Cyclic compounds and methods of use thereof

Abstract

The present application relates to compounds of formula (I) as defined herein and pharmaceutically acceptable salts thereof. Also described are pharmaceutical compositions comprising the compounds of Formula (I) and pharmaceutically acceptable salts thereof, as well as methods of using the compounds and compositions for the treatment of diseases such as cancer, autoimmune disorders, and inflammatory disorders. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 391,548, filed on July 22, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present application relates to tricyclic compounds that are useful for treating proliferative disorders such as cancer, as well as autoimmune disorders and inflammatory disorders. Background Art

[0004] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is an intracellular protein that participates in lymphocyte proliferation through upstream signaling of NF-κB to control the activation, survival, proliferation and differentiation of lymphocytes. Together with CARMA or CARD scaffold proteins (e.g., CARD11 (caspase recruitment domain family member 11, also known as CARMA1), CARD14 (caspase recruitment domain family member 14, also known as CARMA2), CARD10 (caspase recruitment domain family member 10, also known as CARMA3) or CARD9 (caspase recruitment domain family member 9)) and BCL10 (B cell CLL / lymphoma 10), MALT1 is one of the three subunits of the CBM complex formed when the cell surface antigen receptor is activated. 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 through at least two mechanisms: first, MALT1 acts as a scaffold protein, recruiting NF-κB signaling proteins such as TRAF6, TAB (e.g., TAB1, TAB2, TAB3), TAK1, and NEMO-IKKβ; second, it acts as a cysteine ​​protease, which cleaves and inactivates negative regulators of NF-κB signaling (such as RelB, A20, or CYLD). See Rosebeck et al., Science, 2011, 331, 468-472.

[0005] The protease activity of MALT1 has become a potential therapeutic target, especially in cases where NF-κB and related pathways are believed to play an important role. Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoma that is often characterized by overactivation of NF-κB, and studies have shown that MALT1 protease inhibition can significantly inhibit the growth of highly aggressive ABC-type DLBCL and promote its apoptosis. 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 fusion protein API2-MALT1 include A20, CYLD, BCL10, RelB, regnase-1, roquin-1, NIK and LIMA la. See Rebeaud et al., Nat Immunol 2008, 9, 272-281; ​​see also Coornaert et al., Nat Immunol 20008, 9, 263-271; Staal et al., EMBO J 2011, 30, 1742-1752; Hailfinger et al., PNAS 2011, 108, 14596-14601; Jeltsch et al., Nat Immunol 2014, 15, 1079-1089; Uehata et al., Cell 2013, 153, 1036-1049; Nie et al., Nat Commun 2015, 6, 5908; and Baens et al., PLoS ONE 2014, 9, e103774. A general overview of MALT1 substrates is described in Kasperkiewicz et al. Scientific Reports 8.1 (2018): 1-10.

[0006] Additionally, several chromosomal translocations that lead to constitutively active MALT1 have been identified in ABC-DLBCL, and the identification of MALT1 fusion protein API2-MALT1 / IgH-MALT1 leading to NF-κB activation independent of upstream stimulation further highlights the importance of this protein in cancer and various diseases. See Farinha et al., J Clinical Oncology 2005, 23, 6370-6378. Further, MALT1 has been shown to be associated with several different types of cancer, such as hematological malignancies (such as mantle cell lymphoma), chronic lymphocytic leukemia (CLL) and 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 have an impact on several inflammatory conditions, such as psoriasis, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, ulcerative colitis and different types of allergic conditions caused by chronic inflammation. See Afofina et al., FEBS Journal 2015, DOI: 10.1111 / febs.13325; see also Lowes et al., Ann Review Immunology 2014, 32, 227-255; Jabara et al., J Allergy Clin Immunology 2013, 132, 151-158; Streubel et al., Clin Cancer Research 2004, 10, 476-480; and Liu et al., Oncotarget 2016, 1-14. Recently, research results have also shown the importance of MALT1 in controlling regulatory T cell (Treg) function and homeostasis. Studies are underway to confirm the potential of MALT1 inhibitors to treat patients with solid tumors alone or in combination with immune checkpoint mechanisms. However, no MALT1 inhibitors have been approved for therapeutic use. Summary of the invention

[0007] Therefore, the present invention provides a compound of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, Q, n, RX , R 1 , R 2 , R 3 ,m,R 4 and R 5 As defined herein.

[0010] 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.

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

[0012] Also provided is a method for treating cancer in a subject in need thereof, the method comprising:

[0013] (a) identifying the cancer as a CBM complex pathway-related cancer; and

[0014] (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0015] Also provided is a method for treating cancer in a subject in need thereof, the method comprising:

[0016] An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, is administered to a subject identified as having a CBM complex pathway-related cancer.

[0017] Also provided is a method for treating a MALT1-related cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a MALT1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0018] Also provided is a method for treating cancer in a subject in need thereof, the method comprising:

[0019] (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the MALT1 gene, MALT1 protease, or any of them; and

[0020] (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0021] Also provided is a method for inhibiting metastasis in a subject in need of such treatment, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

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

[0023] Also provided is a method for treating a CBM complex pathway-related disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0024] Also provided are methods for treating a disease or condition in a subject in need thereof, the method comprising:

[0025] (a) identifying the disease or disorder as a CBM complex pathway-related disease or disorder; and

[0026] (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0027] Also provided are methods for treating a disease or condition in a subject in need thereof, the method comprising:

[0028] To the Subject An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, is administered to a subject identified as having a disease or disorder associated with the CBM complex pathway.

[0029] Also provided is a method for treating a MALT1-associated autoimmune disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a MALT1-associated autoimmune disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

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

[0031] Also provided is a method for treating an autoimmune disorder in a subject in need thereof, the method comprising:

[0032] (a) determining that the autoimmune disorder is associated with dysregulation of the expression or activity or level of the MALT1 gene, MALT1 protease, or either thereof; and

[0033] (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0034] Also provided is a method for treating a MALT1-associated autoimmune disorder in a subject, the method 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 as described herein.

[0035] Also provided is a method for treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0036] Also provided is a method for treating a MALT1-associated inflammatory disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a MALT1-associated inflammatory disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

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

[0038] Also provided are methods for treating an inflammatory disorder in a subject in need thereof, the method comprising:

[0039] (a) determining that the inflammatory disorder is associated with dysregulation of the expression or activity or level of the MALT1 gene, MALT1 protease, or either thereof; and

[0040] (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0041] Also provided is a method for treating a MALT1-associated inflammatory disorder in a subject in need thereof, the method 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 as described herein.

[0042] Also provided is a method for inhibiting the CBM complex pathway activity of a mammalian cell, the method comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0043] Also provided is a method for inhibiting MALT1 protease activity in mammalian cells, the method comprising contacting the mammalian cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0044] Also provided is the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disease or disorder related to the CBM complex pathway.

[0045] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in preparing a medicament for treating a disease or disorder related to a CBM complex pathway.

[0046] Also provided are methods of treating an individual having a MALT1-related cancer, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof before, during, or after administration of other anticancer agents (eg, a first MALT1 inhibitor or another MALT1 inhibitor).

[0047] Also provided herein is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0048] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof obtained by a process for preparing a compound as defined herein.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those of ordinary skill in the art to which the present disclosure belongs. Methods and materials for use in the present disclosure are described herein; other suitable methods and materials known in the art may also be used. These materials, methods and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0050] Other features and advantages of the disclosure will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0051] As used herein, the term "compound" is intended to encompass all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. Unless otherwise stated, compounds identified herein as one particular tautomeric form by name or structure are intended to encompass other tautomeric forms.

[0052] As used herein, the term "tautomer" refers to a compound whose structure is significantly different in atomic arrangement, but exists in easy and rapid equilibrium, and it is understood that the compounds provided herein can be depicted as different tautomers, and when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of the compound does not exclude any tautomer. The following are examples of tautomeric forms included:

[0053]

[0054] It will be appreciated that certain compounds provided herein may contain one or more asymmetric centers and, therefore, can be prepared and isolated as mixtures of isomers (eg, racemic mixtures) or in enantiomerically pure form.

[0055] The term "halo or halogen" refers to one of the halogens of Group 17 of the Periodic Table of Elements. In particular, this term refers to fluorine, chlorine, bromine and iodine. Preferably, this term refers to fluorine or chlorine.

[0056] 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, C1-C3 alkyl is a straight or branched hydrocarbon chain containing 1, 2 or 3 carbon atoms.

[0057] The term "C1-C6 haloalkyl" refers to a hydrocarbon chain substituted by at least one halogen atom (e.g., fluorine, chlorine, bromine and iodine) independently selected at each occurrence. The halogen atom may be present in any position on the hydrocarbon chain. Similarly, C1-C3 haloalkyl is a straight or branched hydrocarbon chain containing 1, 2 or 3 carbon atoms substituted by at least one halogen atom. For example, C1-C3 haloalkyl may refer to chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloroethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0058] The term "C1-C3 alkoxy" refers to a C1-C3 alkyl group attached to the molecule through an oxygen. This includes moieties where the alkyl portion can be straight or branched, such as methoxy, ethoxy, n-propoxy and isopropoxy.

[0059] The term "C1-C3 haloalkoxy" refers to a C1-C3 alkyl group which is attached to the molecule via an oxygen and wherein at least one of the hydrogen atoms of the alkyl group is replaced by a halogen. This includes that the alkyl portion may be a linear or branched portion, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or trifluoropropoxy.

[0060] When valence permits, represents a single bond or a double bond. For example,

[0061]

[0062] As used herein, the term "cyano" refers to a -CN group.

[0063] As used herein, the term "hydroxyl" refers to an -OH group.

[0064] As used herein, the term "amino" refers to -NH 2 Group.

[0065] As used herein, the term "aryl" refers to a 6-10 all-carbon monocyclic or bicyclic group, wherein at least one ring in the system is aromatic. Non-limiting examples of aryl include phenyl, naphthyl, tetrahydronaphthyl. In a bicyclic system in which only one ring is aromatic, the non-aromatic ring can be a cycloalkyl group as defined herein.

[0066] As used herein, the term "heteroaryl" refers to a 5-10 or 5-9 monocyclic or bicyclic group, wherein at least one ring in the system is aromatic; wherein one or more carbon atoms in at least one ring in the system are replaced by heteroatoms independently selected from N, O and S. Heteroaryl groups include rings (e.g., carbon, nitrogen and sulfur) in which one or more atoms are oxidized, such as pyridone moieties. Non-limiting examples of heteroaryl groups include pyridine, pyrimidine, pyridazine, pyrimidone, pyrrole, pyrazole, imidazole, triazole, thiazole and indole. In a bicyclic system in which only one ring is aromatic, the non-aromatic ring can be a cycloalkyl or heterocyclyl group as defined herein.

[0067] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated 3-10 or 3-7 monocyclic or bicyclic hydrocarbon group, or a 3-6 membered monocyclic hydrocarbon group; wherein the bicyclic system includes a fused ring system, a spirocyclic system (optionally referred to as a "spirocycloalkyl" group) and a bridged ring system. Non-limiting examples of cycloalkyl include cyclopropyl, cyclohexyl, spiro[2.3]hexyl and bicyclo[1.1.1]pentyl.

[0068] The term "heterocyclyl" refers to a saturated or partially unsaturated 3 to 12-membered, 3 to 8-membered or 4 to 6-membered hydrocarbon monocyclic or bicyclic ring system, which is not aromatic, having at least one heteroatom selected from N, O and S in the ring. Bicyclic heterocyclyl groups include fused ring systems, spiro ring systems (optionally referred to as "spiroheterocyclyl" groups) and bridged ring systems. The heterocyclyl ring system may contain oxy substitutions at one or more C, N or S ring members. The heterocyclyl group may be represented, for example, as a "5- to 10-membered heterocyclyl", which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The heterocyclyl group may be bonded to the rest of the molecule via any carbon atom or via a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidin-2-one, sulfolane, isothiazolinyl S,S-dioxide, and decahydronaphthyl.

[0069] As used herein, the term "oxy" refers to a "=0" group attached to a carbon atom.

[0070] As used herein, the notation Depicts the point of attachment of an atom or moiety to a specified atom or group in the rest of the molecule.

[0071] It will be appreciated that the ring comprising the atoms X, Y and Z in the compounds of formula (I) does not contain more than two adjacent nitrogen atoms.

[0072] Formula (I) compound includes its pharmaceutically acceptable salt. In addition, formula (I) compound also includes other salts of such compound, which are not necessarily pharmaceutically acceptable salts, and can be used as intermediates for preparing and / or purifying formula (I) compound and / or for separating the enantiomers of formula (I) compound. Non-limiting examples of pharmaceutically acceptable salts of formula (I) compound include trifluoroacetate and hydrochloride.

[0073] It will be further understood that the compounds of formula (I) or their salts may be isolated in the form of solvates, and therefore any such solvates are included within the scope of the present disclosure. For example, the compounds of formula (I) and their salts may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.).

[0074] In some embodiments, the compound of formula (I) comprises the compound of example 1-196 and its stereoisomer and pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) comprises the compound of example 1-196 and its pharmaceutically acceptable salt. In some embodiments, the compound of example 1-196 is in the form of free base. In some embodiments, the compound of example 1-196 is in the form of pharmaceutically acceptable salt.

[0075] The term "pharmaceutically acceptable" means that the compound or salt or composition thereof is chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the subject to be treated with the formulation.

[0076] Blocking group can be the temporary substituent that protects potential reactive functional group from undesirable chemical transformation impact.The selection of employed specific blocking group is fully within the skill range of those of ordinary skill in the art.Many considerations can determine the selection of blocking group, including but not limited to protected functional group, molecule other functional groups present, the reaction conditions of each step of synthesis sequence, molecule other blocking groups present, functional groups to the tolerance of removing the required condition of blocking group, and the reaction conditions of compound thermal decomposition provided herein.The field of blocking group chemistry has been reviewed (Greene, TW and Wuts, PGM Protective Groups in Organic Synthesis, 2.sup. edited Wiley:New York, 1991).

[0077] The nitrogen protecting group can be any temporary substituent that protects the amine moiety from undesirable chemical transformations. Examples of moieties formed when such protecting groups are bonded to amines include, but are not limited to, allylamine, benzylamine (e.g., benzylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and tritylamine), acetamide, trichloroacetamide, trifluoroacetamide, pent-4-eneamide, phthalimide, carbamate (e.g., methyl carbamate, tert-butyl carbamate, benzyl carbamate, allyl carbamate, 2,2,2-trichloroethyl carbamate, and 9-fluorenylmethyl carbamate), imines, and sulfonamides (e.g., benzenesulfonamide, p-toluenesulfonamide, and p-nitrobenzenesulfonamide).

[0078] The oxygen protecting group can be any temporary substituent that protects the hydroxyl moiety from undesirable chemical transformations. Examples of moieties formed when such protecting groups are bonded to the hydroxyl group include, but are not limited to, esters (e.g., acetyl, tert-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, and acetals, and ethers.

[0079] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. That is, an atom (particularly when referred to in relation to a compound of formula (I)) includes all isotopes and isotopic mixtures of such atom that are naturally occurring or synthetically produced, either in natural abundance or in isotopically enriched form. For example, when referring to hydrogen, it is understood to refer to 1 H. 2 H. 3 H or mixtures thereof; when carbon is mentioned, it is understood to mean 11 C. 12 C. 13 C. 14 C or mixtures thereof; when nitrogen is mentioned, it is understood to mean 13 N. 14 N. 15 N or mixtures thereof; when oxygen is mentioned, it is understood to mean 14 O. 15 O. 16 O. 17 O. 18 O or mixtures thereof; when fluorine is mentioned, it is understood to mean 18 F. 19 F or mixtures thereof; unless otherwise expressly stated. For example, in deuterated alkyl and deuterated alkoxy groups, one or more hydrogen atoms are replaced by deuterium ( 2 H) is specifically replaced. Because some of the above-mentioned isotopes are radioactive, the compounds provided herein also include compounds with one or more isotopes of one or more atoms and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms have been replaced by one of their rich radioactive isotopes. Radiolabeled compounds can be used as therapeutic agents, such as cancer therapeutic agents, research reagents (e.g., assay reagents) and diagnostic agents (e.g., in vivo imaging agents). All isotopic changes of the compounds provided herein, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the present disclosure.

[0080] For illustrative purposes, general methods and key intermediates for preparing compounds are provided herein. For a more detailed description of each reaction step, see the Examples section below. It will be appreciated by those skilled in the art that other synthetic pathways may be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the scheme and discussed below, other starting materials and reagents may also be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, according to the present disclosure, conventional chemical methods well known to those skilled in the art may be used to further modify many of the compounds prepared by the following methods.

[0081] The ability of selected compounds to act as MALT1 inhibitors can be demonstrated by the biological assays described herein. 50 The values ​​are shown in Table A.

[0082] The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful for treating diseases and conditions that can be treated with MALT1 inhibitors, such as MALT1-related cancers, including hematological cancers and solid tumors, MALT1-related autoimmune disorders, and MALT1-related inflammatory disorders.

[0083] As used herein, the term "treat" or "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, complete or partial relief of symptoms associated with a disease or disorder or condition, reduction of disease extent, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state (e.g., one or more disease symptoms), and relief (whether partial or total), whether detectable or undetectable. "Treatment" can also mean an extension of survival compared to the expected survival without treatment.

[0084] As used herein, the term "subject" refers to any animal, including mammals, such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented.

[0085] As used herein, the term "pediatric subject" refers to a subject who is under 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into different subgroups, including: neonates (from birth to the first month of life); infants (1 month to 2 years); children (2 years to 12 years); and adolescents (12 to 21 years (up to but not including the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Edition Philadelphia: WB Saunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st Edition New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Edition Baltimore: Williams & Wilkins; 1994. In some embodiments, the age of the pediatric subject is from birth to the first 28 days of life, from 29 days to less than two years old, from two years to less than 12 years old, or from 12 years to 21 years old (up to but not including the twenty-second birthday). In some embodiments, the age of the pediatric subject is from birth to the first 28 days of life, from 29 days to less than 1 year old, from one month to less than four months old, from three months to less than seven months old, from six months to less than 1 year old, from 1 year old to less than 2 years old, from 2 years old to less than 3 years old, from 2 years old to less than 7 years old, from 3 years old to less than 5 years old, from 5 years old to less than 10 years old, from 6 years old to less than 13 years old, from 10 years old to less than 15 years old, or from 15 years old to less than 22 years old.

[0086] In certain embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof can be used to prevent diseases and disorders defined herein (e.g., autoimmune disorders, inflammatory disorders, and cancer). As used herein, the term "prevention" refers to the complete or partial prevention of the onset, recurrence, or spread of a disease or condition described herein, or a symptom thereof.

[0087] The term "regulatory agency" refers to an agency of a country that approves the medical use of a pharmaceutical agent in that country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0088] Signaling through the NF-κB pathway is associated with many cancers. See, for example, Staudt, Cold Spring Harbor Perspectives in Biology 2.6 (2010): a000109, Xia et al. Cancer Immunol. Res. 2.9 (2014): 823-830, Xia et al. OncoTargets and Therapy 11 (2018): 2063. NF-κB is a family of transcription factors, including p50, p52, p65 (RelA), RelB and c-Rel, which can bind to kB enhancer elements as various homologous and heterologous dimers to induce transcription of many genes. After activation of certain cell surface receptors (e.g., CD28, BCR, HER1 (also known as EGFR (epidermal growth factor receptor) and ERBB1) or HER2 (also known as HER2 / neu or ERBB2)), the CBM complex is formed by CARD or CARMA proteins, possibly by phosphorylation of protein kinase C (e.g., protein kinase Cβ or protein kinase Cθ) and recruitment of the BCL10-MALT1 complex. See, e.g., Xia et al. OncoTargets and Therapy 11 (2018): 2063, Shi and Sun. Mol. Immunol. 68.2 (2015): 546-557, Xia et al. Cancer Immunol. Res. 2.9 (2014): 823-830, and Pan, Mol. Cancer Res. 14.1 (2016): 93-102.

[0089] As described above, the CBM complex can function as a scaffold protein in the activation of the NF-κB pathway. Once formed, the CBM complex can activate the IKK complex (e.g., IKKγ (also known as NEMO), IKKα, and IKKβ), possibly through ubiquitination (e.g., K63-linked ubiquitination) of MALT1, which causes the recruitment, ubiquitination (e.g., K63-linked ubiquitination), and degradation of IKKγ, thereby releasing IKKα and IKKβ to phosphorylate IκB, thereby causing ubiquitination (e.g., K48-linked ubiquitination) and degradation of IκB, thereby releasing NF-κB transcription factors (usually NF-κB1 isoforms: p50-RelA and p50-cRel) to the nucleus. This cascade may be mediated by the ubiquitin ligase TRAF6 (tumor necrosis factor receptor (TNFR) associated factor 6). The CBM complex may also affect NF-κB signaling through additional protein complexes, such as TAB1 / 2-TAK and the linear ubiquitin chain assembly complex (LUBAC). See, e.g., 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 there is less research in this area. See, for example, Juilland, Front. Immunol. 9 (2018): 1927, and Wang et al., Oncogenesis 6.7 (2017): e365-e365.

[0090] In addition, MALT1 has cysteine ​​protease activity. Non-limiting examples of wild-type MALT1 substrates include BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, and HOIL1. In addition, API2-MALT1 (also known as cIAP2; amino terminal of inhibitor of apoptosis 2) fusion protein has also been shown to cleave NIK and LIMA1α. MALT1 cleavage of BCL10 is believed to result in BCL10-independent NF-κB activation. By cleaving A20 (TNFα-induced protein 3), MALT1 can reduce the negative regulation of the NF-κB pathway because A20 is a deubiquitinating enzyme that has been suggested to reduce the ubiquitination of MALT1, thereby reducing the recruitment and activation of the IKK complex. CYLD (CYLD lysine 63 deubiquitinase) is a deubiquitinating enzyme, and by cleaving this enzyme, it is believed that MALT1 increases signaling through the NF-κB pathway and / or the JNK pathway. Cleavage of RelB normally relieves negative regulation of the NF-κB pathway, as RelB forms a transcriptionally inactive complex with RelA and c-Rel. By cleaving HOIL1 (also known as RBCK1), negative regulation of NF-κB is believed to be relieved, as HOIL1 is thought to reduce linear ubiquitination. MALT1 can also be autoprocessed to promote signaling through the NF-κB pathway by a mechanism that is not fully understood. By cleaving NIK (NF-κB inducing kinase), the API2-MALT1 protease generates a c-terminal fragment of NIK that is resistant to proteasomal degradation, thereby increasing non-canonical NF-κB signaling. By cleaving LIMA1α (LIM domain and actin binding protein 1), the tumor suppressor properties of this protein are relieved, and the remaining fragment is believed to have oncogenic properties and enhance cell proliferation, colony formation, and cell adhesion. Regnase 1 (regulatory RNase 1, also known as MCPIP-1 or Zc3h12a) and roquin-1 (also known as RC3H1) cleavage is thought to lead to mRNA stabilization, including stabilization of mRNAs for cytokines, chemokines, and co-stimulatory proteins such as ICOS, OX40, and TNF. This activity may be independent of MALT1 activity in the NF-κB and JNK pathways. See, for example, Afonina et al. FEBS J. 282.17 (2015): 3286-3297 Klein et al. Nat. Comm. 6.1 (2015): 1-17, Baens et al. PloS one 9.8 (2014): e103774, and Juilland, Front. Immunol. 9 (2018): 1927.MALT1 is also involved in oncogenic BCR signaling in ibrutinib-responsive cell lines and biopsy samples, coordinated by a multiprotein supercomplex formed by MYD88, TLR9, and BCR (hereinafter referred to as the My-T-BCR supercomplex). The My-T-BCR supercomplex colocalizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signaling. See Phelan et al., Nature, August 2018; 560(7718): 387-391.

[0091] Therefore, inhibition of MALT1 may provide beneficial effects for many types of conditions associated with aberrant signaling in the NF-κB pathway or the JNK pathway. For example, inhibition of MALT1 may reduce flux through the NF-κB or JNK pathway caused by one or more of the following:

[0092] (1) Inactivated tumor suppressor genes. Non-limiting examples of tumor suppressor genes that can be inactivated include BRCA1 and p53 (e.g., p53 H61L or I123T). See, for example, Sau et al. Cell Stem Cell 19.1 (2016): 52-65, Xia et al. Cancer Immunol. Res. 2.9 (2014): 823-830, Johansson et al. Oncotarget 7.38 (2016): 62627.

[0093] (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.

[0094] (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.

[0095] (4) Deregulation of one or more MALT1 protease substrates (e.g., wild-type MALT1 protease or deregulated MALT1 protease). Non-limiting examples of MALT1 protease substrates include BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, HOIL1, NIK, and LIMA1α.

[0096] (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.

[0097] (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).

[0098] (7) Disregulation of one or more fusion proteins caused by chromosomal translocation of MALT1 gene. Non-limiting examples include cIAP-MALT1 fusion protein.

[0099] (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.

[0100] As used herein, the term "CBM complex pathway" includes genes, transcripts, and proteins in a signaling pathway that includes a CBM. For example, many aspects of the NF-κB pathway are part of a CBM complex pathway. A CBM complex pathway can include, for example, a cell surface receptor (e.g., CD28, BCR, HER1, and HER2), a signal transducer between a cell surface receptor and a CBM complex (e.g., protein kinase Cβ or protein kinase Cθ), a component of a CBM complex (e.g., MALT1, CARD11, CARD14, CARD10, CARD9, or BCL10), a substrate of a MALT1 protease (e.g., BCL10, A20, CYLD, RelB, Regnase 1, roquin-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).

[0101] As used herein, the term "CBM complex pathway-related disease or condition" refers to a disease or condition associated with or having an imbalance (e.g., any type of imbalance in the expression or activity or level of a gene in a CBM complex pathway, a protein in a CBM complex pathway, or any of them (e.g., one or more) in a CBM complex pathway. Non-limiting examples of diseases or conditions associated with a CBM complex pathway include, for example, CBM-related primary immunodeficiency diseases, autoimmune disorders, multiple sclerosis, colitis, psoriasis, and cancer. See, for example, McGuire et al. J. Neuroinflamm. 11.1 (2014): 1-12, Lu et al., Front. Immunol. 9 (2018): 2078, Jaworski et al., EMBO J. 33.23 (2014): 2765-2781. Non-limiting examples of CBM complex pathway-associated diseases or disorders include MALT1-associated diseases or disorders, such as MALT1-associated cancers, MALT1-associated autoimmune disorders, and MALT1-associated inflammatory disorders.

[0102] As used herein, the term "CBM complex pathway-associated autoimmune disorder" refers to an autoimmune disorder that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression or activity or level of a CBM complex pathway gene, a CBM complex pathway protein, or any of them (e.g., one or more) described herein). Non-limiting examples of CBM complex pathway-associated autoimmune disorders are described herein.

[0103] As used herein, the term "CBM complex pathway-associated inflammatory disorder" refers to an inflammatory disorder that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression or activity or level of a CBM complex pathway gene, a CBM complex pathway protein, or any of them (e.g., one or more) of a CBM complex pathway gene, a CBM complex pathway protein, or any of them described herein). Non-limiting examples of CBM complex pathway-associated inflammatory disorders are described herein.

[0104] In some embodiments, the CBM complex pathway-associated disease or disorder is a CBM complex pathway-associated cancer, such as a CBM complex pathway cell surface receptor-associated cancer (e.g., a CD28-associated cancer, a BCR-associated cancer, a HER1-associated cancer, or a HER2-associated cancer), a cancer associated with a signal transducer between a cell surface receptor and a CBM complex (e.g., a protein kinase Cβ (PKCβ)-associated cancer or a protein kinase Cθ (PCKθ)-associated cancer), a component of a CBM complex-associated cancer (e.g., a MALT1-associated cancer, a CARD11-associated cancer, a CARD14-associated cancer, a CARD10-associated cancer, a CARD9-associated cancer, or a BCL10-associated cancer), a MALT1 protease substrate-associated cancer (e.g., a BCL10-associated cancer, an A20-associated cancer, a CYLD-associated cancer, a RelB-associated cancer cancer, Regnase1-related cancer, roquin-1-related cancer, HOIL1-related cancer, NIK-related cancer, or LIMA1α-related cancer), cancer associated with a component of the NF-κB pathway downstream of the CBM complex (e.g., TAK1-related cancer, TRAF6-related cancer, TAB1-related cancer, TAB2-related cancer, TAB3-related cancer, MKK7-related cancer, IKKα-related cancer, IKKβ-related cancer, IKKγ-related cancer, IkBα-related cancer, p50-related cancer, p65(RelA)-related cancer, or c-Rel-related cancer), cancer associated with a component of the JNK pathway downstream of the CBM complex (e.g., JNK1-related cancer, JNK2-related cancer, JNK3-related cancer, or AP-1 transcription factor-related cancer), MYD88-related cancer, or a combination thereof.

[0105] As used herein, the term "CBM complex pathway-associated cancer" refers to a cancer that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression or activity or level of a gene in the CBM complex pathway, a protein in the CBM complex pathway, or any of them (e.g., one or more) (e.g., as described herein, a gene in the CBM complex pathway, a protein in the CBM complex pathway, or any of them) (e.g., after diagnosis or after resistance to previous therapy). Non-limiting examples of CBM complex pathway-associated cancers are described herein. In some embodiments, the CBM complex pathway-associated cancer can be 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 a CBM complex (e.g., protein kinase Cβ (PKCβ)-associated cancer or protein kinase Cθ (PCKθ)-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, Regnase 1-related cancer, roquin-1-related cancer, HOIL1-related cancer, NIK-related cancer, or LIMA1α-related cancer), cancer associated with a component of the NF-κB pathway downstream of the CBM complex (e.g., TAK1-related cancer, TRAF6-related cancer, TAB1-related cancer, TAB2-related cancer, TAB3-related cancer, MKK7-related cancer, IKKα-related cancer, IKKβ-related cancer, IKKγ-related cancer, IkBα-related cancer, p50-related cancer, p65(RelA)-related cancer, or c-Rel-related cancer), cancer associated with a component of the JNK pathway downstream of the CBM complex (e.g., JNK1-related cancer, JNK2-related cancer, JNK3-related cancer, or AP-1 transcription factor-related cancer), or a combination thereof.

[0106] In certain embodiments, disorder can be disorder that causes the expression or activity or abnormal activation of gene, protein or any one thereof.Activation can be carried out by any suitable mechanism, including but not limited to the overexpression of the protein product of gene amplification, activating mutation, activating translocation, transcriptional activation, epigenetic change and / or oncogene.In certain embodiments, disorder can be disorder that causes the expression or activity or abnormal inactivation of gene, protein or any one thereof.Inactivation can be carried out by any suitable mechanism, including but not limited to gene deletion, inactivating mutation, inactivating translocation, transcriptional silencing, epigenetic change and the degradation of mRNA and / or protein product of gene.Generally, as used herein, disorder (whether activation or inactivation) is disorder that causes the increase of signal transduction by NF-κB or JNK signal transduction pathway.

[0107] The term "wild type" describes a nucleic acid (e.g., MALT1 gene or MALT1 mRNA) or protein (e.g., MALT1 protein) found in a subject that does not have a disease or condition associated with a nucleic acid or protein (e.g., MALT1 gene, MALT1 mRNA or MALT1 protein) (and optionally also does not have an increased risk of having a disease or condition associated with the nucleic acid or protein and / or is not suspected of having a disease or condition associated with the gene or protein), or found in cells or tissues from a subject that does not have a disease or condition associated with the gene or protein (e.g., MALT1-related cancer, autoimmune disorder, or inflammatory disorder) (and optionally also does not have an increased risk of having a disease or condition associated with the nucleic acid or protein and / or is not suspected of having a disease or condition associated with the nucleic acid or protein).

[0108] In some embodiments, the subject has been identified or diagnosed as having a cancer (CBM complex pathway-related cancer) with a disorder of expression, activity or level of a CBM complex pathway-related gene (e.g., MALT1 gene), a CBM complex pathway-related protein (e.g., MALT1 protein), or any of them (e.g., as determined using a regulatory agency-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has a cancer that is resistant to one or more prior therapies. In some embodiments, the subject has a tumor that is positive for a disorder of expression, activity or level of a CBM complex pathway-related gene (e.g., MALT1 gene), a CBM complex pathway-related protein (e.g., MALT1 protein), or any of them (e.g., as determined using a regulatory agency-approved (e.g., FDA-approved) assay or kit). The subject may be a subject with a tumor that is positive for a disorder of expression, activity or level of a CBM complex pathway-related gene (e.g., MALT1 gene), a CBM complex pathway-related protein (e.g., MALT1 protein), or any of them (e.g., identified as positive using a regulatory agency-approved (e.g., FDA-approved) assay or kit). The subject may be a subject whose tumor has a disorder of expression or activity or level of a CBM complex pathway-related gene (e.g., MALT1 gene), a CBM complex pathway-related protein (e.g., MALT1 protein), or both (e.g., in the case of identifying a tumor using an assay or kit approved by a regulatory agency (e.g., FDA approved)). In some embodiments, the subject suffers from a tumor that is resistant to one or more previous therapies. In some embodiments, the subject is suspected of having a CBM complex pathway-related cancer. In some embodiments, the subject suffers from a tumor suspected of being resistant to one or more previous therapies. In some embodiments, the subject has a clinical record indicating that the subject suffers from a tumor that has a disorder of expression or activity or level of a CBM complex pathway-related gene (e.g., MALT1 gene), a CBM complex pathway-related protein (e.g., MALT1 protein), or any one of them (and optionally, the clinical record indicates that the subject should be treated with any composition provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has a clinical record indicating that the subject suffers from a tumor that is resistant to one or more previous therapies. In some embodiments, the subject has been identified or diagnosed as having a cancer that is determined based on histological examination to be associated with a dysregulation of the expression or activity or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (CBM complex pathway-associated cancer).

[0109] In some embodiments, the subject has been identified or diagnosed as having an autoimmune disorder (CBM complex pathway-associated autoimmune disorder) with a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or a dysregulation of expression, activity, or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency (e.g., FDA approved)). In some embodiments, the subject has a tumor that is positive for a dysregulation of expression, activity, or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (e.g., as determined using an assay or kit approved by a regulatory agency (e.g., FDA approved)). In some embodiments, the subject is suspected of having a CBM complex pathway-associated autoimmune disorder. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with a dysregulation of expression, activity, or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any of them (and optionally, the clinical record indicates that the subject should be treated with any composition provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having an autoimmune disorder determined based on histological examination to be associated with a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or a dysregulation of expression or activity or level of any of them (CBM complex pathway-associated autoimmune disorder).

[0110] In some embodiments, the subject has been identified or diagnosed as having an inflammatory disorder (CBM complex pathway-associated inflammatory disorder) with a disorder of expression or activity or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any thereof (e.g., as determined using an assay or kit approved by a regulatory agency (e.g., FDA approved)). In some embodiments, the subject has a tumor that is positive for a disorder of expression or activity or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any thereof (e.g., as determined using an assay or kit approved by a regulatory agency (e.g., FDA approved)). In some embodiments, the subject is suspected of having a CBM complex pathway-associated inflammatory disorder. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with a disorder of expression or activity or level of a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or any thereof (and optionally, the clinical record indicates that the subject should be treated with any composition provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having an inflammatory disorder determined based on histological examination to be associated with a CBM complex pathway-associated gene (e.g., MALT1 gene), a CBM complex pathway-associated protein (e.g., MALT1 protein), or a dysregulation of expression or activity or level of any of them (CBM complex pathway-associated inflammatory disorder).

[0111] As used herein, the term "CBM complex pathway cell surface receptor associated cancer" refers to a cancer associated with or having an imbalance in the expression or activity or level of a gene, protein, or any of them (e.g., one or more), the imbalance being 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.

[0112] As used herein, the term "*-related cancer" refers to a cancer that is associated with or has a disorder (e.g., any type of disorder in the expression, activity or level of a * gene, * protein, or any of them (e.g., one or more) described herein), wherein "*" refers to a specific CBM complex pathway gene or protein described herein. In some embodiments, the *-associated cancer is selected from the group consisting of: CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, HER2-associated cancer, PKCβ-associated cancer, PKCθ-associated cancer, MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, A20-associated cancer, CYLD-associated cancer, RelB-associated cancer, HOIL1-associated cancer, NIK-associated cancer, Regnase1-associated cancer, LIMA1α-associated cancer, roquin-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 *-related cancer is a BCR-related cancer. In some embodiments, the *-related cancer is a HER1-related cancer. In some embodiments, the *-related cancer is a HER2-related cancer. In some embodiments, the *-related cancer is a PKCβ-related cancer. In some embodiments, the *-related cancer is a PKCθ-related cancer. In some embodiments, the *-related cancer is a MALT1-related cancer. In some embodiments, the *-related cancer is a CARD11-related cancer. In some embodiments, the *-related cancer is a CARD14-related cancer. In some embodiments, the *-related cancer is an A20-related cancer. In some embodiments, the *-related cancer is a CYLD-related cancer. In some embodiments, the *-related cancer is a RelB-related cancer. In some embodiments, the *-related cancer is a HOIL1-related cancer. In some embodiments, the *-related cancer is a NIK-related cancer. In some embodiments, the *-related cancer is a Regnase 1-related cancer. In some embodiments, the *-related cancer is a LIMA1α-related cancer. In some embodiments, the *-related cancer is a roquin-1-related cancer. In some embodiments, the *-related cancer is a TRAF6-related cancer. In some embodiments, the *-related cancer is a TAK1-related cancer. In some embodiments, the *-related cancer is a TAB1-related cancer. In some embodiments, the *-related cancer is a TAB2-related cancer.In some embodiments, the *-related cancer is a TAB3-related cancer. In some embodiments, the *-related cancer is a MKK7-related cancer and an IKKα-related cancer. In some embodiments, the *-related cancer is an IKKβ-related cancer. In some embodiments, the *-related cancer is an IKKγ-related cancer. In some embodiments, the *-related cancer is an IkBα-related cancer. In some embodiments, the *-related cancer is a p50-related cancer. In some embodiments, the *-related cancer is a p65-related cancer. In some embodiments, the *-related cancer is a c-Rel-related cancer. In some embodiments, the *-related cancer is a JNK1-related cancer. In some embodiments, the *-related cancer is a JNK2-related cancer. In some embodiments, the *-related cancer is a JNK3-related cancer. In some embodiments, the *-related cancer is an AP-1 transcription factor-related cancer. In some embodiments, the *-related cancer is a MYD88 transcription factor-related cancer.

[0113] The phrase "dysregulation of expression or activity or level of a *gene, *protein, or any thereof" (wherein * is a specific CBM complex pathway gene or protein described herein) refers to a genetic mutation (e.g., a chromosomal translocation that results in expression of a fusion protein comprising a *domain and a fusion partner; a mutation in a *gene that results in expression of a *protein comprising at least one amino acid deletion compared to the wild-type *protein; a mutation in a *gene that results in expression of a *protein having one or more point mutations compared to the wild-type *protein; a mutation in a *gene that results in expression of a *protein having at least one inserted amino acid compared to the wild-type *protein; a gene duplication that results in increased levels of the *protein in the cell; or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in increased levels of the *protein in the cell); an alternative splice form of a *mRNA that results in a *protein having at least one amino acid deletion in the *protein compared to the wild-type *protein; or increased expression (e.g., increased levels) of a wild-type *protein in a mammalian cell (e.g., compared to a control non-cancer cell). This is caused by abnormal cellular signaling and / or dysregulated autocrine / paracrine signaling. As another example, increased copies of a gene can cause overexpression of a protein. For example, a disorder of the expression or activity or level of a gene, a protein, or any of them can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first portion of a gene and a second portion of a partner protein (i.e., not a gene). In some instances, a disorder of the expression or activity or level of a gene, a protein, or any of them can be the result of a gene translocation of a gene with another non-gene. In some embodiments, the expression or activity or level of a gene, a protein, or any of them is selected from the group consisting of CD28, BCR, HER1, HER2, PKCβ, PKCθ, MALT1, CARD11, CARD14, A20, CYLD, RelB, HOIL1, NIK, Regnase 1, LIMA1α, roquin-1, TRAF6, TAK1, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65, c-Rel, JNK1, JNK2, JNK3, MYD88, and AP-1 transcription factors. In some embodiments, the gene or protein is CD28. In some embodiments, the gene or protein is BCR. In some embodiments, the gene or protein is HER1. In some embodiments, the gene or protein is HER2. In some embodiments, the gene or protein is PKCβ. In some embodiments, the gene or protein is PKCθ. In some embodiments, the *gene or *protein is MALT1.In some embodiments, the *gene or *protein is CARD11. In some embodiments, the *gene or *protein is CARD14. In some embodiments, the *gene or *protein is A20. In some embodiments, the *gene or *protein is CYLD. In some embodiments, the *gene or *protein is RelB. In some embodiments, the *gene or *protein is HOIL1. In some embodiments, the *gene or *protein is NIK. In some embodiments, the *gene or *protein is Regnase 1. In some embodiments, the *gene or *protein is LIMA1α. In some embodiments, the *gene or *protein is roquin-1. In some embodiments, the *gene or *protein is TRAF6. In some embodiments, the *gene or *protein is TAK1. In some embodiments, the *gene or *protein is TAB1. In some embodiments, the *gene or *protein is TAB2. In some embodiments, the *gene or *protein is TAB3. In some embodiments, the *gene or *protein is MKK7. In some embodiments, the *gene or *protein is IKKα. In some embodiments, the *gene or *protein is IKKβ. In some embodiments, the *gene or *protein is IKKγ. In some embodiments, the *gene or *protein is IkBα. In some embodiments, the *gene or *protein is p50. In some embodiments, the *gene or *protein is p65. In some embodiments, the *gene or *protein is c-Rel. In some embodiments, the *gene or *protein is JNK1. In some embodiments, the *gene or *protein is JNK2. In some embodiments, the *gene or *protein is JNK3. In some embodiments, the *gene or *protein is MYD88 transcription factor. In some embodiments, the *gene or *protein is AP-1 transcription factor.

[0114] In some embodiments, the disorder of the expression or activity or level of a *gene, a *protein, or any of them can be a mutation in a *gene encoding a *protein, which is constitutively active or has increased activity compared to a protein encoded by a *gene that does not contain a mutation. In some embodiments, the increased *gene copy number can cause overexpression of a *protein. In some embodiments, the expression or activity or level of a *gene, a *protein, or any of them is CD28. In some embodiments, the expression or activity or level of a *gene, a *protein, or any of them is BCR. In some embodiments, the expression or activity or level of a *gene, a *protein, or any of them is HER1. In some embodiments, the expression or activity or level of a *gene, a *protein, or any of them is HER2. In some embodiments, the expression or activity or level of a *gene, a *protein, or any of them is PKCβ. In some embodiments, the expression or activity or level of a *gene, a *protein, or any of them is PKCθ. In some embodiments, the expression or activity or level of a *gene, a *protein, or any of them is CARD14. In some embodiments, the expression or activity or level of a *gene, a *protein, or any of them is CARD9. In some embodiments, the expression or activity or level of the *gene, *protein, or any thereof is CARD10. In some embodiments, the expression or activity or level of the *gene, *protein, or any thereof is CARD11. In some embodiments, the expression or activity or level of the *gene, *protein, or any thereof is MALT1.

[0115] As another example, the dysregulation of the expression or activity or level of a *gene, a *protein, or any thereof can be a mutation in a *gene encoding a *protein that is constitutively inactive or has reduced activity compared to a protein encoded by a *gene that does not contain the mutation. In some embodiments, the expression or activity or level of a *gene, a *protein, or any thereof is A20. In some embodiments, the expression or activity or level of a *gene, a *protein, or any thereof is CYLD. In some embodiments, the expression or activity or level of a *gene, a *protein, or any thereof is RelB. In some embodiments, the expression or activity or level of a *gene, a *protein, or any thereof is HOIL1. In some embodiments, the expression or activity or level of a *gene, a *protein, or any thereof is NIK.

[0116] A disease or condition "associated with" a specific gene or protein as described herein refers to a disease or condition associated with or having a disorder (e.g., a specific gene, a specific protein, or any one of them, e.g., one or more) of the expression or activity or level thereof. Non-limiting examples of such diseases or conditions are described herein. Similarly, a cancer "associated with" a specific gene or protein as described herein refers to a cancer associated with or having a disorder (e.g., a specific gene, a specific protein, or any one of them, e.g., one or more) of the expression or activity or level thereof. Non-limiting examples of such cancers are described herein.

[0117] Exemplary sequences of proteins described herein are shown below.

[0118] An exemplary sequence of human CD28 is shown below:

[0119] SEQ ID NO: 1 (UniParc accession number UPI0000043F4D)

[0120] MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRASLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQTDIY FCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0121] 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.

[0122] An exemplary sequence of a human BCR is shown below:

[0123] SEQ ID NO: 2 (UniParc accession number UPI000016A088)

[0124]

[0125] Non-limiting examples of dysregulation of BCR genes or BCR proteins (e.g., BCR-ABL fusions) can be found in, e.g., Yang and Fu, Crit. Rev. Oncol. / Hematol. 93.3 (2015): 277-292, Weisber et al. Nat. Rev. Cancer 7.5 (2007): 345-356, and Jabbour et al. Cancer 117.9 (2011): 1800-1811.

[0126] An exemplary sequence of human HER1 is shown below:

[0127] SEQ ID NO:3 (UniParc accession number UPI000003E750)

[0128]

[0129] 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.

[0130] An exemplary sequence of human HER2 is shown below:

[0131] SEQ ID NO:4 (UniParc accession number UPI000003F55F)

[0132]

[0133] Non-limiting examples of dysregulation of the HER2 gene or HER2 protein can be found in, for example, Petrelli, Fausto et al., Breast Cancer Research and Treatment 166.2 (2017): 339-349, Yan et al., Cancer and Metastasis Reviews 34.1 (2015): 157-164, Koshkin et al., Bladder Cancer 5.1 (2019): 1-12, and Connell et al., ESMO Open 2.5 (2017).

[0134] As used herein, the term "cancer associated with a signal transducer between a cell surface receptor and a CBM complex" refers to a cancer associated with or having an imbalance in the expression or activity or level of a gene, protein, or any of them (e.g., one or more), the imbalance being associated with 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 PKCβ-associated cancer, PCKθ-associated cancer, and a combination thereof. A cancer "associated" with a specific gene or protein described in this paragraph refers to a cancer associated with or having an imbalance in the expression or activity or level of a specific gene, a specific protein, or any of them (e.g., one or more) (e.g., any type of imbalance in the expression or activity or level of a specific gene, a specific protein, or any of them described herein). Non-limiting examples of such cancers are described herein.

[0135] An exemplary sequence of human PKCβ is shown below:

[0136] SEQ ID NO:5 (UniParc accession number UPI000012DF67)

[0137] MADPAAGPPPSEGEESTVRFARKGALRQKNVHEVKNHKFTARFFKQPTFCSHCTDFIWGFGKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPASDDPRSKHKFKIHTYSSPTFCDHCGSLLYGLIHQGMKCDTCMMNVHKRCVMNVPSLCGTDHTERRGRIYIQAHIDRDVLIVLVRDAKNLVPMDPNGLSDPYVKLKLIPDPKSESKQKTKTIKCSLNPEWNETFRFQLKESDKDRRLSVEIWDWDLTSRNDFMGSLSFGISELQKASVDGWFKLLSQEEGEYFNVPVPPEGSEANEELRQKFERAKISQGTKVPEEKTTNTVSKFDNNGNRDRMKLTDFNFLMVLGKGSFGKVMLSERKGTDELYAVKILKKDVVIQDDDVECTMVEKRVLALPGKPPFLTQLHSCFQTMDRLYFVMEYVNGGDLMYHIQQVGRFKEPHAVFYAAEIAIGLFFLQSKGIIYRDLKLDNVMLDSEGHIKIADFGMCKENIWDGVTTKTFCGTPDYIAPEIIAYQPYGKSVDWWAFGVLLYEMLAGQAPFEGEDEDELFQSIMEHNVAYPKSMSKEAVAICKGLMTKHPGKRLGCGPEGERDIKEHAFFRYIDWEKLERKEIQPPYKPKARDKRDTSNFDKEFTRQPVELTPTDKLFIMNLDQNEFAGFSYTNPEFVINV

[0138] An exemplary sequence of human PKCθ is shown below:

[0139] SEQ ID NO:6 (UniParc accession number UPI000012DF74)

[0140] MSPFLRIGLSNFDCGSCQSCQGEAVNPYCAVLVKEYVESENGQMYIQKKPTMYPPWDSTFDAHINKGRVMQIIVKGKNVDLISETTVELYSLAERCRKNNGKTEIWLELKPQGRMLMNARYFLEMSDTKDMNEFETEGFFALHQRRGAIKQAKVHHVKCHEFTATFFPQPTFCSVCHEFVWGLNKQGYQCRQCNAAIHKKCIDKVIAKCTGSAINSRETMFHKERFKIDMPHRFKVYNYKSPTFCEHCGTLLWGLARQGLKCDACGMNVHHRCQTKVANLCGINQKLMAEALAMIESTQQARCLRDTEQIFREGPVEIGLPPCSIKNEARPPPCLPTPGKREPQGISWESPLDEV DKMCHLPEPELNKERPSLQIKLKIEDFILHKMLGKGSFGKVFLAEFKKTNQFFAIKALKKDVVLMDDVECTMVEKRVLSLAWEHPFLTHMFCTFQTKENLFFVMEYLNGGDLMYHIQSCHKFDLSRATFYAAEIILGLQFLHSKGIVYRDLKLDNILLDKDGHIKIADFGMCKENMLGDAKTNTFCGTPDYIAPEILLGQKYNHSVDWWSFGVLLYEMLIGQSPFHGQDEELELFHSIRMDNPFYPRWLEKEAKDLLVKLFVREPEKRLGVRGDIRQHPLFREINWEELERKEIDPPFRPKVKSPFDCSNFDKEFLNEKPRLSFADRALINSMDQNMFRNFSFNMPGMERLIS

[0141] As used herein, the term "component of a CBM complex-associated cancer" refers to a cancer associated with or having an imbalance in the expression or activity or level of a gene, protein, or any one of them (e.g., one or more), the imbalance being associated with a component of the CBM complex. In some embodiments, the component of a 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 a combination thereof. In some embodiments, a CBM complex-associated cancer is selected from the group consisting of: MALT1-associated cancer, CARD11-associated cancer, BCL10-associated cancer, and a combination thereof. A cancer "associated" with a specific gene or protein described in this paragraph refers to a cancer associated with or having an imbalance in the expression or activity or level of a specific gene, a specific protein, or any one of them (e.g., one or more) (e.g., any type of imbalance in the expression or activity or level of a specific gene, a specific protein, or any one of them described herein). Non-limiting examples of such cancers are described herein.

[0142] As used herein, the term "MALT1-associated autoimmune disorder" refers to an autoimmune disorder associated with or having an imbalance in the expression or activity or level of a MALT1 gene, a MALT1 protein (also referred to herein as a MALT1 protease protein or MALT1 protease), or any one of them (e.g., one or more) (e.g., any type of imbalance in the expression or activity or level of a MALT1 gene, a MALT1 protease, a MALT1 protease domain, or any of the three described herein). Non-limiting examples of MALT1-associated autoimmune disorders are described herein.

[0143] As used herein, the term "MALT1-associated inflammatory disorder" refers to an inflammatory disorder associated with or having an imbalance (e.g., any type of imbalance in the expression or activity or level of a MALT1 gene, a MALT1 protein (also referred to herein as a MALT1 protease protein or a MALT1 protease), or any one of them (e.g., one or more) (e.g., a MALT1 gene, a MALT1 protease, a MALT1 protease domain, or any of the three described herein). Non-limiting examples of MALT1-associated inflammatory disorders are described herein.

[0144] As used herein, the term "MALT1-associated cancer" refers to a cancer that is associated with or has a disorder (e.g., any type of disorder of expression or activity or level of a MALT1 gene, a MALT1 protein (also referred to herein as a MALT1 protease protein or MALT1 protease), or any one of them (e.g., one or more) . Non-limiting examples of MALT1-associated cancers are described herein.

[0145] The phrase "dysregulation of the expression or activity or level of the MALT1 gene, MALT1 protein, or any of them" refers to a genetic mutation of the wild-type MALT1 protein in a mammalian cell (e.g., compared to a control non-cancerous cell) (e.g., a chromosomal translocation that results in the expression of a fusion protein comprising a MALT1 protease domain and a fusion partner; a mutation in the MALT1 gene that results in the expression of a MALT1 protein comprising at least one amino acid deletion compared to the wild-type MALT1 protein; a mutation in the MALT1 gene that results in the expression of a MALT1 protein having one or more point mutations compared to the wild-type MALT1 protein; a mutation in the MALT1 gene that results in the expression of a MALT1 protein having at least one inserted amino acid compared to the wild-type MALT1 protein; a gene duplication that results in an increased level of MALT1 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 MALT1 protein in a cell); MALT1 An alternative splicing form of mRNA, which causes a MALT1 protein having at least one amino acid deletion in the MALT1 protein compared to the wild-type MALT1 protein; or increased expression (e.g., increased levels), which is caused by abnormal cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, the MALT1 gene, MALT1 protein, or the dysregulation of expression or activity or level thereof can be a mutation in the MALT1 gene encoding the MALT1 protein, the MALT1 protein being constitutively active or having increased activity compared to the protein encoded by the MALT1 gene that does not contain the mutation. As another example, the increased MALT1 gene copy number can cause overexpression of the MALT1 protease. For example, the dysregulation of expression or activity or level of the MALT1 gene, MALT1 protein, or any of them can be the result of a gene or chromosomal translocation, which causes the expression of a fusion protein containing a first portion of MALT1 (this portion comprising a functional protease domain) and a second portion of a chaperone protein (i.e., not MALT1). In some examples, the dysregulation of expression or activity or level of a MALT1 gene, MALT1 protein, or either thereof may be the result of a genetic translocation of a MALT1 gene with another non-MALT1 gene.

[0146] An exemplary sequence of human MALT1 is shown below:

[0147] SEQ ID NO:7 (UniParc accession number UPI000004D05E)

[0148] MSLLGDPLQALPPSAAPTGPLAPPAGATLNRLREPLLRRLSELLDQAPEGRGWRRLAELAGSRGRLRLSCLDLEQCSLKVLEPEGSPLSLCLKLMGEKGCTVTELSDFLQAMEHTEVLQLLSPPGIKITVNPESKAVLAGQFVKLCCRATGHPFVQYQWFKMNKEIPNGNTSELIFNAVHVKDAGFYVCRVNNNFTFEFSQWSQL DVCDIPESFQRSVDGVSESKLQICVEPTSQKLMPGSTLVLQCVAVGSPIHYQWFKNELPLTHETKKLYMVPYVDLEHQGTYWCHVYNDRDSQDSKKVEIIIGRTDEAVECTEDELNNLGHPDNKEQTTDQPLAKDKVALLIGNMNYREHPKLKAPLVDVYELTNLLRQLDFKVVSLLDLTEYEMRNAVDEFLLLDKGVYGLLYY AGHGYENFGNSFMVPVDAPNPYRSENCLCVQNILKLMQEKETGLNVFLLDMCRKRNDYDDTIPILDALKVTANIVFGYATCQGAEAFEIQHSGLANGIFMKFLKDRLLEDKKITVLLDEVAEDMGKCHLTKGKQALEIRSSLSEKRALTDPIQGTEYSAESLVRNLQWAKAHELPESMCLKFDCGVQIQLGFAAEFSNVMIIYTSI VYKPPEIIMCDAYVTDFPLDLDIDPKDANKGTPEETGSYLVSKDLKPHCLYTRLSSLQKLKEHLVFTVCLSYQYSGLEDTVEDKQEVNVGKPLIAKLDMHRGLGRKTCFQTCLMSNGPYQSSAATSGGAGHYHSLQDPFHGVYHSHPGNPSNVTPADSCHCSRTPDAFISSFAHHASCHFSRSNVPVETTDEIPFSDRLRISEK

[0149] Non-limiting examples of MALT1 gene or MALT1 protein perturbation are shown in the lower table B1.

[0150] Table B1.

[0151]

[0152] 1US Patent 10,711,036

[0153] 2 US Patent Application Publication No. US20190160045A1

[0154] 3 US Patent Application Publication No. US20130096021A1

[0155] 4 US Patent Application Publication No. US20150320754A1

[0156] As used herein, the term "CARD11-associated autoimmune disorder" refers to an autoimmune disorder that is associated with or has a disorder (e.g., any type of disorder in the expression, activity or level of the CARD11 gene, CARD11 protein, or any of them (e.g., one or more) described herein).

[0157] As used herein, the term "CARD11-associated inflammatory disorder" refers to an inflammatory disorder that is associated with or has a disorder (e.g., any type of disorder in the expression, activity or level of the CARD11 gene, CARD11 protein, or any of them (e.g., one or more) described herein).

[0158] As used herein, the term "CARD11-related cancer" refers to a cancer associated with or having a disorder (e.g., any type of disorder of expression, activity or level of a CARD11 gene, CARD11 protein, or any of them (e.g., one or more)). Non-limiting examples of CARD11-related cancers are described herein.

[0159] The phrase “dysregulation of the expression or activity or level of the CARD11 gene, CARD11 protein, or any of them” refers to a genetic mutation of a wild-type CARD11 protein in a mammalian cell (e.g., compared to a control non-cancerous cell) (e.g., a chromosomal translocation that results in the expression of a fusion protein comprising a CARD11 domain and a fusion partner; a mutation in the CARD11 gene that results in the expression of a CARD11 protein comprising at least one amino acid deletion compared to the wild-type CARD11 protein; a mutation in the CARD11 gene that results in the expression of a CARD11 protein having one or more point mutations compared to the wild-type CARD11 protein; a mutation in the CARD11 gene that results in the expression of a CARD11 protein having at least one inserted amino acid compared to the wild-type CARD11 protein; a gene duplication that results in an increased level of the CARD11 protein in the cell; or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of the CARD11 protein in the cell); CARD11 An alternative splicing form of mRNA, which causes a CARD11 protein having at least one amino acid deletion in the CARD11 protein compared to the wild-type CARD11 protein; or increased expression (e.g., increased levels), which is caused by abnormal cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, the CARD11 gene, CARD11 protein, or the dysregulation of expression, activity, or level thereof can be a mutation in a CARD11 gene encoding a CARD11 protein, the CARD11 protein being constitutively active or having increased activity compared to a protein encoded by a CARD11 gene that does not contain a mutation. As another example, an increased CARD11 gene copy number can cause overexpression of a CARD11 protein. For example, the dysregulation of expression, activity, or level of a CARD11 gene, CARD11 protein, or any of them can be the result of a gene or chromosomal translocation, which causes the expression of a fusion protein containing a first portion of CARD11 and a second portion of a chaperone protein (i.e., not CARD11). In some examples, the dysregulation of expression or activity or level of the CARD11 gene, CARD11 protein, or any of them may be the result of a gene translocation of a CARD11 gene with another non-CARD11 gene.

[0160] An exemplary sequence of human CARD11 is shown below:

[0161] SEQ ID NO:8 (UniParc accession number UPI00003FED38)

[0162]

[0163] Non-limiting examples of dysregulation of the CARD11 gene or CARD11 protein are shown in Table B2 below.

[0164] Table B2.

[0165]

[0166] 1 Wu et al., Oncotarget 7.25 (2016): 38180.

[0167] 2 Watt et al. The American Journal of Pathology 185.9(2015):2354-2363.

[0168] As used herein, the term "CARD14-associated autoimmune disorder" refers to an autoimmune disorder that is associated with or has a disorder (e.g., any type of disorder in the expression, activity or level of the CARD14 gene, CARD14 protein, or any of them (e.g., one or more) described herein).

[0169] As used herein, the term "CARD14-associated inflammatory disorder" refers to an inflammatory disorder that is associated with or has a disorder in the expression or activity or level of the CARD14 gene, CARD14 protein, or any of them (e.g., one or more) (e.g., any type of disorder in the expression or activity or level of the CARD14 gene, CARD14 protein, or any of them described herein).

[0170] As used herein, the term "CARD14-related cancer" refers to a cancer that is associated with or has a disorder (e.g., any type of disorder in the expression, activity or level of the CARD14 gene, CARD14 protein, or any of them (e.g., one or more) described herein).

[0171] An exemplary sequence of human CARD14 is shown below:

[0172] SEQ ID NO:9 (UniParc accession number UPI000013D81B)

[0173]

[0174] As used herein, the term "CARD10-associated autoimmune disorder" refers to an autoimmune disorder that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity or level of the CARD10 gene, CARD10 protein, or any of them (e.g., one or more)) of the CARD10 gene, CARD10 protein, or any of them.

[0175] As used herein, the term "CARD10-associated inflammatory disorder" refers to an inflammatory disorder that is associated with or has a dysregulation of the expression or activity or level of a CARD10 gene, a CARD10 protein, or any of them (e.g., one or more) (e.g., any type of dysregulation of the expression or activity or level of a CARD10 gene, a CARD10 protein, or any of them described herein).

[0176] As used herein, the term "CARD10-associated cancer" refers to a cancer that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity or level of the CARD10 gene, CARD10 protein, or any of them (e.g., one or more) described herein).

[0177] The phrase "dysregulation of the expression or activity or level of the CARD10 gene, CARD10 protein, or any of them" refers to a genetic mutation of a wild-type CARD10 protein in a mammalian cell (e.g., compared to a control non-cancer cell) (e.g., a chromosomal translocation that results in the expression of a fusion protein comprising a CARD10 domain and a fusion partner; a mutation in the CARD10 gene that results in the expression of a CARD10 protein comprising at least one amino acid deletion compared to the wild-type CARD10 protein; a mutation in the CARD10 gene that results in the expression of a CARD10 protein having one or more point mutations compared to the wild-type CARD10 protein; a mutation in the CARD10 gene that results in the expression of a CARD10 protein having at least one inserted amino acid compared to the wild-type CARD10 protein; a gene duplication that results in an increased level of the CARD10 protein in the cell; or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of the CARD10 protein in the cell); An alternative splice form of mRNA that causes a CARD10 protein having at least one amino acid deletion in the CARD10 protein compared to the wild-type CARD10 protein; or increased expression (e.g., increased levels) due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, the dysregulation of expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them can be a mutation in a CARD10 gene encoding a CARD10 protein that is constitutively active or has increased activity compared to a protein encoded by a CARD10 gene that does not contain a mutation. As another example, an increased CARD10 gene copy number can cause overexpression of the CARD10 protein. For example, the dysregulation of expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first portion of CARD10 and a second portion of a chaperone protein (i.e., not CARD10). In some examples, the dysregulation of expression or activity or level of a CARD10 gene, a CARD10 protein, or any of them may be the result of a genetic translocation of a CARD10 gene with another non-CARD10 gene.

[0178] An exemplary sequence of human CARD10 is shown below:

[0179] SEQ ID NO: 10 (UniParc Accession No. UPI0000044645)

[0180] MPGRAEAGEAEEEAGAGSGSEAEEDALWERIEGVRHRLARALNPAKLTPYLRQCRVIDEQDEEEVLSTYRFPCRVNRTGRLMDILRCRGKRGYEAFLEALEFYYPEHFTLLTGQEPAQRCSMILDEEGPEGLTQFLMTEVRRLREARKSQLQREQQLQARGRVLEEERAGLEQRLRDQQQAQERCQRLREDWEAGSLELLRLKDENYMIAMRLAQLSEEKNSAVLRSRDLQLAVDQLKLKVSRLEEECALLRRARGPPPGAEEKEKEKEKEKEPDNVDLVSELRAENQRLTASLRELQEGLQQEASRPGAPGSERILLDILEHDWREAQDSRQELCQKLHAVQGELQWAEELRDQYLQEMEDLRLKHRTLQKDCDLYKHRMATVLAQLEEIEKERDQAIQSRDRIQLQYSQSLIEKDQYRKQVRGLEAERDELLTTLTSLEGTKALLEVQLQRAQGGTCLKACASSHSLCSNLSSTWSLSEFPSPLGGPEATGEAAVMGGPEPHNSEEATDSEKEINRLSILPFPPSAGSILRRQREEDPAPPKRSFSSMSDITGSVTLKPWSPGLSSSSSSDSVWPLGKPEGLLARGCGLDFLNRSLAIRVSGRSPPGGPEPQDKGPDGLSFYGDRWSGAVVRRVLSGPGSARMEPR EQRVEAAGLEGACLEAEAQQRTLLWNQGSTLPSLMDSKACQSFHEALEAWAKGPGAEPFYIRANLTLPERADPHALCVKAQEILRLVDSAYKRRQEWFCTRVDPLTLRDLDRGTVPNYQRAQQLLEVQ EKCLPSSRHRGPRSNLKKRALDQLRLVRPKPVGAPAGDSPDQLLLEPCAEPERSLRPYSLVRPLLVSALRPVVLLPECLAPRLIRNLLDLPSRLDFQVCPAESLSGEELCPSSAPGAPKAQPATPGL GSRIRAIQESVGKKHCLLELGARGVRELVQNEIYPIVIHVEVTEKNVREVRGLLGRPGWRDSELLRQCRGSEQVLWGLPCSWVQVPAHEWGHAEELAKVVRGRILQEQARLVWVECGSSRGCPSSSEA

[0181] As used herein, the term "CARD9-associated autoimmune disorder" refers to an autoimmune disorder that is associated with or has a disorder (e.g., any type of disorder in the expression, activity or level of the CARD9 gene, CARD9 protein, or any of them (e.g., one or more) described herein).

[0182] As used herein, the term "CARD9-associated inflammatory disorder" refers to an inflammatory disorder that is associated with or has a disorder (e.g., any type of disorder in the expression, activity or level of the CARD9 gene, CARD9 protein, or any of them (e.g., one or more) described herein).

[0183] As used herein, the term "CARD9-associated cancer" refers to a cancer that is associated with or has a disorder (e.g., any type of disorder in the expression, activity or level of the CARD9 gene, CARD9 protein, or any of them (e.g., one or more) described herein).

[0184] The phrase "dysregulation of the expression or activity or level of the CARD9 gene, CARD9 protein, or any of them" refers to a genetic mutation of a wild-type CARD9 protein in a mammalian cell (e.g., a chromosomal translocation that results in the expression of a fusion protein comprising a CARD9 domain and a fusion partner; a mutation in the CARD9 gene that results in the expression of a CARD9 protein comprising at least one amino acid deletion compared to the wild-type CARD9 protein; a mutation in the CARD9 gene that results in the expression of a CARD9 protein having one or more point mutations compared to the wild-type CARD9 protein; a mutation in the CARD9 gene that results in the expression of a CARD9 protein having at least one inserted amino acid compared to the wild-type CARD9 protein; a gene duplication that results in an increased level of CARD9 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 CARD9 protein in a cell); CARD9 An alternative splicing form of mRNA, which causes a CARD9 protein having at least one amino acid deletion in the CARD9 protein compared to the wild-type CARD9 protein; or increased expression (e.g., increased levels), which is caused by abnormal cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, the CARD9 gene, CARD9 protein, or the dysregulation of expression or activity or level of any one thereof can be a mutation in a CARD9 gene encoding a CARD9 protein, the CARD9 protein being constitutively active or having increased activity compared to a protein encoded by a CARD9 gene that does not contain a mutation. As another example, an increased CARD9 gene copy number can cause overexpression of a CARD9 protein. For example, the dysregulation of expression or activity or level of a CARD9 gene, CARD9 protein, or any one thereof can be the result of a gene or chromosomal translocation, which causes the expression of a fusion protein containing a first portion of CARD9 and a second portion of a chaperone protein (i.e., not CARD9). In some examples, the dysregulation of expression or activity or level of a CARD9 gene, CARD9 protein, or any of them may be the result of a genetic translocation of a CARD9 gene with another non-CARD9 gene.

[0185] An exemplary sequence of human CARD9 is shown below:

[0186] SEQ ID NO: 11 (UniParc accession number UPI000013E4EB)

[0187] MSDYENDDECWSVLEGFRVTTLTSVIDPSRITPYLRQCKVLNPDDEEQVLSDPNLVIRKRKVGVLLDILQRTGHKGYVAFLESLELYYPQLYKKVTGKEPARVFSMIIDASGESGLTQLLMTEVMKLQKKVQDLT ALLSSKDDFIKELRVKDSLLRKHQERVQRLKEECEAGSRELKRCKEENYDLAMRLAHQSEEKGAALMRNRDLQLEIDQLKHSLMKAEDDCKVERKHTLKLRHAMEQRPSQELLWELQQEKALLQARVQELEASV QEGKLDRSSPYIQVLEEDWRQALRDHQEQANTIFSLRKDLRQGEARRLRCMEEKEMFELQCLALRKDSKMYKDRIEAILLQMEEVAIERDQAIATREELHAQHARGLQEKDALRKQVRELGEKADELQLQVFQC EAQLLAVEGRLRRQQLETLVLSSDLEDGSPRRSQELSLPQDLEDTQLSDKGCLAGGGSPKQPFAALHQEQVLRNPHDAGLSSGEPPEKERRRLKESFENYRRKRALRKMQKGWRQGEEDRENTTGSDNTDTEGS

[0188] As used herein, the term "BCL10-associated autoimmune disorder" refers to an autoimmune disorder that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity or level of a BCL10 gene, a BCL10 protein, or any of them (e.g., one or more)) of a BCL10 gene, a BCL10 protein, or any of them.

[0189] As used herein, the term "BCL10-associated inflammatory disorder" refers to an inflammatory disorder that is associated with or has a dysregulation (e.g., any type of dysregulation in the expression, activity or level of a BCL10 gene, a BCL10 protein, or any of them (e.g., one or more)) of a BCL10 gene, a BCL10 protein, or any of them.

[0190] As used herein, the term "BCL10-related cancer" refers to a cancer that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity or level of a BCL10 gene, a BCL10 protein, or any of them (e.g., one or more) described herein).

[0191] The phrase "dysregulation of the expression or activity or level of the BCL10 gene, BCL10 protein, or any of them" refers to a genetic mutation of the wild-type BCL10 protein in a mammalian cell (e.g., compared to a control non-cancer cell) (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 comprising 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 having one or more point mutations ... fusion protein comprising a BCL10 domain and a fusion partner; a mutation in the BCL10 gene that results in the A mutation in a BCL10 protein that causes expression of a BCL10 protein having at least one inserted amino acid compared to a wild-type BCL10 protein; a gene duplication that causes elevated levels of BCL10 protein in a cell; or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that causes elevated levels of BCL10 protein in a cell); an alternative splicing form of BCL10 mRNA that causes a BCL10 protein having at least one amino acid deletion in the BCL10 protein compared to a wild-type BCL10 protein; or increased expression (e.g., increased levels) due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling. For example, dysregulation of the expression or activity or level of a BCL10 gene, a BCL10 protein, or any of them can be the result of a gene or chromosomal translocation that causes expression of a fusion protein containing a first portion of BCL10 and a second portion of a partner protein (i.e., not BCL10). In some examples, the dysregulation of the expression or activity or level of a BCL10 gene, a BCL10 protein, or any of them may be the result of a genetic translocation of a BCL10 gene with another non-BCL10 gene.

[0192] An exemplary sequence of human BCL10 is shown below:

[0193] SEQ ID NO: 12 (UniParc accession number UPI000012682F)

[0194] MEPTAPSLTEEDLTEVKKDALENLRVYLCEKIIAERHFDHLRAKKILSREDTEEEISCRTSSRKRAGKLLDYLQENPKGLDTLVESIRREKTQNFLIQKITDEVLKLRNIKLEHLKG LKCSSCEPFPDGATNNLSRSNSDESNFSEKLRASTVMYHPEGESSTTPFFSTNSSLNLPVLEVGRTENTIFSSTTLPRPGDPGAPPLPPDLQLEEEGTCANSSEMFLPLRSRTVSRQ

[0195] Non-limiting examples of dysregulation of the BCL10 gene or BCL10 protein are shown in Table B3 below.

[0196] Table B3.

[0197]

[0198]

[0199] 1 Willis et al. Cell 96.1 (1999): 35-45.

[0200] 2 Zhang et al. Nature Genetics 22.1 (1999): 63-68.

[0201] As used herein, the term "MALT1 protease substrate-associated cancer" refers to a cancer associated with or having a disorder in the expression or activity or level of a gene, protein, or any one thereof (e.g., one or more thereof), the disorder being associated with a MALT1 protease substrate. In some embodiments, a 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, roquin-1-associated cancer, HOIL1-associated cancer, NIK-associated cancer, LIMA1α-associated cancer, and combinations thereof. In some embodiments, a 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 specific gene or protein described in this paragraph refers to a cancer associated with or having a disorder in the expression or activity or level of a specific gene, a specific protein, or any one thereof (e.g., one or more thereof) (e.g., any type of disorder in the expression or activity or level of a specific gene, a specific protein, or any one thereof described herein). Non-limiting examples of such cancers are described herein.

[0202] An exemplary sequence of Person A20 is shown below:

[0203] SEQ ID NO:13 (UniParc accession number UPI000000D92D)

[0204] MAEQVLPQALYLSNMRKAVKIRERTPEDIFKPTNGIIHHFKTMHRYTLEMFRTCQFCPQFREIIHKALIDRNIQATLESQKKLNWCREVRKLVALKTNGDGNCLMHATSQYMWGVQDTDLVLRKALFSTLKETDTRNFKFRWQLESLKSQEFVETGLCYDTRNWNDEWDNLIKMASTDTPMARSGLQYNSLEEIHIFVLCNILRRPIIVISDKMLRSLESGSNFAPLKVGGIYLPLHWPAQECYRYPIVLGYDSHHFVPLVTLKDSGPEIRAVPLVNRDRGRFEDLKVHFLTDPENEMKEKLLKEYLMVIEIPVQGWDHGTTHLINAAKLDEANLPKEINLVDDYFELVQHEYKKWQENSEQGRREGHAQNPMEPSVPQLSLMDVKCETPNCPFFMSVNTQPLCHECSERRQKNQNKLPKLNSKPGPEGLPGMALGASRGEAYEPLAWNPEESTGGPHSAPPTAPSPFLFSETTAMKCRSPGCPFTLNVQHNGFCERCHNARQLHASHAPDHTRHLDPGKCQACLQDVTRTFNGICSTCFKRTTAEASSSLSTSLPPSCHQRSKSDPSRLVRSPSPHSCHRAGNDAPAGCLSQAARTPGDRTGTSKCRKAGCVYFGTPENKGFCTLCFIEYRENKHFAAASGKVSPTASRFQNTIPCLGRECGTLGSTMFEGYCQKCFIEAQNQRFHEAKRTEEQLRSSQRRDVPRTTQSTSRPKCARASCKNILACRSEELCMECQHPNQRMGPGAHRGEPAPEDPPKQRCRAPACDHFGNAKCNGYCNECFQFKQMYG

[0205] Non-limiting examples of A20 gene or A20 protein dysregulation are shown in Table B4 below.

[0206] Table B4.

[0207]

[0208] 1 Johansson et al. Oncotarget 7.38 (2016): 62627.

[0209] 2 Novak et al. Blood 113.20 (2009): 4918-4921.

[0210] An exemplary sequence of human CYLD is shown below:

[0211] SEQ ID NO: 14 (UniParc Accession No. UPI0000073A15)

[0212] MSSGLWSQEKVTSPYWEERIFYLLLQECSVTDKQTQKLLKVPKGSIGQYIQDRSVGHSRIPSAKGKKNQIGLKILEQPHAVLFVDEKDVVEINEKFTELLLAITNCEERFSLFKNRNRLSKGLQIDVGCPVKVQLRSGEEKFPGVVRFRGPLLAERTVSGIFFGVELLEEGRGQGFTDGVYQGKQLFQCDEDCGVFVALDKLELIEDDDTALESDYAGPGDTMQVELPPLEINSRVSLKVGETIESGTVIFCDVLPGKESLGYFVGVDMDNPIGNWDGRFDGVQLCSFACVESTILLHINDIIPALSESVTQERRPPKLAFMSRGVGDKGSSSHNKPKATGSTSDPGNRNRSELFYTLNGSSVDSQPQSKSKNTWYIDEVAEDPAKSLTEISTDFDRSSPPLQPPPVNSLTTENRFHSLPFSLTKMPNTNGSIGHSPLSLSAQSVMEELNTAPVQESPPLAMPPGNSHGLEVGSLAEVKENPPFYGVIRWIGQPPGLNEVLAGLELEDECAGCTDGTFRGTRYFTCALKKALFVKLKSCRPDSRFASLQPVSNQIERCNSLAFGGYLSEVVEENTPPKMEKEGLEIMIGKKKGIQGHYNSCYLDSTLFCLFAFSSVLDTVLLRPKEKNDVEYYSETQELLRTEIVNPLRIYGYVCATKIMKLRKILEKVEAASGFTSEEKDPEEFLNILFHHILRVEPLLKIRSAGQKVQDCYFYQIFMEKNEKVGVPTIQQLLEWSFINSNLKFAEAPSCLIIQMPRFGKDFKLFKKIFPSLELNITDLLEDTPRQCRICGGLAMYECRECYDDPDISAGKIKQFCKTCNTQVHLHPKRLNHKYNPVSLPKDLPDWDWRHGCIPCQNMELFAVLCIETSHYVAFVKYGKDDSAWLFFDSMADRDGGQNGFNIPQVTPCPEVGEYLKMSLEDLHSLDSRRIQGCARRLLCDAYMCMYQSPTMSLYK

[0213] Non-limiting examples of dysregulation of the CYLD gene or CYLD protein can be found in, for example, Massoumi, Future Oncology 7.2 (2011): 285-297, Alameda, JP et al., Oncogene 29.50 (2010): 6522-6532, Williams et al., Modern Pathology (2020): 1-13, and Courtois and Gilmore. Oncogene 25.51 (2006): 6831-6843.

[0214] An exemplary sequence of human ReIB is shown below:

[0215] SEQ ID NO: 15 (UniParc Accession No. UPI00000012B7)

[0216] MLRSGPASGPSVPTGRAMPSRRVARPPAAPELGALGSPDLSSLSLAVSRSTDELEIIDEYIKENGFGLDGGQPGPGEGLPRLVSRGAASLSTVTLGPVAPPATPPPWGCPLGRLVSPAPGPGPQPHLVITEQPKQRGMRFRYEC EGRSAGSILGESSTEASKTLPAIELRDCGGLREVEVTACLVWKDWPHRVHPHSLVGKDCTDGICRVRLRPHVSPRHSFNNLGIQCVRKKEIEAAIERKIQLGIDPYNAGSLKNHQEVDMNVVRICFQASYRDQQGQMRRMDPVLS EPVYDKKSTNTSELRICRINKESGPCTGGEELYLLCDKVQKEDISVVFSRASWEGRADFSQADVHRQIAIVFKTPPYEDLEIVEPVTVNVFLQRLTDGVCSEPLPFTYLPRDHDSYGVDKKRKRGMPDVLGELNSSDPHGIESKR RKKKPAILDHFLPNHGSGPFLPPSALLPDPDFFSGTVSLPGLEPPGGPDLLDDGFAYDPTAPTLFTMLDLLPPAPPHASAVVCSGGAGAVVGETPGPEPLTLDSYQAPGPGDGGTASLVGSNMFPNHYREAAFGGGLLSPGPEAT

[0217] An exemplary sequence of human Regnase 1 is shown below:

[0218] SEQ ID NO:16 (UniParc accession number UPI000004D30E)

[0219] MSGPCGEKPVLEASPTMSLWEFEDSHSRQGTPRPGQELAAEEASALELQMKVDFFRKLGYSSTEIHSVLQKLGVQADTNTVLGELVKHGTATERERQTSPDPCPQLPLVPRGGGTPKAPNLEPPLPEEEKEGSDLRPVVIDGSNVAMSHGNKEVFSCRGILLAVNWFLERGHTDITVFVPSWRKEQPRPDVPITDQHILRELEKKKILVFTPSRRVGGKRVVCYDDRFIVKLAYESDGIVVSNDTYRDLQGERQEWKRFIEERLLMYSFVNDKFMPPDDPLGRHGPSLDNFLRKKPLTLEHRKQPCPYGRKCTYGIKCRFFHPERPSCPQRSVADELRANALLSPPRAPSKDKNGRRPSPSSQSSSLLTESEQCSLDGKKLGAQASPGSRQEGLTQTYAPSGRSLAPSGGSGSSFGPTDWLPQTLDSLPYVSQDCLDSGIGSLESQMSELWGVRGGGPGEPGPPRAPYTGYSPYGSELPATAAFSAFGRAMGAGHFSVPADYPPAPPAFPPREYWSEPYPLPPPTSVLQEPPVQSPGAGRSPWGRAGSLAKEQASVYTKLCGVFPPHLVEAVMGRFPQLLDPQQLAAEILSYKSQHPSE

[0220] An exemplary sequence of human roquin-1 is shown below:

[0221] SEQ ID NO:17 (UniParc accession number UPI00001D7DA8)

[0222]

[0223] An exemplary sequence of human HOIL1 is shown below:

[0224] SEQ ID NO: 18 (UniParc Accession No. UPI000006F045)

[0225] MDEKTKKAEEMALSLTRAVAGGDEQVAMKCAIWLAEQRVPLSVQLKPEVSPTQDIRLWVSVEDAQMHTVTIWLTVRPDMTVASLKDMVFLDYGFPPVLQQWVIGQRLARDQETLHSHGVRQNGDSAY LYLLSARNTSLNPQELQRERQLRMLEDLGFKDLTLQPRGPLEPGPPKPGVPQEPGRGQPDAVPEPPPVGWQCPGCTFINKPTRPGCEMCCRARPEAYQVPASYQPDEEERARLAGEEEALRQYQQRKQ QQQEGNYLQHVQLDQRSLVLNTEPAECPVCYSVLAPGEAVVLRECLHTFCRECLQGTIRNSQEAEVSCPFIDNTYSCSGKLLEREIKALLTPEDYQRFLDLGISIAENRSAFSYHCKTPDCKGWCFF EDDVNEFTCPVCFHVNCLLCKAIHEQMNCKEYQEDLALRAQNDVAARQTTEMLKVMLQQGEAMRCPQCQIVVQKKDGCDWIRCTVCHTEICWVTKGPRWGPGGPGDTSGGCRCRVNGIPCHPSCQNCH

[0226] An exemplary sequence of human NIK is shown below:

[0227] SEQ ID NO: 19 (UniParc Accession No. UPI0000074220)

[0228] MAVMEMACPGAPGSAVGQQKELPKAKEKTPPLGKKQSSVYKLEAVEKSPVFCGKWEILNDVITKGTAKEGSEAGPAAISIIAQAECENSQEFSPTFSERIFIAGSKQYSQSESLDQIPNNVAHATEGKMARVCWKGKRRSKARKKRKKKSSKSLAHAGVALAKPLPRTPEQESCTIPVQEDESPLGAPYVRNTPQFTKPLKEPGLGQLCFKQLGEGLRPALPRSELHKLISPLQCLNHVWKLHHPQDGGPLPLPTHPFPYSRLPHPFPFHPLQPWKPHPLESFLGKLACVDSQKPLPDPHLSKLACVDSPKPLPGPHLEPSCLSRGAHEKFSVEEYLVHALQGSVSSGQAHSLTSLAKTWAARGSRSREPSPKTEDNEGVLLTEKLKPVDYEYREEVHWATHQLRLGRGSFGEVHRMEDKQTGFQCAVKKVRLEVFRAEELMACAGLTSPRIVPLYGAVREGPWVNIFMELLEGGSLGQLVKEQGCLPEDRALYYLGQALEGLEYLHSRRILHGDVKADNVLLSSDGSHAALCDFGHAVCLQPDGLGKSLLTGDYIPGTETHMAPEVVLGRSCDAKVDVWSSCCMMLHMLNGCHPWTQFFRGPLCLKIASEPPPVREIPPSCAPLTAQAIQEGLRKEPIHRVSAAELGGKVNRALQQVGGLKSPWRGEYKEPRHPPPNQANYHQTLHAQPRELSPRAPGPRPAEETTGRAPKLQPPLPPEPPEPNKSPPLTLSKEESGMWEPLPLSSLEPAPARNPSSPERKATVPEQELQQLEIELFLNSLSQPFSLEEQEQILSCLSIDSLSLSDDSEKNPSKASQSSRDTLSSGVHSWSSQAEARSSSWNMVLARGRPTDTPSYFNGVKVQIQSLNGEHLHIREFHRVKVGDIATGISSQIPAAAFSLVTKDGQPVRYDMEVPDSGIDLQCTLAPDGSFAWSWRVKHGQLENRP

[0229] An exemplary sequence of human LIMA1α is shown below:

[0230] SEQ ID NO:20 (UniParc accession number UPI000002A906)

[0231] MENCLGESRHEVEKSEISENTDASGKIEKYNVPLNRLKMMFEKGEPTQTKILRAQSRSASGRKISENSYSLDDLEIGPGQLSSSTFDSEKNESRRNLELPRLSETSIKDRMAKYQAAVSKQSSSTNYTNELKASGGEIKIHKMEQKENVPPGPEVCITHQEGEKISANENSLAVRSTPAEDDSRDSQVKSEVQQPVHPKPLSPDSRASSLSESSPPKAMKKFQAPARETCVECQKTVYPMERLLANQQVFHISCFRCSYCNNKLSLGTYASLHGRIYCKPHFNQLFKSKGNYDEGFGHRPHKDLWASKNENEEILERPAQLANARETPHSPGVEDAPIAKVGVLAASMEAKASSQQEKEDKPAETKKLRIAWPPPTELGSSGSALEEGIKMSKPKWPPEDEISKPEVPEDVDLDLKKLRRSSSLKERSRPFTVAASFQSTSVKSPKTVSPPIRKGWSMSEQSEESVGGRVAERKQVENAKASKKNGNVGKTTWQNKESKGETGKRSKEGHSLEMENENLVENGADSDEDDNSFLKQQSPQEPKSLNWSSFVDNTFAEEFTTQNQKSQDVELWEGEVVKELSVEEQIKRNRYYDEDEDEE

[0232] As used herein, the term "cancer associated with a component of the NF-κB pathway downstream of the CBM complex" refers to a cancer associated with or having an imbalance in the expression or activity or level of a gene, protein, or any of them (e.g., one or more), the imbalance being 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 specific gene or protein described in this paragraph refers to a cancer that is associated with or has a disorder (e.g., any type of disorder in the expression or activity or level of a specific gene, a specific protein, or any of them (e.g., one or more) described herein). Non-limiting examples of such cancers are described herein.

[0233] An exemplary sequence of human TAK1 is shown below:

[0234] SEQ ID NO:21 (UniParc accession number UPI000012EAD6) MSTASAASSSSSSSAGEMIEAPSQVLNFEEIDYKEIEVEEVVGRGAFGVVCKAKWRAKDVAIKQIESESERKAFIVELRQLSRVNHPNIVKLYGACLNPVCLVMEYAEGGSLYNVLHGAEPLPYYTAAHAMSWCLQCSQGVAYLHSMQPKALIHRDLKPPNLLLVAGGTVLKICDFGTACDIQTHMTNNKGSAAWMAPEVFEGSNYSEKCDVFSWGIILWEVITRRKPFDEIGGPAFRIMWAVHNGTRPPLIKNLPKPIESLMTRCWSKDPSQRPSMEEIVKIMTHLMRYFPGADEPLQYPCQYSDEGQSNSATSTGSFMDIASTNTSNKSDTNMEQVPATNDTIKRLESKLLKNQAKQQSESGRLSLGASRGSSVESLPPTSEGKRMSADMSEIEARIAATTAYSKPKRGHRKTASFGNILDVPEIVISGNGQPRRRSIQDLTVTGTEPGQVSSRSSSPSVRMITTSGPTSEKPTRSHPWTPDDSTDTNGSDNSIPMAYLTLDHQLQPLAPCPNSKESMAVFEQHCKMAQEYMKVQTEIALLLQRKQELVAELDQDEKDQQNTSRLVQEHKKLLDENKSLSTYYQQCKKQLEVIRSQQQKRQGTS

[0235] An exemplary sequence of human TRAF6 is shown below:

[0236] SEQ ID NO:22 (UniParc accession number UPI000000D924) MSLLNCENSCGSSQSESDCCVAMASSCSAVTKDDSVGGTASTGNLSSSFMEEIQGYDVEFDPPLESKYECPICLMALREAVQTPCGHRFCKACIIKSIRDAGHKCPVDNEILLENQLFPDNFAKREILSLMVKCPNEGCLHKMELRHLEDHQAHCEFALMDCPQCQRPFQKFHINIHILKDCPRRQVSCDNCAASMAFEDKEIHDQNCPLANVICEYCNTILIREQMPNHYDLDCPTAPIPCTFSTFGCHEKMQRNHLARHLQENTQSHMRMLAQAVHSLSVIPDSGYISEVRNFQETIHQLEGRLVRQDHQIRELTAKMETQSMYVSELKRTIRTLEDKVAEIEAQQCNGIYIWKIGNFGMHLKCQEEEKPVVIHSPGFYTGKPGYKLCMRLHLQLPTAQRCANYISLFVHTMQGEYDSHLPWPFQGTIRLTILDQSEAPVRQNHEEIMDAKPELLAFQRPTIPRNPKGFGYVTFMHLEALRQRTFIKDDTLLVRCEVSTRFDMGSLRREGFQPRSTDAGV

[0237] An exemplary sequence of human TAB1 is shown below:

[0238] SEQ ID NO:23 (UniParc accession number UPI0000136861)

[0239] MAAQRRSLLQSEQQPSWTDDLPLCHLSGVGSASNRSYSADGKGTESHPPEDSWLKFRSENNCFLYGVFNGYDGNRVTNFVAQRLSAELLLGQLNAEHAEADVRRVLLQAFDVVERSFLESIDDALAEKASLQSQLPEGVPQHQLPPQYQKILERLKTLEREISGGAMAVVAVLLNNKLYVANVGTNRALLCKSTVDGLQVTQLNVDHTTENEDELFRLSQLGLDAGKIKQVGIICGQESTRRIGDYKVKYGYTDIDLLSAAKSKPIIAEPEIHGAQPLDGVTGFLVLMSEGLYKALEAAHGPGQANQEIAAMIDTEFAKQTSLDAVAQAVVDRVKRIHSDTFASGGERARFCPRHEDMTLLVRNFGYPLGEMSQPTPSPAPAAGGRVYPVSVPYSSAQSTSKTSVTLSLVMPSQGQMVNGAHSASTLDEATPTLTNQSPTLTLQSTNTHTQSSSSSSDGGLFRSRPAHSLPPGEDGRVEPYVDFAEFYRLWSVDHGEQSVVTAP

[0240] An exemplary sequence of human TAB2 is shown below:

[0241] SEQ ID NO:24 (UniParc accession number UPI0000073C75)

[0242] MAQGSHQIDFQVLHDLRQKFPEVPEVVVSRCMLQNNNNLDACCAVLSQESTRYLYGEGDLNFSDDSGISGLRNHMTSLNLDLQSQNIYHHGREGSRMNGSRTLTHSISDGQLQGGQSNSELFQQEPQTAPAQVPQGFNVFGMSSSSGASNSAPHLGFHLGSKGTSSLSQQTPRFNPIMVTLAPNIQTGRNTPTSLHIHGVPPPVLNSPQGNSIYIRPYITTPGGTTRQTQQHSGWVSQFNPMNPQQVYQPSQPGPWTTCPASNPLSHTSSQQPNQQGHQTSHVYMPISSPTTSQPPTIHSSGSSQSSAHSQYNIQNISTGPRKNQIEIKLEPPQRNNSSKLRSSGPRTSSTSSSVNSQTLNRNQPTVYIAASPPNTDELMSRSQPKVYISANAATGDEQVMRNQPTLFISTNSGASAASRNMSGQVSMGPAFIHHHPPKSRAIGNNSATSPRVVVTQPNTKYTFKITVSPNKPPAVSPGVVSPTFELTNLLNHPDHYVETENIQHLTDPTLAHVDRISETRKLSMGSDDAAYTQALLVHQKARMERLQRELEIQKKKLDKLKSEVNEMENNLTRRRLKRSNSISQIPSLEEMQQLRSCNRQLQIDIDCLTKEIDLFQARGPHFNPSAIHNFYDNIGFVGPVPPKPKDQRSIIKTPKTQDTEDDEGAQWNCTACTFLNHPALIRCEQCEMPRHF

[0243] An exemplary sequence of human TAB3 is shown below:

[0244] SEQ ID NO:25 (UniParc accession number UPI0000071648)

[0245] MAQSSPQLDIQVLHDLRQRFPEIPEGVVSQCMLQNNNNLEACCRALSQESSKYLYMEYHSPDDNRMNRNRLLHINLGIHSPSSYHPGDGAQLNGGRTLVHSSSDGHIDPQHAAGKQLICLVQEPHSAPAVVAATPNYNPFFMNEQNRSAATPPSQPPQQPSSMQTGMNPSAMQGPSPPPPPPSYMHIPRYSTNPITVTVSQNLPSGQTVPRALQILPQIPSNLYGSPGS IYIRQTSQSSSGRQTPQSTPWQSSPQGPVPHYSQRPLPVYPHQQNYQPSQYSPKQQQIPQSAYHSPPPSQCPSPFSSPQHQVQPSQLGHIFMPPSPSTTPPHPYQQGPPSYQKQGSHSVAYLPYTASSLSKGSMKKIEITVEPSQRPGTAINRSPSPISNQPSPRNQHSLYTATTPPSSSPSRGISSQPKPPFSVNPVYITYTQPTGPSCTPSPSPRVIPNPTTVFKITVGRATTENLLNLVDQEERSAAPEPIQPISVIPGSGGEKGSHKYQRSSSSGSDDYAYTQALLLHQRARMERLAKQLKLEKEELERLKSEVNGMEHDLMQRRLRRVSCTTAIPTPEEMTRLRSMNRQLQINVDCTLKEVDLLQSRGNFDPKAMNNFYDNIEPGPVVPPKPSKKDSSDPCTIERKARRISVTSKVQADIHDTQAAAADEHRTGSTQSPRTQPRDEDYEGAPWNCDSCTFLNHPALNRCEQCEMPRYT

[0246] An exemplary sequence of human MKK7 is shown below:

[0247] SEQ ID NO:26 (UniParc accession number UPI000012F494)

[0248] MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPTLQLPLANDGGSRSPSSESSPQHPTPPARPRHMLGLPSTLFTPRSMESIEIDQKLQEIMKQTGYLTIGGQRYQAEINDLENLGEMGSGTCGQVWKMRFRKTGHVIAVKQMRRSGNKEENKRILMDLDVVLKSHDCPYIVQCFGTFITNTDVFIAMELMGTCAEKLKKRMQGPIPERILGKMTVAIVKALYYLKEKHGVIHRDVKPSNILLDERGQIKLCDFGISGRLVDSKAKTRSAGCAAYMAPERIDPPDPTKPDYDIRADVWSLGISLVELATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDCLTKDHRKRPKYNKLLEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR

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

[0250] SEQ ID NO:27 (UniParc accession number UPI000013D6C7)

[0251] MERPPGLRPGAGGPWEMRERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCHEIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTSFVGTLQYLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPKCIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRCFVLMDHILNLKIVHILNMTSAKIISFLLPPDESLHSLQSRIERETGINTGSQELLSETGISLDPRKPASQCVLDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPIIQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKLEFFHKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYAEVGVIGYLEDQIMSLHAEIMELQKSPYGRRQGDLMESLEQRAIDLYKQLKHRPSDHSYSDSTEMVKIIVHTVQSQDRVLKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQSSARSLVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHLSTIIHEANEEQGNSMMNLDWSWLTE

[0252] An exemplary sequence of human IKKβ is shown below:

[0253] SEQ ID NO:28 (UniParc accession number UPI0000033729)

[0254] MSWSPSLTTQTCGAWEMKERLGTGGFGNVIRWHNQETGEQIAIKQCRQELSPRNRERWCLEIQIMRRLTHPNVVAARDVPEGMQNLAPNDLPLLAMEYCQGGDLRKYLNQFENCCGLREGAILTLLSDIASALRYLHENRIIHRDLKPENIVLQQGEQRLIHKIIDLGYAKELDQGSLCTSFVGTLQYLAPELLEQQKYTVTVDYWSFGTLAFECITGFRPFLPNWQPVQWHSKVRQKSEVDIVVSEDLNGTVKFSSSLPYPNNLNSVLAERLEKWLQLMLMWHPRQRGTDPTYGPNGCFKALDDILNLKLVHILNMVTGTIHTYPVTEDESLQSLKARIQQDTGIPEEDQELLQEAGLALIPDKPATQCISDGKLNEGHTLDMDLVFLFDNSKITYETQISPRPQPESVSCILQEPKRNLAFFQLRKVWGQVWHSIQTLKEDCNRLQQGQRAAMMNLLRNNSCLSKMKNSMASMSQQLKAKLDFFKTSIQIDLEKYSEQTEFGITSDKLLLAWREMEQAVELCGRENEVKLLVERMMALQTDIVDLQRSPMGRKQGGTLDDLEEQARELYRRLREKPRDQRTEGDSQEMVRLLLQAIQSFEKKVRVIYTQLSKTVVCKQKALELLPKVEEVVSLMNEDEKTVVRLQEKRQKELWNLLKIACSKVRGPVSGSPDSMNASRLSQPGQLMSQPSTASNSLPEPAKKSEELVAEAHNLCTLLENAIQDTVREQDQSFTALDWSWLQTEEEEHSCLEQAS

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

[0256] SEQ ID NO:29 (UniParc accession number UPI0000000CC4)

[0257] MNRHLWKSQLCEMVQPSGGPAADQDVLGEESPLGKPAMLHLPSEQGAPETLQRCLEENQELRDAIRQSNQILRERCEELLHFQASQREEKEFLMCKFQEARKLV ERLGLEKLDLKRQKEQALREVEHLKRCQQQMAEDKASVKAQVTSLLGELQESQSRLEAATKECQALEGRARAASEQARQLESEREALQQQHSVQVDQLRMQGQSV EAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSERKRGMQLEDLKQQLQQAEEALVAKQEVIDKLKEEAEQHKIVMETVPVLKAQADIYKADFQA ERQAREKLAEKKELLQEQLEQLQREYSKLKASCQESARIEDMRKRHVEVSQAPLPPAPAYLSSPLALPSQRRSPPEEPPDFCCPKCQYQAPDMDTLQIHVMECIE

[0258] Non-limiting examples of dysregulation of the IKKγ gene or IKKγ protein are described in, eg, Courtois and Gilmore, Oncogene 25.51 (2006): 6831-6843.

[0259] An exemplary sequence of human IkBα is shown below:

[0260] SEQ ID NO:30(UniParc registration number UPI000004F0A9)MFQAAERPQEWAMEGPRDGLKKERLLDDRHDSGLDSMKDEEYEQMVKELQEIRLEPQEVPRGSEPWKQQLTEDGDSFLHLAIIHEEKALTMEVIRQVKGDLAFLNFQNNLQQTPLHLAVITNQPEIAEALLGAGCDPELRDFR GNTPLHLACEQGCLASVGVLTQSCTTPHLHSILKATNYNGHTCLHLASIHGYLGIVELLVSLGADVNAQEPCNGRTALHLAVDLQNPDLVSLLLKCGADVNRVTYQGYSPYQLTWGRPSTRIQQQLGQLTLENLQMLPESEDEESYDTESEFTEFTEDELPYDDCVFGGQRLTL

[0261] An exemplary sequence of human p105 processed to p50 is shown below:

[0262] SEQ ID NO:31 (UniParc Accession No. UPI000000D917)

[0263] MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYVCEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCEDGICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQAEGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIYDSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDFSPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQRKRQKLMPNFSDFGGSGAGAGGGGMFGSGGGGTGSTGPGYSFPHYGFPTYGGITFHPGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGEVTLT YATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQDENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVEDLLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMMSNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGTTPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMATSWQVFDILNGKPYEPEFTSDDLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLGLGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQAHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQEGPLEGKI

[0264] An exemplary sequence of human p65 is shown below:

[0265] SEQ ID NO:32 (UniParc accession number UPI000013ED68)

[0266] MDELFPLIFPAEPAQASGPYVEIIEQPKQRGMRFRYKCEGRSAGSIPGERSTDTTKTHPTIKINGYTGPGTVRISLVTKDPPHRPHPHELVGKDCRDGFYEAELCPDRCIHSFQNLGIQCVKKRDLEQAISQRIQTNNNPFQVPIEEQRGDYDLNAVRLCFQVTVRDPSGRPLRLPPVLSHPIFDNRAPNTAELKICRVNRNSGSCLGGDEIFLLCDKVQKEDIEVYFTGPGWEARGSFSQADVHRQVAIVFRTPPYADPSLQAPVRVSMQLRRPSDRELSEPMEFQYLPDTDDRHRIEEKRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAPQPYPFTSSLSTINYDEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQAPAPVPVLAPGPPQAVAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDLASVDNSEFQQLLNQGIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNGLLSGDEDFSSIADMDFSALLSQISS

[0267] An exemplary sequence of human c-Rel is shown below:

[0268] SEQ ID NO:33 (UniParc accession number UPI000013367B)

[0269] MASGAYNPYIEIIEQPRQRGMRFRYKCEGRSAGS IPGEHSTDDNNRTYPS IQIMNYYGKGKVRITLVTKNDPYKPHPHDLVGKDCRDGYYEAEFGQERRPLFFQNLGIRCVKKKEVKEAIITRIKAGINPFNVPEKQLNDIEDCDLNVVRLCFQVFLPDEHGNLTTALPPVVSNPIYDNRAPNTAELRICRV NKNCGSVRGGDEIFLLCDKVQKDDIEVRFVLNDWEAKGIFSQADVHRQVAIVFKTPPYCKAITEPVTVKMQLRRPSDQEVSESMDFRYLPDEKDTYGNKAKKQKTTLLFQKLCQDHVETGFRHVDQDGLELLTSGDPPTLASQ SAGITVNFPERPRPGLLGSIGEGRYFKKEPNLFSHDAVVREMPTGVSSQAESYYPSPGPISSGLSHHASMAPLPSSSWSSVAHPTPRSGNTNPLSSFSTRTLPSNSQGIPPFLRIPVGNDLNASNACIYNNADDIVGMEASS MPSADLYGISDPNMLSNCSVNMMTTSSDSMGETDNPRLLSMNLENPSCNSVLDPRDLRQLHQMSSSSMSAGANSNTTVFVSQSDAFEGSDFSCADNSMINESGPSNSTNPNSHGFVQDSQYSGIGSMQNEQLSDSFPYEFFQV

[0270] As used herein, the term "cancer associated with a component of the JNK pathway downstream of the CBM complex" refers to a cancer associated with or having an imbalance in the expression or activity or level of a gene, protein, or any of them (e.g., one or more), the imbalance being associated with a component of the JNK pathway downstream of the CBM complex. In some embodiments, the cancer associated with a component of the JNK pathway downstream of the CBM complex is selected from the group consisting of: JNK1-related cancer, JNK2-related cancer, JNK3-related cancer, MYD88 transcription factor-related cancer, AP-1 transcription factor-related cancer, and a combination thereof. A cancer "associated" with a specific gene or protein described in this paragraph refers to a cancer associated with or having an imbalance in the expression or activity or level of a specific gene, a specific protein, or any of them (e.g., one or more) (e.g., any type of imbalance in the expression or activity or level of a specific gene, a specific protein, or any of them described herein). Non-limiting examples of such cancers are described herein.

[0271] An exemplary sequence of human JNK1 is shown below:

[0272] SEQ ID NO:34 (UniParc accession number UPI000012F17A)

[0273] MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRPFQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYI VMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAPEVILGMGYKENVDLWSVGC IMGEMVCHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARDLLSKMLVIDASKRISVDEALQHPY INVWYDPSEAEAPPPKIPDKQLDEREHTIEEWKELIYKEVMDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAAGPLGCCR

[0274] An exemplary sequence of human JNK2 is shown below:

[0275] SEQ ID NO:35 (UniParc accession number UPI000006E3AD)

[0276] MSDSKCDSQFYSVQVADSTFTVLKRYQQLKPIGSGAQGIVCAAFDTVLGINVAVKKLSRPFQNQTHAKRAYRELVLLKCVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIHMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTACTNFMMTPYVVTRYYRAPEVILGMGYKENVDIWSVGCIMGELVKGCVIFQGTDHIDQWNKVIEQLGTPSAEFMKKLQPTVRNYVENRPKYPGIKFEELFPDWIFPSESERDKIKTSQARDLLSKMLVIDPDKRISVDEALRHPYITVWYDPAEAEAPPPQIYDAQLEEREHAIEEWKELIYKEVMDWEERSKNGVVKDQPSDAAVSSNATPSQSSSINDISSMSTEQTLASDTDSSLDASTGPLEGCR

[0277] An exemplary sequence of human JNK3 is shown below:

[0278] SEQ ID NO:36 (UniParc accession number UPI0000049042)

[0279] MSLHFLYYCSEPTLDVKIAFCQGFDKQVDVSYIAKHYNMSKSKVDNQFYSVEVGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAVLDRNVAIKKLSRPFQNQTHAKRAYRELVLMK CVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAP EVILGMGYKENVDIWSVGCIMGEMVRHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRNYVENRPKYAGLTFPKLFPDSLFPADSEHNKLKASQARDLLSKMLVIDPAKRI SVDDALQHPYINVWYDPAEVEAPPPQIYDKQLDEREHTIEEWKELIYKEVMNSEEKTKNGVVKGQPSPSGAAVNSSESLPPSSSVNDISSMSTDQTLASDTDSSLEASAGPLGCCR

[0280] Compound of formula (I)

[0281] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0282]

[0283] in:

[0284] Each is a single bond or a double bond;

[0285] Q is –CH 2 –, O or NH;

[0286] X is N or C;

[0287] Y is N or C;

[0288] Z is N or CR 6 ;

[0289] When one of X and Y is N, the other of X and Y is C;

[0290] n is 1, 2 or 3;

[0291] R X is hydrogen or halogen;

[0292] R 1is hydrogen, halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR A R B , or C1-C3 alkyl optionally substituted by 1-3 substituents selected from hydroxyl and C1-C3 alkoxy;

[0293] R 2 is hydrogen, halogen, amino or C1-C3 alkyl;

[0294] Each R 3 are independently deuterium, halogen, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 haloalkyl;

[0295] m is 0, 1, 2 or 3;

[0296] R 4 is a 5- to 10-membered heteroaryl group optionally substituted with one to three substituents, each of which is independently selected from R 7 ;

[0297] R 5 is phenyl or a 5- to 9-membered heteroaryl group, wherein each R 5 The group is optionally composed of 1-3 independently selected R 8 Substituents are substituted;

[0298] R 6 is hydrogen, halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR C R D and C1-C3 alkyl;

[0299] Each R 7 independently selected from halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, oxetanyl, -NR C R D , the group consisting of C1-C3 alkyl optionally substituted by one cyclopropyl; and C3-C7 cycloalkyl optionally substituted by one C1-C3 alkyl;

[0300] Each R 8 Independently selected from halogen; cyano; amino; -N=(S=O)(C1-C3 alkyl) 2 ; –S(=O) p (C1-C3 alkyl); 1-imino-1-λ 6 -Thienyl 1-oxide, (C=O)NR E R FC1-C3 alkoxy; C1-C3 haloalkyl optionally substituted by hydroxy; C1-C3 haloalkoxy; 5- to 6-membered heteroaryl optionally substituted by halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4- to 6-membered heterocyclyl or optionally substituted by hydroxy or -NR E R F Substituted C1-C3 alkyl; C1-C4 alkyl, which is optionally substituted with hydroxyl, -NR E R F or C1-C3 alkoxy substituted; 3 to 8 membered heterocyclic group; and C3-C6 cycloalkoxy;

[0301] p is 1 or 2; and

[0302] 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 Together with the nitrogen atom to which they are attached they are combined to form a 4 to 6 membered heterocyclic group optionally substituted by 1-2 halogens.

[0303] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0304]

[0305] In some embodiments, Q is -CH 2 –. In some embodiments, Q is O. In some embodiments, Q is NH.

[0306] In some embodiments, the five-membered nitrogen-containing ring formed in part by X and Y is a heteroaromatic ring.

[0307] In some embodiments, X is C and Y is C.

[0308] In some embodiments, X is N and Y is C.

[0309] In some embodiments, X is C and Y is N.

[0310] In some embodiments, Z is N. In some embodiments, Z is CR 6 In some embodiments, Z is CR 6 , where R 6For hydrogen.

[0311] In some embodiments, X is C; Y is C; and Z is CR 6 In some embodiments, X is N; Y is C; and Z is CR 6 In some embodiments, X is C; Y is N; and Z is CR 6 In some embodiments, X is C; Y is N; and Z is CR 6 , where R 6 is hydrogen. In some embodiments, X is C; Y is C; and Z is N. In some embodiments, X is N; Y is C; and Z is N. In some embodiments, X is C; Y is N; and Z is N.

[0312] In some embodiments, R 6 For hydrogen.

[0313] In some embodiments, R 6 is a halogen. For example, R 6 is fluorine. For example, R 6 In some embodiments, R 6 In some embodiments, R 6 It is hydroxyl.

[0314] In some embodiments, R 6 is C1-C3 alkoxy. 6 It is methoxy or ethoxy.

[0315] In some embodiments, R 6 is C1-C3 haloalkoxy. 6 It is trifluoromethoxy, difluoromethoxy or fluoromethoxy.

[0316] In some embodiments, R 6 is a C1-C3 haloalkyl group. 6 is trifluoromethyl or 2,2,2-trifluoroethyl.

[0317] In some embodiments, R 1 is halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkyl, –NR A R B or a C1-C3 alkyl group optionally substituted by 1 to 3 substituents selected from hydroxy and C1-C3 alkoxy.

[0318] 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, R1 In some embodiments, R 1 is fluorine or chlorine. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is hydroxyl.

[0319] In some embodiments, R 1 is C1-C3 alkoxy. 1 It is methoxy or ethoxy.

[0320] In some embodiments, R 1 is C1-C3 haloalkoxy. 1 It is trifluoromethoxy, difluoromethoxy or fluoromethoxy.

[0321] In some embodiments, R 1 is a C1-C3 haloalkyl group. 1 is difluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl.

[0322] In some embodiments, R 1 It is a C1-C3 alkyl group which is optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxy and C1-C3 alkoxy.

[0323] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is a C1-C3 alkyl group, such as a methyl group.

[0324] 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.

[0325] 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.

[0326] In some embodiments, each R 3 are independently deuterium, halogen, hydroxy, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy.

[0327] In some embodiments, each R 3 are independently halogen. In some embodiments, R 3 In some embodiments, R 3 In some embodiments, each R 3 are independently hydroxyl.

[0328] In some embodiments, each R 3 are independently C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 haloalkyl.

[0329] In some embodiments, each R 3 are independently C1-C3 alkyl. 3 is methyl or ethyl. In some embodiments, each R 3 are independently C1-C3 alkoxy. 3 is methoxy or ethoxy. In some embodiments, each R 3 are independently C1-C3 haloalkoxy. 3 is trifluoromethoxy, difluoromethoxy or fluoromethoxy. In some embodiments, each R 3 are independently C1-C3 haloalkyl. 3 is trifluoromethyl or 2,2,2-trifluoroethyl.

[0330] In some embodiments, m is 1, and R 3 is methyl or trifluoromethyl.

[0331] In some embodiments, R 4 is optionally composed of one to three independently selected 7A 5-membered or 6-membered heteroaryl group substituted with a substituent.

[0332] In some embodiments, R 4 is optionally composed of one to three independently selected 7 A 6-membered heteroaryl group substituted with a substituent.

[0333] In some embodiments, R 4 is optionally composed of one to three independently selected 7 A 5-membered heteroaryl group substituted with a substituent.

[0334] In some embodiments, R 4 is optionally composed of one to three independently selected 7 4H-pyrazolyl, 3H-pyrazolyl or thiazolyl substituted with a substituent.

[0335] In some embodiments, R 4 is unsubstituted. For example, R 4 is unsubstituted 4H-pyrazolyl, 3H-pyrazolyl or thiazolyl.

[0336] In some embodiments, R 4 is one to three independently selected from R 7 In other embodiments, R 4 For a selected 7 A 5-membered or 6-membered heteroaryl group substituted with a substituent.

[0337] In some embodiments, each R 7 is independently selected from the group consisting of C1-C3 haloalkyl, C1-C3 alkyl and cycloalkyl. 7 is methyl, ethyl, cyclopropyl or difluoromethyl.

[0338] In some embodiments, each R 7 Independently selected from the group consisting of C1-C3 alkyl optionally substituted with one cyclopropyl.

[0339] In some embodiments, each R 7 Independently selected from the group consisting of C3-C7 cycloalkyl optionally substituted with one C1-C3 alkyl. In some embodiments, the C3-C7 alkyl is cyclopropyl.

[0340] In some embodiments, R 4 for:

[0341]

[0342] In some embodiments, R 4 for:

[0343]

[0344] In some embodiments, R 4 for:

[0345]

[0346] In some embodiments, R 4 for:

[0347]

[0348] In some embodiments, R 4 for:

[0349]

[0350] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0351]

[0352] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0353]

[0354] In some embodiments, R 5 is phenyl or a 5- to 6-membered heteroaryl; wherein each R 5 The group is optionally replaced by 1-2 independently selected R 8 In some embodiments, R 5 is phenyl or a 5- to 6-membered heteroaryl; wherein each R 5 The group is optionally replaced by 2-3 independently selected R 8 In some embodiments, R 5 is phenyl or a 5- to 6-membered heteroaryl; wherein each R 5 The group is optionally replaced by 1 to 3 independently selected R 8 In some embodiments, R 5 is phenyl or a 5- to 6-membered heteroaryl; wherein each R 5 The group is optionally replaced by 1 R 8 In some embodiments, R 5 is phenyl or a 5- to 6-membered heteroaryl; wherein each R 8 The group is optionally replaced by 2 independently selected R 8 In some embodiments, R 5 is phenyl or a 5- to 6-membered heteroaryl; wherein each R 5 The group is optionally replaced by 3 independently selected R 8replace.

[0355] In some embodiments, R 5 is phenyl or 5-membered heteroaryl; wherein each R 5 The group is optionally composed of 1-3 independently selected R 8 In some embodiments, R 5 is phenyl or 6-membered heteroaryl; wherein each R 5 The group is optionally composed of 1-3 independently selected R 8 substituted by a substituent.

[0356] In some embodiments, R 5 is optionally 1-3 independently selected R 8 In certain embodiments, R 5 is optionally replaced by 1 R 8 In certain embodiments, R 5 is optionally 2 independently selected R 8 In certain embodiments, R 5 is optionally 3 independently selected R 8 Substituted phenyl.

[0357] In some embodiments, R 5 It is an unsubstituted phenyl group.

[0358] In some embodiments, R 5 is optionally 1-3 (eg, 2) independently selected from R 8 In some embodiments, R 5 is optionally 1-3 (eg, 2) independently selected from R 8 A 6-membered heteroaryl group substituted with a substituent.

[0359] In some embodiments, R 5 is an unsubstituted 5- to 6-membered heteroaryl group.

[0360] In some embodiments, R 5 is 1 to 3 independently selected from R 8 A 5- to 6-membered heteroaryl group substituted with a substituent.

[0361] In some embodiments, R 5 is an unsubstituted 5- to 6-membered heteroaryl. 8 In some embodiments, at least one of R 8 In some embodiments, at least one of R 8 In some embodiments, at least one of R 8In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, two of R 8 In some embodiments, two of R 8 In some embodiments, two of R 8 In some embodiments, three of R 8 In some embodiments, three of R 8 In some embodiments, three of R 8 In some embodiments, at least one of R 8 At least one of them is an amino group.

[0362] In some embodiments, R 8 In some embodiments, at least one of R 8 At least one of them is a methoxy group or an ethoxy group.

[0363] In some embodiments, R 8 At least one of is a C1-C3 haloalkyl group optionally substituted with a hydroxyl group. 8 In some embodiments, at least one of R 8 At least one of is a C1-C3 haloalkyl substituted with a hydroxyl group. 8 At least one of is trifluoromethyl, 2,2-difluoroethyl or 2,2,2-trifluoroethyl. In some embodiments, R 8 At least one of the groups is 1-hydroxy-2,2-difluoroethyl.

[0364] In some embodiments, R 8 In some embodiments, at least one of R 8 At least one of them is a trifluoromethoxy group.

[0365] In some embodiments, R 8 At least one of the following is a 5- to 6-membered heteroaryl group optionally substituted by halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4- to 6-membered heterocyclyl or optionally substituted by hydroxyl or -NR E R F In some embodiments, R 8At least one of them is a 5- to 6-membered heteroaryl group optionally substituted by halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, optionally substituted by hydroxy or -NR E R F substituted C1-C3 alkyl, amino or C1-C3 haloalkyl. 8 is a 5- to 6-membered heteroaryl group optionally substituted by a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted by a hydroxyl group or a -NR E R F In some embodiments, R 8 At least one of them is a 5- to 6-membered heteroaryl group optionally substituted by halogen, C1-C3 haloalkyl or optionally substituted by hydroxyl or -NR E R F In some embodiments, R 8 is a 5- to 6-membered heteroaryl group substituted by a C1-C3 alkyl group, wherein the C1-C3 alkyl group is substituted by a hydroxyl group or a -NR E R F In some embodiments, R 8 is a 5- to 6-membered heteroaryl substituted with hydroxymethyl, aminomethyl, hydroxyethyl, aminoethyl, propan-2-ol or propan-2-amine. 8 At least one of is a 5- to 6-membered heteroaryl group optionally substituted by a 4- to 6-membered heterocyclic group.

[0366] In some embodiments, R 5 is pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl or imidazolyl; wherein each group is separated by two R 8 Replaces: One R 8 is triazolyl, imidazolyl, oxazolyl, pyrazolyl or pyrrolidinyl; and the other R 8 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro or cyano. In some embodiments, R 5 is pyridyl, pyrimidinyl or pyrazinyl; wherein each group is separated by two R 8 Replaces: One R 8 is triazolyl, imidazolyl, oxazolyl, pyrazolyl or pyrrolidinyl; and the other R 8 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro or cyano. In some embodiments, R 5 For the two R 8 Substituted pyridyl, one R 8 is triazolyl, imidazolyl or oxazolyl; and another R 8 is methyl, methoxy, trifluoromethyl, trifluoromethoxy, chloro or cyano.

[0367] In some embodiments, R5 is 1-3 independently selected R 8 Substituted 3-pyridyl or 4-pyridyl.

[0368] In some embodiments, R 5 By two R 8 Replace one of the R 8 R is selected from the group consisting of cyano, fluorine, chlorine, methyl, ethyl, methoxy, trifluoromethyl, and another R8 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, 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-4-yl, 1-methyl-pyrazol-5-yl, pyrrol-1-yl, thiazol-2-yl, isothiazolidin-2-yl-1,1-dioxide, pyrrolidin-2-one-1-yl, oxazol-2-yl, oxadiazol-2-yl, 2-amino-pyrimidin-4-yl, -(C=O)4-methylpiperazin-1-yl, 2-oxoazetidin-1-yl, azetidin-1-yl, -(C=O)N(CH 3 ) 2 、-(C=O)NHCH 3 、-(C=O)NHCH 2 CH 3、 -(C=O)NH cyclopropyl, -(C=O)(3,3-difluoroazetidin-1-yl), 2-hydroxypropan-2-yl, 1-hydroxyethyl, dimethyl(oxo)λ 6 -sulfydene, methoxy, ethoxy, difluoromethoxy, methyl, cyano.

[0369] In some embodiments, R 5 for:

[0370]

[0371] In some embodiments, R 5 for:

[0372]

[0373] In some embodiments, R 5 for:

[0374]

[0375] In some embodiments, R 5 for:

[0376]

[0377] In some embodiments, R 5 for:

[0378]

[0379] In some embodiments, R 5 for:

[0380]

[0381] In some embodiments, R X is hydrogen. In some embodiments, R X In some embodiments, R X In some embodiments, R X For chlorine.

[0382] In some embodiments, R A , R B , R C , R D , R E and R F are independently hydrogen or C1-C3 alkyl.

[0383] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0384]

[0385] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0386]

[0387] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0388]

[0389] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure:

[0390]

[0391] Table 1. Representative examples include the following:

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422] *See Experimental Procedures for details on isomer separation. The absolute stereochemistry of each isolated isomer was not determined.

[0423] Preparation process

[0424] Provided herein are methods of preparing a compound of formula (I) (eg, any compound described herein), comprising:

[0425] The compound of formula (Ih)

[0426]

[0427] With R 5 -NH 2 reaction;

[0428] To form the compound of formula (I).

[0429] In some embodiments, the compound of formula (Ih) is reacted with R 5 -NH 2 (e.g., 5-chloro-6-(triazolyl)pyridin-3-amine) in the presence of POCl 3 and pyridine.

[0430] In some embodiments, the compound of formula (Ih) is reacted with R 5 -NH 2 The reaction is carried out in the presence of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH).

[0431] In some embodiments, the compound of formula (Ih) is reacted with R 5 -NH 2 The reaction is carried out in the presence of N-methylimidazole (NMI).

[0432] In some embodiments, the compound of formula (Ih) is prepared from a compound of formula (Ih-N):

[0433]

[0434] In some embodiments (when the compound of formula (Ih) is prepared from a compound of formula (Ih-N)), the process comprises reacting a compound of formula (Ih-Ni) with

[0435]

[0436] Reaction with a compound of formula (Ih-N-ii)

[0437]

[0438] To form the compound of formula (Ih-N).

[0439] In certain embodiments, reacting the compound of formula (Ih-Ni) with the compound of formula (Ih-N-ii) is performed in the presence of an acid.

[0440] In certain of these embodiments, the acid is selected from the group consisting of hydrochloric acid and acetic acid.

[0441] Provided herein are methods of preparing a compound of formula (I) (eg, any compound described herein), comprising:

[0442] The compound of formula (Ij)

[0443]

[0444] With R 5 -Hal reaction, wherein Hal is selected from Cl, Br, I and OSO 2 CF 3 The group composed of;

[0445] To form the compound of formula (I).

[0446] In some embodiments, the compound of formula (Ij) is reacted with R 5 -Hal reaction is carried out in the presence of a catalyst and a ligand.

[0447] In some embodiments (when the compound of formula (Ij) is combined with R 5 -Hal reaction is carried out in the presence of a catalyst and a ligand), the catalyst being tris(dibenzylideneacetone)dipalladium(0).

[0448] In some embodiments (when the compound of formula (Ij) is combined with R 5 -Hal reaction is carried out in the presence of a catalyst and a ligand), the ligand being 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

[0449] In some embodiments, the compound of formula (Ij) is prepared from a compound of formula (Ih-N):

[0450]

[0451] In some embodiments, the process comprises making a compound of formula (Ih-Ni)

[0452]

[0453] Reaction with a compound of formula (Ih-N-ii)

[0454]

[0455] To form the compound of formula (Ih-N).

[0456] In some embodiments, reacting the compound of formula (Ih-Ni) with the compound of formula (Ih-N-ii) is performed in the presence of an acid.

[0457] In some embodiments (when reacting the compound of formula (Ih-Ni) with the compound of formula (Ih-N-ii) is carried out in the presence of an acid), the acid is selected from the group consisting of hydrochloric acid and acetic acid.

[0458] Treatment

[0459] Some embodiments provide a method of treating an autoimmune disorder (e.g., a MALT1-related autoimmune disorder) in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the autoimmune disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE).

[0460] Some embodiments provide a method of treating an inflammatory disorder (e.g., a MALT1-related inflammatory disorder) in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the inflammatory disorder is chronic graft-versus-host disease (cGVHD).

[0461] Some embodiments provide a method of treating a cancer (e.g., a MALT1-related cancer) in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein is a method for treating a MALT1-related cancer in a subject in need of such treatment, the method comprising: a) detecting a disorder of expression or activity or level of a MALT1 gene, a 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 disorder of expression or activity or level of a MALT1 gene, a MALT1 protease, or any of them comprises one or more fusion proteins.

[0462] In some embodiments of any method or use described herein, the cancer (e.g., MALT1-related cancer) is a blood cancer. In some embodiments of any method or use described herein, the cancer (e.g., MALT1-related cancer) is a solid tumor. In some embodiments of any method or use described herein, the cancer (e.g., MALT1-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer (e.g., sporadic medullary thyroid cancer or hereditary medullary thyroid cancer), differentiated thyroid cancer, recurrent thyroid cancer or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland tumor, lung adenocarcinoma, bronchiolar lung cancer, 2A or 2B type multiple endocrine neoplasia (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast cancer, breast tumor, breast tumor, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, 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 selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma (Burkitt lymphoma). lymphoma), carcinoid tumor, cancer of unknown primary, heart tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, tumors by location, tumors, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct cancer, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma sarcoma), extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, bone fibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hair cell tumor, hairy cell leukemia, head and neck cancer, thoracic tumor, head and neck tumor, CNS tumor, primary CNS tumor, heart disease, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosiscellhistiocytosis), laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline cancer, oral cancer, multiple endocrine neoplasms syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, tumors by location, tumors, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung tumors, lung cancer, lung tumors, respiratory tract tumors, Bronchial cancer, bronchial tumors, oral cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell tumor, pleuropulmonary blastoma, pregnancy-related breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon tumors, renal cell carcinoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome syndrome), skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach cancer, T-cell lymphoma, testicular cancer, laryngeal 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.

[0463] In some embodiments, the cancer is a blood cancer, such as a leukemia or lymphoma. In some embodiments, the blood cancer (e.g., a blood cancer that is a MALT1-associated cancer) is selected from the group consisting of: leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also known as Hodgkin lymphoma), and myeloma, for example, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), lymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myelodysplasia (MPD), and multiple myeloma (MM). Additional examples of blood cancers include myelodysplasia (MPD), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the blood cancer (e.g., a blood cancer that is a MALT1-associated cancer) is AML or CMML.

[0464] In some embodiments, the cancer is glioblastoma, chronic myeloid leukemia, granulocytic leukemia, or non-Hodgkin's lymphoma.

[0465] In some embodiments, the cancer is non-Hodgkin lymphoma. In other embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In other embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In other embodiments, the cancer is mantle cell lymphoma (MCL). In other embodiments, the cancer is marginal zone lymphoma (MZL). In other embodiments, the cancer is chronic lymphatic leukemia (CLL). In other embodiments, the cancer is a mature B-cell tumor.

[0466] In some embodiments, the cancer is T-cell acute lymphoblastic leukemia.

[0467] In some embodiments, the cancer (e.g., MALT1-related cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are MALT1-related cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal carcinoma, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, neuroblastoma, and melanoma. See, 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.

[0468] In some embodiments, the subject is a human.

[0469] The compounds of formula (I) and their pharmaceutically acceptable salts can also be used to treat MALT1-related cancers. The compounds of formula (I) and their pharmaceutically acceptable salts can also be used to treat MALT1-related autoimmune disorders. The compounds of formula (I) and their pharmaceutically acceptable salts can also be used to treat MALT1-related inflammatory disorders.

[0470] Therefore, also provided herein is a method for treating a subject diagnosed with or identified as having a MALT1-related cancer (e.g., any exemplary MALT1-related cancer disclosed herein), the method comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0471] In some embodiments of any of the methods provided herein, the compound of Formula (I) is selected from Examples 1-196.

[0472] The expression or activity or level of MALT1 protease, MALT1 gene or any one thereof (e.g., one or more) may contribute to tumorigenesis. For example, the fusion protein may have increased protease activity compared to the wild-type MALT1 protein, the expression of the wild-type MALT1 protease in mammalian cells is increased (e.g., the level is increased) due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells), and MALT1 mRNA splice variants may also cause MALT1 dysregulation.

[0473] In some aspects, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a CBM complex pathway-related cancer (such as any cancer disclosed herein) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method for treating cancer in a subject in need thereof, comprising (a) identifying the cancer as a CBM complex pathway-related cancer; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0474] Identifying a subject's cancer as a CBM complex pathway-related cancer can be performed by any appropriate method. In some embodiments, the step of identifying a subject's cancer as a CBM complex pathway-related cancer includes performing an assay to detect CBM complex pathway-related genes, CBM complex pathway-related protease proteins, or the expression or activity or level of any one thereof 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 appropriate assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrophosphate sequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0475] In addition, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a subject identified as having a CBM complex pathway-related cancer.

[0476] Also provided herein is a method for treating a subject's MALT1-related cancer, 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 as having a MALT1-related cancer. Also provided herein is a method for treating a subject's cancer in need thereof, comprising: (a) determining that the cancer is associated with a disorder in the expression or activity or level of a MALT1 gene, a MALT1 protease, or any of them; and (b) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0477] Determining that the cancer is related to the disorder of expression or activity or level of MALT1 gene, MALT1 protease or any one thereof can be performed using any appropriate method. In some embodiments, the step of determining that the cancer of the subject is a MALT1-related cancer comprises performing an assay to detect the disorder of expression or activity or level of MALT1 gene, MALT1 protease protein or any one thereof 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 appropriate assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrophosphate sequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0478] As described herein, the CBM complex pathway-related cancer can be any appropriate CBM complex pathway-related cancer (such as any cancer described herein). In some embodiments, the CBM complex pathway-related cancer is selected from the group consisting of: CBM complex pathway cell surface receptor-related cancer, cancer associated with a signal transducer between a cell surface receptor and a CBM complex, a component of a CBM complex-related cancer, a MALT1 protease substrate-related 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 a combination thereof. In some embodiments, the CBM complex pathway cell surface receptor-related cancer is selected from the group consisting of: CD28-related cancer, BCR-related cancer, HER1-related cancer, HER2-related cancer, and a combination thereof. In some embodiments, the cancer associated with a signal transducer between a cell surface receptor and a CBM complex is a protein kinase Cβ (PKCβ)-related cancer, a protein kinase Cθ (PCKθ)-related cancer, or a combination thereof. In some embodiments, the components of the CBM complex-associated cancer are 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 components of the CBM complex-associated cancer are selected from the group consisting of: MALT1-associated cancer, CARD11-associated cancer, BCL10-associated cancer, and combinations thereof. For exemplary disorders in MALT1, CARD11, and BCL10, see, e.g., Tables B1, B2, and B3. 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, roquin-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. For exemplary dysregulation in BCL10 and A20, see, e.g., Tables B3 and B4. 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. In some embodiments, the cancer associated with a component of the JNK pathway downstream of the CBM complex is selected from the group consisting of: JNK1-associated cancer, JNK2-associated cancer, JNK3-associated cancer, MYD88 transcription factor-associated cancer, AP-1 transcription factor-associated cancer, and combinations thereof.

[0479] In some embodiments, the CBM complex pathway-associated cancer is a MALT1-associated cancer. The MALT1-associated cancer can have any suitable disorder, such as any of the disorders 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.

[0480] Also provided herein are methods for treating diseases or disorders associated with the CBM complex pathway, autoimmune disorders, and inflammatory disorders. Thus, provided herein is a method for treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a subject's MALT1-related autoimmune disorder, the method comprising administering to a subject identified or diagnosed as having a MALT1-related autoimmune disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some cases, provided herein is a method for treating an autoimmune disorder in a subject in need thereof, comprising: (a) determining that the autoimmune disorder is associated with a disorder in the expression or activity or level of a MALT1 gene, a MALT1 protease, or any of them; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a subject's MALT1-related autoimmune disorder, the method comprising administering to a subject determined to have a MALT1-related autoimmune disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In addition, provided herein is a method for treating an inflammatory condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some cases, provided herein is a method for treating a MALT1-related inflammatory condition in a subject, the method comprising administering to a subject identified or diagnosed as having a MALT1-related inflammatory condition an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating an inflammatory condition in a subject in need thereof, comprising: (a) determining that the inflammatory condition is associated with a disorder in the expression, activity or level of a MALT1 gene, a MALT1 protease or any of them; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a MALT1-related inflammatory condition in a subject, the method comprising administering to a subject determined to have a MALT1-related inflammatory condition an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0481] Further provided herein is a method for treating a CBM complex pathway-related disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method for treating a disease or condition in a subject in need thereof, comprising: (a) identifying the cancer as a CBM complex pathway-related disease or condition; and (b) administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In addition, provided herein is a method for treating a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject identified as having a CBM complex pathway-related disease or condition.

[0482] The CBM complex pathway-related disease or disorder can be any appropriate CBM complex pathway-related disease or disorder, such as any disease or disorder described herein. In some embodiments, the CBM complex pathway-related disease or disorder is an autoimmune disease. In some embodiments, the CBM complex pathway-related disease or disorder is an inflammatory disorder. In some embodiments, the CBM complex pathway-related cancer is selected from the group consisting of: CBM complex pathway cell surface receptor-related cancer, diseases or disorders associated with signal transducers between cell surface receptors and CBM complexes, components of CBM complex-related cancers, MALT1 protease substrate-related cancers, diseases or disorders associated with components of the NF-κB pathway downstream of the CBM complex, diseases or disorders associated with components of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, the CBM complex pathway-related disease or disorder is a MALT1-related disease or disorder.

[0483] In some cases, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to inhibit cellular processes, such as inhibiting cell proliferation. Therefore, a method for inhibiting mammalian cell proliferation is provided herein, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method for inhibiting CBM complex pathway activity of a mammalian cell is also provided herein, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method for inhibiting MALT1 protease activity of a mammalian cell is also provided herein, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, contact occurs in vivo. In some embodiments, contact 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-related cancer cell. In some embodiments, the mammalian cancer cell is a mammalian MALT1-related cancer cell. In some embodiments, the mammalian cell has a disorder of expression or activity or level of a MALT1 gene, a MALT1 protease protein, or any one thereof. In some embodiments, the dysregulation of the expression or activity or level of the MALT1 gene, MALT1 protease protein, or either thereof is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0484] The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be used to prepare a drug. Therefore, the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a CBM complex pathway-related disease or condition. The CBM complex pathway-related disease or condition can be any appropriate CBM complex pathway-related disease or condition, such as a disease or condition described herein. In some embodiments, the CBM complex pathway-related disease or condition is selected from the group consisting of: CBM complex pathway cell surface receptor-related cancer, a disease or condition associated with a signal transducer between a cell surface receptor and a CBM complex, a component of a CBM complex-related cancer, a MALT1 protease substrate-related cancer, a disease or condition associated with a component of the NF-κB pathway downstream of the CBM complex, a disease or condition associated with a component of the JNK pathway downstream of the CBM complex, and a combination thereof. In some embodiments, the CBM complex pathway-related disease or condition is a CBM complex pathway-related autoimmune disorder. In some embodiments, the CBM complex pathway-related disease or condition is a CBM complex pathway-related inflammatory disorder. In some embodiments, the CBM complex pathway-related disease or condition is a CBM complex pathway-related cancer. In some embodiments, the CBM complex pathway-related disease or condition is a MALT1-related disease or condition. In some embodiments, the MALT1-related disease or condition comprises a disorder of the expression or activity or level of the MALT1 gene, the MALT1 protease protein, or any of them. In some embodiments, the disorder of the expression or activity or level of the MALT1 gene, the MALT1 protease protein, or any of them is IAP2-MALT1 fusion, IGH-MALT1 fusion, or a combination thereof.

[0485] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) permeability. Such compounds can cross the blood-brain barrier and inhibit the MALT1 protease in the brain and / or other CNS structures. In some embodiments, the compounds provided herein can cross the blood-brain barrier in an effective amount. For example, the treatment of a subject suffering from cancer (e.g., MALT1-related cancers, such as MALT1-related brain cancers or CNS cancers) can include administering (e.g., orally administering) the compound to the subject. In some such embodiments, the compounds provided herein can be used to treat primary brain tumors or metastatic brain tumors. For example, the compounds can be used to treat one or more gliomas, such as glioblastomas (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas and mixed gliomas, meningiomas, medulloblastomas, intracranial gangliogliomas, schwannomas / neurilemmomas and craniopharyngiomas (see, for example, tumors listed in the following literature: Louis, DN et al. Acta Neuropathol 131 (6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the subject has been previously treated with another anticancer agent, for example, another protease inhibitor (e.g., a compound 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 been previously treated with another anticancer agent, for example, another protease inhibitor (e.g., a compound that is not a compound of formula (I)).

[0486] In some embodiments of any of the methods or uses described herein, the assay for determining whether the subject has a disorder of the expression or activity or level of a gene (e.g., MALT1 gene), or a protein (e.g., MALT1 protein) or any of them using a sample from the subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, FISH separation analysis, Southern blot, protein blot, FACS analysis, Northern blot, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is usually 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 the disorder of the expression or activity or level of a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or any of them. In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a MALT1-related cancer, a subject having one or more symptoms of a MALT1-related cancer, and / or a subject with an increased risk of suffering from a MALT1-related cancer).

[0487] In some embodiments, liquid biopsy (variously referred to as liquid biopsy or liquid phase biopsy) can be used to identify the disorder of expression or activity or level of a gene (e.g., MALT1 gene), a MALT1 protein (e.g., MALT1 protein), or any of them. Liquid biopsy methods can be used to detect the disorder of expression or activity or level of total tumor load and / or a gene (e.g., MALT1 protein), a MALT1 protein (e.g., MALT 1 protein), or any of them. Liquid biopsy can be performed on biological samples that are relatively easy to obtain from a subject (e.g., by a simple blood draw), and the liquid biopsy is less invasive than traditional methods for detecting tumor load and / or a disorder of expression or activity or level of a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or any of them. In some embodiments, liquid biopsy can be used at an earlier stage to detect the presence or absence of a disorder of expression or activity or level of a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or any of them compared to traditional methods. In certain embodiments, the biological sample for liquid biopsy can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymphatic fluid, cyst fluid, feces, ascites and combinations thereof. In certain embodiments, liquid biopsy can be used to detect circulating tumor cells (CTC). In certain embodiments, liquid biopsy can be used to detect cell-free DNA. In certain embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA), which is derived from tumor cells. Analysis of ctDNA (for example, using sensitive detection techniques, such as but not limited to next generation sequencing (NGS), traditional PCR, digital PCR or microarray analysis) can be used to identify gene (for example, MALT1 gene), protein (for example, MALT1 protein) or any one of them expression or activity or level disorder.

[0488] In certain embodiments, liquid biopsy can be used to detect ctDNA derived from a single gene. In certain embodiments, liquid biopsy can be used to detect ctDNA derived from multiple genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more genes, or any number of genes between these numbers). In certain embodiments, any one of a variety of commercially available test panels (e.g., designed to detect gene (e.g., MALT1 gene), protein (e.g., MALT1 protein) or any one of them The expression or activity or level of the disordered commercial test panel) can be used to detect ctDNA derived from multiple genes. Liquid biopsy can be used to detect a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or a disorder of expression or activity or level of any of them, including but not limited to point mutations or single nucleotide variants (SNVs), copy number variants (CNVs), gene fusions (e.g., translocations or rearrangements), insertions, deletions, or any combination thereof. In some embodiments, liquid biopsy can be used to detect germline mutations. In some embodiments, liquid biopsy can be used to detect somatic mutations. In some embodiments, liquid biopsy can be used to detect primary gene mutations (e.g., primary mutations or primary fusions associated with the initial development of a disease, such as cancer). In some embodiments, a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or a disorder of expression or activity or level of 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, liquid biopsy can be used to detect a disorder of expression or activity or level of a gene (e.g., MALT1 gene), a protein (e.g., MALT1 protein), or any of them described herein. In some embodiments, the genetic mutation identified by liquid biopsy can be used to identify the subject as a candidate for a specific treatment. For example, the detection of a gene (e.g., MALT1 gene), protein (e.g., MALT1 protein) or an imbalance in the expression or activity or level of any one thereof in the subject can indicate that the subject will respond to a treatment comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0489] Liquid biopsies may be performed multiple times during the diagnostic process, monitoring process, and / or treatment process to determine one or more clinically relevant parameters, including but not limited to the progression of the disease and / or the efficacy of the treatment. For example, during the diagnostic process, monitoring process, and / or treatment process, a first liquid biopsy may be performed at a first time point, and a second liquid biopsy may be performed at a second time point. In some embodiments, the first time point may be a time point before the subject is diagnosed with the disease (e.g., when the subject is healthy), and the second time point may be a time point after the subject has the disease (e.g., the second time point may be used to diagnose the subject with the disease). In some embodiments, the first time point may be a time point before the subject is diagnosed with the disease (e.g., when the subject is healthy), after which the subject is monitored, and the second time point may be a time point after monitoring the subject. In some embodiments, the first time point may be a time point after the subject is diagnosed with the disease, after which the subject is treated, and the second time point may be a time point after the treatment is applied; in such cases, the second time point may be used to assess the efficacy of the treatment (e.g., if the abundance of the gene mutation detected at the first time point is reduced or undetectable). In some embodiments, the treatment to be administered to a subject may comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0490] In some embodiments, the efficacy of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by evaluating the allele frequency of a gene (e.g., MALT1 gene) dysregulated in cfDNA obtained from a subject at different time points (e.g., cfDNA obtained from a subject at a first time point and cfDNA obtained from a subject at a second time point), wherein at least one dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject between the first time point and the second time point. Some embodiments of these methods may further comprise administering at least one dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject between the first time point and the second time point. For example, the allele frequency (AF) of a gene (e.g., MALT1 gene) dysregulated in the cfDNA obtained from the subject at the first time point is reduced (e.g., reduced by 1% to about 99%, reduced by 1% to about 95%, reduced by 1% to about 90%, reduced by 1% to about 85%, reduced by 1% to about 80%, reduced by 1% to about 75%, reduced by 1% to about 70%, reduce by 1% to about 65%, reduce by 1% to about 60%, reduce by 1% to about 55%, reduce by 1% to about 50%, reduce by 1% to about 45%, reduce by 1% to about 40%, reduce by 1% to about 35%, reduce by 1% to about 30%, reduce by 1% to about 25%, reduce by 1% to about 20%, reduce by 1% to about 15%, reduce by 1% to about 10%, reduce by 1% to about 5%, reduce by about 5% to about 99%, reduce by about 10% to about 99%, about 15% to about 99% reduction, about 20% to about 99% reduction, about 25% to about 99% reduction, about 30% to about 99% reduction, about 35% to about 99% reduction, about 40% to about 99% reduction, about 45% to about 99% reduction, about 50% to about 99% reduction, about 55% to about 99% reduction, about 60% to about 99% reduction, about 65% to about 99% reduction, about 70% to about 99% reduction, about 75% to about 95% reduction, about 80% to about 99%, about 90% to about 99%, about 95% to about 99%, about 5% to about 10%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 50%, about 35% to about 55%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, or about 65% to about 85%), indicating that the compound of formula (I) or a pharmaceutically acceptable salt thereof is effective in the subject. In some embodiments, AF is reduced to a level below the detection limit of the instrument.Alternatively, the allele frequency (AF) of the disordered gene (e.g., MALT1 gene) in the cfDNA obtained from the subject at the first time point is increased compared to the allele frequency (AF) of the disordered gene (e.g., MALT1 gene) in the cfDNA obtained from the subject at the second time point, indicating that the compound of formula (I) or its pharmaceutically acceptable salt is ineffective for the subject. Some embodiments of these methods may further include administering an additional dose of the compound of formula (I) or its pharmaceutically acceptable salt to the subject in which the compound of formula (I) or its pharmaceutically acceptable salt is determined to be effective. Some embodiments of these methods may further include administering a different treatment (e.g., not including the treatment of administering the compound of formula (I) or its pharmaceutically acceptable salt as a monotherapy) to the subject in which the compound of formula (I) or its pharmaceutically acceptable salt is determined to be ineffective.

[0491] In some examples of these methods, the time difference between the first time point and the second time point can be 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 Days to about 1 year, about 1 month to about 1 year, about 6 weeks to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year, about 4 months to about 1 year, about 5 months to about 1 year, about 6 months to about 1 year, about 7 months to about 1 year, about 8 months to about 1 year, about 9 months to about 1 year, about 10 months to about 1 year, about 11 months to about 1 year, about 1 day to about 7 days, about 1 day to about 14 days, about 5 days to about 10 days, about 5 days to about 20 days, about 10 days to about 20 days, about 15 days to about 1 month, about 15 days to about 2 months, about 1 week to about 1 month, about 2 weeks to about 1 month, about 1 month to about 3 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 8 months or about 7 months to about 9 months. In some embodiments of these methods, the subject can be previously identified as having a cancer with a dysregulated gene (e.g., any example of a dysregulated gene described herein) (e.g., a MALT1 gene). In some embodiments of these methods, the subject may have been previously diagnosed with any type of cancer described herein. In some embodiments of these methods, the subject may have one or more metastases (e.g., one or more brain metastases).

[0492] In some of the above embodiments, cfDNA includes ctDNA, such as MALT1-associated ctDNA. For example, cfDNA is ctDNA, such as MALT1-associated ctDNA. In some embodiments, at least a portion of the cfDNA is determined to be MALT1-associated ctDNA, for example, the total cfDNA sequenced and / or quantified amount is determined to have MALT1 fusions and / or overexpression of MALT1.

[0493] Although the genetic basis of tumorigenesis may differ between 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 their growth inhibitory responses, undergo changes in adhesion, and produce enzymes that can degrade components of the extracellular matrix. This leads to tumor cell detachment from the original tumor, infiltration into the circulation through newly formed vasculature, and migration and extravasation of tumor cells at favorable distal sites where they may form colonies.

[0494] Therefore, there is also provided herein a method for inhibiting, preventing, helping to prevent or alleviating the metastatic symptoms of cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Such methods can be used to treat one or more cancers described herein. See, for example, U.S. Publication No. 2013 / 0029925; International Publication No. WO 2014 / 083567; and U.S. Patent No. 8,568,998. See also, for example, Hezam K et al., Rev Neurosci January 26, 2018; 29:93-98; Gao L et al., Pancreas January 2015; 44:134-143; Ding K et al., J Biol Chem June 6, 2014; 289:16057-71; and Amit M et al., Oncogene June 8, 2017; 36:3232-3239. In some embodiments, the cancer is a MALT1-related cancer. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent as described herein. For example, a first or second MALT1 protease inhibitor.

[0495] The term "metastasis" is an art-recognized term and refers to the formation of additional tumors (eg, solid tumors) in a subject at sites distant from the primary tumor, wherein the additional tumors contain the same or similar cancer cells as the primary tumor.

[0496] Also provided is a method of reducing the risk of metastasis or additional metastasis in a subject with a MALT1-related cancer, the method comprising: selecting, identifying or diagnosing a subject with a MALT1-related 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-related cancer. Also provided is a method of reducing the risk of metastasis or additional metastasis in a subject with a MALT1-related cancer, the method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject with a MALT1-related cancer. The reduction in the risk of metastasis or additional metastasis in a subject with a MALT1-related cancer can be compared to the risk of metastasis or additional metastasis in the subject before treatment, or compared to a subject or subject population with a similar or identical MALT1-related cancer who has not received any treatment or who has received a different treatment.

[0497] The phrase "risk of developing metastasis" means the risk that a subject with a primary tumor develops additional tumors (e.g., solid tumors) at sites distant from the primary tumor in the subject within a set period of time, wherein the additional tumors contain cancer cells that are the same or similar to the primary tumor. Methods for reducing the risk of metastasis in a subject with cancer are described herein.

[0498] The phrase "risk of developing additional metastases" means that a subject who has a primary tumor and one or more additional tumors at a site distant from the primary tumor (wherein the one or more additional tumors contain cancer cells that are the same or similar to the primary tumor) will develop the risk of one or more additional tumors distant from the primary tumor, wherein the additional tumors contain cancer cells that are the same or similar to the primary tumor. Methods of reducing the risk of developing additional metastases are described herein.

[0499] Some embodiments described herein provide methods for treating autoimmune disorders such as rheumatoid arthritis, multiple sclerosis and SLE (e.g., MALT1-related autoimmune disorders), comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0500] Some embodiments described herein provide methods of treating inflammatory disorders such as chronic graft-versus-host disease (eg, MALT1-related autoimmune disorders), comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0501] Also provided is a method for inhibiting the MALT1 protease activity of a mammalian cell, the method comprising contacting the mammalian cell with a compound of formula (I). In some embodiments, the contact is performed in vitro. In some embodiments, the contact is performed in vivo. In some embodiments, the contact is performed in vivo, wherein 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 having 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.

[0502] Also provided is a method for inhibiting the MALT1 protease activity of a mammalian mammalian cell, the method comprising contacting the mammalian cell with a compound of formula (I). In some embodiments, the contact is performed in vitro. In some embodiments, the contact is performed in vivo. In some embodiments, the contact is performed in vivo, wherein the method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal having a mammalian cell having 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.

[0503] As used herein, the term "contacting" refers to bringing the indicated parts of an in vitro system or an in vivo system together. For example, "contacting" a MALT1 protease with a compound provided herein includes administering a compound provided herein to a subject (such as a human) having a MALT1 protease, and, for example, introducing a compound provided herein into a sample containing mammalian cells or a purified preparation containing a MALT1 protease.

[0504] Also provided herein is a method of inhibiting mammalian cell proliferation in vitro or in vivo, the method comprising contacting the mammalian cell with an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0505] As defined herein, a "MALT1 protease inhibitor" includes any compound that exhibits MALT1 inhibitory activity. In some embodiments, a MALT1 protease inhibitor is selective for MALT1 protease. Exemplary MALT1 protease inhibitors may exhibit an inhibitory activity (IC) 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 against MALT1 protease. 50 ), as measured in an assay described herein. In some embodiments, a MALT1 protease inhibitor can exhibit an inhibitory activity (IC) of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM against MALT1 protease. 50 ), as measured in the assays provided herein.

[0506] As used herein, a "first MALT1 protease inhibitor" or "first MALT1 inhibitor" is a MALT1 protease inhibitor as defined herein, but does not include a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof. As used herein, a "second MALT1 protease inhibitor" or "second MALT1 inhibitor" is a MALT1 protease inhibitor as defined herein, but does not include a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof. When the first and second MALT1 inhibitors are present simultaneously in the methods provided herein, the first and second MALT1 protease inhibitors are different.

[0507] Exemplary first and second MALT1 protease inhibitors are described herein. In some embodiments, the first or second MALT1 protease inhibitor can be, for example, JNJ-67856633 or CTX-177 (ONO-7018)

[0508] The phrase "effective amount" refers to an amount of a compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a MALT1-related disease or condition (e.g., a MALT1-related cancer); (ii) alleviate, 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof corresponding to the stated amount will vary depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject in need of treatment (e.g., body weight), but can still be routinely determined by one skilled in the art.

[0509] Another embodiment features a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0510] Another embodiment features a compound of Formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting MALT1 in a subject.

[0511] Another embodiment features a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating cancer, an autoimmune disorder, or an inflammatory disorder.

[0512] Other embodiments provide a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating an autoimmune disorder (e.g., a MALT1-related autoimmune disorder) in a subject. In some embodiments, the autoimmune disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE).

[0513] Some embodiments provide a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating an inflammatory disorder (e.g., a MALT1-related inflammatory disorder) in a subject. In some embodiments, the inflammatory disorder is chronic graft-versus-host disease (cGVHD).

[0514] Some embodiments provide a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating a cancer (e.g., a MALT1-related cancer) in a subject. In some embodiments, the disorder of expression or activity or level of the MALT1 gene, MALT1 protease, or any of them comprises one or more fusion proteins.

[0515] Therefore, also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating a subject diagnosed with or identified as having a MALT1-related cancer (e.g., any of the exemplary MALT1-related cancers disclosed herein).

[0516] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method of treating diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL) or mature B-cell tumors.

[0517] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof for use in a method for treating T-cell acute lymphoblastic leukemia.

[0518] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating a CBM complex pathway-related cancer (such as any of those cancers disclosed herein) in a subject.

[0519] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating cancer in a subject identified as having a CBM complex pathway-related cancer.

[0520] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating a MALT1-related cancer in a subject.

[0521] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating a CBM complex pathway-related disease or disorder, an autoimmune disorder, and an inflammatory disorder in a subject.

[0522] Therefore, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method for treating an autoimmune disorder in a subject. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method for treating a MALT1-related autoimmune disorder in a subject. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method for treating a MALT1-related autoimmune disorder in a subject.

[0523] In addition, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method for treating an inflammatory disorder in a subject. In some cases, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method for treating a MALT1-related inflammatory disorder in a subject identified or diagnosed as having a MALT1-related inflammatory disorder. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method for treating a MALT1-related inflammatory disorder in a subject identified as having a MALT1-related inflammatory disorder.

[0524] Further provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions for use in methods of treating a subject's CBM complex pathway-related disease or condition. In addition, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions for use in methods of treating a disease or condition in a subject identified as having a CBM complex pathway-related disease or condition.

[0525] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of inhibiting mammalian cell proliferation. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of inhibiting CBM complex pathway activity in a mammalian cell. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of inhibiting MALT1 protease activity in a mammalian cell. The mammalian cell may 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-related cancer cell. In some embodiments, the mammalian cancer cell is a mammalian MALT1-related cancer cell. In some embodiments, the mammalian cell has a disorder of expression or activity or level of a MALT1 gene, a MALT1 protease protein, or any one thereof. In some embodiments, the disorder of expression or activity or level of a MALT1 gene, a MALT1 protease protein, or any one thereof is IAP2-MALT1 fusion, IGH-MALT1 fusion, or a combination thereof.

[0526] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method of inhibiting, preventing, helping to prevent or alleviating the symptoms of cancer metastasis in a subject. Such methods can be used to treat one or more cancers described herein. See, for example, U.S. Publication No. 2013 / 0029925; International Publication No. WO 2014 / 083567; and U.S. Patent No. 8,568,998. See also, for example, Hezam K et al., Rev Neurosci January 26, 2018; 29:93-98; Gao L et al., Pancreas January 2015; 44:134-143; Ding K et al., J Biol Chem June 6, 2014; 289:16057-71; and Amit M et al., Oncogene June 8, 2017; 36:3232-3239. In some embodiments, the cancer is a MALT1-related 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, such as a first or second MALT1 protease inhibitor.

[0527] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method of reducing the risk of metastasis or additional metastasis in a subject with a MALT1-related cancer. The reduction in the risk of metastasis or additional metastasis in a subject with a MALT1-related cancer can be compared to the risk of metastasis or additional metastasis in the subject before treatment, or to a subject or subject population with a similar or identical MALT1-related cancer who has not received any treatment or who has received a different treatment.

[0528] Some embodiments described herein provide a compound of Formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating an autoimmune disorder (e.g., a MALT1-associated autoimmune disorder), such as rheumatoid arthritis, multiple sclerosis, and SLE, in a subject.

[0529] Some embodiments described herein provide a compound of Formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating an inflammatory disorder (eg, a MALT1-related autoimmune disorder), such as chronic graft-versus-host disease, in a subject.

[0530] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method for inhibiting MALT1 protease activity in a mammalian 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 any cancer described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell.

[0531] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method for inhibiting mammalian cell proliferation.

[0532] In another aspect, the invention features a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method wherein a subject is treated with one or more additional therapeutic agents that are administered simultaneously with, before, or after treatment with an effective amount of the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

[0533] In another aspect, the present invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof for the manufacture of a medicament.

[0534] In another aspect, the present invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in inhibiting MALT1 in a subject.

[0535] In another aspect, the present invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating cancer, an autoimmune disorder, or an inflammatory disorder in a subject.

[0536] Some embodiments provide the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a medicament for use in treating an autoimmune disorder (e.g., a MALT1-related autoimmune disorder) in a subject. In some embodiments, the autoimmune disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE).

[0537] Some embodiments provide the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a medicament for use in treating an inflammatory disorder (e.g., a MALT1-related inflammatory disorder) in a subject. In some embodiments, the inflammatory disorder is chronic graft-versus-host disease (cGVHD).

[0538] Some embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the manufacture of a medicament for use in treating a cancer (e.g., a MALT1-related cancer) in a subject. In some embodiments, the disorder of expression or activity or level of the MALT1 gene, MALT1 protease, or any of them comprises one or more fusion proteins.

[0539] Therefore, also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating a subject diagnosed with or identified as having a MALT1-related cancer (e.g., any of the exemplary MALT1-related cancers disclosed herein).

[0540] Therefore, also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the manufacture of a medicament for use in treating a subject with diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL) or mature B-cell tumors.

[0541] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the manufacture of a medicament for use in treating a subject suffering from T-cell acute lymphoblastic leukemia.

[0542] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating a CBM complex pathway-related cancer (such as any of those cancers disclosed herein) in a subject.

[0543] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in the manufacture of a medicament for use in treating cancer in a subject identified as having a CBM complex pathway-related cancer.

[0544] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in the manufacture of a medicament for use in treating a MALT1-related cancer in a subject.

[0545] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating a CBM complex pathway-related disease or disorder, an autoimmune disorder, and an inflammatory disorder in a subject. Therefore, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating an autoimmune disorder in a subject. Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating a MALT1-related autoimmune disorder in a subject. Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating a MALT1-related autoimmune disorder in a subject. In addition, also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating an inflammatory disorder in a subject. In some cases, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating a MALT1-related inflammatory disorder in a subject identified or diagnosed as having a MALT1-related inflammatory disorder. Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in the manufacture of a medicament for use in treating a MALT1-associated inflammatory disorder in a subject determined to have a MALT1-associated inflammatory disorder.

[0546] Further provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the manufacture of a medicament for use in treating a CBM complex pathway-related disease or condition in a subject. In addition, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the manufacture of a medicament for use in treating a disease or condition in a subject identified as having a CBM complex pathway-related disease or condition.

[0547] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in inhibiting mammalian cell proliferation. Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in inhibiting CBM complex pathway activity in mammalian cells. Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in inhibiting MALT1 protease activity in mammalian cells. The mammalian cell may 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-related cancer cell. In some embodiments, the mammalian cancer cell is a mammalian MALT1-related cancer cell. In some embodiments, the mammalian cell has a disorder of expression, activity or level of a MALT1 gene, a MALT1 protease protein, or any of them. In some embodiments, the disorder of expression, activity or level of a MALT1 gene, a MALT1 protease protein, or any of them is IAP2-MALT1 fusion, IGH-MALT1 fusion, or a combination thereof.

[0548] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the manufacture of a drug for use in inhibiting, preventing, helping to prevent or alleviating the metastatic symptoms of a subject's cancer. In some embodiments, the cancer is a MALT1-related cancer. In some embodiments, as described herein, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with another therapy or another therapeutic agent. For example, a first or second MALT1 protease inhibitor.

[0549] Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the manufacture of a medicament for use in reducing the risk of metastasis or additional metastasis in a subject with a MALT1-related cancer. The reduction in the risk of metastasis or additional metastasis in a subject with a MALT1-related cancer can be compared to the risk of metastasis or additional metastasis in the subject before treatment, or to a subject or subject population with a similar or identical MALT1-related cancer who has not received any treatment or who has received a different treatment.

[0550] Some embodiments described herein provide the use of a compound of Formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in the manufacture of a medicament for use in treating an autoimmune disorder (e.g., a MALT1-related autoimmune disorder) such as rheumatoid arthritis, multiple sclerosis, and SLE in a subject.

[0551] Some embodiments described herein provide the use of a compound of Formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for use in treating an inflammatory disorder (eg, a MALT1-related autoimmune disorder), such as chronic graft-versus-host disease, in a subject.

[0552] Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the manufacture of a medicament for use in inhibiting MALT1 protease activity in a mammalian 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 any cancer described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell.

[0553] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in the manufacture of a medicament for use in inhibiting mammalian cell proliferation.

[0554] In yet another aspect, the present invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in combination with one or more additional therapeutic agents, which are administered simultaneously with, before or after treatment with the compound or pharmaceutical composition.

[0555] In the field of medical oncology, it is common practice to use a combination of different forms of therapy to treat each subject with cancer. In medical oncology, in addition to the compositions provided herein, one or more other components of such combined therapy or therapy can also be, for example, surgery, radiation therapy, and chemotherapeutic agents, such as other protease inhibitors, kinase inhibitors, signal transduction inhibitors and / or monoclonal antibodies.

[0556] For example, surgery can be open surgery or minimally invasive surgery. Therefore, the compound of formula (I) or its pharmaceutically acceptable salt can also be used as an adjuvant for cancer treatment, that is, it can be used in combination with one or more other therapies or therapeutic agents (e.g., chemotherapeutic agents that work by the same or different mechanisms of action). In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt can be administered before administering another therapeutic agent or another therapy. For example, one or more doses of the compound of formula (I) or its pharmaceutically acceptable salt can be administered to a subject in need thereof within a period of time, and then the tumor is at least partially removed. In some embodiments, before at least partially removing the tumor, treatment with one or more doses of the compound of formula (I) or its pharmaceutically acceptable salt can reduce the size of the tumor (e.g., tumor load). In some embodiments, one or more doses of the compound of formula (I) or its pharmaceutically acceptable salt can be administered to a subject in need thereof within a period of time and under one or more rounds of radiotherapy. In some embodiments, before performing one or more rounds of radiotherapy, treatment with one or more doses of the compound of formula (I) or its pharmaceutically acceptable salt can reduce the size of the tumor (e.g., tumor load).

[0557] In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a first MALT1 inhibitor, a kinase inhibitor, an immunotherapy, a cell or gene therapy, or radiation (e.g., radioactive iodine). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a previous therapy (e.g., administration of a chemotherapeutic agent, such as a first MALT1 inhibitor or another protease inhibitor, an immunotherapy, a cell or gene therapy, or radiation (e.g., radioactive iodine). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) for which there is no standard therapy. In some embodiments, the subject has not been treated with a MALT1 protease inhibitor. For example, the subject has not been treated with a selective MALT1 protease inhibitor. In some embodiments, the subject has been treated with a MALT1 protease inhibitor.

[0558] In some embodiments of any of the methods described herein, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic agents (e.g., chemotherapy or immunomodulators). The additional therapy or therapeutic agent can be any appropriate additional therapy or therapeutic agent, such as any additional therapy or therapeutic agent described herein.

[0559] Non-limiting examples of additional therapeutic agents include: other MALT1 targeted therapeutics (i.e., a first or second MALT1 protease inhibitor, such as JNJ-67856633 or CTX-177 (ONO-7018)), other protease inhibitors, kinase inhibitors (e.g., receptor tyrosine kinase targeted therapeutics, such as BTK or EGFR inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptotic pathways (e.g., venetoclax or obataclax); cytotoxic chemotherapeutics, angiogenesis targeted therapies, immune targeted agents (including antibodies and cell-based immunotherapies, as well as antibody-drug conjugates), and radiation therapy.

[0560] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously in separate doses. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered sequentially in any order in separate doses.

[0561] In some embodiments, the other MALT1 targeted therapeutic agent is another protease inhibitor that exhibits MALT1 inhibitory activity. In some embodiments, the other MALT1 targeted therapeutic agent is selective for MALT1 protease. Exemplary MALT1 protease inhibitors may exhibit an inhibitory activity (IC) 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 against MALT1 protease. 50 ), as measured in an assay described herein. In some embodiments, a MALT1 protease inhibitor can exhibit an inhibitory activity (IC) of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM against MALT1 protease. 50 ), as measured in an assay as provided herein.

[0562] Non-limiting examples of protease targeted therapeutics (eg, a first MALT1 inhibitor or a second MALT1 inhibitor) include JNJ-67856633 and CTX-177 (ONO-7018).

[0563] Non-limiting examples of multikinase inhibitors include icotinib (9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile); umavatinib (MP470, HPK56) (N-(1,3-benzodioxan-5-ylmethyl)-4-([1]benzofurano[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide); apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl)phenyl-2-(4-pyridylmethyl)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-dihydrobenzimidazol-2-ylidene]quinolin-2-one); famitinib (5-[2-(diethylamino)ethyl]-2-[(Z) -(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one); Filtratinib (SAR302503, TG101348) (N-(2-methyl-2-propyl)-3-{[5-methyl-2-({4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4-pyrimidinyl]amino}benzenesulfonamide); Foretinib (XL880, EXEL-2880, GSK13 63089, 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-dicarboxamide) methyl-4-[(phosphonooxy)methyl]-, sodium salt (1:2)); ilosatinib (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-methoxycarbonyl-2-indolone); Ponatinib (AP24534) (3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl) phenyl] benzamide); PP242 (torkinib) (2-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indol-5-ol); quizartinib (1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]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, agorafenib)(1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazol-3-yl)urea); simasanib( SU5416)((3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one); Strutinib (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-chlorophenyl)-4- AD-57 (N-[4-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-N'-[3-(trifluoromethyl)phenyl]-urea); AD-80 (1-[4-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea);AD-81 (1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea); ALW-II-41-27 (N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide); BPR1K871 (1-(3-chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)propoxy)quinazolin-4-yl)amino)ethyl)thiazol-2-yl)urea); CLM3 (1-phenylethyl-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)carbamoyl d]pyrimidin-4-amine); EBI-907 (N-(2-chloro-3-(1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]isoquinolin-7-yl)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide); NVP-AST-487 (N-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-N'-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]-urea); NVP-BBT594 (BBT594) (5-((6-acetamidopyrimidin-4-yl)oxy)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide); PD17 3955 (6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylthioanilino)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-pyrazol-4-yl)-1Hbenzo[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)methylene]-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]-phenylacetonitrile); SPP86 (1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); SU4984 (4-[4-[(E)-(2-oxo-1H-indol-3-ylidene)methyl]phenyl]piperazine-1-carboxaldehyde); Sunitinib (SU11248) (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide);TG101209 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide); 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-imidazole-2-yl)amino)- )methylene)indolin-2-one); BPR1J373 (5-phenylthiazol-2-ylamine-pyrimidine 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 (cyclophenyl hydrochloride zalin); XMD15-44 (N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide (generated from 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)pyrimidin-2-yl)cyclohexane-1-carboxamide); BLU6864; DS-5010; GSK3179106; GSK3352589; NMS-E668; TAS0286 / HM05; TPX0046; and N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide. ;

[0564] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeted therapeutics include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurinib, estaurtinib), nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, l-((3S,4R)-4-(3-fluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazol-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, 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'-bipyridine]-2'-yl)piperidin-4-ol.

[0565] 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.

[0566] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, the EGFR inhibitor can include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix) and vandetanib (Caprelsa).

[0567] In some embodiments, the additional therapeutic agent is a Ras-Raf-MEK-ERK pathway inhibitor (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib), a PI3K-Akt-mTOR-S6K pathway inhibitor (e.g., everolimus, rapamycin, perifosine, temsirolimus), and other kinase inhibitors such as baricitinib. citinib), brigatinib, capmatinib, danusertib, ibrutinib, milciclib, quercetin, regorafenib, ruxolitinib, semasanib, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736 ((R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106, RXDX108, and TG101209 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide).

[0568] In some embodiments, the additional therapeutic agent is a BTK inhibitor. Non-limiting examples of BTK inhibitors include ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib, and NX-2127.

[0569] In some embodiments, the additional therapeutic agent is a Bcl-2 inhibitor. Non-limiting examples of Bcl-2 inhibitors include venetoclax, navitoclax, oblimersen, obetok, and AT-101.

[0570] 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.

[0571] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include everolimus, temsirolimus, and ridaforolimus.

[0572] In some embodiments, the additional therapeutic agent is an HDAC inhibitor. Non-limiting examples of HDAC inhibitors include vorinostat, romidepsin, belinostat, chidamide, panobinostat, CXD101, and abexinostat.

[0573] 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.

[0574] In some embodiments, the additional therapeutic agent is a cytotoxic chemotherapy. In some embodiments, the cytotoxic chemotherapy comprises arsenic trioxide, bleomycin, bendamustine, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, C), oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

[0575] In some embodiments, the additional therapeutic agent is an angiogenesis-targeted therapeutic agent. Non-limiting examples of therapies targeting angiogenesis include lenalidomide, enzastaurine, aflibercept, and bevacizumab.

[0576] In some embodiments, the additional therapy or therapeutic agent may comprise a histidyl-tRNA synthetase (HRS) polypeptide or an expressible nucleotide encoding a HRS polypeptide.

[0577] The term "immunotherapy" refers to an agent that modulates the immune system. In some embodiments, immunotherapy can increase the expression and / or activity of an immune system modulator. In some embodiments, immunotherapy can reduce the expression and / or activity of an immune system modulator. In some embodiments, immunotherapy can recruit and / or enhance the activity of immune cells.

[0578] In some embodiments, the immunotherapy is a cellular immunotherapy (e.g., adoptive T cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge TM;Plosker (2011) Drugs 71 (1): 101-108). In some embodiments, 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.

[0579] 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 TM , ), trastuzumab Avelumab Rituximab (MabThera TM , ), Rituxan Hycela TM ), edrecolomab (Panorex), daratumuab Olaratumab (Lartruvo TM ), ofatumumab Alemtuzumab Cetuximab Oregovomab, pembrolizumab Dinutiximab Obinutuzumab Tremelimumab (CP-675, 206), ramucirumab Urituximab (TG-1101), panitumumab Elotuzumab (EmplicitiTM ), avelumab Nexituzumab (Portrazza TM ), cirmtuzumab (UC-961), ibritumomab Isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab Ficlatuzumab (AV-299), denosumab lenzilumab, avelumab, spartalizumab, pembrolizumab, utomilumab, urituximab, blinatumomab, ganitumab, urelumab, pidilizumab, amatuximab, mosunetuzumab (BTCT4465A), CD20-TCB, RO7082859, XmAb13676, glofitamab, CD20-TDB, odronextamab (REGN1979), IGM-2323, BTCT4465A, AMG-562, or TTI-621.

[0580] In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg TM ), inotuzumab ozogamicin Brentuximab vedotin ado-trastuzumab emtansine (TDM-1; ), mirvetuximab soravtansine (IMGN853), anetumabravtansine, polatuzumab vedotine, loncastuximabtesirine (ADCT-402), camidanlumab tesirine (ADCT-301), or naratuximab emtansine (Debio 1562).

[0581] In some embodiments, the immunotherapy comprises blinatumomab (AMG103; ) or midostaurin (Rydapt).

[0582] In some embodiments, the immunotherapy comprises a toxin. In some embodiments, the immunotherapy is denileukin diftitox.

[0583] In some embodiments, the immunotherapy is a 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 therapy 15 (IL-15) therapy, interleukin 7 (IL-7) therapy, or erythropoietin alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin. In some embodiments, IFNα therapy is In some embodiments, the G-CSF therapy is filgrastim

[0584] 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. Or tremelimumab (CP-675, 206). In some embodiments, the PD-1 inhibitor is pembrolizumab Nivolumab In some embodiments, the PD-L1 inhibitor is atezolizumab Avelumab or durvalumab (Imfinzi TM ).

[0585] 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).

[0586] In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG) therapy.

[0587] In some embodiments, the immunotherapy is an oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC; ).

[0588] 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 or In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is Recombivax or GI-13020 In some embodiments, the cancer vaccine is or In some embodiments, the cancer vaccine is GVAX, ADXS11-001, ALVAC-CEA, CimaVax-EGF, lapuleucel-T (APC8024; Neuvenge TM ), GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlisimut-L(Hepko-V5), SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, DPX-Survivac or viagenpumatucel-L(HS-110).

[0589] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax TM ), IMA901 or SurVaxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic personal neoantigen vaccine (see, 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 lactoglobulin-A DNA vaccine (see, e.g., Kim et al. (2016) OncoImmunology 5 (2): e1069940).

[0590] In some embodiments, the immune targeting agent is selected from aldesleukin, interferon alpha-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

[0591] In some embodiments, the additional therapy is radiation therapy. Non-limiting examples of radiation therapy include radioiodine therapy, external beam radiation, and radium 223 therapy.

[0592] In some embodiments, the additional therapeutic agent is GSK-3368715, PF-06821497, ceralasertib; AZD6738, BI-894999, MAK-683, AZD-6738, taminadenant, TAK-981, MIK-665, or danvatirsen.

[0593] Additional kinase inhibitors include those described in, for example, U.S. Patent Nos. 7,514,446; 7,863,289; 8,026,247; 8,501,756; 8,552,002; 8,815,901; 8,912,204; 9,260,437; 9,273,051; U.S. Publication No. US2015 / 0018336; International Publication Nos. WO 2007 / 002325; WO 2007 / 002433; WO 2008 / 080001; WO 2008 / 079906; WO 2008 / 079903; WO 2008 / 079909; WO 2008 / 080015; WO 2009 / 007748; WO 2009 / 012283;WO 2009 / 143018;WO 2009 / 143024;WO 2009 / 014637;2009 / 152083;WO 2010 / 111527;WO 2012 / 109075;WO 2014 / 194127;WO 2015 / 112806; WO 2007 / 110344; WO 2009 / 071480; WO 2009 / 118411; WO 2010 / 031816; WO 2010 / 145998; WO 2011 / 092120; WO 2012 / 101032; WO 2012 / 139930;WO 2012 / 143248; WO 2012 / 152763; WO 2013 / 014039; WO 2013 / 102059; WO 2013 / 050448; WO 2013 / 050446; WO 2014 / 019908; WO 2014 / 072220; WO 2014 / 184069; WO 2016 / 075224; WO 2016 / 081450; WO 2016 / 022569; WO 2016 / 011141; WO 2016 / 011144; WO 2016 / 011147; WO 2015 / 191667; WO 2012 / 101029;WO 2014 / 011900, each of which is hereby incorporated by reference in its entirety.

[0594] In some embodiments, the subject has been previously administered one or more standard of care therapies for lymphoma. In some embodiments, the previously administered standard of care therapies are vetin-pollotuzumab, selinexor, akilencel (Yescarta), tesalencel (Kymriah), a combination of bendamustine with rituximab and vetin-pollotuzumab, a combination of tancitumomab with lenalidomide, or a combination of rituximab with human hyaluronidase (Rituxan Hycela).

[0595] In some embodiments, the subject is receiving standard of care therapy for lymphoma at the same time. In some embodiments, the standard of care therapy is a combination of vetin-pollotuzumab, selinexor, akilencel (Yescarta), tesalencel (Kymriah), bendamustine with rituximab and vetin-pollotuzumab, a combination of tancitumomab and lenalidomide, or a combination of rituximab and human hyaluronidase (Rituxan Hycela).

[0596] Pharmaceutical composition

[0597] When used as a drug, the compound of formula (I) (including its pharmaceutically acceptable salt) can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical field, and can be administered by a variety of routes, depending on whether local treatment or systemic treatment is desired and depending on the site to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and mucosal administration, including intranasal, vaginal and rectal delivery), pulmonary administration (e.g., by inhalation or insufflation of powder or aerosol, including by a nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration may include a dosage form formulated for once a day or twice a day (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial administration, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be performed, for example, by a continuous infusion 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.

[0598] Also provided herein is a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and 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 oral administration. When preparing the composition provided herein, the active ingredient is usually mixed with an excipient, diluted with an excipient or encapsulated in such a carrier, and the carrier is in the form of, for example, a capsule, a medicine bag, paper or other container. When the excipient is used as a diluent, it can be a solid, semi-solid or liquid material, and the material can act as a medium, carrier or medium for the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, medicine bags, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or capsule.

[0599] Further provided herein is a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by fully mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional drug mixing techniques. Depending on the desired route of administration (e.g., oral, parenteral), the carrier can take various forms. In certain embodiments, the composition is a solid oral composition.

[0600] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Society.

[0601] Methods of formulating pharmaceutical compositions have been described in many publications, such as Pharmaceutical Dosage Forms: Tablets, 2nd Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0602] When preparing a composition in oral dosage form, any conventional pharmaceutical medium can be used. Therefore, for liquid oral preparations (such as suspensions, elixirs and solutions), suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, colorants, etc.; for solid oral preparations (such as powders, capsules and tablets), suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants, etc. Suitable binders include but are not limited to starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or sodium oleate), sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include but are not limited to starch, methylcellulose, agar, bentonite, xanthan gum, etc. Solid oral preparations can also be coated or enteric-coated with substances such as sugar to adjust the main site of absorption. For parenteral administration, the carrier will generally consist of sterile water, and other ingredients may be added to increase solubility or preservation. Aqueous carriers and appropriate additives may also be used to prepare injectable suspensions or solutions. The pharmaceutical compositions herein will contain an amount of active ingredient necessary to deliver an effective dose as described herein in each dosage unit (e.g., tablets, capsules, powders, injections, teaspoons, etc.).

[0603] Compositions including compounds of formula (I) or pharmaceutically acceptable salts thereof can be formulated into unit dosage forms, each dose containing from about 5 to about 1,000 mg (1 g) of active ingredient, more typically from about 100 mg to about 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other subjects, each unit containing a predetermined amount of active material (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.

[0604] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of active ingredient. Those of ordinary skill in the art will appreciate that this embodies a compound or composition containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of active ingredient.

[0605] In certain embodiments, provided herein are compositions containing about 50mg to about 500mg of active ingredient. It will be appreciated by those of ordinary skill in the art that this embodies a compound or composition containing about 50mg to about 100mg, about 100mg to about 150mg, about 150mg to about 200mg, about 200mg to about 250mg, about 250mg to about 300mg, about 350mg to about 400mg or about 450mg to about 500mg of active ingredient. In certain embodiments, provided herein are compositions containing about 10mg, about 20mg, about 80mg or about 160mg of active ingredient.

[0606] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies a compound or composition containing from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1,000 mg of active ingredient.

[0607] The daily dose of formula (I) compound or its pharmaceutically acceptable salt can change in a wide range of 1.0 to 10,000mg or higher per adult per day or in any range thereof. For oral administration, the composition is preferably provided in tablet form, the tablet 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 ingredients, for symptomatic adjustment of the dosage of the subject to be treated. The medicine of effective amount is usually provided at a dosage level of about 0.1mg / kg to about 1000mg / kg body weight (or any range therein) per day. Preferably, the scope is about 0.5 to about 500mg / kg body weight per day, or any range therein. More preferably, the scope is about 1.0 to about 250mg / kg body weight per day, or any range therein. More preferably, the scope is about 0.1 to about 100 mg / kg body weight per day, or any range therein. In an example, the scope can be about 0.1 to about 50.0 mg / kg body weight per day, or any amount or range therein. In another example, the scope can be about 0.1 to about 15.0 mg / kg body weight per day, or any range therein. In another example, the scope can be about 0.5 to about 7.5 mg / kg body weight per day, or any range therein. The pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered according to a regimen of 1 to 4 times per day or with a single daily dose.

[0608] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. The optimal dose to be administered can be easily determined by one skilled in the art. Therefore, it should be understood that the amount of compound actually administered will generally be determined by the physician and will vary according to the relevant circumstances, including the mode of administration, the compound actually administered, the strength of the preparation, the condition to be treated, and the progression of the disease condition. In addition, factors associated with the specific subject being treated, including subject response, age, weight, diet, time of administration, and severity of the subject's symptoms, will result in the need to adjust the dosage.

[0609] In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 20 mg / kg, from about 5 mg / kg to about 50 mg / kg, from about 10 mg / kg to about 40 mg / kg, from about 15 mg / kg to about 45 mg / kg, from about 20 mg / kg to about 60 mg / kg, or from 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.

[0610] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0611] Those skilled in the art will further recognize that human clinical trials, including first-in-human trials, dose-ranging trials, and efficacy trials, in healthy subjects and / or subjects suffering from a given condition can be accomplished according to methods known in the clinical and medical arts.

[0612] Provided herein are pharmaceutical kits useful, for example, for treating MALT1-related diseases or conditions (such as cancer), comprising one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. As will be apparent to those skilled in the art, such kits may further comprise one or more of the various conventional pharmaceutical kit components, such as a container with one or more pharmaceutically acceptable carriers, additional containers, etc., if desired. Instructions (as an insert or as a label) indicating the amount of the components to be administered, instructions for administration, and / or instructions for mixing the components may also be included in the kit.

[0613] Other embodiments

[0614] Example 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0615]

[0616] in:

[0617] Each is a single bond or a double bond;

[0618] Q is –CH 2 -, O or NH;

[0619] X is N or C;

[0620] Y is N or C;

[0621] Z is N or CR 6 ;

[0622] When one of X and Y is N, the other of X and Y is C;

[0623] n is 1, 2 or 3;

[0624] R X is hydrogen or halogen;

[0625] R 1 is hydrogen, halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR A R B , or C1-C3 alkyl optionally substituted by 1-3 substituents selected from hydroxyl and C1-C3 alkoxy;

[0626] R 2 is hydrogen, halogen, amino or C1-C3 alkyl;

[0627] Each R 3 are independently deuterium, halogen, hydroxy, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 haloalkyl;

[0628] m is 0, 1, 2 or 3;

[0629] R 4 is a 5- to 10-membered heteroaryl group optionally substituted with one to three substituents, each of which is independently selected from R 7 ;

[0630] R 5 is phenyl or a 5- to 9-membered heteroaryl group, wherein each R 5 The group is optionally composed of 1-3 independently selected R 8 Substituents are substituted;

[0631] R 6 is hydrogen, halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR C R D and C1-C3 alkyl;

[0632] Each R7 independently selected from halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, oxetanyl, -NR C R D , a group consisting of C1-C3 alkyl and C3-C7 cycloalkyl;

[0633] Each R 8 Independently selected from halogen; cyano; amino; -N=(S=O)(C1-C3 alkyl) 2 ; -S(=O) p (C1-C3 alkyl); -(C=O)NR E R F C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted by hydroxy; C1-C3 haloalkoxy; 5- to 6-membered heteroaryl optionally substituted by halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4- to 6-membered heterocyclyl or optionally substituted by hydroxy or -NR E R F Substituted C1-C3 alkyl; C1-C4 alkyl, which is optionally substituted with hydroxyl, -NR E R F or C1-C3 alkoxy substituted; 3 to 8 membered heterocyclic group; and C3-C6 cycloalkoxy;

[0634] p is 1 or 2; and

[0635] 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 Together with the nitrogen atom to which they are attached they are combined to form a 4 to 6 membered heterocyclic group optionally substituted by 1-2 halogens.

[0636] Embodiment 2. The compound according to embodiment 1, wherein X is N and Y is C.

[0637] Embodiment 3. The compound according to embodiment 1 or 2, wherein Z is N.

[0638] Embodiment 4. A compound according to any one of embodiments 1 to 3, wherein R X For hydrogen.

[0639] Embodiment 5. A compound according to any one of embodiments 1 to 4, wherein Q is -CH 2 -.

[0640] Embodiment 6. A compound according to any one of embodiments 1 to 5, wherein R 1 For hydrogen.

[0641] Embodiment 7. A compound according to any one of embodiments 1 to 5, wherein R 1 It is a halogen.

[0642] Embodiment 8. A compound according to any one of embodiments 1 to 7, wherein R 2 For hydrogen.

[0643] Embodiment 9. A compound according to any one of embodiments 1 to 7, wherein R 2 It is a halogen.

[0644] Embodiment 10. The compound according to any one of embodiments 1 to 9, wherein n is 1.

[0645] Embodiment 11. A compound according to any one of embodiments 1 to 10, wherein m is 1.

[0646] Embodiment 12. A compound according to any one of embodiments 1 to 11, wherein each R 3 are independently deuterium, halogen, hydroxy, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy.

[0647] Embodiment 13. A compound according to any one of embodiments 1 to 12, wherein m is 1, and R 3 is methyl or trifluoromethyl.

[0648] Embodiment 14. A compound according to any one of embodiments 1 to 13, wherein R 4 is optionally composed of one to three independently selected 7 A 5-membered or 6-membered heteroaryl group substituted with a substituent.

[0649] Embodiment 15. A compound according to any one of embodiments 1 to 13, wherein R 4 is optionally composed of one to three independently selected 7 A 6-membered heteroaryl group substituted with a substituent.

[0650] Embodiment 16. A compound according to any one of embodiments 1 to 13, wherein R 4 is optionally composed of one to three independently selected 7 A 5-membered heteroaryl group substituted with a substituent.

[0651] Embodiment 17. A compound according to any one of embodiments 1 to 13, wherein R 4 is optionally composed of one to three independently selected 7 4H-pyrazolyl, 3H-pyrazolyl or thiazolyl substituted with a substituent.

[0652] Embodiment 18. A compound according to any one of embodiments 1 to 13, wherein R 4 For unsubstituted.

[0653] Embodiment 19. A compound according to any one of embodiments 1 to 13, wherein each R 7 Independently selected from the group consisting of C1-C3 haloalkyl, C1-C3 alkyl and cycloalkyl.

[0654] Embodiment 20. A compound according to any one of embodiments 1 to 19, wherein R 5 is optionally 1-3 independently selected R 8 Substituted 5- to 9-membered heteroaryl.

[0655] Embodiment 21. A compound according to any one of embodiments 1 to 19, wherein R 5 is optionally 1-3 independently selected R 8 Substituted 5- to 6-membered heteroaryl.

[0656] Embodiment 22. A compound according to any one of embodiments 1 to 21, wherein R 5 is optionally 1-3 independently selected R 8 Substituted 3-pyridyl or 4-pyridyl.

[0657] Embodiment 23. A compound according to any one of embodiments 1 to 21, wherein R 8 At least one of them is a halogen.

[0658] Embodiment 24. A compound according to any one of embodiments 1 to 21, wherein R 8 At least one of them is a 5- to 6-membered heteroaryl group optionally substituted by halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, optionally substituted by hydroxy or -NR E R F Substituted C1-C3 alkyl, amino or C1-C3 haloalkyl.

[0659] Embodiment 25. A compound according to any one of embodiments 1 to 21, wherein R 8At least one of them is a 5-membered heteroaryl group optionally substituted by halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, optionally substituted by hydroxyl or -NR E R F Substituted C1-C3 alkyl, amino or C1-C3 haloalkyl.

[0660] Embodiment 26. A compound according to any one of Embodiments 1 to 25, which is a compound according to formula (Ib) or a pharmaceutically acceptable salt thereof

[0661]

[0662] Embodiment 27. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.

[0663] Embodiment 28. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 27.

[0664] Embodiment 29. The method according to embodiment 28, wherein the cancer is a MALT1-related cancer.

[0665] Embodiment 30. The method of embodiment 28 or 29, wherein the cancer is lymphoma.

[0666] Embodiment 31. The method according to embodiment 30, wherein the lymphoma is non-Hodgkin lymphoma, DLBCL, refractory DLBCL, (ABC) subtype of DLBCL, mantle cell lymphoma (MCL) or marginal zone lymphoma (MZL).

[0667] Embodiment 32. The method of embodiment 28 or 29, wherein the cancer is leukemia.

[0668] Embodiment 33. The method according to embodiment 32, wherein the leukemia is chronic lymphocytic leukemia (CLL).

[0669] Embodiment 34. The method of Embodiment 28 or 29, wherein the cancer is a solid tumor.

[0670] Embodiment 35. A method for treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 27.

[0671] Embodiment 36. The method of embodiment 35, wherein the autoimmune disorder is chronic graft-versus-host disease.

[0672] Embodiment 37. The method of any one of Embodiments 30 to 36, further comprising administering an additional therapy or therapeutic agent to the subject.

[0673] Examples

[0674] Materials and Methods

[0675] The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes.

[0676] The reaction for preparing the compound provided herein can be carried out in a suitable solvent, and the suitable solvent can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials (reactants), intermediates or products at a temperature (e.g., a range from the freezing temperature of the solvent to the boiling temperature of the solvent) for the reaction. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on specific reactions steps, the suitable solvent for a specific reaction step can be selected by a technician.

[0677] The preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. One skilled in the art can readily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemistry of protecting groups can be found in, for example, Protecting Group Chemistry, 1st edition, Oxford University Press, 2000; March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, Wiley-Interscience Publication, 2001; and Peturssion, S. et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 74 (11), 1297 (1997).

[0678] Reactions sensitive to moisture or air were carried out under nitrogen or argon using anhydrous solvents and reagents. The progress of the reactions was determined by analytical thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), typically performed with Sanpont pre-coated TLC plates, silica gel GF-254, layer thickness 0.25 mm.

[0679] Typically, the analytical LC-MS system used consists of a Shimadzu LCMS-2020, electrospray ionization with positive ion detection mode, equipped with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS2020MS detector. The chromatographic column is typically HALO a C18 30*5.0 mm, 2.7 μm. Mobile phase A is water containing 0.05% TFA, and mobile phase B is acetonitrile containing 0.05% TFA. The gradient is from 5% mobile phase B to 100% in 2.0 min, held for 0.7 min, then returned to 5% mobile phase B in 0.05 min, and held for 0.25 min. The column oven (CTO-20AC) is operated at a temperature of 40.0°C. The flow rate is 1.5 mL / min, and the injection volume is 1 μl. PDA (SPD-M20A) detection range 190-400nm. MS detector, which is equipped with electrospray ionization as ionizable source; acquisition mode: scanning; nebulizing gas flow: 1.5L / min; drying gas flow: 15L / min; detector voltage: tuning voltage ±0.2kv; DL temperature: 250℃; heating block temperature: 250℃; scanning range: 90.00-900.00m / z. ELSD (Alltech 3300) detector parameters: drift tube temperature: 60℃±5℃; N 2 Flow rate: 1.8 ± 0.2 L / min. Mobile phase gradients were optimized for individual compounds.

[0680] The GC-MS system was usually 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 sec; scan speed: 2000; start m / z: 50.00; end m / z: 550.00; ion source temperature: 200.00 °C; interface temperature: 250.00 °C; solvent cut time: 2.00 min.

[0681] Preparative HPLC purification is usually carried out using a Waters Auto purification system (2545-2767) equipped with a 2489UV detector. The column is a Waters C18, 19x150 mm, 5 μm. The mobile phase consists of a mixture of acetonitrile (5-95%) in water containing 0.1% FA. The flow rate is maintained at 25 mL / min, the injection volume is 1200 μL, and the UV detector uses two channels at 254 nm and 220 nm. The mobile phase gradient is optimized for individual compounds.

[0682] Chiral analytical chromatography was performed on one of Chiralpak AS, AD, Chiralcel OD, OJ Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.); (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Registechnologies, Inc.); CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) with different column sizes (50x4.6 mm, 100x4.6 mm, 150x4.6 mm, 250x4.6 mm, 50x3.0 mm, 100x3.0 mm) with the recorded percentages of ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as the isocratic solvent system.

[0683] Reactions using microwave irradiation are typically performed using an initiator manufactured by Biotage. The solution is concentrated under reduced pressure on a rotary evaporator. Flash column chromatography is typically performed using a Biotage flash chromatography apparatus (Dyax Corp.) on silica gel (40-60 μM, Unless otherwise stated, 1 HNMR spectroscopy in DMSO-d 6 Chemical shifts are reported in parts per million (ppm). 6 Tetramethylsilane (TMS) was used as an internal reference in the solution and in the CD 3 The residual CH 3OH peak or TMS was used as internal reference. Coupling constants (J) were reported in Hertz (Hz). Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA or Chiralcel OJ columns (250 x 4.6 mm) (Daicel Chemical Industries, Ltd.) with the noted percentages of ethanol / hexane (% Et / Hex) or isopropanol / heptane (% IPA / Hep) as isocratic solvent systems. Chiral preparative chromatography was performed on one of the following: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.); (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc.); CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) with different column sizes (250x20mm, 250x30mm, 250x50mm), wherein the required isocratic solvent system was determined on the chiral analytical chromatography.

[0684] Abbreviations used herein include: -C(O)CH 3 (Ac); Acetic acid (AcOH); -OC(O)CH 3 (OAc); aqueous (aq); Cbz (benzyloxycarbonyl); N,N-diisopropylethylamine (DIEA); N; N-dimethylformamide (DMF); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); EtOAc (EtOAc); diethyl ether (ether or Et 2 O); PE (PE); gram (g); hour (h or hr); 2-propanol (IPA); mass spectrometry (ms or MS); microliter (μL); milligram (mg); milliliter (mL); millimole (mmol); minute (min); methyl tert-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); tert-butyloxycarbonyl (Boc or BOC); diethylaminosulfur trifluoride (DAST); DCM (DCM); dimethylacetamide (DMA; DMAC); dimethyl sulfoxide (DMSO); 1,3-bis(diphenylphosphino)propane (DPPP); acetic acid (HOAc); 3-chloroperbenzoic acid (m-CPBA); methyl (Me); methanol (MeOH); N,N,N',N'-tetramethylchloroformamide hexafluorophosphate (TCFH); N-methylimidazole (NMI); N-bromosuccinamide (NBS); thin layer chromatography (TLC).

[0685] The following are representative procedures for preparing compounds used in the following examples, or which may be substituted for compounds used in the following examples that may not be commercially available.

[0686] Method A1

[0687]

[0688] Examples 1 and 2: (6S,8R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6R,8S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0689] Example 3: (cis)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0690] The relative and absolute stereochemistry of each instance was not determined.

[0691] Step 1: 2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-ol

[0692] 4-iodo-1-methyl-pyrazole (48 g, 231.8 mmol) was added to Et 2O (2L) in a solution of n-butyl lithium (14.8g, 231.8mmol, 2.5M in hexane). Under nitrogen, the reaction mixture was stirred at -78 ° C for 30min. To the above mixture, 6-oxabicyclo [3.1.0] hexane (15g, 178.3mmol) and boron trifluoride ether (32.9g, 231.8mmol) were added. The reaction mixture was stirred at -78 ° C for 30min under nitrogen. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (500mL). The resulting mixture was extracted with ethyl acetate (3x 500mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with DCM / MeOH (10: 1) to obtain the title compound (8g, 21% yield) as a yellow oil. 1H NMR (400MHz, chloroform-d) δ7.37 (s, 1H), 7.24 (s, 1H), 3.99-4.07 (m, 1H), 3.87 (s, 3H), 2.79-2.88 (m, 1H), 2.00-2.21 (m, 2H), 1.56-1.92 (m, 4H). LC-MS: m / z 167 [M+H] + .

[0693] Step 2: 2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one

[0694] To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-ol (5 g, 30 mmol) in ethyl acetate (250 mL) was added IBX (27.4 g, 45.1 mmol, 46% purity). The resulting mixture was stirred at 80 °C for 16 h. The mixture was cooled to 25 °C. The reaction mixture was heated to 40 °C with saturated NaHSO 3 The reaction was quenched with aqueous solution (200 mL). The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with saturated sodium bicarbonate aqueous solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (1.6 g, 32% yield) as a yellow oil. LC-MS: m / z 165 [M+H] + .

[0695] Step 3: 2-Methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one (A1-3)

[0696] At 25 ° C, 2- (1-methyl -1H- pyrazol-4-yl) cyclopentane -1-one (3.9 g, 23.7 mmol) in t-BuOH (60 mL) was added in batches of potassium 2-methylpropan-2-ol (2.9 g, 26.1 mmol). The resulting mixture was stirred at 40 ° C for 0.5 h. Iodomethane (3.4 g, 23.7 mmol) was added dropwise at 40 ° C, and the resulting mixture was stirred at 40 ° C for 2 h. The reaction was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with THF / PE (1: 1) to obtain the title compound (A1-3, 3.9 g, 82% yield) as a yellow oil. LC-MS: m / z 179 [M + H] + .

[0697] Step 4: 5-((Dimethylamino)methylene)-2-methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentan-1-one (A1-4)

[0698] A solution of 2-methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentane-1-one (5.5 g, 30.8 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (70 mL) was stirred at 100° C. for 24 h. The mixture was allowed to cool to 25° C. and then concentrated under reduced pressure to give the crude title compound (A1-4, 5.5 g) as a red oil. LC-MS: m / z 234 [M+H] + .

[0699] Step 5: 2-Fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine

[0700] 3-Fluoro-1H-pyrazine-5-amine (1g, 10.3mmol) and AcOH (2mL) were added to a stirred solution of 5-((dimethylamino)methylene)-2-methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentane-1-one (2g, 8.5mmol) in toluene (20mL). The resulting mixture was stirred at 110 ° C for 16h. The mixture was allowed to cool to 25 ° C. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100mL). The resulting solution was extracted with ethyl acetate (3x 100mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with EtOAc / PE (1: 1) to obtain the title compound (2g, 60% yield) as a light yellow solid. 1H NMR (300MHz, DMSO-d6 )δ8.60(s,1H),7.63(s,1H),7.39(s,1H),6.47(d,J=5.1Hz,1H),3.75(s,3 H),2.97-3.21(m,2H),2.39-2.57(m,1H),2.28-2.32(m,1H),1.88(s,3H). LC-MS:m / z 272[M+H] + .

[0701] Step 6: 2-Fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile

[0702] To a stirred solution of 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (2 g, 7.4 mmol) in toluene (80 mL) was added (4R)-4-benzyl-2-[1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (641 mg, 1.8 mmol), acetoxycopper (181 mg, 1.5 mmol), N-fluorobenzenesulfonimide (3.4 g, 11.1 mmol) and TMSCN (3.7 g, 36.9 mmol). The reaction was stirred at 25 °C for 16 h under nitrogen. The solvent was removed under reduced pressure and the residue was applied to a silica gel column and eluted with EtOAc / PE (1:1) to give the crude product. The crude product was further purified by preparative HPLC to give the title compound as a yellow oil (100 mg, 4% yield). LC-MS (ES, m / z): 297 [M+H] + .

[0703] Step 7: 2-Fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (A1-7)

[0704] A solution of 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6carbonitrile (130 mg, 0.44 mmol) in AcOH (2 mL) and HCl (12 M, 2 mL) was stirred at 100 ° C for 2 h. The mixture was allowed to cool to 25 ° C. The mixture was concentrated under reduced pressure and the residue was diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (A1-7, 130 mg, 90% yield) as a yellow oil. LC-MS: m / z 316 [M+H] + .

[0705] Step 8: Example 3 and trans-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0706] To a stirred solution of 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (165mg, 523μmol) and 5-chloro-6-(2H-1,2,3-triazole-2-yl)pyridine-3-amine (123mg, 628μmol) in ACN (10mL), TCFH (587mg, 2.1mmol) and NMI (215mg, 2.6mmol) were added. The reaction mixture was stirred at 25°C for 1h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100mL). The resulting mixture was extracted with ethyl acetate (3x100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with DCM / MeOH (10:1) to obtain a crude product. The crude product was further purified by preparative HPLC to give Example 3 (cis racemic mixture, 80 mg, 29% yield) as a white solid and a racemic mixture of trans-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide (120 mg, 44% yield) as a white solid.

[0707] Example 3: 1 H NMR (300 MHz, DMSO-d 6)δ11.10(s,1H),8.73(d,J=2.4Hz,1H),8.71(s,1H),8.57(d,J=2.4Hz,1H),8.18(s,2H),7.62(s,1H) ,7.35(s,1H),6.55(d,J=5.1Hz,1H),4.51-4.56(m,1H),3.76(s,3H),2.68-2.84(m,2H),1.88(s,3H). LC-MS:m / z 493[M+H] + .

[0708] Step 9: Separation of enantiomers to obtain Example 1 and Example 2

[0709] 120 mg of trans-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART Cellulose-SA, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; isocratic: 50% B in 25 min; wavelength: 220 / 254 nm; RT1 (min): 10.008; RT2 (min): 19.257; sample solvent: EtOH--HPLC; injection volume: 1.5 mL; number of runs: 3). The first eluting isomer was concentrated and lyophilized to give Example 1 (40.7 mg, 33% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 2 (33.9 mg, 28% yield) as a white solid.

[0710] Example 1: 1 H NMR (300 MHz, DMSO-d 6 )δ11.07(s,1H),8.73(d,J=2.4Hz,1H),8.67(s,1H),8.61(d,J=2.4Hz,1H),8.18(s,2H),7.65(s,1H),7.43(s,1H ), 6.58 (d, J = 5.1Hz, 1H), 4.54 (t, J = 8.4Hz, 1H), 3.76 (s, 3H), 2.85-2.98 (m, 1H), 2.50-2.56 (m, 1H), 1.97 (s, 3H). LC-MS:m / z 493[M+H] + .

[0711] Example 2: 1H NMR (300 MHz, DMSO-d 6 )δ11.07(s,1H),8.73(d,J=2.4Hz,1H),8.67(s,1H),8.61(d,J=2.4Hz,1H),8.18(s,2H),7.65(s,1H),7.43(s,1H ), 6.58 (d, J = 5.1Hz, 1H), 4.54 (t, J = 8.4Hz, 1H), 3.76 (s, 3H), 2.85-2.98 (m, 1H), 2.50-2.56 (m, 1H), 1.97 (s, 3H). LC-MS:m / z 493[M+H] + .

[0712] Method A2

[0713]

[0714] Examples 4 and 5: (6R,8S)-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6S,8R)-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0715] Examples 6 and 7: (6R,8R)-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6S,8S)-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0716] The relative and absolute stereochemistry of each instance was not determined.

[0717] Step 1: trans-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and cis-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0718] Analogously to method A1 step 8, but using 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (A1-7, 128 mg, 405.9 μmol) and 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (93 mg, 405.9 μmol), a racemic mixture of the title compound was obtained: the trans isomer as a white solid (65 mg, 30% yield), LC-MS: m / z 527 [M+H] + ; cis isomer as white solid (60 mg, 28% yield), LC-MS: m / z 527 [M+H] + .

[0719] Step 2: Separation of enantiomers to obtain Example 4 and Example 5

[0720] 65 mg of trans-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; isocratic: 50% B in 20 min; wavelength: 220 / 254 nm; RT1 (min): 7.514; RT2 (min): 19.166; sample solvent: EtOH--HPLC; injection volume: 2 mL; number of runs: 2). The first eluting isomer was concentrated and lyophilized to give Example 4 (17 mg, 26% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 5 (24.6 mg, 37% yield) as a white solid.

[0721] Example 4:1 H NMR (300 MHz, DMSO-d 6 )δ:11.21(s,1H),9.02(d,J=2.4Hz,1H),8.83(d,J=2.4Hz,1H),8.69(s,1H),8.20(s,2H),7.65(s,1H),7.42(s, 1H), 6.58 (d, J = 4.8Hz, 1H), 4.53-4.58 (m, 1H), 3.76 (s, 3H), 2.88-2.99 (m, 1H), 2.51-2.58 (m, 1H), 1.97 (s, 3H). LC-MS:m / z 527[M+H] + .

[0722] Example 5: 1 H NMR (300 MHz, DMSO-d 6 )δ:11.21(s,1H),9.02(d,J=2.1Hz,1H),8.83(d,J=2.4Hz,1H),8.69(s,1H),8.20(s,2H),7.65(s,1H),7.43(s, 1H), 6.58 (d, J = 4.8Hz, 1H), 4.53-4.58 (m, 1H), 3.76 (s, 3H), 2.88-2.95 (m, 1H), 2.50-2.58 (m, 1H), 1.97 (s, 3H). LC-MS:m / z 527[M+H] + .

[0723] Step 3: Separation of enantiomers to obtain Example 6 and Example 7

[0724] 60 mg of cis-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; isocratic: 25% B in 13 min; wavelength: 220 / 254 nm; RT1 (min): 8.968; RT2 (min): 11.575; sample solvent: EtOH--HPLC; injection volume: 0.5 mL; number of runs: 8). The first eluting isomer was concentrated and lyophilized to give Example 6 (23 mg, 38% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 7 (24.6 mg, 41% yield) as a white solid.

[0725] Example 6: 1 H NMR (300 MHz, DMSO-d 6 )δ:11.20(s,1H),9.03(d,J=2.1Hz,1H),8.79(d,J=2.4Hz,1H),8.72(s,1H),8.19(s,2H),7.62(s,1H) ,7.35(s,1H),6.55(d,J=4.8Hz,1H),4.54-4.57(m,1H),3.74(s,3H),2.69-2.88(m,2H),1.87(s,3H). LC-MS:m / z 527[M+H] + .

[0726] Example 7: 1 H NMR (300 MHz, DMSO-d 6 )δ:11.21(s,1H),9.03(d,J=2.4Hz,1H),8.79(d,J=2.4Hz,1H),8.72(s,1H),8.19(s,2H),7.62(s,1H) ,7.34(s,1H),6.55(d,J=5.1Hz,1H),4.54-4.57(m,1H),3.75(s,3H),2.69-2.88(m,2H),1.87(s,3H). LC-MS:m / z 527[M+H] + .

[0727] Method A3

[0728]

[0729] Examples 8 and 9: (6S,8R)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6R,8S)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0730] Examples 10 and 11: (6S,8S)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6R,8R)-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0731] The relative and absolute stereochemistry of each instance was not determined.

[0732] Step 1: 2-Chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine

[0733] To a stirred solution of 5-((dimethylamino)methylene)-2-methyl-2-(1-methyl-1H-pyrazol-4-yl)cyclopentane-1-one (A1-4, 2.2 g, 9.43 mmol) in toluene (15 mL) at room temperature, 3-chloro-1H-pyrazole-5-amine (1.3 g, 11.3 mmol) and AcOH (1.5 mL) were added. The resulting mixture was stirred at 110 ° C for 24 h. The mixture was allowed to cool to 25 ° C. The reaction mixture was concentrated under reduced pressure, and the residue was applied to a silica gel column and eluted with EtOAc / PE (10: 1) to obtain 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine (1.5 g, 44% yield) as a light yellow solid. LC-MS: m / z 288[M+H] + .

[0734] Step 2: 2-Chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile

[0735] To a stirred solution of 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (1.1 g, 3.82 mmol) in toluene (40 mL) was added (4R)-4-benzyl-2-[1-[(4R)-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (1.4 g, 3.8 mmol), acetoxycopper (94 mg, 764 μmol), N-fluorobenzenesulfonimide (1.8 g, 5.7 mmol) and TMSCN (1.9 g, 19.1 mmol). The reaction was stirred at 25 ° C for 24 h under nitrogen. The solvent was removed under reduced pressure. The residue was diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with EtOAc / PE (1:1) to give a crude product, which was further purified by HPLC to give the title compound (240 mg, 17% yield) as a yellow oil. LC-MS (ES, m / z): 313 [M+H] + .

[0736] Step 3: 2-Chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (A3-3)

[0737] Analogously to method A1 step 7, but using 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carbonitrile (240 mg, 0.77 mmol), the title compound (A3-3, 235 mg, 94% yield) was obtained as a yellow oil. LC-MS: m / z 332 [M+H] + .

[0738] Step 4: trans-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and cis-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0739] Analogously to Method A1 step 8, but using 2-chloro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (120 mg, 362 μmol) and 5-chloro-6-(triazol-2-yl)pyridin-3-amine (141 mg, 723 μmol) and stirring at 25 °C for 24 h, a racemic mixture of the title compound was obtained: the trans isomer as a white solid (25 mg, 13% yield), LC-MS: m / z 509 [M+H] + ; cis isomer as white solid (15 mg, 8% yield), LC-MS: m / z 509 [M+H] + .

[0740] Step 5: Separation of enantiomers to obtain Example 8 and Example 9

[0741] 25 mg of trans-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: isocratic 50% mobile phase B; wavelength: 220 / 254 nm; RT1 (min): 13.764; RT2 (min): 19.041; sample solvent: EtOH--HPLC; injection volume: 2 mL; number of runs: 2). The second eluting isomer was concentrated and lyophilized to give Example 8 (8.9 mg, 43% yield) as a white solid. The first eluting isomer was concentrated and lyophilized to give Example 9 (8.4 mg, 40% yield) as a white solid.

[0742] Example 8: 1 H NMR (300 MHz, DMSO-d6 )δ11.10(s,1H),8.72(d,J=2.1Hz,1H),8.68(s,1H),8.61(d,J=2.1Hz,1H),8.18(s,2H),7.63(s,1H),7.4 1(s,1H),6.96(s,1H),4.51-4.57(m,1H),3.76(s,3H),2.86-2.93(m,1H),2.50-2.51(m,1H),1.99(s,3H). LC-MS:m / z 509[M+H] + .

[0743] Example 9: 1 H NMR (300 MHz, DMSO-d 6 )δ11.10(s,1H),8.72(d,J=2.1Hz,1H),8.68(s,1H),8.61(d,J=2.1Hz,1H),8.18(s,2H),7.63(s,1H),7.4 1(s,1H),6.96(s,1H),4.50-4.54(m,1H),3.76(s,3H),2.86-2.93(m,1H),2.50-2.51(m,1H),1.99(s,3H). LC-MS:m / z 509[M+H] + .

[0744] Step 6: Separation of enantiomers to obtain Example 10 and Example 11

[0745] 15 mg of cis-2-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: isocratic 50% mobile phase B; wavelength: 220 / 254 nm; RT1 (min): 14.519; RT2 (min): 26.523; sample solvent: EtOH--HPLC; injection volume: 2 mL; number of runs: 2). The first eluting isomer was concentrated and lyophilized to give Example 10 (2.4 mg, 15% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 11 (1.7 mg, 11% yield) as a white solid.

[0746] Example 10: 1H NMR (300 MHz, DMSO-d 6 )δ11.09(s,1H),8.70-8.72(m,2H),8.57(d,J=2.4Hz,1H),8.17(s,2H),7.61(s,1H),7. 34(s,1H),6.94(s,1H),4.51-4.56(m,1H),3.75(s,3H),2.66-2.88(m,2H),1.89(s,3H). LC-MS:m / z 509[M+H] + .

[0747] Example 11: 1 H NMR (300 MHz, DMSO-d 6 )δ11.09(s,1H),8.70-8.72(m,2H),8.57(d,J=2.4Hz,1H),8.17(s,2H),7.61(s,1H),7. 34(s,1H),6.94(s,1H),4.51-4.56(m,1H),3.75(s,3H),2.67-2.88(m,2H),1.89(s,3H). LC-MS:m / z 509[M+H] + .

[0748] Method A4

[0749]

[0750] Examples 12 and 13: (6S,8R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6R,8S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0751] Examples 14 and 15: (6S,8S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6R,8R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0752] The relative and absolute stereochemistry of each instance was not determined.

[0753] Step 1: 2,3-Difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0754] Selectfluor fluorination reagent (2.0 g, 5.63 mmol) in DMF (6 mL) was added to a solution of 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (A1-7, 592 mg, 1.88 mmol) in DCM (18 mL) and MeOH (18 mL). The reaction was stirred at 25 ° C for 16 h under nitrogen. The solvent was concentrated under reduced pressure, and the residue was diluted with water (50 ml). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the title compound (130 mg, 12% yield) as a yellow oil. LC-MS: m / z 334 [M+H] + .

[0755] Step 2: trans-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and cis-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0756] Analogously to Method A1, step 8, but using 2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (124 mg, 372 μmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (109 mg, 557 μmol), a racemic mixture of the title compound was obtained: the trans isomer as a white solid (50 mg, 25% yield), LC-MS: m / z 511 [M+H] + ; cis isomer as white solid (25 mg, 13% yield), LC-MS: m / z 511 [M+H] + .

[0757] Step 3: Separation of enantiomers to obtain Example 12 and Example 13

[0758] 50 mg of trans-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: isocratic 30% mobile phase B; wavelength: 220 / 254 nm; RT1 (min): 9.925; RT2 (min): 16.35; sample solvent: EtOH--HPLC; injection volume: 1 mL; number of runs: 6). The second eluting isomer was concentrated and lyophilized to give Example 12 (22.5 mg, 43% yield) as a white solid. The first eluting isomer was concentrated and lyophilized to give Example 13 (11.6 mg, 23% yield) as a white solid.

[0759] Example 12: 1 H NMR (400 MHz, DMSO-d 6 )δ11.08(s,1H),8.72(d,J=2.4Hz,1H),8.71(s,1H),8.61(d,J=2.4Hz,1H),8.18(s,2H),7.64(s,1H) ,7.42(s,1H),4.53(t,J=8.4Hz,1H),3.74(s,3H),2.87-2.93(m,1H),2.50-2.56(m,1H),1.93(s,3H). LC-MS:m / z 511[M+H] + .

[0760] Example 13: 1 H NMR (400 MHz, DMSO-d 6 )δ11.08(s,1H),8.72(d,J=2.4Hz,1H),8.71(s,1H),8.61(d,J=2.4Hz,1H),8.18(s,2H),7.64(s,1H) ,7.42(s,1H),4.53(t,J=8.4Hz,1H),3.74(s,3H),2.87-2.93(m,1H),2.50-2.56(m,1H),1.93(s,3H). LC-MS:m / z 511[M+H] + .

[0761] Step 4: Separation of enantiomers to obtain Example 14 and Example 15

[0762] 25 mg of cis-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-difluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: isocratic 30% mobile phase B; wavelength: 220 / 254 nm; RT1 (min): 9.465; RT2 (min): 13.025; sample solvent: EtOH--HPLC; injection volume: 1 mL; number of runs: 4). The second eluting isomer was concentrated and lyophilized to give Example 14 (9.8 mg, 38% yield) as a white solid. The first eluting isomer was concentrated and lyophilized to give Example 15 (6.4 mg, 25% yield) as a white solid.

[0763] Example 14: 1 H NMR (400 MHz, DMSO-d 6 )δ11.09(s,1H),8.74(s,1H),8.72(d,J=2.4Hz,1H),8.56(d,J=2.4Hz,1H),8.17(s,2H),7.62(s,1H ),7.34(s,1H),4.52-4.56(m,1H),3.74(s,3H),2.81-2.87(m,1H),2.66-2.71(m,1H),1.86(s,3H). LC-MS:m / z 511[M+H] + .

[0764] Example 15: 1 H NMR (400 MHz, DMSO-d 6 )δ11.08(s,1H),8.74(s,1H),8.72(d,J=2.4Hz,1H),8.56(d,J=2.4Hz,1H),8.17(s,2H),7.62(s,1H ),7.34(s,1H),4.52-4.56(m,1H),3.74(s,3H),2.81-2.87(m,1H),2.66-2.71(m,1H),1.86(s,3H). LC-MS:m / z 511[M+H] + .

[0765] Method A5

[0766]

[0767] Examples 16 and 17: (6S,8R)-3-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6R,8S)-3-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0768] Examples 18 and 19: (6S,8S)-3-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6R,8R)-3-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0769] The relative and absolute stereochemistry of each instance was not determined.

[0770] Step 1: 3-Chloro-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0771] To a solution of 2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (A1-7, 100 mg, 317 μmol) in DMF (10 mL) was added NCS (85 mg, 634 μmol). The reaction was stirred at 60 ° C for 2 h under nitrogen. The reaction was allowed to cool to 25 ° C. The reaction was diluted with water (50 ml), and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to obtain the title compound (100 mg, 81% yield) as a yellow oil. LC-MS: m / z 350 [M+H] + .

[0772] Step 2: trans-3-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide and cis-3-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0773] Analogously to Method A1, step 8, but using 3-chloro-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (130 mg, 372 μmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (110 mg, 556 μmol), a racemic mixture of the title compound was obtained: the trans isomer as a white solid (35 mg, 17% yield), LC-MS: m / z 527 [M+H] + ; cis isomer as white solid (25 mg, 12% yield), LC-MS: m / z 527 [M+H] + .

[0774] Step 3: Separation of enantiomers to obtain Example 16 and Example 17

[0775] 35 mg of trans-3-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: isocratic 40% mobile phase B; wavelength: 220 / 254 nm; RT1 (min): 12.633; RT2 (min): 17.731; sample solvent: EtOH--HPLC; injection volume: 0.5 mL; number of runs: 6). The second eluting isomer was concentrated and lyophilized to give Example 16 (7.1 mg, 19% yield) as a white solid. The first eluting isomer was concentrated and lyophilized to give Example 17 (11.5 mg, 31% yield) as a white solid.

[0776] Example 16: 1 H NMR (400 MHz, DMSO-d 6 )δ11.17(s,1H),8.77(s,1H),8.73(d,J=2.0Hz,1H),8.62(d,J=2.0Hz,1H),8.18(s,2H),7.64(s,1H) ,7.44(s,1H),4.56(t,J=8.4Hz,1H),3.75(s,3H),2.90-2.95(m,1H),2.50-2.56(m,1H),1.95(s,3H). LC-MS:m / z 527[M+H] + .

[0777] Example 17: 1 H NMR (400 MHz, DMSO-d 6 )δ11.22(s,1H),8.77(s,1H),8.73(d,J=2.0Hz,1H),8.62(d,J=2.0Hz,1H),8.18(s,2H),7.64(s,1H) ,7.44(s,1H),4.55(t,J=8.4Hz,1H),3.75(s,3H),2.90-2.95(m,1H),2.50-2.56(m,1H),1.95(s,3H). LC-MS:m / z 527[M+H] + .

[0778] Step 4: Separation of enantiomers to obtain Example 18 and Example 19

[0779] 25 mg of cis-3-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-fluoro-8-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide was subjected to chiral HPLC purification (column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: Hex (0.1% FA)--HPLC, mobile phase B: IPA--HPLC; flow rate: 20 mL / min; gradient: isocratic 30% mobile phase B; wavelength: 220 / 254 nm; RT1 (min): 8.045; RT2 (min): 9.61; sample solvent: EtOH--HPLC; injection volume: 0.5 mL; number of runs: 6). The first eluting isomer was concentrated and lyophilized to give Example 18 (4.1 mg, 15% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 19 (5.5 mg, 21% yield) as a white solid.

[0780] Example 18: 1 H NMR (400 MHz, DMSO-d 6 )δ11.11(s,1H),8.81(s,1H),8.73(d,J=2.0Hz,1H),8.56(d,J=2.0Hz,1H),8.18(s,2H),7.62(s,1H ),7.35(s,1H),4.52-4.58(m,1H),3.74(s,3H),2.82-2.94(m,1H),2.67-2.72(m,1H),1.86(s,3H). LC-MS:m / z 527[M+H] + .

[0781] Example 19: 1 H NMR (400 MHz, DMSO-d 6 )δ11.11(s,1H),8.81(s,1H),8.73(d,J=2.0Hz,1H),8.56(d,J=2.0Hz,1H),8.18(s,2H),7.62(s,1H ),7.35(s,1H),4.53-4.58(m,1H),3.74(s,3H),2.82-2.94(m,1H),2.67-2.72(m,1H),1.86(s,3H). LC-MS:m / z 527[M+H] + .

[0782] Method A6

[0783]

[0784] Examples 20 and 21: (6S,8R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-2-fluoro-8-methyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide; (6R,8S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-2-fluoro-8-methyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0785] Examples 22 and 23: (6S,8S)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-2-fluoro-8-methyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide, (6R,8R)-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-(1-ethyl-1H-pyrazol-4-yl)-2-fluoro-8-methyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxamide

[0786] The relative and absolute stereochemistry of each instance was not determined.

[0787] Step 1: 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0788] At 0 ° C, NaH (30.9 g, 773.3 mmol, 60% in mineral oil) was added to a stirred solution of 4-iodo-1H-pyrazole (100 g, 515.5 mmol) in THF (1.2 L). The mixture was stirred at 0 ° C for 30 min. 2-(Chloromethoxy)ethyl-trimethyl-silane (128.9 g, 773.3 mmol) was added dropwise at 0 ° C, and the mixture was stirred at 25 ° C for 2 h. The reaction mixture was poured into ice water (2500 mL) and extracted with ethyl acetate (3 x 2500 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with EtOAc / PE (1: 3) to obtain the title compound (130 g, 73% yield) as a yellow oil. LC-MS: m / z 325 [M+H] + .

[0789] Step 2: 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclopentan-1-ol

[0790] 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (50.1 g, 154.6 mmol) was added to Et 2 In the stirred mixture in 4% 4H-drylamide (5% dH-drylamide) (800mL), n-butyl lithium (61.8mL, 2.5M in hexane) was added. The reaction mixture was stirred at -90 °C under nitrogen for 1h. 6-oxabicyclo [3.1.0] hexane (10g, 118.9mmol) and boron trifluoride ether (21.9g, 154.6mmol) were added at -90 °C, and the mixture was stirred at -78 °C under nitrogen for 1h. The reaction was quenched with saturated aqueous ammonium chloride solution (100mL), and the resulting mixture was extracted with ethyl acetate (3x200mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with EtOAc / PE (2: 1) to obtain the title compound (9.6g, 25% yield) as a yellow oil. LC-MS: m / z 283[M+H] + .

[0791] Step 3: 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclopentan-1-one

[0792] Analogously to Method A1 Step 2, but using 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclopentan-1-ol (9.6 g, 34.0 mmol), the title compound was obtained as a yellow oil (6.5 g, 61% yield). LC-MS: m / z 281 [M+H] + .

[0793] Step 4: 2-Methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclopentan-1-one (A6-4)

[0794] Analogously to method A1 step 3, but using 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclopentan-1-one (6.5 g, 23.2 mmol), the title compound (A6-4, 3.4 g, 44% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6)δ7.73(s,1H),7.43(s,1H),5.33(s,2H),3.43-3.55(m,2H),2.24-2.34( m,3H),1.76-2.01(m,3H),1.25(s,3H),0.78-0.83(m,2H),-0.06(s,9H). LC-MS:m / z 295[M+H] + .

[0795] Step 5: 5-((dimethylamino)methylene)-2-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclopentan-1-one

[0796] Analogously to Method A1 step 4, but using 2-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclopentan-1-one (3.3 g, 11.2 mmol) in 1-tert-butoxy-N,N,N',N'-tetramethyl-methanediamine (4.63 mL, 22.4 mmol) and stirring at 100 °C for 1 h, the crude title compound (4.5 g) was obtained as a brown oil and used in the next step without further purification. LC-MS: m / z 350 [M+H] + .

[0797] Step 6: 2-Fluoro-8-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine (A6-6)

[0798] To a stirred solution of 5-((dimethylamino)methylene)-2-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)cyclopentane-1-one (3.9 g, 8.9 mmol) in toluene (60 mL), 3-fluoro-1H-pyrazole-5-amine (1.8 g, 17.9 mmol) and AcOH (6 mL) were added. The resulting mixture was stirred at 90 ° C for 16 h. The mixture was allowed to cool to 25 ° C and concentrated under reduced pressure. The residue was dil...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: Each is a single bond or a double bond; Q is –CH2–, O or NH; X is N or C; Y is N or C; Z is N or CR 6 ; When one of X and Y is N, 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, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR A R B , or C1-C3 alkyl optionally substituted by 1-3 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, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 haloalkyl; m is 0, 1, 2 or 3; R 4 is a 5- to 10-membered heteroaryl group optionally substituted with one to three substituents, each of which is independently selected from R 7 ; R 5 is phenyl or a 5- to 9-membered heteroaryl group, wherein each R 5 The group is optionally composed of 1-3 independently selected R 8 Substituents are substituted; R 6 is hydrogen, halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -NR C R D and C1-C3 alkyl; Each R 7 independently selected from halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, oxetanyl, -NR C R D , the group consisting of C1-C3 alkyl optionally substituted by one cyclopropyl; and C3-C7 cycloalkyl optionally substituted by one C1-C3 alkyl; Each R 8 Independently selected from halogen; cyano; amino; -N=(S=O)(C1-C3 alkyl)2; -S(=O) p (C1-C3 alkyl); 1-imino-1-λ 6 -thienyl 1-oxide, -(C=O)NR E R F C1-C3 alkoxy; C1-C3 haloalkyl optionally substituted by hydroxy; C1-C3 haloalkoxy; 5- to 6-membered heteroaryl optionally substituted by halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 haloalkyl, 4- to 6-membered heterocyclyl or optionally substituted by hydroxy or -NR E R F Substituted C1-C3 alkyl; C1-C4 alkyl, which is optionally substituted with hydroxyl, -NR E R F or C1-C3 alkoxy substituted; 3 to 8 membered heterocyclic group; and C3-C6 cycloalkoxy; p is 1 or 2; and 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 Together with the nitrogen atom to which they are attached they are combined to form a 4 to 6 membered heterocyclic group optionally substituted by 1-2 halogens. The compound according to claim 1 , wherein X is N and Y is C. .

3. The compound according to claim 1 or 2, wherein Z is N.

4. A compound according to any one of claims 1 to 3, wherein R X For hydrogen.

5. The compound according to any one of claims 1 to 4, wherein Q is -CH2-.

6. A compound according to any one of claims 1 to 5, wherein R 1 It is a halogen.

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

8. The compound according to any one of claims 1 to 7, wherein n is 1.

9. The compound according to any one of claims 1 to 8, wherein m is 1.

10. A compound according to any one of claims 1 to 9, wherein each R 3 are independently halogen, C3-C6 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy.

11. A compound according to any one of claims 1 to 10, wherein m is 1, and R 3 is methyl or trifluoromethyl.

12. A compound according to any one of claims 1 to 11, which is a compound according to formula (Ic) or a pharmaceutically acceptable salt thereof 13. A compound according to any one of claims 1 to 12, wherein R 4 is optionally one to three independently selected from R 7 A 5-membered or 6-membered heteroaryl group substituted with a substituent.

14. A compound according to any one of claims 1 to 13, wherein R 4 is optionally one to three independently selected from R 7 A 6-membered heteroaryl group substituted with a substituent.

15. A compound according to any one of claims 1 to 13, wherein R 4 is optionally one to three independently selected from R 7 A 5-membered heteroaryl group substituted with a substituent.

16. A compound according to any one of claims 1 to 13 and 15, wherein R 4 is optionally one to three independently selected from R 7 4H-pyrazolyl, 3H-pyrazolyl, triazolyl or thiazolyl substituted with a substituent.

17. A compound according to any one of claims 1 to 16, wherein each R 7 Independently selected from the group consisting of C1-C3 haloalkyl, C1-C3 alkyl optionally substituted with one cyclopropyl, and C3-C7 cycloalkyl optionally substituted with one C1-C3 alkyl.

18. A compound according to any one of claims 1 to 13 and 15 to 17, wherein R 4 for:

19. A compound according to any one of claims 1 to 13 and 15 to 18, wherein R 4 for:

20. A compound according to any one of claims 1 to 13 and 15 to 18, wherein R 4 for:

21. A compound according to any one of claims 1 to 13 and 15 to 18, wherein R 4 for:

22. A compound according to any one of claims 1 to 13, 15 to 18 and 20, wherein R 4 for:

23. A compound according to any one of claims 1 to 22, wherein R 5 Optionally 1 to 3 independently selected R 8 Substituted phenyl.

24. A compound according to any one of claims 1 to 22, wherein R 5 is optionally 1-3 independently selected R 8 Substituted 5- to 9-membered heteroaryl.

25. A compound according to any one of claims 1 to 22 and 24, wherein R 5 is 1 to 3 independently selected R 8 Substituted 5- to 6-membered heteroaryl.

26. A compound according to any one of claims 1 to 22, 24 and 25, wherein R 5 is optionally 1-3 independently selected R 8 Substituted 3-pyridyl or 4-pyridyl.

27. A compound according to any one of claims 1 to 26, wherein R 8 At least one of them is a halogen.

28. A compound according to any one of claims 1 to 27, wherein R 8 At least one of them is a 5- to 6-membered heteroaryl group optionally substituted by halogen, cyano, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, optionally substituted by hydroxy or -NR E R F Substituted C1-C3 alkyl, amino or C1-C3 haloalkyl.

29. A compound according to any one of claims 1 to 28, wherein R 8 At least one of them is a 5-membered heteroaryl group optionally substituted by halogen, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, optionally substituted by hydroxyl or -NR E R F Substituted C1-C3 alkyl, amino or C1-C3 haloalkyl.

30. A compound according to any one of claims 1 to 26, wherein R 5 for:

31. A compound according to any one of claims 1 to 26 and 30, wherein R 5 for:

32. A compound according to any one of claims 1 to 26 and 30, wherein R 5 for:

33. A compound according to any one of claims 1 to 26 and 30, wherein R 5 for:

34. A compound according to any one of claims 1 to 26 and 30, wherein R 5 for:

35. A compound according to any one of claims 1 to 34, which is a compound according to formula (Id) or a pharmaceutically acceptable salt thereof 36. A compound according to any one of claims 1 to 34, which is a compound according to formula (Ie) or a pharmaceutically acceptable salt thereof 37. A compound according to any one of claims 1 to 34, which is a compound according to formula (If) or a pharmaceutically acceptable salt thereof 38. A compound according to any one of claims 1 to 34, which is a compound according to formula (Ig) or a pharmaceutically acceptable salt thereof 39. The compound of claim 1 selected from Table 1 or a pharmaceutically acceptable salt thereof.

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

41. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40.

42. The method of claim 41, wherein the cancer is a MALT1-associated cancer.

43. The method of claim 41 or 42, wherein the cancer is lymphoma.

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

45. The method of claim 41 or 42, wherein the cancer is leukemia.

46. ​​The method of claim 45, wherein the leukemia is chronic lymphocytic leukemia (CLL).

47. The method of claim 41 or 42, wherein the cancer is a solid tumor.

48. A method for treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40.

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

50. The method of any one of claims 41 to 49, further comprising administering to the subject an additional therapy or therapeutic agent.

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