLSKMKNSMASMSQQLKAKLDFFKTSIQIDLEKYSEQTEFGITSDKLLLAWREMEQAVELCGRENEVKLLVERMMALQTDIVDLQRSPMGRKQGGTLDDLEEQA RELYRRLREKPRDQRTEGDSQEMVRLLLQAIQSFEKKVRVIYTQLSKTVVCKQKALELLPKVEEVVSLMNEDEKTVVRLQEKRQKELWNLLKIACSKVRGPVSGSPDSMNASRLSQPGQLMSQPSTASNSLPEPAKKSEELVAEAHNLCTLLENAIQDTVREQDQSFTALDWSWLQTEEEEHSCLEQAS

[0159] An exemplary sequence of human IKKγ is shown below. SEQ ID NO: 28 (UniParc accession number UPI0000000CC4) MNRHLWKSQLCEMVQPSGGPAADQDVLGEESPLGKPAMLHLPSEQGAPETLQRCLEENQELRDAIRQSNQILERCEELLHFQASQREEKEFLMCKFQEARKLV ERLGLEKLDLKRQKEQALREVEHLKRCQQQMAEDKASVKAQVTSLLGELQESQSRLEAATKECQALEGRARAASEQARQLESEREALQQQHSVQVDQLRMQGQSV EAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSERKRGMQLEDLKQQLQQAEEALVAKQEVIDKLKEEAEQHKIVMETVPVLKAQADIYKADFQA ERQAREKLAEKKELLQEQLEQLQREYSKLKASCQESARIEDMRKRHVEVSQAPLPPAPAYLSSPLALPSQRRSPPEEPPDFCCPKCQYQAPDMDTLQIHVMECIE

[0160] 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.

[0161] An exemplary sequence for human IkBα is shown below: SEQ ID NO: 29 (UniParc accession number UPI000004F0A9) MFQAAERPQEWAMEGPRDGLKKERLLDDRHDSGLDSMKDEEYEQMVKELQEIRLEPQEVPRGSEPWKQQLTEDGDSFLHLAIIHEEKALTMEVIRQVKGDLAFLNFQNNLQQTPLHLAVITNQPEIAEALLGAGCDPELRDFRGNTPLHLACEQGCLA SVGVLTQSCTTPHLHSILKATNYNGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVDLQNPDLVSLLLKCGADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQLTLENLQMLPESEDEESYDTESEFTEFTEDELPYDDCVFGGQRLTL

[0162] An exemplary sequence of human p105 that is processed by p50 is shown below. SEQ ID NO: 30 (UniParc accession number UPI000000D917) MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYVCEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCEDGICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQAEGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIYDSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDFSPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQRKRQKLMPNFSDFGGSGAGAGGGGMFGSGGGGTGSTGPGYSFPHYGFPTYGGITFHPGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGEVTLT YATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQDENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVEDLLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMMSNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGTTPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMATSWQVFDILNGKPYEPEFTSDDLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLGLGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQAHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQEGPLEGKI

[0163] An exemplary sequence for human p65 is shown below. SEQ ID NO: 31 (UniParc accession number UPI000013ED68) MDELFPLIFPAEPAQASGPYVEIIEQPKQRGMRFRYKCEGRSAGSIPGERSTDTTKTHPTIKINGYTGPGTVRISLVTKDPPHRPHPHELVGKDCRDGFYEAELCPDRCIHSFQNLGIQCVKKRDLEQAISQRIQTN NNPFQVPIEEQRGDYDLNAVRLCFQVTVRDPSGRPLRLPPVLSHPIFDNRAPNTAELKICRVNRNSGSCLGGDEIFLLCDKVQKEDIEVYFTGPGWEARGSFSQADVHRQVAIVFRTPPYADPSLQAPVRVSMQLRRP SDRELSEPMEFQYLPDTDDRHRIEEKRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAPQPYPFTSSLSTINYDEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQAPAPVPVL APGPPQAVAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDLASVDNSEFQQLLNQGIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNGLLSGDEDFSSIADMDFSALLSQISS

[0164] An exemplary sequence of human c-Rel is shown below. SEQ ID NO: 32 (UniParc accession number UPI000013367B) MASGAYNPYIEIIEQPRQRGMRFRYKCEGRSAGSIPGEHSTDNNRTYPSIQIMNYYGKGKVRITLVTKNDPYKPHPHDLVGKDCRDGYYEAEFGQERRPLFFQNLGIRCVKKKEVKEAIITRIKAGINPFNVPEKQLNDIEDCDLNVVRLCFQVFLPDEHGNLTTALPPVVSNPIYDNRAPNTAELRICRVNKNCGSVRGGDEIFLLCDKVQKDDIEVRFVLNDWEAKGIFSQADVHRQVAIVFKTPPYCKAITEPVTVKMQLRRPSDQEVSESMDFRYLPDEKDTYGNKAKKQKTTLLFQKLCQDHVETGFRHVDQDGLELLTSGDPPTLASQSAGITVNFPERPRPGLLGSIGEGRYFKKEPNLFSHDAVVREMPTGVSSQAESYYPSPGPISSGLSHHASMAPLPSSSWSSVAHPTPRSGNTNPLSSFSTRTLPSNSQGIPPFLRIPVGNDLNASNACIYNNADDIVGMEASSMPSADLYGISDPNMLSNCSVNMMTTSSDSMGETDNPRLLSMNLENPSCNSVLDPRDLRQLHQMSSSSMSAGANSNTTVFVSQSDAFEGSDFSCADNSMINESGPSNSTNPNSHGFVQDSQYSGIGSMQNEQLSDSFPYEFFQV

[0165] The term "cancer associated with a component of the JNK pathway downstream of the CBM complex," as used herein, refers to a cancer associated with or having dysregulation of the expression, activity, or levels 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 a JNK1-associated cancer, a JNK2-associated cancer, a JNK3-associated cancer, a MYD88 transcription factor-associated cancer, an AP-1 transcription factor-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 levels of a particular gene, a particular protein, or any (e.g., one or more) ... protein, described herein. Non-limiting examples of such cancers are described herein.

[0166] An exemplary sequence of human JNK1 is shown below. SEQ ID NO: 33 (UniParc accession number UPI000012F17A) MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRPFQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYI VMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAPEVILGMGYKENVDLWSVGC IMGEMVCHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARDLLSKMLVIDASKRISVDEALQHPY INVWYDPSEEAEAPPPKIPDKQLDEREHTIEEWKELIYKEVMDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAAGPLGCCR

[0167] An exemplary sequence for human JNK2 is shown below. SEQ ID NO: 34 (UniParc accession number UPI000006E3AD) MSDSKCDSQFYSVQVADSTFTVLKRYQQLKPIGSGAQGIVCAAFDTVLGINVAVKKLSRPFQNQTHAKRAYRELVLLKCVNHKNIISLLNVFTPQKTLEEFQDVYL VMELMDANLCQVIHMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTACTNFMMTPYVVTRYYRAPEVILGMGYKENVDIWSVG CIMGELVKGCVIFQGTDHIDQWNKVIEQLGTPSAEFMKKLQPTVRNYVENRPKYPGIKFEELFPDWIFPSESERDKIKTSQARDLLSKMLVIDPDKRISVDEALRH PYITVWYDPAEAEAPPPQIYDAQLEEREHAIEEWKELIYKEVMDWEERSKNGVVKDQPSDAAVSSNATPSQSSSINDISSMSTEQTLASDTDSSLDASTGPLEGCR

[0168] An exemplary sequence of human JNK3 is shown below. SEQ ID NO: 35 (UniParc accession number UPI0000049042) MSLHFLYYCSEPTLDVKIAFCQGFDKQVDVSYIAKHYNMSKSKVDNQFYSVEVGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAVLDRNVAIKKLSRPFQNQTHAKRAYRELVLMK CVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAP EVILGMGYKENVDIWSVGCIMGEMVRHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRNYVENRPKYAGLTFPKLFPDSLFPADSEHNKLKASQARDLLSKMLVIDPAKRI SVDDALQHPYINVWYDPAEVEAPPPQIYDKQLDEREHTIEEWKELIYKEVMNSEEKTKNGVVKGQPSPSGAAVNSSESLPPSSSVNDISSMSTDQTLASDTDSSLEASAGPLGCCR

[0169] Compounds of formula (I) Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, each [ka] is a single or double bond, Q is —CH—, O, or NH; 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, then the other of X and Y is C; n is 1, 2, or 3; R X is hydrogen or halogen, 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 selected from hydroxyl and C1-C3 alkoxy; R 2 is hydrogen, halogen, amino, or C1-C3 alkyl; Each R 3 are independently deuterium, halogen, hydroxyl, C-C cycloalkyl, C-C alkyl, C-C alkoxy, C-C haloalkoxy, or C-C haloalkyl, or two R 3 taken together with the carbon atom to which they are attached form an oxo group, a 4- to 8-membered heterocyclyl, or a C3-C8 cycloalkyl; m is 0, 1, 2, or 3; R 4 is phenyl or 5- to 9-membered heteroaryl, 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; amino; -N=(S=O)(C1-C3 alkyl)2; -S(=O) p (C1-C3 alkyl); -(C=O)NR E R FC1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4- to 6-membered heterocyclyl, or hydroxyl or -NR E R F 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl optionally substituted with -NR E R F or C1-C3 alkoxy optionally substituted; 3- to 8-membered heterocyclyl; and C3-C6 cycloalkoxy; p is 1 or 2; R A , R B , R C , R D , R E , and R F are independently hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or R A and R B , or R C and R D , or R E and R F taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with 1 to 2 halogens.

[0170] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof has the structure: [ka] wherein each [ka] is a single or double bond, Q is —CH—, O, or NH; 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, then 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 selected from hydroxyl and C1-C3 alkoxy; R 2 is hydrogen, halogen, amino, or C1-C3 alkyl; Each R 3 are independently deuterium, halogen, hydroxyl, C-C cycloalkyl, C-C alkyl, C-C alkoxy, C-C haloalkoxy, or C-C haloalkyl, or two R 3 taken together with the carbon atom to which they are attached form an oxo group, a 4- to 8-membered heterocyclyl, or a C3-C8 cycloalkyl; m is 0, 1, 2, or 3; R 4 is phenyl or 5- to 9-membered heteroaryl, 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; amino; -N=(S=O)(C1-C3 alkyl)2; -S(=O) p (C1-C3 alkyl); -(C=O)NR E R FC1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4- to 6-membered heterocyclyl, or hydroxyl or -NR E R F 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl optionally substituted with -NR E R F or C1-C3 alkoxy optionally substituted; 3- to 8-membered heterocyclyl; and C3-C6 cycloalkoxy; p is 1 or 2; R A , R B , R C , R D , R E , and R F are independently hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or R A and R B , or R C and R D , or R E and R F taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with 1 to 2 halogens.

[0171] In some embodiments, Q is -CH2-. In some embodiments, Q is O. In some embodiments, Q is NH.

[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 halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkyl, -NR A R B or C1-C3 alkyl optionally substituted with 1 to 3 substituents selected from hydroxyl and C1-C3 alkoxy.

[0179] In some embodiments, R 1 is halogen or cyano. In some embodiments, R 1 is chloro or cyano. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halogen. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is cyano. In some embodiments, R 1 is a hydroxyl.

[0180] In some embodiments, R 1 is C1-C3 alkoxy. In some embodiments, R 1 is methoxy or ethoxy.

[0181] In some embodiments, R 1 is C1-C3 haloalkoxy. In some embodiments, R 1 is trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

[0182] In some embodiments, R 1 is C1-C3 haloalkyl. In some embodiments, R 1 is difluoromethyl, trifluoromethyl, or 2,2,2-trifluoroethyl.

[0183] 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 A and 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 and R are both hydrogen. A and R B are both C1-C3 alkyl. In some embodiments, R A and RB 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 are both ethyl.

[0184] In some embodiments, R A and R B taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. A and R B are taken together with the nitrogen atom to which they are attached to form a 4-membered heterocyclyl. A and R B are taken together with the nitrogen atom to which they are attached to form a 5-membered heterocyclyl. A and R B taken together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl.

[0185] In some embodiments, R 1 is C1-C3 alkyl optionally substituted with 1 to 3 substituents selected from hydroxyl and C1-C3 alkoxy. 1 is C1-C3 alkyl optionally substituted with one substituent selected from hydroxyl and C1-C3 alkoxy. In some 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, R1 is C-C alkyl optionally substituted with C-C alkoxy (e.g., methoxy). In some embodiments, R 1 is hydroxymethyl or methoxyethyl.

[0186] In some embodiments, R 1 is unsubstituted C1-C3 alkyl (e.g., methyl or ethyl).

[0187] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 is amino. In some embodiments, R 2 is a C1-C3 alkyl such as methyl.

[0188] 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.

[0189] 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.

[0190] In some embodiments, each R 3 are independently deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy.

[0191] In some embodiments, each R 3 is deuterium.

[0192] In some embodiments, each R 3 is independently halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, each R 3 is independently hydroxyl.

[0193] In some embodiments, each R 3 is independently C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl.

[0194] In some embodiments, each R 3are independently C1-C3 alkyl. For example, R 3 is methyl or ethyl. 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.

[0195] In some embodiments, Q is —CH—, m is 1, and each R 3 is C1-C3 alkyl. In some embodiments, Q is -CH2-, m is 2, and each R 3 is C1-C3 alkyl. In some embodiments, Q is -CH2-, m is 2, and R 3 is C1-C3 alkyl, and R 3 In some embodiments, Q is —CH— and each R 3 is independently C1-C3 alkyl. In some embodiments, Q is -CH2-, m is 2, and R 3 In some embodiments, Q is -CH-, m is 2, and each R 3 is C1-C3 haloalkyl. In some embodiments, Q is -CH2- and R 3 In some embodiments, Q is —CH—, m is 2, and one R 3 is C1-C3 alkyl, and the other R 3 is C1-C3 haloalkyl. In some embodiments, Q is -CH2-, m is 2, and one R 3is C1-C3 alkoxy, and the other R 3 is C1-C3 haloalkyl. In some embodiments, Q is -CH2- and R 3 In some embodiments, Q is —CH—, m is 2, and one R 3 is C1-C3 alkyl, and the other R 3 is C-C cycloalkyl. In some embodiments, m is 2 and one R 3 is trifluoromethyl, and the other R 3 In some embodiments, Q is -CH- and R 3 In some embodiments, Q is -CH-, m is 2, and one R 3 is C1-C3 haloalkyl, and the other R 3 is C-C cycloalkyl. In some embodiments, Q is -CH- and R 3 The groups are geminal C1-C3 haloalkyl and C3-C6 cycloalkyl groups.

[0196] In some embodiments, Q is —CH—, m is 1, and each R 3 In some embodiments, Q is -CH-, m is 2, and each R 3 In some embodiments, Q is -CH-, m is 2, and each R 3 is methyl and two R 3 In some embodiments, Q is -CH- and each R 3 is independently methyl. In some embodiments, Q is -CH-, m is 2, and R 3 In some embodiments, Q is -CH-, m is 2, and each R 3 In some embodiments, Q is -CH- and R 3In some embodiments, Q is -CH-, m is 2, and one R 3 is methyl, and the other R 3 In some embodiments, Q is -CH- and R 3 In some embodiments, Q is -CH-, m is 2, and one R 3 is methyl, and the other R 3 In some embodiments, Q is -CH- and R 3 In some embodiments, Q is -CH-, m is 2, and one R 3 is trifluoromethyl, and the other R 3 In some embodiments, Q is -CH- and R 3 The groups are geminal trifluoromethyl and cyclopropyl groups.

[0197] In some embodiments, Q is -CH-, m is 2, and two R 3 taken together with the carbon atom to which they are attached form an oxo group. In some embodiments, m is 2 and two R 3 are taken together with the carbon atom to which they are attached to form a C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). In some embodiments, m is 2 and two R 3 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl.

[0198] In some embodiments, two R 3 are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl. In some embodiments, m is 2 and two R 3are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl. 3 are taken together with the carbon atoms to which they are attached to form a 4- to 6-membered heterocyclyl. 3 taken together with the carbon atoms to which they are attached form a 4-membered heterocyclyl, such as oxetanyl or azetidinyl. In some embodiments, two R 3 are taken together with the carbon atoms to which they are attached to form a 5-membered heterocyclyl. 3 together with the carbon atoms to which they are attached form a 6-membered heterocyclyl such as tetrahydropyranyl. In some embodiments, m is 2 and two R 3 together with the carbon atoms to which they are attached form oxetanyl or tetrahydropyranyl.

[0199] In some embodiments, m is 3 and two R 3 The group is methyl and one R 3 is selected from the group consisting of methyl and hydroxyl.

[0200] In some embodiments, Q is O, m is 1, and each R 3 is C1-C3 alkyl. In some embodiments, Q is O, m is 2, and each R 3 is C1-C3 alkyl. In some embodiments, Q is O, m is 2, and R 3 is C1-C3 alkyl, and R 3 In some embodiments, Q is O and each R 3 is independently C1-C3 alkyl. In some embodiments, Q is O, m is 2, and R 3 In some embodiments, Q is O, m is 2, and each R 3 is C1-C3 haloalkyl. In some embodiments, Q is O and R3 In some embodiments, Q is O, m is 2, and one R 3 is C1-C3 alkyl, and the other R 3 is C1-C3 haloalkyl. In some embodiments, Q is O and R 3 In some embodiments, Q is O, m is 2, and one R 3 is C1-C3 alkyl, and the other R 3 is C-C cycloalkyl. In some embodiments, Q is O and R 3 In some embodiments, Q is O, m is 2, and one R 3 is C1-C3 haloalkyl, and the other R 3 is C-C cycloalkyl. In some embodiments, Q is O and R 3 The groups are geminal C1-C3 haloalkyl and C3-C6 cycloalkyl groups.

[0201] In some embodiments, Q is O, m is 1, and each R 3 In some embodiments, Q is O, m is 2, and each R 3 In some embodiments, Q is O, m is 2, and each R 3 is methyl and two R 3 In some embodiments, Q is O and each R 3 is independently methyl. In some embodiments, Q is O, m is 2, and R 3 In some embodiments, Q is O, m is 2, and each R 3 In some embodiments, Q is O and R 3In some embodiments, Q is O, m is 2, and one R 3 is methyl, and the other R 3 In some embodiments, Q is O and R 3 In some embodiments, Q is O, m is 2, and one R 3 is methyl, and the other R 3 In some embodiments, Q is O and R 3 In some embodiments, Q is O, m is 2, and one R 3 is trifluoromethyl, and the other R 3 In some embodiments, Q is O and R 3 The groups are geminal trifluoromethyl and cyclopropyl groups.

[0202] In some embodiments, Q is O, m is 2, and two R 3 are taken together with the carbon atoms to which they are attached to form an oxo group. In some embodiments, m is 2 and two R 3 taken together with the carbon atom to which they are attached form a C3-C8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

[0203] In some embodiments, Q is NH, m is 1, and each R 3 is C1-C3 alkyl. In some embodiments, Q is NH, m is 2, and each R 3 is C1-C3 alkyl. In some embodiments, Q is NH, m is 2, and R 3 is C1-C3 alkyl, and R 3In some embodiments, Q is NH and each R 3 is independently C1-C3 alkyl. In some embodiments, Q is NH, m is 2, and R 3 In some embodiments, Q is NH, m is 2, and each R 3 is C1-C3 haloalkyl. In some embodiments, Q is NH and R 3 In some embodiments, Q is NH, m is 2, and one R 3 is C1-C3 alkyl, and the other R 3 is C1-C3 haloalkyl. In some embodiments, Q is NH and R 3 In some embodiments, Q is NH, m is 2, and one R 3 is C1-C3 alkyl, and the other R 3 is C-C cycloalkyl. In some embodiments, Q is NH and R 3 In some embodiments, Q is NH, m is 2, and one R 3 is C1-C3 haloalkyl, and the other R 3 is C-C cycloalkyl. In some embodiments, Q is NH and R 3 The groups are geminal C1-C3 haloalkyl and C3-C6 cycloalkyl groups.

[0204] In some embodiments, Q is NH, m is 1, and each R 3 In some embodiments, Q is NH, m is 2, and each R 3 In some embodiments, Q is NH, m is 2, and each R 3 is methyl and two R 3In some embodiments, Q is NH and each R 3 is independently methyl. In some embodiments, Q is NH, m is 2, and R 3 In some embodiments, Q is NH, m is 2, and each R 3 In some embodiments, Q is NH and R 3 In some embodiments, Q is NH, m is 2, and one R 3 is methyl, and the other R 3 In some embodiments, Q is NH and R 3 In some embodiments, Q is NH, m is 2, and one R 3 is methyl, and the other R 3 In some embodiments, Q is NH and R 3 In some embodiments, Q is NH, m is 2, and one R 3 is trifluoromethyl, and the other R 3 In some embodiments, Q is NH and R 3 The groups are geminal trifluoromethyl and cyclopropyl groups.

[0205] In some embodiments, Q is NH, m is 2, and two R 3 are taken together with the carbon atoms to which they are attached to form an oxo group. In some embodiments, m is 2 and two R 3 taken together with the carbon atom to which they are attached form a C3-C8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

[0206] In some embodiments, R 4 is phenyl or 5- to 6-membered heteroaryl, and each R 4 The group is selected from one to two independently selected R 6 In some embodiments, R 4 is phenyl or 5- to 6-membered heteroaryl, and each R 4 The group is selected from two to three independently selected R 6 In some embodiments, R 4 is phenyl or 5- to 6-membered heteroaryl, and each R 4 The group may be one or three independently selected R 6 In some embodiments, R 4 is phenyl or 5- to 6-membered heteroaryl, and each R 4 The group is one independently selected R 6 In some embodiments, R 4 is phenyl or 5- to 6-membered heteroaryl, and each R 4 The group is selected from two independently selected R 6 In some embodiments, R 4 is phenyl or 5- to 6-membered heteroaryl, and each R 4 The group is selected from three independently selected R 6 are substituted as necessary by

[0207] 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 and optionally substituted with 1 to 3 substituents independently selected from:

[0208] In some embodiments, R 4is 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 by

[0209] In some embodiments, R 4 is unsubstituted phenyl.

[0210] In some embodiments, R 4 is R 6 In certain embodiments, R is phenyl substituted with 1 to 3 substituents independently selected from 4 is R 6 In certain embodiments, R 4 are two independently selected R 6 In some embodiments, R 4 are three independently selected R 6 is phenyl substituted by

[0211] In some embodiments, R 4 is R 6 In some embodiments, R is a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 (e.g., 2) substituents independently selected from 4 is R 6 and 6-membered heteroaryl optionally substituted with 1 to 3 (eg, 2) substituents independently selected from:

[0212] In some embodiments, R 4 is an unsubstituted 5-6 membered heteroaryl.

[0213] In some embodiments, R 4 is R 6 is a 5- to 6-membered heteroaryl substituted by 1 to 3 substituents independently selected from:

[0214] In some embodiments, R 4 is one to three (e.g., one or two) independently selected R 6 In some embodiments, R is a 5- to 9-membered heteroaryl optionally substituted with 4 is R 6 In some embodiments, R is a 5-9 membered heteroaryl substituted with 1-3 (e.g., 2) substituents independently selected from 4 is R 6 In some embodiments, R is a 9-membered heteroaryl optionally substituted with 1 to 3 (e.g., 2) substituents independently selected from 4 is R 6 In some embodiments, R is a 9-membered heteroaryl substituted with one substituent selected from 4 is a 9-membered heteroaryl containing pyridyl. In some embodiments, R 4 teeth, [ka] and ring B is R 6 In some embodiments, R is a 4- to 5-membered heterocyclyl optionally substituted with 1 to 2 (e.g., 1) substituents selected from 4 teeth, [ka] is.

[0215] In some embodiments, R 4 is an unsubstituted 5-6 membered heteroaryl. In some embodiments, R 6 At least one of R is halogen. 6At 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 is amino.

[0216] In some embodiments, R 6 At least one of the groups is —(C═O)NR E R F In some embodiments, R E and R F is independently hydrogen or C1-C3 alkyl. In some 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 C-C cycloalkyl. In some embodiments, R E and R F is C1-C3 alkyl, and R E and R Fand the other is C-C cycloalkyl. 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 The other of R is ethyl. E and R F is hydrogen and R E and R F The other of R is cyclopropyl. E and R F is methyl, and R E and R F and the other is cyclopropyl. In certain embodiments, R E and R F and R are both hydrogen. 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 are both ethyl.

[0217] In some embodiments, R E and R F are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl. E and R F taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with 1-2 halogens. E and R Ftaken together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl. E and R F are taken together with the nitrogen atom to which they are attached to form azetidin-1-yl or 3,3-difluoro-azetidin-1-yl. In some embodiments, R E and R F are taken together with the nitrogen atom to which they are attached to form a 5-membered heterocyclyl. E and R F taken together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl.

[0218] In some embodiments, R 6 At least one of is -N=(S=O)(C1-C3 alkyl). In some embodiments, each (C1-C3 alkyl) is the same. In some embodiments, each (C1-C3 alkyl) is different. In some embodiments, each (C1-C3 alkyl) is methyl.

[0219] In some embodiments, R 6 At least one of the following is -S(=O) p (C1-C3 alkyl). In some embodiments, each (C1-C3 alkyl) is the same. In some embodiments, each (C1-C3 alkyl) is different. In some embodiments, each (C1-C3 alkyl) is methyl.

[0220] In some embodiments, p is 1. In some embodiments, p is 2.

[0221] In some embodiments, R 6 At least one of R is C-C alkoxy. 6 At least one of is methoxy or ethoxy.

[0222] In some embodiments, R 6At least one of R is C-C haloalkyl optionally substituted with hydroxyl. 6 At least one of R is an unsubstituted C-C haloalkyl. 6 At least one of R is C-C haloalkyl substituted with hydroxyl. 6 At least one of R is trifluoromethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl. 6 At least one of is 1-hydroxy-2,2-difluoroethyl.

[0223] In some embodiments, R 6 At least one of R is C-C haloalkoxy. 6 At least one of is trifluoromethoxy.

[0224] In some embodiments, R 6 At least one of is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4- to 6-membered heterocyclyl, 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 At least one of is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxyl, or -NR E R F In some embodiments, R is C1-C3 alkyl optionally substituted with C1-C3 alkyl, amino, or 5-6 membered heteroaryl optionally substituted with C1-C3 haloalkyl. 6 is hydroxyl or -NR E R FIn 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. 6 At least one of is a 5- to 6-membered heteroaryl optionally substituted with a 4- to 6-membered heterocyclyl.

[0225] In certain embodiments, R 6 At 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. 6is a 6-membered heteroaryl substituted by hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, propan-2-ol, or propan-2-amine.

[0226] 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 some embodiments, R 6 At least one of the groups is hydroxyl, -NR E R F or C1-C4 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. In some embodiments, R 6 At least one of is 1-hydroxyethyl or 2-hydroxypropan-2-yl.

[0227] In some embodiments, R E and R F is independently hydrogen or C1-C3 alkyl. In some 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 Fand the other is C-C cycloalkyl. In some embodiments, R E and R F is C1-C3 alkyl, and R E and R F and the other is C-C cycloalkyl. 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 The other of R is ethyl. E and R F is hydrogen and R E and R F The other of R is cyclopropyl. E and R F is methyl, and R E and R F and the other is cyclopropyl. In certain embodiments, R E and R F and R are both hydrogen. 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 are both ethyl.

[0228] In some embodiments, R E and R F taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. E and RF taken together with the nitrogen atom to which they are attached form a 4-membered heterocyclyl. E and R F taken together with the nitrogen atom to which they are attached form azetidinyl or 2-oxoazetidin-1-yl. In some embodiments, R E and R F taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl. E and R F are taken together with the nitrogen atom to which they are attached to form 2-oxopyrrolidin-1-yl. In some embodiments, R E and R F taken together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl.

[0229] 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 6-membered heterocyclyl. 6 At least one of R is a 7-membered heterocyclyl. 6 At least one of is an 8-membered heterocyclyl.

[0230] In some embodiments, R 6 At least one of R is C-C cycloalkoxy. 6 At least one of is cyclopropoxy or cyclobutoxy.

[0231] In some embodiments, R 4 is pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, or imidazolyl, each of which is a group consisting of two R 6 and one R 6 is triazolyl, imidazolyl, oxazolyl, pyrazolyl, or pyrrolidinyl, and the other R 6 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. 4 is pyridyl, pyrimidinyl, or pyrazinyl, each of which is a group consisting of two R 6 and one R 6 is triazolyl, imidazolyl, oxazolyl, pyrazolyl, or pyrrolidinyl, and the other R 6 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano. 4 are two R 6 and one R is a pyridyl substituted by 6 is triazolyl, imidazolyl, or oxazolyl, and the other R 6 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro, or cyano.

[0232] In some embodiments, each R 6 are independently selected from halogen, cyano, amino, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkyl, and C3-C6 cycloalkoxy.

[0233] In some embodiments, R 4 is one to three independently selected R 6 and 3-pyridyl or 4-pyridyl substituted by:

[0234] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0235] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0236] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0237] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0238] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0239] In some embodiments, R 4 teeth, [ka] where the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0240] In some embodiments, R 4 but, [ka] If R 6 is selected from the group consisting of cyano, halogen, C1-C3 haloalkyl, and C1-C3 alkoxy.

[0241] In some embodiments, R 4 but, [ka] If R 6 is selected from the group consisting of C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 alkoxy optionally substituted with cyano, halogen, hydroxyl.

[0242] In some embodiments, R 4 but, [ka] If R 6 is selected from the group consisting of cyano, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and methoxy. For example, R 4 but, [ka] If R 6 is chloro or trifluoromethyl (eg chloro).

[0243] In some embodiments, R 4 teeth, [ka] and R 6A and R 6B is R 6 and the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0244] In some embodiments, R 4 teeth, [ka] and R 6A and R 6B is R 6 and the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0245] In some embodiments, R 4 teeth, [ka] and R 6A and R 6B is R 6 and the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0246] In some embodiments, R 4 teeth, [ka] and R 6A and R 6B is R 6 and the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0247] In some embodiments, R 4 but, [ka] If so.

[0248] R 6A is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R 6Bis cyano, C1-C3 alkyl optionally substituted with hydroxyl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl optionally substituted with amino; -N=(S=O)(C1-C3 alkyl)2; -(C=O)NR E R F C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; cyano; C3-C6 cycloalkoxy; and C1-C3 alkyl optionally substituted with hydroxyl.

[0249] In some embodiments, R 4 but, [ka] If 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-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-on-1-yl, 1-methyl-pyrazol-3-yl, 1-methyl-pyrazol-4-yl, 1-methyl-pyrazol-5-yl, pyrrol-1-yl, thiazol-2-yl, isothiazolidine-2-yl-1,1-dioxide, pyrrolidin-2-on-1-yl, oxazol-2-yl, oxadiazol-2-yl, 2-amino-pyrimidine -4-yl, -(C=O)4-methylpiperazin-1-yl, 2-oxoazetidin-1-yl, azetidin-1-yl, -(C=O)N(CH3)2, -(C=O)NHCH3, -(C=O)NHCH2CH3, -(C=O)NHcyclopropyl, -(C=O)(3,3-difluoroazetidin-1-y), 2-hydroxypropan-2-yl, 1-hydroxyethyl, dimethyl(oxo)-λ 6 -sulfanylidene, methoxy, ethoxy, difluoromethoxy, methyl, cyano.

[0250] In some embodiments, R 4 but, [ka] If R 6A is selected from the group consisting of cyano, chloro, methyl, and trifluoromethyl; R6B 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.

[0251] In some embodiments, R 4 but, [ka] If 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.

[0252] In some embodiments, R 4 teeth, [ka] and R 6A , R 6B , and R 6C is R 6 and the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0253] In some embodiments, R 4 teeth, [ka] and R 6A , R 6B , and R 6C is R6 and the wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I).

[0254] In some embodiments, R 4 but, [ka] If 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- to 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.

[0255] In some embodiments, R 4 but, [ka] If 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-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(CH3)2, -(C=O)NHCH3, methoxy, ethoxy, difluoromethoxy, methyl, cyano; R 6C is selected from the group consisting of cyano, fluoro, chloro, methyl, ethyl, methoxy, methyl, and trifluoromethyl.

[0256] In some embodiments, R 4 but, [ka] If 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.

[0257] In some embodiments, R 4 but, [ka] If 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.

[0258] In some embodiments, R 5 is hydrogen.

[0259] 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.

[0260] In some embodiments, R5 is C1-C3 alkoxy. In some embodiments, R 5 is methoxy or ethoxy.

[0261] In some embodiments, R 5 is C1-C3 haloalkoxy. In some embodiments, R 5 is trifluoromethoxy, difluoromethoxy, or fluoromethoxy.

[0262] In some embodiments, R 5 is C1-C3 haloalkyl. In some embodiments, R 5 is trifluoromethyl or 2,2,2-trifluoroethyl.

[0263] 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 and R are both hydrogen. C and R D are both C1-C3 alkyl. In some embodiments, R C 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 are both ethyl.

[0264] In some embodiments, R C and R D taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. C and R D are taken together with the nitrogen atom to which they are attached to form a 4-membered heterocyclyl. C and R D are taken together with the nitrogen atom to which they are attached to form a 5-membered heterocyclyl. C and R D taken together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl.

[0265] In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl or ethyl.

[0266] In some embodiments, R X is hydrogen. In some embodiments, R X is halogen. In some embodiments, R X is fluoro. In some embodiments, R X is chloro.

[0267] In some embodiments, the compound is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. [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

[0268] 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] R 4 -NH2, A process is provided that includes forming a compound of formula (I).

[0269] In some embodiments, the compound of formula (IA) is 4 The reaction with -NH2 (for example, 5-chloro-6-(triazolyl)pyridin-3-amine) is carried out in the presence of POCl3 and pyridine.

[0270] In some embodiments, the compound of formula (IA) is 4 The reaction with -NH2 is carried out in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH).

[0271] In some embodiments, the compound of formula (IA) is 4 The reaction with -NH2 is carried out in the presence of N-methylimidazole (NMI).

[0272] In some embodiments, the compound of formula (IA) is a compound of formula (IAN): [ka] It is prepared from

[0273] In some embodiments (when a compound of formula (IA) is prepared from a compound of formula (IAN)), the process comprises reacting a compound of formula (IANi) with [ka] reacting with a compound of formula (IAN-ii), [ka] forming a compound of formula (IAN):

[0274] 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.

[0275] In some of these embodiments, the acid is selected from the group consisting of hydrochloric acid and acetic acid.

[0276] Provided herein is a process for preparing a compound of formula (I) (e.g., any compound described herein), comprising: Compounds of formula (IB) [ka] R 4 -Hal, wherein Hal is selected from the group consisting of Cl, Br, I, and OSO2CF3; A process is provided that includes forming a compound of formula (I).

[0277] In some embodiments, the compound of formula (IB) is 4 The reacting with -Hal is carried out in the presence of a catalyst and a ligand.

[0278] In some embodiments, the compound of formula (IB) is 4 -Hal is carried out in the presence of a catalyst and a ligand), the catalyst is tris(dibenzylideneacetone)dipalladium(0).

[0279] In some embodiments, the compound of formula (IB) is 4 -Hal is carried out in the presence of a catalyst and a ligand), the ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0280] In some embodiments, the compound of formula (IB) is a compound of formula (IAN): [ka] It is prepared from

[0281] In some embodiments, the process comprises reacting a compound of formula (IANi) [ka] reacting with a compound of formula (IAN-ii), [ka] forming a compound of formula (IAN):

[0282] In some embodiments, reacting a compound of Formula (IANi) with a compound of Formula (IAN-ii) is carried out in the presence of an acid.

[0283] In some embodiments (when reacting a compound of Formula (IANi) with a compound of Formula (IAN-ii) is carried out in the presence of an acid), the acid is selected from the group consisting of hydrochloric acid and acetic acid.

[0284] Treatment method Some embodiments provide a method of treating an autoimmune disorder (e.g., a MALT1-associated 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 thereof. In some embodiments, the autoimmune disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE).

[0285] Some embodiments provide a method of treating an inflammatory disorder (e.g., a MALT1-associated 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 thereof. In some embodiments, the inflammatory disorder is chronic graft-versus-host disease (cGVHD).

[0286] Some embodiments provide methods for treating cancer (e.g., MALT1-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 thereof. For example, provided herein are methods for treating MALT1-associated cancer in a subject in need thereof, 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.

[0287] 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 selected from the group consisting of 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, and 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., a MALT1-associated cancer) is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adolescents, 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, carcinoma-like tumor, cancer of unknown primary, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, site-specific neoplasm, neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, nasal nerve Blastoma, 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, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, breast neoplasm, head and neck neoplasm, CNS tumor, primary CNS tumor, cardiac cancer, hepatocellular carcinoma, Histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, 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 of the neck, midline duct carcinoma, mouth cancer 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, respiratory tract neoplasm, bronchogenic carcinoma, bronchial neoplasm, oral cancercancer), oral cavity cancer, 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.

[0288] 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 a 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 (CMM), or myeloma. The hematological cancer is selected from the group consisting of acute myelodysplastic leukemia (ALCL), 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 syndromes (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.

[0289] In some embodiments, the cancer is glioblastoma, chronic myeloid leukemia, myeloid leukemia, or non-Hodgkin's lymphoma.

[0290] In some embodiments, the cancer (e.g., a 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, e.g., 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.

[0291] In some embodiments, the subject is a human.

[0292] The compound of formula (I) and its pharmaceutically acceptable salts are also useful for treating MALT1-associated cancers. 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.

[0293] 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) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0294] In some embodiments of any of the methods provided herein, the compound of Formula (I) is selected from Examples 1-168.

[0295] Dysregulation of the expression, activity, or levels 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 levels) 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.

[0296] In some embodiments, 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 herein 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.

[0297] 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 comprises performing an assay to detect dysregulation in the expression, activity, or level 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 comprises obtaining a sample (e.g., a biopsy sample) from the subject. The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0298] 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 a CBM complex pathway-associated cancer.

[0299] Also provided herein is a method for treating a MALT1-associated cancer in a subject, the method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject identified or diagnosed with a MALT1-associated cancer. Also provided herein is a method for treating cancer in a subject in need of cancer treatment, the method comprising: (a) determining that the cancer is associated with dysregulation of the MALT1 gene, MALT1 protease, or the expression, activity, or level of any of them; and (b) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0300] 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 comprises 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 comprises obtaining a sample (e.g., a biopsy sample) from the subject. The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0301] 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 transducer between a cell surface receptor and the CBM complex, a component of a CBM complex-associated cancer, a MALT1 protease substrate-associated cancer, a cancer 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 transducer 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 dysregulation in 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 in BCL10 and A20. In some embodiments, the cancer associated with an NF-κB pathway component downstream of the CBM complex is selected from the group consisting of a TAK1-associated cancer, a TRAF6-associated cancer, a TAB1-associated cancer, a TAB2-associated cancer, a TAB3-associated cancer, an MKK7-associated cancer, an IKKα-associated cancer, an IKKβ-associated cancer, an IKKγ-associated cancer, an IkBα-associated cancer, a p50-associated cancer, a p65(RelA)-associated cancer, a c-Rel-associated cancer, and a combination thereof. In some embodiments, the cancer associated with an NF-κB pathway component downstream of the CBM complex is an IKKγ-associated cancer. In some embodiments, the cancer associated with a JNK pathway component downstream of the CBM complex is selected from the group consisting of a JNK1-associated cancer, a JNK2-associated cancer, a JNK3-associated cancer, a MYD88 transcription factor-associated cancer, an AP-1 transcription factor-associated cancer, and a combination thereof.

[0302] 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.

[0303] Also provided herein are methods for treating CBM complex pathway-related diseases or disorders, autoimmune disorders, and inflammatory disorders. Accordingly, provided herein are methods 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 are methods for treating a MALT1-associated autoimmune disorder in a subject, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject identified or diagnosed with a MALT1-associated autoimmune disorder. In some cases, provided herein are methods 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 are methods for treating a MALT1-associated autoimmune disorder in a subject, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject determined to have a MALT1-associated autoimmune disorder. Additionally, provided herein are methods for treating an inflammatory disorder in a subject in need of such treatment, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject. In some cases, provided herein are methods for treating a MALT1-associated inflammatory disorder in a subject, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject identified or diagnosed as having a MALT1-associated inflammatory disorder.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 MALT1 gene, MALT1 protease, or the expression, activity, or level of any of them; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a MALT1-associated inflammatory disorder in a subject, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject determined to have a MALT1-associated inflammatory disorder.

[0304] Additionally provided herein is a method for treating a CBM complex pathway-associated disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a disease or disorder in a subject in need thereof, the method comprising: (a) identifying cancer as a CBM complex pathway-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, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the subject having been identified as having a CBM complex pathway-associated disease or disorder.

[0305] 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 pathway cell surface receptor-associated cancer, a disease or disorder associated with a signal transducer between a cell surface receptor and the CBM complex, a component of a CBM complex-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.

[0306] 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 dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protease protein, or any of them. In some embodiments, the dysregulated expression, activity, or levels of the MALT1 gene, MALT1 protease protein, or any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0307] 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 transducer 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.

[0308] In some embodiments, 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, 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, compounds provided herein are useful for treating primary or metastatic brain tumors. For example, the compounds may be used to treat one or more gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglioma, ependymoma, and mixed glioma, meningioma, medulloblastoma, ganglioglioma, schwannoma (schwannoma), 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)).

[0309] In some embodiments of any of the methods or uses described herein, the assay used to determine whether a subject has dysregulated expression, activity, or level of a gene (e.g., the MALT1 gene), or protein (e.g., the MALT1 protein), or any of them, using a sample from the subject, can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay can utilize other detection methods known in the art to detect dysregulated expression, activity, or level of a gene (e.g., the MALT1 gene), 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 suspected of having a MALT1-associated cancer, has one or more symptoms of a MALT1-associated cancer, and / or is at high risk of developing a MALT1-associated cancer).

[0310] 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 a fluid-phase biopsy). Liquid biopsy methods can be used to detect total 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 biological samples that are relatively easily obtained from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them. In some embodiments, 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., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them.

[0311] In some embodiments, ctDNA derived from a single gene can be detected using liquid biopsy. In some embodiments, ctDNA derived from multiple genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more genes, or any number in between) 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, activity, or levels of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them). Liquid biopsy 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 biopsy can be used to detect germline mutations. In some embodiments, liquid biopsy can be used to detect somatic mutations. In some embodiments, liquid biopsy can be used to detect primary genetic mutations (e.g., primary mutations or primary fusions associated with the early onset 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 foregoing 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 a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or the expression, activity, or levels of any of them in a subject can indicate that the subject will respond to a treatment comprising administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0312] 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 (e.g., if the genetic mutation detected at the first time point is reduced in abundance or undetectable). In some embodiments, the treatment administered to the subject can include a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the efficacy of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be determined by assessing the dysregulated allele frequency of a gene (e.g., the MALT1 gene) in cfDNA obtained from the subject at different time points, e.g., cfDNA obtained from the subject at a first time point and cfDNA obtained from the subject at a second time point, wherein at least one dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject between the first and second time points. Some embodiments of these methods 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 and second time points.For example, a reduction (e.g., 1% to about 99% reduction, 1% to about 95% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% reduction, 1% to about 75% reduction ... % reduction, 1% reduction to 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% ~approximately 99% reduction, approximately 15% to approximately 99% reduction, approximately 20% to approximately 99% reduction, approximately 25% to approximately 99% reduction, approximately 30% to approximately 99% reduction, approximately 35% to approximately 99% reduction, approximately 40% to approximately 99% reduction, approximately 45% to approximately 99% reduction, approximately 50% to approximately 99% reduction, approximately 55% to approximately 99% reduction, approximately 60% to approximately 99% reduction, approximately 65% ​​to approximately 99% reduction, approximately 70% to approximately 99% reduction, approximately 75% to approximately 95% reduction, approximately 80% to approximately 99% reduction, approximately 90% to approximately A 99% reduction, about 95% to about 99% reduction, about 5% to about 10% reduction, about 5% to about 25% reduction, about 10% to about 30% reduction, about 20% to about 40% reduction, about 25% to about 50% reduction, about 35% to about 55% reduction, about 40% to about 60% reduction, about 50% to about 75% reduction, about 60% to about 80% reduction, or about 65% to about 85% reduction) indicates that a 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 was not effective in the subject.Some embodiments of these methods may further include administering an additional dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject for whom the compound of Formula (I) or a pharmaceutically acceptable salt thereof has been determined to be effective. Some embodiments of these methods may further include administering a different treatment (e.g., a treatment that does not include administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof as monotherapy) to a subject for whom the compound of Formula (I) or a pharmaceutically acceptable salt thereof has been determined to be ineffective.

[0314] In some examples of these methods, the time difference between the first time point and the second time point is about 1 day to about 1 year, about 1 day to about 11 months, about 1 day to about 10 months, about 1 day to about 9 months, about 1 day to about 8 months, about 1 day to about 7 months, about 1 day to about 6 months, about 1 day to about 5 months, about 1 day to about 4 months, about 1 day to about 3 months, about 1 day to about 10 weeks, about 1 day to about 2 months, about 1 day to about 6 weeks, about 1 day to about 1 month, about 1 day to about 25 days, about 1 day to about 20 days, about 1 day to about 15 days, about 1 day to about 10 days, about 1 day to about 5 days, about 2 days to about 1 year, about 5 days to about 1 year, about 10 days to about 1 year, about 15 days to about 1 year, about 20 days to about 1 year, about 25 ... The period may be from days to about 1 year, from about 1 month to about 1 year, from about 6 weeks to about 1 year, from about 2 months to about 1 year, from about 3 months to about 1 year, from about 4 months to about 1 year, from about 5 months to about 1 year, from about 6 months to about 1 year, from about 7 months to about 1 year, from about 8 months to about 1 year, from about 9 months to about 1 year, from about 10 months to about 1 year, from about 11 months to about 1 year, from about 1 day to about 7 days, from about 1 day to about 14 days, from about 5 days to about 10 days, from about 5 days to about 20 days, from about 10 to about 20 days, from about 15 days to about 1 month, from about 15 days to about 2 months, from about 1 week to about 1 month, from about 2 weeks to about 1 month, from about 1 month to about 3 months, from about 3 months to about 6 months, from about 4 months to about 6 months, from about 5 months to about 8 months, or from about 7 months to about 9 months. In some embodiments of these methods, the subject may have previously been identified as having a cancer with a dysregulated gene (e.g., any of the examples of dysregulated genes described herein) (e.g., the MALT1 gene). In some embodiments of these methods, the subject may have previously been diagnosed with 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).

[0315] In some of the above embodiments, the cfDNA comprises ctDNA, such as MALT1-associated ctDNA. For example, the cfDNA is ctDNA, such as MALT1-associated ctDNA. In some embodiments, at least some portion of the cfDNA is determined to be MALT1-associated ctDNA, e.g., a sequenced and / or quantified amount of total cfDNA is determined to have a MALT1 fusion and / or MALT1 overexpression.

[0316] In the field of medical oncology, it is common practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology, in addition to the compositions provided herein, other components of such conjoint treatment or therapy can be, for example, surgery, radiation therapy, and other chemotherapeutic agents such as protease inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies.

[0317] For example, the surgery may be open surgery or minimally invasive surgery. Accordingly, the compounds of Formula (I) or pharmaceutically acceptable salts thereof may also be useful as adjuvants for cancer treatment, i.e., they may be used in combination with one or more additional therapies or therapeutic agents, e.g., chemotherapeutic agents that function by the same or different mechanisms of action. In some embodiments, the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be used prior to the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof may be administered one or more doses of the 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 the 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 the compound of Formula (I) or a pharmaceutically acceptable salt thereof for a period of time, followed by one or more rounds of radiation therapy. 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 rounds of radiation therapy.

[0318] In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumors) 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 cancer (e.g., locally advanced or metastatic tumors) that is refractory or intolerant to 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 cancer (e.g., locally advanced or metastatic tumors) 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.

[0319] 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 therapeutic or therapeutic agent can be any suitable additional therapeutic or therapeutic agent, such as any of those described herein.

[0320] Non-limiting examples of additional therapeutic agents include other MALT1-targeted therapeutic agents (i.e., a first or second MALT1 protease inhibitor, e.g., JNJ-67856633 or CTX-177), other protease inhibitors, kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents such as BTK or EGFR inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., venetoclax or obataclax), cytotoxic chemotherapy, angiogenesis-targeted therapy, immune-targeted agents (including antibody- and cell-based immunotherapies, and antibody-drug conjugates), and radiation therapy.

[0321] 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.

[0322] 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 about 25 nM, less than about 10 nM, or less than about 1 nM, as measured in the assays 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 the assays provided herein. 50 ) can be shown.

[0323] Non-limiting examples of protease-targeted therapeutic agents (e.g., first MALT1 inhibitors or second MALT1 inhibitors) include JNJ-67856633 and CTX-177.

[0324] 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, Agelafenib) (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)-4-yl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide), PD173955 (6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one), PP2 (4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine), PZ-1 (N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazole)-4-yl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide), -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)indolin-2-one), 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-methylbenzamide), SW-01 (cyclobenzaprine hydrochloride), XMD15-44 (N-(4-((4-ethylpiperazin-1-yl)methyl) -3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide (generated from the structure)), ITRI-305 (DON5TB, 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 ... N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide), 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.

[0325] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeted therapeutic agents 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'-bipyridin]-2'-yl)piperidin-4-ol.

[0326] In some embodiments, the additional therapeutic agent is a BRAF inhibitor.Non-limiting examples of BRAF inhibitors include dabrafenib, vemurafenib (also known as RG7204 or PLX4032), sorafenib tosylate, PLX-4720, GDC-0879, BMS-908662 (Bristol-Meyers Squibb), LGX818 (Novartis), PLX3603 (Hofmann-LaRoche), RAF265 (Novartis), RO5185426 (Hofmann-LaRoche), and GSK2118436 (GlaxoSmithKline).Additional examples of BRAF inhibitors are known in the art.

[0327] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors can include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0328] 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).

[0329] In some embodiments, the additional therapeutic agent is a BTK inhibitor. Non-limiting examples of BTK inhibitors include ibrutinib, acalabrutinib, and zanubrutinib.

[0330] 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.

[0331] 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.

[0332] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include everolimus, temsirolimus, and ridaforolimus.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] In some embodiments, the additional therapeutic agent is an angiogenesis-targeted therapeutic agent. Non-limiting examples of angiogenesis-targeted therapeutic agents include lenalidomide, enzastaurin, aflibercept, and bevacizumab.

[0337] In some embodiments, the additional therapeutic or therapeutic agent can comprise a histidyl-tRNA synthetase (HRS) polypeptide or an expressible nucleotide encoding an HRS polypeptide.

[0338] The term "immunotherapy" refers to an agent that modulates the immune system. In some embodiments, immunotherapy can increase the expression and / or activity of regulators of the immune system. In some embodiments, immunotherapy can decrease the expression and / or activity of regulators of the immune system. In some embodiments, immunotherapy can recruit and / or enhance the activity of immune cells.

[0339] 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 ciloleucel (Yescarta). In some embodiments, the CAR-T cell therapy is brexucabtagene autoleucel (Tecartus). In some embodiments, the CAR-T cell therapy is relmacabtagene autoleucel. In some embodiments, the CAR-T cell therapy is ALLO-501.

[0340] 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®), dinutiximab (U nituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza®), (trademark), cirumutuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), lenzilumab, avelumab, spartalizumab, pembu lorizumab, utomilumab, ublituximab, blinatumomab, ganitumab, urelumab, pidilizumab, amatuximab, mosunetuzumab (BTCT4465A), CD20-TCB, RO7082859, XmAb13676, glofitamab, CD20-TDB, odronextamab (REGN1979), IGM-2323, BTCT4465A, AMG-562, or TTI-621.

[0341] In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM-1, Kadcyla®), mirvetuximab soravtansine (IMGN853), anetumab ravtansine, polatuzumab vedotin, loncastuximab tesirin (ADCT-402), kamidanlumab tesirin (ADCT-301), or naratuximab emtansine (Debio 1562).

[0342] In some embodiments, the immunotherapy comprises blinatumomab (AMG103, Blincyto®) or midostaurin (Rydapt).

[0343] In some embodiments, the immunotherapy comprises a toxin, hi some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

[0344] 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®).

[0345] 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™).

[0346] In some embodiments, the immunotherapy is an mRNA-based immunotherapy. In some embodiments, the mRNA-based immunotherapy is CV9104 (see, e.g., Rausch et al. (2014) Human Vaccin Immunother 10(11):3146-52, and Kubler et al. (2015) J. Immunother Cancer 3:26).

[0347] In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG) therapy.

[0348] In some embodiments, the immunotherapy is oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC, Imlygic®).

[0349] 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, lapleucel-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).

[0350] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is neripepimto-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).

[0351] In some embodiments, the immune targeting agent is selected from aldesleukin, interferon alpha-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

[0352] In some embodiments, the additional therapy is radiation therapy, non-limiting examples of which include radioactive iodide therapy, external beam radiation, and radium-223 therapy.

[0353] 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.

[0354] Additional kinase inhibitors are described in, e.g., U.S. Patent Nos. 7,514,446, 7,863,289, 8,026,247, 8,501,756, 8,552,002, 8,815,901, 8,912,204, 9,260,437, 9,273,051, U.S. Publication No. 2015 / 0018336, WO2007 / 002325, WO2007 / 002433, WO2008 / 080001, WO2008 / 079906, WO2008 / 079903, WO2008 / 0799 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, WO2012 / 101032, WO2012 / 139930, WO2012 / 143248, WO2012 / 152763, WO2013 / 014039, WO2013 / 102059, WO2013 / 050448, WO2013 / 050446, WO2014 / 0 19908, WO2014 / 072220, WO2014 / 184069, WO2016 / 075224, WO2016 / 081450, WO2016 / 022569, WO2016 / 011141, WO2016 / 011144, WO2016 / 011147, WO 2015 / 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.

[0355] 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).

[0356] 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).

[0357] 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 changes in adhesion, 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.

[0358] Therefore, also provided herein is a method for inhibiting, preventing, or assisting in the prevention of cancer metastasis or reducing symptoms 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 thereof. Such a method can be used to treat one or more of the cancers described herein. For example, see U.S. Publication No. 2013 / 0029925, WO 2014 / 083567, and U.S. 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, a 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.

[0359] The term "metastasis" is an art-recognized term that refers to the formation of additional tumors (e.g., solid tumors) in a subject at a site distant from the primary tumor, wherein the additional tumors contain the same or similar cancer cells as the primary tumor.

[0360] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject with a MALT1-associated cancer, comprising selecting, identifying, or diagnosing the subject as having a MALT1-associated cancer and administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having a MALT1-associated cancer. Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject with a 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 a 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.

[0361] 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 primary tumor in the subject 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.

[0362] 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.

[0363] 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.

[0364] 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.

[0365] Also provided is a method for inhibiting MALT1 protease activity in a mammalian cell, the method 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 described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell.

[0366] Also provided is a method for inhibiting MALT1 protease activity in a mammalian cell, the method 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 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.

[0367] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro system or an 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, that has MALT1 protease, and introducing a compound provided herein into a sample containing, for example, mammalian cells or a purified preparation containing MALT1 protease.

[0368] Also provided herein is a method of 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.

[0369] 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 25 nM, less than about 10 nM, or less than about 1 nM, as measured in the assays 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 the assays provided herein. 50 ) can be shown.

[0370] 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.

[0371] Exemplary first and second MALT1 protease inhibitors are described herein. In some embodiments, the first or second MALT1 protease inhibitor can be, for example, JNJ-67856633 or CTX-177.

[0372] 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) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. 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 disease state and its severity, and the individual characteristics (e.g., body weight) of the subject in need of treatment, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0373] Pharmaceutical Compositions When used 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 art 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, ophthalmic, and mucosal membranes, 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 dosage forms 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.

[0374] The present invention also provides pharmaceutical compositions containing 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 within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions 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, for example, containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the compositions are formulated for oral administration. In some embodiments, the compositions are solid oral dosage forms. In some embodiments, the compositions are formulated as tablets or capsules.

[0375] Further provided herein is a pharmaceutical composition comprising 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 wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0376] 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 British Pharmaceutical Society.

[0377] Methods for 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.

[0378] When preparing compositions in oral dosage form, any of the usual pharmaceutical media can be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.; for solid oral preparations such as powders, capsules, and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Solid oral preparations can also be coated with a substance such as sugar to modify the primary absorption site, or enteric coated. For parenteral administration, the carrier usually consists of sterile water, and other ingredients may be added to increase solubility or preservation. Injection suspensions or solutions may also be prepared using aqueous carriers with appropriate additives. The pharmaceutical compositions herein will contain the amount of active ingredient necessary to deliver an effective dose as described herein per dosage unit, e.g., tablet, capsule, powder, injection, teaspoon, etc.

[0379] Compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may 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 physically discrete units suitable as unit dosages 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.

[0380] In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One of skill in the art will appreciate that this embodies compounds or compositions containing from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, or from about 45 mg to about 50 mg of the active ingredient.

[0381] 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.

[0382] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. One of skill in the art will appreciate that this embodies compounds or compositions containing from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1,000 mg of the active ingredient.

[0383] 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 dosage to the subject being treated. An effective amount of drug is usually supplied at a dosage level of about 0.1 mg / kg to about 1000 mg / kg of body weight per day, or any range therein. Preferably, the range is about 0.5 to about 500 mg / kg of body weight per day, or any range therein. More preferably, the dose is about 1.0 to about 250 mg / kg of body weight per day, or any range therein. More preferably, the dose is about 0.1 to about 100 mg / kg of body weight per day, or any range therein. In one example, the range may be about 0.1 to about 50.0 mg / kg of body weight per day, or any amount or range therein. In another example, the range may be about 0.1 to about 15.0 mg / kg of body weight per day, or any range therein. In yet another example, the range may be about 0.5 to about 7.5 mg / kg of body weight per day, or any amount or range therein. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered on a regimen of 1 to 4 times per day, or in a single daily dose.

[0384] Active compound can be effective in a wide dosage range, and is 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 will 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 state.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.

[0385] In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein may 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.

[0386] 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.

[0387] 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.

[0388] Provided herein are pharmaceutical kits 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 kits can further comprise, if desired, one or more of a variety of conventional pharmaceutical kit components, such as, for example, 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 amounts of components to be administered, guidelines for administration, and / or guidelines for mixing the components, may also be included in the kit. [Example]

[0389] Materials and Methods The compounds provided herein, including the salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0390] 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.

[0391] 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 of ordinary skill in the art. Protecting group chemistry is described, for example, in Protecting Group Chemistry, 1 st Ed.,Oxford University Press,2000,March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,5 th Ed., Wiley-Interscience Publication, 2001, and Peturssion, S. et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 74(11), 1297 (1997).

[0392] 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), usually performed using Sanpont pre-coated TLC plates, silica gel GF-254, 0.25 mm layer thickness, or by liquid chromatography-mass spectrometry (LC-MS).

[0393] Typically, the analytical LC-MS system used 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 usually a HALO a C18 30 * The column diameter was 5.0 mm, 2.7 μm. 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. Detection of the PDA (SPD-M20A) was in the range of 190–400 nm. The MS detector was configured with electrospray ionization as the ionization source, acquisition mode: scan, nebulization gas flow: 1.5 L / min, drying gas flow: 15 L / min, detector voltage: tuning voltage ±0.2 kV, DL temperature: 250 °C, heating block temperature: 250 °C, scan range: 90.00 - 900.00 m / z. ELSD (Alltech 3300) detector parameters: drift tube temperature: 60 ±5 °C, N2 flow rate: 1.8 ±0.2 L / min. The mobile phase gradient was optimized for each compound.

[0394] The GC-MS system was typically performed using a Shimadzu GCMS-QP2010 Ultra with FID and MS detectors. MS detector in acquisition mode: 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.

[0395] 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.

[0396] 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 percentages of either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as the isocratic solvent system.

[0397] Reactions carried out using microwave irradiation were typically carried out using an initiator manufactured by Biotage. Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash column chromatography was typically carried out using a Biotage flash chromatography system (Dyax Corp.) on silica gel (40-60 μM, 60 Å pore size) in pre-packed cartridges of the stated size. Unless otherwise noted, 1 H NMR spectra were obtained on a 400 MHz spectrometer in DMSO-d6 solution. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in DMSO-d6 solution, and the residual CH3OH peak or TMS was used as an internal reference in CD3OD solution. Coupling constants (J) are reported in hertz (Hz). Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250 × 4.6 mm) (Daicel Chemical Industries, Ltd.) using the indicated percentages of either ethanol in hexane (%Et / Hex) or isopropanol in heptane (%IPA / Hep) as the isocratic solvent system. Chiral preparative chromatography was performed on one of the following columns (250 × 20 mm, 250 × 30 mm, 250 × 50 mm) using the desired isocratic solvent system specified for chiral analytical chromatography: 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.).

[0398] Abbreviations used herein include: -C(O)CH3(Ac), acetic acid (AcOH), -OC(O)CH3(OAc), aqueous solution (aq), Cbz (benzyloxycarbonyl), N,N-diisopropylethylamine (DIEA), N,N-dimethylformamide (DMF), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), EtOAc (EtOAc), diethyl ether (ether or Et2O), PE (PE), 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 solution (brine), trifluoroacetic acid (TFA), tetrahydrofuran (THF), flash chromatography (FC), liquid chromatography (LC), liquid chromatography mass spectrometry (LCMS or LC-MS), supercritical fluid chromatography (SFC), t-butyloxycarbonyl (Boc or BOC), diethylaminosulfur trifluoride (DAST), DCM (DCM), dimethylacetamide (DMA or DMAC), dimethyl sulfoxide (DMSO), 1,3-bis(diphenylphosphino)propane (DPPP), acetic acid (HOAc), 3-chloroperoxybenzoic acid (m-CPBA), methyl (Me), methanol (MeOH), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), N-methylimidazole (NMI), N-bromosuccinamide (NBS), thin layer chromatography (TLC).

[0399] 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.

[0400] [ka] Examples 1 and 2: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. Step 1: 3-chloro-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine [ka] A 500 mL flask was charged with 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). 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 EtOAc (300 mL). The organic layer was washed with water (2 × 300 mL), brine (1 × 300 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. To the residue was added DCM (50 mL). 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(400MHz,DMSO-d6)δ:8.39(d,J=2.4Hz,1H),8.14(d,J=2.4Hz,1H),8.33(s,2H).LC-MS:m / z 226[M+H] + .

[0401] Step 2: 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine [ka] A 1.0 L flask was charged with 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). HCl (50 mL) was added at 0 °C, followed by SnCl2.2H2O (33.0 g, 146.3 mmol, 5.0 equiv), which were added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (300 mL), and the pH was adjusted to 9 using 3N NaOH solution in water. The resulting mixture was extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-chloro-6-(1,2,3-triazol-2-yl)pyridin-3-amine (Step 2 of Method A1, 5.4 g, 94% yield) as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δ:8.05(s,2H),7.83(d,J=2.5Hz,1H),7.21(d,J=2.5Hz,1H),6.19(s,2H).LC-MS:m / z 196[M+H] + .

[0402] Step 3: 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one [ka] A solution of 2,2-dimethylcyclopentanone (2 g, 17.8 mmol) in DMF-DMA (20 mL) was stirred at 100° C. for 16 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. This gave 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one (Method A1, Step 3, 2 g, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): 168 [M+H] + .

[0403] Step 4: 2-Chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine [ka] To a stirred solution of 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one (1.5 g, 8.9 mmol) in toluene (20 mL) was added 5-chloro-1H-pyrazol-3-amine (1.5 g, 12.7 mmol) and AcOH (2 mL) at room temperature. The resulting mixture was stirred at 95 °C for 16 h. The mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL). The pH was adjusted to 6-7 using saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:5) to give 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (1.4 g, 63.3% yield). 1 HNMR(300MHz,DMSO-d6)δ:8.56(s,1H),6.86(s,1H),2.88-3.03(m,2H),2.01-2.12(m,1H),1.27(s,3H).LC-MS(ES,m / z):222[M+H] + .

[0404] Step 5: 2-Chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile [ka] To a stirred solution of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (1.4 g, 6.3 mmol) in toluene (30 mL) was added (4R)-4-benzyl-2-[1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (274 mg, 0.8 mmol), acetoxycopper (154 mg, 1.2 mmol), N-fluorobenzenesulfonimide (3 g, 9.4 mmol), and TMSCN (3.1 g, 31.5 mmol). The reaction was stirred under nitrogen at room temperature for 16 hours. The solvent was removed under vacuum, and the residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:5) to give 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (Step 5 of Method A1, 690 mg, 17.7% yield). 1 HNMR(300MHz,DMSO-d6)δ:8.74(s,1H),7.00(s,1H),4.71-4.76(m,1H),2.54-2. 67(m,H),2.32-2.45(m,1H),1.63(s,3H),1.51(s,3H).LC-MS(ES,m / z):247[M+H] + .

[0405] Step 6: 2-Chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ka] To a 30 mL vial was added 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (690 mg, 2.8 mmol) in AcOH (6 mL) and HCl (6 mL). The resulting mixture was stirred at 100 °C for 2 h. The mixture was allowed to cool to room temperature. The solvent was concentrated in vacuo, and the residue was diluted with water (100 mL), and the pH was adjusted to 5-6 with NaHCO3. The resulting solution was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column and eluted with MeOH / DCM (1:10) to give 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Step 6 of Method A1, 300 mg, 32.3% yield). 1 HNMR(400MHz,DMSO-d6)δ:12.75(s,1H),8.63(s,1H),6.92(s,1H),4.26-4.29(m,1H),2. 40-2.45(m,1H),2.28-2.33(m,1H),1.56(s,3H),1.52(s,3H).LC-MS(ES,m / z):266[M+H] + .

[0406] Step 7: 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide [ka] To a stirred solution of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (390 mg, 1.4 mmol) in ACN (20 mL) was added 5-chloro-6-(triazol-2-yl)pyridin-3-amine (430.69 mg, 2.2 mmol), TCFH (1.65 g, 5.8 mmol), and NMI (482.06 mg, 5.87 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL). The resulting solution was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to preparative HPLC, and the collected fractions were lyophilized to give a racemic mixture of 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (200 mg, 60% yield) as a white solid. LC-MS (ES, m / z): 443 [M+H].

[0407] Step 8: Separation of enantiomers to obtain (R)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. [ka] 200 mg of racemic 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (CHIRALPAK IE, 2 × 25 cm, 5 μm, mobile phase A: Hex (8 mmol / L NH3.MeOH), mobile phase B: EtOH, flow rate: 17 mL / min, isocratic: 50B, 220 / 254 nm, RT1: 8.332, RT2: 12.438, injection volume: 1 ml, number of runs: 5). The first eluted isomer was concentrated and lyophilized to give Example 1 (74.3 mg, 11.4% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 2 (69.6 mg, 10.6% yield) as a white solid.

[0408] Example 1: 1 H NMR (300MHz, methanol-d4) δ:8.71(d,J=2.4Hz,1H),8.66(d,J=2.4Hz,1H),8.55(s,1H),8.04(s,2H),6.72(s,1H) ,4.42-4.47(m,1H),2.62-2.70(m,1H),2.45-2.48(m,1H),1.76(s,3H),1.65(s,3H).LCMS(ES,m / z):443[M+H] + .

[0409] Example 2: 1 H NMR (300MHz, methanol-d4) δ:8.71(d,J=2.4Hz,1H),8.66(d,J=2.4Hz,1H),8.55(s,1H),8.04(s,2H),6.73(s,1H) ,4.42-4.47(m,1H),2.62-2.66(m,1H),2.45-2.48(m,1H),1.76(s,3H),1.65(s,3H).LC-MS(ES,m / z):443[M+H] + .

[0410] The absolute stereochemistry for each separated isomer was not determined.

[0411] [ka] Examples 3 and 4: Single enantiomers obtained from a racemic mixture containing (R)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. Step 1: 8,8-Dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-2-carbonitrile [ka] A solution of 3-amino-1H-pyrazole-5-carbonitrile (258 mg, 2.4 mmol) and (Z)-5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one (Step 3 of Method A1, 400 mg, 2.4 mmol) in AcOH (1 mL) and toluene (10 mL) was stirred at 90 °C under nitrogen for 3 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was applied to a silica gel column and eluted with 0 to 50% EtOAc in PE to give 8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-2-carbonitrile (220 mg, 43% yield) as a brown solid. 1 H NMR(300MHz,DMSO-d6)δ 8.71(s,1H),7.53(s,1H),3.09-2.98(m,2H),2.09-2.14(m,2H),1.52(s,6H).LC-MS:m / z 213[M+H] + .

[0412] Step 2: 8,8-Dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-2,6-dicarbonitrile [ka] To a stirred solution of 8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-2-carbonitrile (220 mg, 1 mmol), N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (490 mg, 1.6 mmol), (4R)-4-benzyl-2-[1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (45.1 mg, 124.4 μmol), and acetoxycopper (25 mg, 207.3 μmol) in toluene (10 mL) was added trimethylsilyl cyanide (514 mg, 5.2 mmol) in portions at room temperature, and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo, diluted with water (100 mL), and then extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo. The residue was applied to a silica gel column and eluted with 0-30% EtOAc in PE to give 8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-2,6-dicarbonitrile (130 mg, 53% yield) as an off-white solid. LC-MS: m / z 238 [M+H] + .

[0413] Step 3: 2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide [ka] A solution of 8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-2,6-dicarbonitrile (130 mg, 547.9 μmol) in HCl (1 mL) and AcOH (3 mL) was stirred at room temperature for 6 h. The resulting mixture was concentrated in vacuo. The residue was diluted with water (2 mL), and the pH was adjusted to 8–9 with NaHCO3. The resulting mixture was concentrated in vacuo and purified by HPLC to give 2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (60 mg, 43% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 8.67(s,1H),7.70(s,1H),7.55(s,1H),7.21(s,1H),4.20-4.03(m,1H),2.41(dd,J= 13.2,9.1Hz,1H),2.22(dd,J=13.2,6.3Hz,1H),1.59(s,3H),1.49(s,3H).LC-MS:m / z 256[M+H] + .

[0414] Step 4: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide [ka] To a stirred mixture of 5-bromo-3-chloro-2-(triazol-2-yl)pyridine (60 mg, 235.0 μmol) and 2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (60 mg, 235.0 μmol) in toluene (1 mL) was added (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (13 mg, 23.5 μmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (13 mg, 23.5 μmol), and cesium carbonate (114 mg, 352.6 μmol). Aluminum trifluoromethanesulfonate (11 mg, 23.5 μmol) was added in portions at room temperature under nitrogen. The resulting mixture was stirred under nitrogen at 110° C. for 16 hours. The mixture was allowed to cool to room temperature, diluted with water (50 mL), and then extracted with DCM (3×50 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo. The crude product (70 mg) was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 19 x 250 mm, 5 μm, Mobile phase A: water (0.05% TFA), Mobile phase B: ACN, Flow rate: 25 mL / min, Gradient: 46B to 66B in 7 min, 220 nm, RT: 6.12, Injection volume: 1.5 mL, Run number: 2) to give N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (22 mg, 22% yield) as a white solid. LC-MS: m / z 434 [M+H] + .

[0415] Step 5: Separation of enantiomers to obtain (R)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. [ka] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (22 mg, 50.4 μmol) was purified by chiral HPLC (column: Chiralpak ID-2, 2 * The column was then pumped to a 25 cm column, 5 μm column, mobile phase A: MTBE (2 mM NH3-MEOH), mobile phase B: EtOH, flow rate: 17 mL / min, isocratic: 30B, 254 / 220 nm, RT1: 6.593, RT2: 8.779, injection volume: 1 mL, run number: 2). The first eluting isomer was concentrated and lyophilized to give Example 3 as a white solid (7.3 mg, 33% yield). The second eluting isomer was concentrated and lyophilized to give Example 4 as a white solid (6.2 mg, 28% yield).

[0416] Example 3: 1 H NMR(400MHz, methanol-d4)δ 8.69(s,1H),8.63(d,J=2.4Hz,1H),8.02(s,2H),7.29(s,1H),4.48(dd,J=9.2,6.8Hz,1H),2. 71(dd,J=13.2,9.2Hz,1H),2.48(dd,J=13.2,6.8Hz,1H),1.75(s,3H),1.65(s,3H).LC-MS:m / z 434[M+H] + .

[0417] Example 4:1 H NMR(400MHz, methanol-d4)δ 8.69(s,1H),8.63(d,J=2.4Hz,1H),8.02(s,2H),7.28(s,1H),4.48(dd,J=9.2,6.8Hz,1H),2. 71(dd,J=13.2,9.2Hz,1H),2.47(dd,J=13.2,6.8Hz,1H),1.75(s,3H),1.65(s,3H).LC-MS:m / z 434[M+H] + .

[0418] The absolute stereochemistry for each separated isomer was not determined.

[0419] [ka] Examples 5 and 6: Single enantiomers obtained from a racemic mixture containing (R)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. Step 1: 2-Bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine [ka] To a stirred solution of 5-(dimethylaminomethylene)-2,2-dimethyl-cyclopentan-1-one (Step 3 of Method A1, 10 g, 59.8 mmol) in toluene (150 mL) was added 5-bromo-1H-pyrazol-3-amine (11.6 g, 71.8 mmol) and AcOH (15 mL) at room temperature. The resulting mixture was stirred at 90 °C for 16 h. The mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL). The pH was adjusted to 6-7 with sodium bicarbonate (saturated, aqueous solution). The resulting solution was extracted with EtOAc (3 × 200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied onto a silica gel column and eluted with EtOAc / PE (1:2) to give 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (4 g, 20% yield). 1 H NMR(300MHz,DMSO-d6)δ:8.54(s,1H),6.93(s,1H),2.94-3.05(m,2H),2.07-2.12(m,2H),1.52(s,6H).LC-MS:m / z 266[M+H] + .

[0420] Step 22-Bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile [ka] To a stirred solution of 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (440 mg, 1.65 mmol) in toluene (10 mL) was added (4R)-4-benzyl-2-[1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (72 mg, 198.4 μmol), acetoxycopper (40 mg, 330.7 μmol), N-fluorobenzenesulfonimide (782 mg, 2.5 mmol), and TMSCN (820 mg, 8.3 mmol). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The solvent was removed under vacuum, and the residue was applied to a silica gel column and eluted with EtOAc / PE (1:2) to give 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (390 mg, 41% yield). 1 H NMR(300MHz,DMSO-d6)δ:8.72(s,1H),7.06(s,1H),4.71-4.76(m,1H),2.54-2.64(m,H),2.35-2.47(m,1H),1.64(s,3H),1.51(s,3H).LC-MS:m / z 291[M+H] + .

[0421] Step 3: 2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile [ka] To a mixture of 2-bromo-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (370 mg, 1.3 mmol) in dioxane (4 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (638 mg, 2.5 mmol), Pd(dppf)Cl (93 mg, 127.1 μmol), KCO (351 mg, 2.5 mmol, 153.4 μL), and HO (1 mL). The mixture was stirred under nitrogen at 100 °C for 2 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with water (50 mL), extracted with EtOAc (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column and eluted with EtOAc / PE (1:2) to give 2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (105 mg, 36% yield). 1 H NMR(300MHz,DMSO-d6)δ:8.58(s,1H),6.63(s,1H),4.66-4.73(m,1H),2.55-2.62(m,1H),2.33-2.43(m,1H),1.65(s,3H),1.53(s,3H).LC-MS:m / z 227[M+H] + .

[0422] Step 4: 2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid [ka] A solution of 2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (97 mg, 428.7 μmol) in AcOH (2 mL) and HCl (2 mL) was stirred at 100 °C for 2 h. The mixture was allowed to cool to room temperature. The mixture was concentrated in vacuo, and the residue was diluted with water (50 mL), and the pH was adjusted to 5–6 with NaHCO3. The resulting solution was extracted with EtOAc (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column and eluted with DCM / MeOH (10:1) to give 2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (56 mg, 182.6 μmol, 43% yield). LC-MS: m / z 246 [M+H] + .

[0423] Step 5. N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide [ka] To a solution of 2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (56 mg, 228.3 μmol) in ACN (3 mL) was added 5-chloro-6-(triazol-2-yl)pyridin-3-amine (67 mg, 342.5 μmol), TCFH (320 mg, 1.1 mmol), and NMI (94 mg, 1.1 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL). The resulting solution was extracted with EtOAc (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column and eluted with EA / PE (1:1) to give the crude product. The crude product was sent for HPLC purification and the collected fractions were lyophilized to give N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (30 mg, 31%) as a white solid. LC-MS: m / z 423 [M+H] + .

[0424] Step 6: Separation of enantiomers to obtain (S)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (R)—N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. [ka] 30 mg of N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,8,8-trimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was purified by chiral HPLC (column: Chiralpak ID-2, 2 *The column was then pumped to a 25 cm column, 5 μm column, mobile phase A: MTBE (2 mM NH3-MEOH), mobile phase B: EtOH, flow rate: 14 mL / min, isocratic 50B, 254 / 220 nm, RT1: 11.394, RT2: 17.177, injection volume: 2 mL, run number: 2). The first eluting isomer was concentrated and lyophilized to give Example 5 (6 mg, 6.2% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 6 (8.6 mg, 8.9% yield) as a white solid.

[0425] Example 5: 1 H NMR (300MHz, methanol-d4):8.71(d,J=2.4Hz,1H),8.66(d,J=2.4Hz,1H),8.42(s,1H),8.04(s,2H),6.53(s,1H) ,4.41-4.87(m,1H),2.60-2.67(m,1H),2.54(s,3H),2.40-2.47(m,1H),1.80(s,3H),1.66(s,3H).LC-MS:m / z 423[M+H] + .

[0426] Example 6: 1 H NMR (300MHz, methanol-d4):8.71(d,J=2.4Hz,1H),8.66(d,J=2.4Hz,1H),8.42(s,1H),8.04(s,2H),6.53(s,1H) ,4.41-4.87(m,1H),2.60-2.67(m,1H),2.54(s,3H),2.40-2.47(m,1H),1.80(s,3H),1.66(s,3H).LC-MS:m / z 423[M+H] + .

[0427] The absolute stereochemistry for each separated isomer was not determined.

[0428] Example 7: 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline-6-carboxamide [ka] The title compound was prepared analogously to Example 1 using Method A1, starting from 2,2-dimethylcyclohexanone. 1 H NMR(400MHz,DMSO-d6)δ:10.98(s,1H),8.71(d,J=2.4Hz,1H),8.56(d,J=2.4Hz,1H),8.45(s,1H),8.16(s,2H),6.88(s ,1H),4.11-4.16(m,1H),2.05-2.27(m,2H),1.87-1.99(m,1H),1.75-1.85(m,1H),1.64(s,3H),1.59(s,3H).LC-MS:m / z 457[M+H] + .

[0429] Examples 8 and 9: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline-6-carboxamide. [ka] 100 mg of 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-9,9-dimethyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline-6-carboxamide was subjected to chiral HPLC purification (CHIRALPAK IE, 2 × 25 cm, 5 μm, mobile phase A: Hex (8 mmol / L NH3.MeOH), mobile phase B: EtOH, flow rate: 17 mL / min, isocratic: 50B, 220 / 254 nm, RT1: 8.332, RT2: 12.438, injection volume: 1 ml, number of runs: 5). The first eluted isomer was concentrated and lyophilized to give Example 8 as a white solid (34.6 mg, 35% yield). The second eluting isomer was concentrated and lyophilized to give Example 9 as a white solid (31.1 mg, 31% yield).

[0430] Example 8: 1 H NMR(300MHz,DMSO-d6)δ 11.00(s,1H),8.71(d,J=2.1Hz,1H),8.57(d,J=2.1Hz,1H),8.46(s,1H),8.17(s,2H),6.89(s,1H) ),4.10-4.18(m,1H),2.04-2.32(m,2H),1.74-2.03(m,2H),1.65(s,3H),1.59(s,3H).LC-MS:m / z 457[M+H] + .

[0431] Example 9: 1 HNMR(300MHz,DMSO-d6)δ 11.00(s,1H),8.71(d,J=2.1Hz,1H),8.57(d,J=2.1Hz,1H),8.45(s,1H),8.17(s,2H),6.89(s,1H) ),4.10-4.18(m,1H),2.04-2.32(m,2H),1.74-2.03(m,2H),1.65(s,3H),1.59(s,3H).LC-MS:m / z 457[M+H] + .

[0432] The absolute stereochemistry for each separated isomer was not determined.

[0433] [ka] Examples 10 and 11: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. Step 1: 5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine [ka] To a solution of 5,6-dichloropyridin-3-amine (1 g, 6.1 mmol) in dioxane (16 mL) and HO (4 mL) was added 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 g, 6.1 mmol), Pd(dppf)Cl (513 mg, 610 μmol), and NaCO (2.6 g, 4 mmol) under N. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (150 mL). The resulting solution was extracted with EtOAc (3 × 150 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was applied onto a silica gel column and eluted with EtOAc / PE (1:3) to give 5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine (1.2 g, crude) as a yellow oil. LC-MS: m / z 209 [M+H] + .

[0434] Step 2: 2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide [ka] To a solution of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Step 6 of Method A1, 100 mg, 376.3 μmol) in ACN (6 mL) was added 5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-amine (117 mg, 564.5 μmol), TCFH (422 mg, 1.5 mmol), and NMI (123 mg, 1.5 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (100 mL). The resulting solution was extracted with EtOAc (3 × 100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was applied to a silica gel column and eluted with DCM / MeOH (10:1). The resulting product was further purified by preparative HPLC to give 2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (28.6 mg, 17% yield) as a white solid. LC-MS: m / z 456 [M+H] + .

[0435] Step 3: Separation of enantiomers to obtain (R)-2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. [ka] 28.6 mg of 2-chloro-N-(5-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was purified by chiral HPLC (column: Chiralpak ID-2, 2 * The column was then pumped to a 25 cm column, 5 μm column, mobile phase A: MTBE (0.5% 2M NH3-MeOH), mobile phase B: EtOH, flow rate: 15 mL / min, isocratic: 50B, 254 / 220 nm, RT1: 12.336, RT2: 26.017, injection volume: 1.5 mL, run number: 1. The first eluting isomer was concentrated and lyophilized to give Example 10 as a white solid (7.8 mg, 27% yield). The second eluting isomer was concentrated and lyophilized to give Example 11 as a white solid (7.2 mg, 27% yield).

[0436] Example 10: 1 H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),8.72(d,J=2.0Hz,1H),8.63(s,1H),8.34(d,J=2.0Hz,1H),7.77(d,J=2.0Hz,1H),6.94(s,1H) ),6.72(d,J=2.0Hz,1H),4.39-4.44(m,1H),3.92(s,3H),2.50-2.52(m,1H),2.27-2.33(m,1H),1.64(s,3H),1.56(s,3H).LC-MS:m / z 456[M+H] + .

[0437] Example 11: 1 H NMR(400MHz,DMSO-d6)δ:10.79(s,1H),8.72(d,J=2.0Hz,1H),8.64(s,1H),8.34(d,J=2.0Hz,1H),7.77(d,J=2.0Hz,1H),6.94(s,1H) ),6.72(d,J=2.0Hz,1H),4.39-4.45(m,1H),3.92(s,3H),2.50-2.51(m,1H),2.28-2.35(m,1H),1.64(s,3H),1.56(s,3H).LC-MS:m / z 456[M+H] + .

[0438] The absolute stereochemistry for each separated isomer was not determined.

[0439] [ka] Examples 12 and 13: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. Step 1: 3-chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine [ka] To a stirred solution of 2,3-dichloro-5-nitro-pyridine (5 g, 25.9 mmol) in MeCN (100 mL) was added 1H-pyrazole (7 g, 28.5 mmol) and K2CO3 (2 g, 51.8 mmol). The resulting mixture was stirred at 40 °C for 16 h. The mixture was allowed to cool to room temperature. The reaction mixture was filtered and the collected solid was washed with EtOAc (3 × 50 mL). The resulting solution was concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with EtOAc / PE (1:10) to give 3-chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine (4 g, 68% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ:9.30(d,J=2.4Hz,1H),9.00(d,J=2.4Hz,1H),8.50-8.51(m,1H),7.67-7.68(m,1H),6.67-6.68(m,1H).LC-MS:m / z 225[M+H] + .

[0440] Step 2: 5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-amine [ka] To a stirred solution of 3-chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine (2 g, 8.9 mmol) in THF (33 mL) and HO (33 mL) was added ammonium chloride (3.8 g, 71.2 mmol). Then, Fe (4.0 g, 71.2 mmol) was added to the mixture at 80 °C for 1 h. The mixture was cooled to room temperature and filtered through a pad of diatomaceous earth, and the pad was washed with EtOAc (3 × 10 mL). The resulting solution was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was applied to a silica gel column and eluted with EtOAc / PE (1:1) to give 5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-amine (0.38 g, 22% yield) as a yellow solid. 1 H NMR (300 MHz, chloroform-d) δ: 7.87-7.90 (m, 2H), 7.78 (d, J = 1.8 Hz, 1H), 7.15 (d, J = 2.6 Hz, 1H), 6.45-6.47 (m, 1H), 4.50 (s, 2H). LC-MS: m / z 195 [M+H] + .

[0441] Step 3: 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide [ka] To a stirred solution of 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Step 6 of Method A1, 50 mg, 188.2 μmol) in ACN (5 mL) was added 3-chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine (55 mg, 282.3 μmol), TCFH (211 mg, 752.7 μmol), and NMI (62 mg, 752.7 μmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL). The resulting solution was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was sent for preparative HPLC purification, and the collected fractions were lyophilized to give 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (60 mg, 84% yield) as a white solid. LC-MS: m / z 442 [M+H] + .

[0442] Step 4: Separation of enantiomers to obtain (R)-2-chloro-N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. [ka] 60 mg of 2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was purified by chiral HPLC (column: Chiralpak IA, 2 *The column was then pumped to a 25 cm column, 5 μm column, mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH, flow rate: 18 mL / min, isocratic: 50B, 220 / 254 nm, RT1: 7.267, RT2: 12.331, injection volume: 2 mL, run number: 4). The fractions containing the first eluting isomer were concentrated and lyophilized to give Example 12 as a white solid (25.8 mg, 31% yield). The fractions containing the second eluting isomer were concentrated and lyophilized to give Example 13 as a white solid (32.1 mg, 38% yield).

[0443] Example 12: 1 H NMR(400MHz, methanol-d4)δ:8.65(d,J=2.4Hz,1H),8.56(d,J=2.0Hz,1H),8.51(s,1H),8.13(d,J=2.4Hz,1H),7.78(d,J=1.2Hz,1H ),6.70(s,1H),6.55-6.56(m,1H),4.38-4.41(m,1H),2.60-2.65(m,1H),2.40-2.43(m,1H),1.73(s,3H),1.62(s,3H).LC-MS:m / z 442[M+H] + .

[0444] Example 13: 1 H NMR(400MHz, methanol-d4)δ:8.65(d,J=2.4Hz,1H),8.56(d,J=2.0Hz,1H),8.51(s,1H),8.13(d,J=2.4Hz,1H),7.78(d,J=1.2Hz,1H ),6.70(s,1H),6.55-6.56(m,1H),4.38-4.41(m,1H),2.60-2.65(m,1H),2.40-2.43(m,1H),1.73(s,3H),1.62(s,3H).LC-MS:m / z 442[M+H] + .

[0445] The absolute stereochemistry for each separated isomer was not determined.

[0446] [ka] Examples 14 and 15: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. Step 1: 1-(3-chloro-5-nitropyridin-2-yl)-1H-pyrazole-4-carbonitrile [ka] A mixture of 2,3-dichloro-5-nitro-pyridine (3 g, 15.6 mmol), 1H-pyrazole-4-carbonitrile (1.59 g, 17.1 mmol), and potassium carbonate (6.45 g, 46.6 mmol) in DMF (40 mL) was stirred at 25° C. for 4 hours. The resulting mixture was poured into ice / water (100 mL). The precipitated solid was collected by filtration and washed with water (5×20 mL). The resulting solid was dried under infrared light. This afforded 1-(3-chloro-5-nitro-2-pyridyl)pyrazole-4-carbonitrile (3.4 g, 88% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ:9.34(d,J=2.4Hz,1H),9.30(s,1H),9.10(d,J=2.4Hz,1H),8.51(s,1H).

[0447] Step 2: 1-(5-amino-3-chloropyridin-2-yl)-1H-pyrazole-4-carbonitrile [ka] To a stirred mixture of 1-(3-chloro-5-nitro-2-pyridyl)pyrazole-4-carbonitrile (1 g, 4.0 mmol) in EtOH (15 mL) and HO (15 mL) was added iron (940 mg, 16.8 mmol) and ammonium chloride (900 mg, 16.8 mmol). The resulting mixture was stirred at 95 °C for 1 h. The mixture was allowed to cool to room temperature, filtered, and concentrated under reduced pressure to remove EtOH. The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (92:8) to afford 1-(5-amino-3-chloro-2-pyridyl)pyrazole-4-carbonitrile (630 mg, 72% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.89(s,1H),8.26(s,1H),7.79(d,J=2.4Hz,1H),7.18(d,J=2.4Hz,1H),6.14(s,2H).LC-MS:m / z 220[M+H] + .

[0448] Step 3: 2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide [ka] To a stirred mixture of 1-(5-amino-3-chloro-2-pyridyl)pyrazole-4-carbonitrile (100 mg, 0.46 mmol) and 2-chloro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Step 6 of Method A1, 121 mg, 0.46 mmol) in ACN (10 mL) was added TCFH (383 mg, 1.37 mmol) and NMI (187 mg, 2.28 mmol). The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (7:3) to give the crude product, which was sent for HPLC purification. The collected fractions were lyophilized to give 2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (34.3 mg, 16% yield) as a white solid. LC-MS: m / z 467 [M+H] + .

[0449] Step 4: Separation of enantiomers to obtain (R)-2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. [ka] 30 mg of 2-chloro-N-(5-chloro-6-(4-cyano-1H-pyrazol-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: Chiralpak ID-2, 2 × 25 cm, 5 μm, mobile phase A: Hex (0.5% 2M NH3-MeOH), mobile phase B: EtOH, flow rate: 18 mL / min, isocratic: 50B, 254 / 220 nm, RT1: 15.609, RT2: 19.773, injection volume: 0.7 ml, number of runs: 4). The fractions containing the first eluting isomer were concentrated and lyophilized to give Example 14 as a white solid (5.7 mg, 19% yield). The fractions containing the second eluting isomer were concentrated and lyophilized to Example 15 as a white solid (5.6 mg, 19% yield).

[0450] Example 14: 1 H NMR(400MHz,DMSO-d6)δ 11.04(s,1H),9.10(s,1H),8.70(d,J=2.4Hz,1H),8.65(s,1H),8.54(d,J=2.4Hz,1H),8.40(s,1H),6.9 5(s,1H),4.42-4.48(m,1H),2.53-2.60(m,1H),2.29-2.37(m,1H),1.64(s,3H),1.56(s,3H).LC-MS:m / z 467[M+H] + .

[0451] Example 15: 1 H NMR(400MHz,DMSO-d6)δ 11.04(s,1H),9.10(s,1H),8.70(d,J=2.4Hz,1H),8.65(s,1H),8.54(d,J=2.4Hz,1H),8.40(s,1H),6.9 5(s,1H),4.42-4.48(m,1H),2.53-2.60(m,1H),2.29-2.37(m,1H),1.64(s,3H),1.56(s,3H).LC-MS:m / z 467[M+H] + .

[0452] The absolute stereochemistry for each separated isomer was not determined.

[0453] [ka] Examples 16 and 17: Single enantiomers obtained from a racemic mixture containing (R)-2-chloro-N-(5-chloro-6-(pyrrolidin-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and (S)-2-chloro-N-(5-chloro-6-(pyrrolidin-1-yl)pyridin-3-yl)-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide. Step 1: 3-chloro-5-nitro-2-(pyrrolidin-1-yl)pyridine [ka] To a stirred solution of 2,3-dichloro-5-nitro-pyridine (2.00 g, 10.4 mmol) in DMF (20 mL) was added pyrrolidine (884 mg, 12.4 mmol) and K2CO3 (1.43 g, 10.4 mmol). The mixture was stirred at 25 °C for 16 h. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:1) to afford 3-chloro-5-nitro-2-(pyrrolidin-1-yl)pyridine (2.00 g, 85% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.90(d,J=2.4Hz,1H),8.23(d,J=2.4Hz,1H),3.85-3.91(m,4H),1.95-2.05(m,4H).LC-MS:m / z 228[M+H] + .

[0454] Step 2: 5-chloro-6-(pyrrolidin-1-yl)pyridin-3-amine [ka] To a stirred solution of 5-chloro-6-(pyrrolidin-1-yl)pyridin-3-amine (500 mg, 2.2 mmol) in HO (5 mL) and EtOH (15 mL) was added NH4Cl (352 mg, 6.6 mmol) and iron (613 mg, 11.0 mmol). The mixture was stirred at 80 °C for 3 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:1) to afford 5-chloro-6-(pyrrolidin-1-yl)pyridin-3-amine (300 mg, 69% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.66(d,J=...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein each 【Chemistry 2】 is a single bond or a double bond, Q is -CH ２ -, O, or NH; 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; R Ｘ is hydrogen or halogen; 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 selected from hydroxyl and C1-C3 alkoxy; R ２ is hydrogen, halogen, amino, or C1-C3 alkyl; Each R ３ are independently deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 haloalkyl, or two R ３ taken together with the carbon atom to which they are attached form an oxo group, a 4- to 8-membered heterocyclyl, or a C3-C8 cycloalkyl; m is 0, 1, 2, or 3; R ４ is phenyl or 5- to 9-membered heteroaryl, 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; amino; -N=(S=O)(C1-C3 alkyl) ２ -S(=O) ｐ (C1-C3 alkyl); -(C=O)NR Ｅ R Ｆ C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; 5-6 membered heteroaryl which is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4-6 membered heterocyclyl, or C1-C3 alkyl which is hydroxyl or -NR Ｅ R Ｆ 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl optionally substituted with -NR Ｅ R Ｆ or C1-C4 alkyl optionally substituted with C1-C3 alkoxy; 3- to 8-membered heterocyclyl; and C3-C6 cycloalkoxy; p is 1 or 2; R Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ , and R Ｆ are independently hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or R Ａ and R Ｂ , or R Ｃ and R Ｄ , or R Ｅ and R Ｆ taken together with the nitrogen atom to which they are attached to form a 4-6 membered heterocyclyl optionally substituted with 1 to 2 halogens, or a pharma- ceutically acceptable salt thereof.

2. X is C and Y is C; or X is N and Y is C; or 2. The compound of claim 1, wherein X is C and Y is N, or a pharma- ceutically acceptable salt thereof.

3. Z is N, or Z is CR ５ 2. The compound of claim 1, wherein:

4. Q is -CH ２ -or- 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Q is O.

5. R １ or a pharma- ceutically acceptable salt thereof. The compound of claim 1, wherein is hydrogen, halogen, cyano, hydroxyl, C1-C3 haloalkyl, or C1-C3 alkyl optionally substituted with 1 to 3 substituents selected from hydroxyl and C1-C3 alkoxy.

6. R ２ The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, halogen, or C1-C3 alkyl.

7. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein n is 1 or 2.

8. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein m is 2 or 3.

9. Each R ３ is independently deuterium, halogen, hydroxyl, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy, or a pharma- ceutically acceptable salt thereof.

10. m is 2, and each R ３ is methyl, or m is 2, and one of R ３ is methyl, and the other R ３ is trifluoromethyl; or m is 2, and one of R ３ is trifluoromethyl, and the other R ３ is ethoxy, or m is 2, and two R ３ taken together with the carbon atom to which they are attached form a 4- to 8-membered heterocyclyl; or m is 2, and two R ３ taken together with the carbon atom to which they are attached form oxetanyl or tetrahydropyranyl; or m is 2, and two R ３ taken together with the carbon atom to which they are attached form a C3-C8 cycloalkyl; or m is 2, and two R ３ taken together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl; or m is 3 and two R ３ is methyl, and one R ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of methyl and hydroxyl.

11. R ４ is one to three independently selected R ６ 2. The compound of claim 1, which is a 5-9 membered heteroaryl optionally substituted by: or a pharma- ceutically acceptable salt thereof.

12. (i) R ６ At least one of is a halogen; or (ii) R ６ is cyano; or (iii) R ６ At least one of the groups is -(C=O)NR Ｅ R Ｆ and, if necessary, (a) R Ｅ and R Ｆ is independently hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl; or (b) R Ｅ and R Ｆ is hydrogen, and R Ｅ and R Ｆ the other is C1-C3 alkyl or C3-C6 cycloalkyl; or (c) R Ｅ and R Ｆ is C1-C3 alkyl, and R Ｅ and R Ｆ the other is a C3-C6 cycloalkyl; or (d) R Ｅ and R Ｆ taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with 1 to 2 halogens; or (iv) R ６ At least one of the groups is -N=(S=O)(C1-C3 alkyl) ２ or (v) R ６ At least one of the groups is -S(=O) ｐ (C1-C3 alkyl), or (vi) R ６ at least one of is a C1-C3 haloalkyl optionally substituted with hydroxyl; or (vii) R ６ at least one of is C1-C3 haloalkoxy; or (viii) R ６ At least one of the following is a 5-6 membered heteroaryl: halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkyl, and is not hydroxyl or -NR Ｅ R Ｆ or a 5-6 membered heteroaryl optionally substituted with C1-C3 alkyl, amino, or C1-C3 haloalkyl; (ix) R ６ At least one of the groups is C1-C4 alkyl, and is not hydroxyl, -NR Ｅ R Ｆ or C1-C4 alkyl optionally substituted with C1-C3 alkoxy; (x) R ６ at least one of is 3- to 8-membered heterocyclyl; or (xi) R ６ at least one of is C3-C6 cycloalkoxy; or (xii) R ６ or a pharma- ceutically acceptable salt thereof. The compound of claim 1, wherein at least one of is cyclopropoxy.

13. R ４ is one to three independently selected R ６ 2. The compound of claim 1, which is 3-pyridyl or 4-pyridyl substituted by: or a pharma- ceutically acceptable salt thereof.

14. R ４ but, 【Chemistry 3】 、 【Chemistry 4】 or 【Chemistry 5】 and a wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I), or a pharma- ceutically acceptable salt thereof.

15. R ６ is selected from the group consisting of C1-C3 haloalkyl optionally substituted with cyano, halogen, hydroxyl, C1-C3 haloalkoxy, and C1-C3 alkoxy, or a pharma- ceutically acceptable salt thereof.

16. The compound of claim 14, or a pharma- ceutically acceptable salt thereof, wherein R6 is selected from the group consisting of C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 alkoxy optionally substituted with cyano, halogen, and hydroxyl.

17. R ４ but, 【Chemistry 6】 、 【Chemistry 7】 、 【Chemistry 8】 or 【Chemistry 9】 and R ６Ａ and R ６Ｂ But, R ６ and a wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I), or a pharma- ceutically acceptable salt thereof.

18. R ６Ａ is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R ６Ｂ is 5-6 membered heteroaryl, optionally substituted with cyano, C1-C3 alkyl, optionally substituted with hydroxyl, 4-6 membered heterocyclyl, or amino; -N=(S=O)(C1-C3 alkyl) ２ -(C=O)NR Ｅ R Ｆ 18. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted with hydroxyl; C1-C3 haloalkoxy; cyano; C3-C6 cycloalkoxy; and C1-C3 alkyl optionally substituted with hydroxyl.

19. R ４ but, 【Chemistry 10】 or 【Chemistry 11】 and R ６Ａ , R ６Ｂ , and R ６Ｃ But, R ６ and a wavy line crosses the bond connecting to the -C(=O)NH- moiety of formula (I), or a pharma- ceutically acceptable salt thereof.

20. 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- to 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 20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl.

21. R ５ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or halogen, optionally wherein said halogen is fluoro.

22. R Ｘ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or halogen, optionally wherein said halogen is fluoro.

23. The compound is 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 【Chemistry 12-5】 【Chemistry 12-6】 【Chemistry 12-7】 【Chemistry 12-8】 【Chemistry 12-9】 【Chemistry 12-10】 【Chemistry 12-11】 【Chemistry 12-12】 【Chemistry 12-13】 【Chemistry 12-14】 【Chemistry 12-15】 【Chemistry 12-16】 【Chemistry 12-17】 【Chemistry 12-18】 【Chemistry 12-19】 【Chemistry 12-20】 【Chemistry 12-21】 【Chemistry 12-22】 【Chemistry 12-23】 【Chemistry 12-24】 【Chemistry 12-25】 2. The compound of claim 1, selected from the group consisting of:

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

25. A composition for use in treating cancer, said composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof; Optionally, the composition for use, wherein the cancer is a MALT1-associated cancer.

26. The composition for use according to claim 25, characterized in that the composition is administered to the subject in combination with an additional therapy or therapeutic agent.

27. A composition for use in treating an autoimmune disorder, said composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof; Optionally, the composition for use, wherein said autoimmune disorder is a MALT1-associated autoimmune disorder.

28. A composition for use in treating an inflammatory disorder, the composition comprising a compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof; Optionally, the composition for use, wherein the inflammatory disorder is a MALT1-associated inflammatory disorder.

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