Cyclopenta[e]pyrazolo[1,5-a]pyrimidine derivatives as malt1 inhibitors

Abstract

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

Description

Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) CYCLIC COMPOUNDS AND METHODS OF USING SAME CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 537,637, filed September 11, 2023, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] This present application relates to tricyclic, and other multi-cyclic compounds that are useful for treating proliferative disorders such as cancer, as well as autoimmune and inflammatory disorders. BACKGROUND

[0003] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is an intracellular protein involved in lymphocyte proliferation via upstream signaling of NF-κB to control lymphocyte activation, survival, proliferation, and differentiation. Together with a CARMA or CARD scaffold protein, (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 which is formed upon cell-surface antigen receptor activation. See Jaworski et al., Cell Mol Life Science 2016, 73, 459-473, and Juilland and Thome. Frontiers in Immunology 2018, 9, 1927. MALT1 is known to mediate NF-κB signaling by at least two mechanisms: firstly, MALT1 functions as a scaffold protein, recruiting NF-κB signaling proteins such as TRAF6, TABs (e.g., TAB1, TAB2, TAB3), TAK1 and NEMO-IKKα / β; and secondly, as a cysteine protease, it cleaves and deactivates negative regulators of NF-κB signaling, such as RelB, A20, or CYLD. See Rosebeck et al., Science, 2011, 331, 468-472.

[0004] The protease activity of MALT1 has emerged as a potential therapeutic target, particularly where NF-κB and related pathways are believed to play a significant role. Activated B cell-like diffuse large B cell lymphomas (ABC-DLBCLs) are aggressive lymphomas that are often characterized by NF-κB hyperactivation, and it has been shown that MALT1 protease inhibition can dramatically inhibit growth and promote apoptosis of the highly aggressive ABC type DLBCLs. 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 etAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) al., Nat Immunol 20008, 9, 263-271; Staal et al., EMBO J 2011, 30, 1742-1752; Hailfinger et al., PNAS 2011, 108, 14596-14601; Jeltsch et al., Nat Immunol 2014, 15, 1079-1089; Uehata et al., Cell 2013, 153, 1036-1049; Nie et al., Nat Commun 2015, 6, 5908; and Baens et al., PLoS ONE 2014, 9, e103774. One general profile of MALT1 substrates is described in Kasperkiewicz, et al. Scientific Reports 8.1 (2018): 1- 10.

[0005] Additionally, several chromosomal translocations that lead to the generation of constitutively active MALT1 have been identified in ABC-DLBCLs and the identification of the MALT1 fusion protein API2-MALT1 / IgH-MALT1 that leads 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 involved in several different types of cancers, for example 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 effects on several inflammatory disorders, e.g., psoriasis, multiple sclerosis, rheumatoid arthritis, Sjogren’s syndrome, ulcerative colitis, and different types of allergic disorders resulting from chronic inflammation. See Afofina et al., FEBS Journal 2015, DOI: 10.1111 / 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, findings also suggest the importance of MALT1 in the control of regulatory T cell (Treg) function and homeostasis. Studies are ongoing to confirm the potential of MALT1 inhibitors for the treatment of patients with solid tumors alone or in combination with immune-checkpoint mechanisms. However, no MALT1 inhibitors are currently approved for therapeutic use.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) SUMMARY

[0006] Accordingly, provided herein is a compound of the Formula (I): , or a pharmaceutically acceptable salt R1, R2, R3, R4, R5, R6, R7, and R8are asdefined herein.

[0007] Also provided herein is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0008] Also provided are methods for treating a CBM complex pathway-associated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0009] Also provided are methods for treating a CBM complex pathway-associated cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0010] Also provided are methods for treating a MALT1-associated cancer in a subject, comprising administering to a subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In certain aspects, the subject is identified or diagnosed as having a MALT1-associated cancer.

[0011] Also provided are methods for inhibiting metastasis in a subject having a cancer in need of such treatment, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0012] Also provided are methods for treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0013] Also provided are methods for treating a MALT1-associated autoimmune disorder in a subject, comprising administering to a subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In certain aspects, the subject is identified or diagnosed as having a MALT1-associated autoimmune disorder

[0014] Also provided are methods for treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0015] Also provided are methods for treating a MALT1-associated inflammatory disorder in a subject, comprising administering to a subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In certain aspects, the subject is identified or diagnosed as having a MALT1-associated inflammatory disorder

[0016] Also provided are methods for inhibiting CBM complex pathway activity in a subject, comprising contacting the mammalian cell with a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0017] Also provided are methods for inhibiting MALT1 protease activity in a subject, comprising contacting the mammalian cell with a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entireties. In case of conflict, the present specification, including definitions, will control.

[0019] Other features and advantages of the disclosure will be apparent from the following detailed description and figures, and from the claims.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) DETAILED DESCRIPTION Definitions

[0020] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0021] The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0022] As used herein, the term “compounds of the invention” refers to the compounds of formula (I) and all of the embodiments thereof (e.g., formulas (I-1), (I-2a), (I-2b), (I-A), (I-A-1), (I-A-2a), (I-A-2b), (I-B), (I-B-1), (I-B-2a), (I-B-2b), etc.), as described herein, and to the compounds identified in Table A.

[0023] As described herein, the compounds of the invention comprise multiple variable groups (e.g., X, Y, R0, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0024] The term “tautomer,” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer.

[0025] Unless otherwise specified, the compounds of the invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. In addition, single stereoisomers, double bondAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) isomers, conformational isomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers are within the scope of the invention. It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.

[0026] As used herein, in any chemical structure or formula, a non-bold, straight bond attached to one or more stereocenters of a compound, such as in denotes that the The compound may haveany configuration, or a mixture of configurations, at the one or more stereocenters.

[0027] The term “halo” refers to one of the halogens, group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0028] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a “C1-C6 alkyl” group is an alkyl group having between one and six carbon atoms. The term “C1-C6 alkyl” refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Similarly, a C1-C3 alkyl group is linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms.

[0029] As used herein, the term “haloalkyl” refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups. The term “C1-C6 haloalkyl” refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. Similarly, a C1-C3 haloalkyl group is linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms substituted with at least one halogen atom. For example, C1-C3 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloroethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 2,2,2- trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0030] A represents a single or double bond, valence permitting. For example, .

[0031] As used herein, the term group.

[0032] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated 3–10 mono- or bicyclic hydrocarbon group; wherein bicyclic systems include fused, spiro (optionally referred to as “spirocycloalkyl” groups), and bridged ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0033] The term “heterocyclyl” refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system, that is not aromatic, having at least one heteroatom within the ring selected from N, O and S. Bicyclic heterocyclyl groups include fused, spiro (optionally referred to as “spiroheterocyclyl” groups), and bridged ring systems. The heterocyclyl ring system may include oxo substitution at one or more C, N, or S ring members. The heterocyclyl group may be denoted as, for example, a “5-10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being 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 through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidin-2- one, sulfolane, isothiazoline S,S-dioxide, and decahydronaphthalenyl.

[0034] As used herein, the term “oxo” refers to an “=O” group attached to a carbon atom.

[0035] As used herein, the symbol depicts the point of attachment of an atom or moiety to the indicated atom or group in thethe molecule.

[0036] The compounds of the invention include pharmaceutically acceptable salts thereof. In addition, the compounds of the invention also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and / or purifying compounds of the invention and / or for separating enantiomers of compounds of the invention. Non-limiting examples of pharmaceutically acceptable salts of compounds of the invention include trifluoroacetic acid and hydrochloride salts.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0037] It will further be appreciated that the compounds of the invention or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present disclosure. For example, compounds of the invention and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0038] The term “pharmaceutically acceptable” indicates that the compound, or salt or composition thereof is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the subject being treated therewith.

[0039] Protecting groups can be a temporary substituent which protects a potentially reactive functional group from undesired chemical transformations. The choice of the particular protecting group employed is well within the skill of one of ordinary skill in the art. A number of considerations can determine the choice of protecting group including, but not limited to, the functional group being protected, other functionality present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, functional group tolerance to conditions required to remove the protecting group, and reaction conditions for the thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed (Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, 2.sup. ed. Wiley: New York, 1991).

[0040] A nitrogen protecting group can be any temporary substituent which protects an amine moiety from undesired chemical transformations. Examples of moieties formed when such protecting groups are bonded to an amine include, but are not limited to allylamine, benzylamines (e.g., bezylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and tritylamine), acetylamide, trichloroacetammide, trifluoroacetamide, pent-4-enamide, phthalimides, carbamates (e.g., methyl carbamate, t-butyl carbamate, benzyl carbamate, allyl carbamates, 2,2,2-trichloroethyl carbamate, and 9-fluorenylmethyl carbamate), imines, and sulfonamides (e.g., benzene sulfonamide, p-toluenesulfonamide, and p-nitrobenzenesulfonamide).

[0041] An oxygen protecting group can be any temporary substituent which protects a hydroxyl moiety from undesired chemical transformations. Examples of moieties formed when such protecting groups are bonded to a hydroxyl include, but are not limited to esters (e.g., acetyl, t-butyl carbonyl, and benzoyl), benzyl (e.g., benzyl, p-methoxybenzyl, and 2,4-dimethoxybenzyl, and trityl), carbonates (e.g., methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate and benzyl carbonate) ketals, and acetals, and ethers.

[0042] In the specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope inAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.

[0043] As used herein, the term “stable,” when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0044] As used herein in the specification and claims, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely1H and D. In the Examples, where an atom is designated as “H,” no effort was made to enrich that atom in a particular isotope of hydrogen, and therefore a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.

[0045] As used herein, “1H” refers to protium. Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as protium, protium is present at the specified position with at least the natural abundance concentration of protium.

[0046] As used herein, “D,” “d,” and “2H” refer to deuterium.

[0047] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include each constituent atom at approximately the natural abundance isotopic composition of the specified element.

[0048] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts). Examples of stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example2H,13C,15N,18O,17O, and31P, respectively.

[0049] The isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medicaments. In some embodiments, the isotope-labeled compounds and salts are deuterium (2H)- labeled. Deuterium (2H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non-2H-labeled compounds. In general, deuterium (2H)-labeled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labeled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half- life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. The isotope-labeled compounds and salts can usually be prepared by carrying out theAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) procedures disclosed in the synthesis schemes, the Examples and the related description, replacing a non- isotope-labeled reactant by a readily available isotope-labeled reactant.

[0050] The deuterium (2H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For example, if deuterium is bonded to a carbon atom at a non- exchangeable position, rate differences of kH / kD = 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem.2011, 46, 403-417, incorporated in its entirety herein by reference.

[0051] The concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope- labeled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratio between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.

[0052] For illustrative purposes, general methods for preparing the compounds are provided herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0053] The ability of selected compounds to act as MALT1 inhibitors may be demonstrated by the biological assays described herein. IC50values are shown in Table 1.

[0054] Compounds of the invention, or a pharmaceutically acceptable salt thereof, are useful for treating diseases and disorders which can be treated with a MALT1 inhibitor, such as MALT1-associated cancers, including hematological cancers and solid tumors, MALT1-associated autoimmune disorders, and MALT1-associated inflammatory disorders.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0055] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0056] 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 exhibited at least one symptom of the disease or disorder to be treated and / or prevented.

[0057] In certain embodiments, compounds of the invention, or a pharmaceutically acceptable salt thereof are useful for preventing diseases and disorders as defined herein (for example, autoimmune disorders, inflammatory disorders, and cancer). The term "preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0058] Signaling through the NF-κB pathway has been implicated in many cancers. See, e.g., Staudt, Cold Spring Harbor Perspectives in Biology 2.6 (2010): a000109, Xia, et al. Cancer Immunol. Res. 2.9 (2014): 823-830, Xia, et al. OncoTargets and Therapy 11 (2018): 2063. NF-κB is a family of transcription factors, including p50, p52, p65 (RelA), RelB, and c-Rel, which can bindto the kB enhancer element as various homo- and heterodimers to induce transcription of a number of genes. Following activation of certain cell-surface receptors (e.g., CD28, BCR, HER1 (also known as EGFR (Epidermal Growth Factor Receptor) and ERBB1), or HER2 (also known as HER2 / neu or ERBB2)), a CBM complex is formed via phosphorylation of a CARD or CARMA protein, likely by a protein kinase C (e.g., protein kinase C beta or protein kinase C theta) and recruitment of the BCL10-MALT1 complex. See, e.g., Xia, et al. OncoTargets and Therapy 11 (2018): 2063, Shi, and Sun. Mol. Immunol.68.2 (2015): 546-557, Xia, et al. Cancer Immunol. Res.2.9 (2014): 823-830, and Pan, Mol. Cancer Res.14.1 (2016): 93-102.

[0059] As noted hereinabove, the CBM complex can function as a scaffold protein in the activation of the NF-κB pathway. When formed, the CBM complex can activate the IKK complex (e.g., IKKγ (also called NEMO), IKKα, and IKKβ), likely by ubiquintination (e.g., K63-linked ubiquitination) of MALT1, which results in the recruitment, ubiquitination (e.g., K63-linked ubiquitination), and degredation of IKKγ, thereby releasing IKKα and IKKβ to phosphorylate IκB, resulting in the ubiquitination (e.g., K48-linked ubiquitination) and degradation of IκB, releasing the NF-κB transcription factors (typically of the NF-κB1 subtype: p50-RelA and p50-cRel) to the nucleus. This cascade is likely mediated by the ubiquitin ligaseAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) TRAF6 (Tumor necrosis factor receptor (TNFR)-associated factor 6). The CBM complex may also affect NF-κB signaling through addtitional protein complexes, such as TAB1 / 2-TAK and the linear ubiquitin chain assembly complex (LUBAC). See, e.g., Israël, Cold Spring Harbor Perspectives in Biology 2.3 (2010): a000158, Xia, et al. OncoTargets and Therapy 11 (2018): 2063, Juilland, Front. Immunol.9 (2018): 1927. MALT1 can also activate the JNK pathway (also called the JNK / AP-1 pathway), though less work has been done to study this area. See, e.g., Juilland, Front. Immunol. 9 (2018): 1927, and Wang, et al., Oncogenesis 6.7 (2017): e365-e365.

[0060] In addition, MALT1 has cysteine protease activity. Non-limiting examples of substrates of wild-type MALT1 include BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, and HOIL1. In addition, the API2-MALT1 (also called cIAP2; amino terminus of inhibitor of apoptosis 2) fusion protein has also been shown to cleave NIK and LIMA1α. BCL10 cleavage by MALT1 is believed to result in BCL10- independent NF-κB activation. By cleaving A20 (TNF Alpha Induced Protein 3), MALT1 can reduce negative regulation of the NF-κB pathway, as A20 is a deubiquitinating enzyme that has been suggested to reduce the ubiquitination of MALT1 and thus recruitment and activation of the IKK complex. CYLD (CYLD Lysine 63 Deubiquitinase) is a deubiquitinating enzyme, and by cleavage of this enzyme, it is believed that MALT1 increases signaling through the NF-κB pathway and / or JNK pathway. Cleavage of RelB typically results in relief of negative regulation of the NF-κB pathway, as RelB forms transcriptionally inactive complexes with RelA and c-Rel. By cleaving HOIL1 (also known as RBCK1), it is believed that negative regulation of the NF-κB is relieved, as HOIL1 is thought to decrease linear ubiquitination. MALT1 can also autoprocess, which promotes signaling through the NF-κB pathway through a mechanism that is not fully understood. By cleaving NIK (NF-κB inducing kinase), the API2-MALT1 protease generates a c-terminal fragment of NIK that is resistant to proteasomal degradation and thereby increases noncanonical NF-κB signaling. By cleaving LIMA1α (LIM domain and actin-binding protein 1), the tumor- suppressing properties of this protein are diminished, and it believed that the remaining fragment has oncogenic properties and enhances cell proliferation, colony formation, and cell adhesion. Cleavage of Regnase 1 (Regulatory RNase 1, also known as MCPIP-1 or Zc3h12a), and roquin-1 (also known as RC3H1) is believed to result in the stabilization of mRNAs, including those of cytokines, chemokines, and costimulatory proteins such as ICOS, OX40, and TNF. This activity may be independent of MALT1 activity in the NF-κB and JNK pathways. See, e.g., Afonina, et al. FEBS J. 282.17 (2015): 3286-3297 Klein et al. Nat. Comm.6.1 (2015): 1-17, Baens, et al. PloS one 9.8 (2014): e103774, and Juilland, Front. Immunol.9 (2018): 1927. MALT1 is also involved in oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsie samples, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTORAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. See Phelan et al., Nature 2018 Aug;560(7718):387-391.

[0061] Accordingly, inhibition of MALT1 can provide beneficial effects to many types of disorders associated with aberrant signaling in the NF-κB pathway or JNK pathway. For example, inhibition of MALT1 can decrease flux through the NF-κB or JNK pathways resulting from one or more of: (1) An inactivated tumor suppressor gene. Non-limiting examples of tumor suppressor genes that can be inactivated include BRCA1 and p53 (e.g., p53 H61L or I123T). See, e.g., Sau, et al. Cell Stem Cell 19.1 (2016): 52-65, Xia, et al. Cancer Immunol. Res.2.9 (2014): 823-830, Johansson, et al. Oncotarget 7.38 (2016): 62627. (2) A dysregulated cell surface receptor. Non-limiting examples of cell surface receptors include HER1 and HER2. See, e.g., Xia, et al. Cancer Immunol. Res. 2.9 (2014): 823-830 and Pan, Mol. Cancer Res.14.1 (2016): 93-102. (3) Dysreguation of one or more components of a CBM complex. Non-limiting examples of components of a CBM complex include MALT1, CARD11, CARD14, CARD10, CARD9, and BCL10. (4) Dysregulation of one or more substrates of a MALT1 protease (e.g., a wild-type MALT1 protease or a dysregulated MALT1 protease). Non-limiting examples of substrates of a MALT1 protease include BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, HOIL1, NIK, and LIMA1α. (5) Dysregulation of one or more components of the NF-κB pathway downstream of a CBM complex. Non-limiting examples of a component of the NF-κB pathway downstream of a CBM complex include TRAF6, IKKα, IKKβ, IKKγ (also called NEMO), IkBα, p50, p52, p65 (RelA), RelB, and c-Rel. (6) Dysregulation of one or more components of the JNK pathway downstream of a CBM complex. Non-limiting examples of a component of the JNK pathway downstream of a CBM complex include JNK1 (Mitogen-Activated Protein Kinase 8), JNK2 (Mitogen-Activated Protein Kinase 9), JNK3 (Mitogen-Activated Protein Kinase 10), or an AP-1 transcription factor (e.g., a heterodimer of any of the c-Fos, c-Jun, ATF, or JDP families). (7) Dysregulation of one or more fusion proteins caused by chromosome translocation of MALT1 gene. Non-limiting example includes the cIAP-MALT1 fusion protein. (8) Dysregulation of one or more components of the My-T-BCR supercomplex. Non-limiting examples of a component of the My-T-BCR supercomplex include MYD88, TLR9, and mTOR.

[0062] The term “CBM complex pathway” as associated herein 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, cell surface receptors (e.g., CD28, BCR, HER1, and HER2), a signal transducer between a cell surface receptor and aAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) CBM complex (e.g, a protein kinase C beta or protein kinase C theta), a component of a CBM complex (e.g., MALT1, CARD11, CARD14, CARD10, CARD9, or BCL10), substrates of a MALT1 protease (e.g., BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, HOIL1, NIK, and LIMA1α), a component of the NF-κB pathway downstream of a CBM complex (e.g., TAK1, TRAF6, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, p65 (RelA), or c-Rel), a component of the JNK pathway downstream of a CBM complex (e.g., JNK1, JNK2, JNK3, or an AP-1 transcription factor), or a components of the My-T-BCR supercomplex (e.g., MYD88, TLR9, or mTOR).

[0063] As used herein, the term "CBM complex pathway-associated disease or disorder" refers to diseases or disorders associated with or having a dysregulation of a gene in a CBM complex pathway, a protein in a CBM complex pathway, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a gene in a CBM complex pathway, a protein in a CBM complex pathway, or the expression or activity or level of any of the same, as described herein). Non-limiting examples of a CBM complex pathway-associated diseases or disorders include, for example, CBM-related primary immunodeficiency diseases, autoimmune disorders, multiple sclerosis, colitis, psoriasis, and cancer. See, e.g., McGuire, et al. J. Neuroinflamm. 11.1 (2014): 1-12, Lu, et al., Front. Immunol. 9 (2018): 2078, Jaworski, et al., EMBO J. 33.23 (2014): 2765-2781. Non-limiting examples of a CBM complex pathway-associated disease or disorder include MALT1-associated diseases or disorders such as MALT1-associated cancers, MALT1-associated autoimmune disorders, and MALT1-associated inflammatory disorders.

[0064] The term “CBM complex pathway-associated autoimmune disorder” as used herein refers to autoimmune disorders associated with or having a dysregulation of a CBM complex pathway gene, a CBM complex pathway protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CBM complex pathway gene, a CBM complex pathway protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a CBM complex pathway-associated autoimmune disorders are described herein.

[0065] The term “CBM complex pathway-associated inflammatory disorder” as used herein refers to inflammatory disorders associated with or having a dysregulation of a CBM complex pathway gene, a CBM complex pathway protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CBM complex pathway gene, a CBM complex pathway protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a CBM complex pathway-associated inflammatory disorders are described herein.

[0066] In some embodiments, a CBM complex pathway-associated disease or disorder is a CBM complex pathway-associated cancer, such as a CBM complex pathway cell surface receptor-associatedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) 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 C beta (PKCβ)-associated cancer or a protein kinase C theta (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, a Regnase 1-associated cancer, a roquin-1-associated cancer, a HOIL1-associated cancer, a NIK associated cancer, or a LIMA1α-associated cancer), a cancer associated with a component of the NF-κB pathway downstream of a CBM complex (e.g., TAK1-associated cancer, a TRAF6-associated cancer, a TAB1- associated cancer, a TAB2-associated cancer, a TAB3-associated cancer, a MKK7-associated cancer, an IKKα-associated cancer, an IKKβ-associated cancer, an IKKγ-associated cancer, an IkBα-associated cancer, a p50-associated cancer, a p65 (RelA)-associated cancer, or a c-Rel-associated cancer), a cancer associated with a component of the JNK pathway downstream of a CBM complex (e.g., a JNK1-associated cancer, a JNK2-associated cancer, a JNK3-associated cancer, or an AP-1 transcription factor-associated cancer), a MYD88-associated cancer, or a combination thereof.

[0067] In some embodiments, a dysregulation can be a dysregulation that results in aberrant activation of a gene, protein, or expression or activity or level of any of the same. Activation can be through any appropriate mechanism, including, but not limited to, gene amplification, activating mutation, activating translocation, transcriptional activation, epigenetic alteration, and / or overexpression of the protein product of the oncogene. In some embodiments, a dysregulation can be a dysregulation that results in aberrant inactivation of a gene, protein, or expression or activity or level of any of the same. Inactivation can be through any appropriate mechanism, including, but not limited to, gene deletion, inactivating mutation, inactivating translocation, transcriptional silencing, epigenetic alteration, and degradation of mRNA and / or protein products of the gene. Typically, as used herein, a dysregulation, whether it be activation or inactivation, is a dysregulation that results in increased signaling through the NF-κB or JNK signaling pathways.

[0068] The term “wild-type” describes a nucleic acid (e.g., a MALT1 gene or a MALT1 mRNA) or protein (e.g., a MALT1 protein) that is found in a subject that does not have a disease or disorder associated with the nucleic acid or the protein (e.g., the MALT1 gene, MALT1 mRNA, or MALT1 protein) (and optionally also does not have an increased risk of developing a disease or disorder associated with the nucleic acid or the protein and / or is not suspected of having a disease or disorder associated with the gene or the protein), or is found in a cell or tissue from a subject that does not have a disease or disorder associatedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) with the gene or the protein (e.g., a MALT1-associated cancer, autoimmune disorder, or inflammatory disorder) (and optionally also does not have an increased risk of developing a disease or disorder associated with the nucleic acid or the protein and / or is not suspected of having a disease or disorder associated with the nucleic acid or the protein.

[0069] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (a CBM complex pathway-associated-associated cancer) (e.g., as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has has a cancer resistant to one or more previous therapies. In some embodiments, the subject has a tumor that is positive for a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency- approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject has a tumor resistant to one or more previous therapies. In some embodiments, the subject is suspected of having a CBM complex pathway-associated-associated cancer. In some embodiments, the subject has a tumor that is suspected of being resistant to one or more previous therapies. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has a clinical record indicating that the subject has a tumor resistant to one or more previous therapies. In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associatedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (a CBM complex pathway-associated-associated cancer).

[0070] In some embodiments, the subject has been identified or diagnosed as having an autoimmune disorder with a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (a CBM complex pathway-associated-associated autoimmune disorder) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject is suspected of having a CBM complex pathway-associated- associated autoimmune disorder. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having an autoimmune disorder that, based on histological examination, is determined to be associated with a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (a CBM complex pathway- associated-associated autoimmune disorder).

[0071] In some embodiments, the subject has been identified or diagnosed as having an inflammatory disorder with a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (a CBM complex pathway-associated-associated inflammatory disorder) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject is suspected of having a CBM complex pathway-associated- associated inflammatory disorder. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression orAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed as having an inflammatory disorder that, based on histological examination, is determined to be associated with a dysregulation of a CBM complex pathway-associated gene (e.g., a MALT1 gene), a CBM complex pathway-associated protein (e.g., a MALT1 protein), or expression or activity, or level of any of the same (a CBM complex pathway-associated-associated inflammatory disorder).

[0072] The term “CBM complex pathway cell surface receptor-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a gene, a protein, or the expression or activity or level of any (e.g., one or more) of the same associated with a CBM complex pathway cell surface receptor. In some embodiments, a CBM complex pathway cell surface receptor-associated cancer is selected from the group consisting of a CD28-associated cancer, a BCR-associated cancer, a HER1- associated cancer, a HER2-associated cancer, and combinations thereof.

[0073] The term “*-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a * gene, a * protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a * gene, a * protein, or the expression or activity or level of any of the same described herein), where “*” refers to a particular CBM complex pathway gene or protein, described herein. In some embodiments, the *-associated cancer is selected from the group consisting of: CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, HER2-associated cancer, PKCβ-associated cancer, PKCθ-associated cancer, MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, A20-associated cancer, CYLD-associated cancer, RelB-associated cancer, HOIL1-associated cancer, NIK-associated cancer, Regnase 1-associated cancer, LIMA1α- associated cancer, 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 an AP-1 transcription factor-associated cancer. In some embodiments, the *-associated cancer is a CD28-associated cancer. In some embodiments, the *-associated cancer is a BCR-associated cancer. In some embodiments, the *-associated cancer is a HER1-associated cancer. In some embodiments, the *-associated cancer is a HER2-associated cancer. In some embodiments, the *-associated cancer is a PKCβ-associated cancer. In some embodiments, the *-associated cancer is a PKCθ-associated cancer. In some embodiments, the *- associated cancer is a MALT1-associated cancer. In some embodiments, the *-associated cancer is aAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) CARD11-associated cancer. In some embodiments, the *-associated cancer is a CARD14-associated cancer. In some embodiments, the *-associated cancer is an A20-associated cancer. In some embodiments, the *-associated cancer is a CYLD-associated cancer. In some embodiments, the *-associated cancer is a RelB-associated cancer. In some embodiments, the *-associated cancer is a HOIL1-associated cancer. In some embodiments, the *-associated cancer is a NIK-associated cancer. In some embodiments, the *- associated cancer is a Regnase 1-associated cancer. In some embodiments, the *-associated cancer is a LIMA1α-associated cancer. In some embodiments, the *-associated cancer is a roquin-1-associated cancer. In some embodiments, the *-associated cancer is a TRAF6-associated cancer. In some embodiments, the *-associated cancer is a TAK1-associated cancer. In some embodiments, the *-associated cancer is a TAB1- associated cancer. In some embodiments, the *-associated cancer is a TAB2-associated cancer. In some embodiments, the *-associated cancer is a TAB3-associated cancer. In some embodiments, the *-associated cancer is a MKK7-associated cancer, and an IKKα-associated cancer. In some embodiments, the *- associated cancer is an IKKβ-associated cancer. In some embodiments, the *-associated cancer is an IKKγ- associated cancer. In some embodiments, the *-associated cancer is an IkBα-associated cancer. In some embodiments, the *-associated cancer is a p50-associated cancer. In some embodiments, the *-associated cancer is a p65-associated cancer. In some embodiments, the *-associated cancer is a c-Rel-associated cancer. In some embodiments, the *-associated cancer is a JNK1-associated cancer. In some embodiments, the *-associated cancer is a JNK2-associated cancer. In some embodiments, the *-associated cancer is a JNK3-associated cancer. In some embodiments, the *-associated cancer is a AP-1 transcription factor- associated cancer. In some embodiments, the *-associated cancer is a MYD88 transcription factor- associated cancer.

[0074] Diseases or disorders “associated” with a particular gene or protein described herein refer to diseases or disorder associated with or having a dysregulation of the particular gene, the particular protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of the particular gene, the particular protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of such diseases or disorders are described herein. Likewise, cancers “associated” with a particular gene or protein described herein refer to cancers associated with or having a dysregulation of the particular gene, the particular protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of the particular gene, the particular protein, or the expression or activity or level of any of the same described herein). Non- limiting examples of such cancers are described herein.

[0075] The term “cancer associated with a signal transducer between a cell surface receptor and a CBM complex” as used herein refers to cancers associated with or having a dysregulation of a gene, aAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) protein, or the expression or activity or level of any (e.g., one or more) of the same associated with a signal transducer between a cell surface receptor and a CBM complex. In some embodiments, a cancer associated with a signal transducer between a cell surface receptor and a CBM complex is selected from the group consisting of a PKCβ-associated cancer, PCKθ-associated cancer, and a combination thereof. The cancers “associated” with a particular gene or protein described in this paragraph refer to cancers associated with or having a dysregulation of the particular gene, the particular protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of the particular gene, the particular protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of such cancers are described herein.

[0076] The term “component of a CBM complex-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a gene, a protein, or the expression or activity or level of any (e.g., one or more) of the same associated with a component of a CBM complex. In some embodiments, a component of a CBM complex-associated cancer is selected from the group consisting of a MALT1- associated cancer, a CARD11-associated cancer, a CARD14-associated cancer, a CARD10-associated cancer, a CARD9-associated cancer, a BCL10-associated cancer, and combinations thereof. In some embodiments, a CBM complex-associated cancer is selected from the group consisting of a MALT1- associated cancer, a CARD11-associated cancer, a BCL10-associated cancer, and combinations thereof. The cancers “associated” with a particular gene or protein described in this paragraph refer to cancers associated with or having a dysregulation of the particular gene, the particular protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of the particular gene, the particular protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of such cancers are described herein.

[0077] The term “MALT1-associated autoimmune disorder” as used herein refers to autoimmune disorders associated with or having a dysregulation of a MALT1 gene, a MALT1 protein (also called herein MALT1 protease protein or MALT1 protease), or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a MALT1 gene, a MALT1 protease, a MALT1 protease domain, or the expression or activity or level of any of the same described herein). Non-limiting examples of a MALT1-associated autoimmune disorders are described herein.

[0078] The term “MALT1-associated inflammatory disorder” as used herein refers to inflammatory disorders associated with or having a dysregulation of a MALT1 gene, a MALT1 protein (also called herein MALT1 protease protein or MALT1 protease), or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a MALT1 gene, a MALT1 protease, a MALT1Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) protease domain, or the expression or activity or level of any of the same described herein). Non-limiting examples of a MALT1-associated inflammatory disorders are described herein.

[0079] The term “MALT1-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a MALT1 gene, a MALT1 protein (also called herein MALT1 protease protein or MALT1 protease), or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a MALT1 gene, a MALT1 protein, a MALT1 protease domain, or the expression or activity or level of any of the same described herein). Non-limiting examples of a MALT1- associated cancer are described herein.

[0080] The phrase “dysregulation of a MALT1 gene, a MALT1 protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a MALT1 protease domain and a fusion partner, a mutation in a MALT1 gene that results in the expression of a MALT1 protein that includes a deletion of at least one amino acid as compared to a wild-type MALT1 protein, a mutation in a MALT1 gene that results in the expression of a MALT1 protein with one or more point mutations as compared to a wild-type MALT1 protein, a mutation in a MALT1 gene that results in the expression of a MALT1 protein with at least one inserted amino acid as compared to a 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), an alternative spliced version of a MALT1 mRNA that results in a MALT1 protein having a deletion of at least one amino acid in the MALT1 protein as compared to the wild-type MALT1 protein, or increased expression (e.g., increased levels) of a wild-type MALT1 protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a MALT1 gene, a MALT1 protein, or expression or activity, or level of any of the same, can be a mutation in a MALT1 gene that encodes a MALT1 protein that is constitutively active or has increased activity as compared to a protein encoded by a MALT1 gene that does not include the mutation. As a further example, an increased copy number of the MALT1 gene can result in overexpression of MALT1 protease. For example, a dysregulation of a MALT1 gene, a MALT1 protein, or expression or activity, or level of any of the same, can be the result of a gene or chromosome translocation which results in the expression of a fusion protein that contains a first portion of MALT1 that includes a functional protease domain, and a second portion of a partner protein (i.e., that is not MALT1). In some examples, dysregulation of a MALT1 gene, a MALT1 protein, or expression or activity or level of any of the same can be a result of a gene translocation of one MALT1 gene with another non-MALT1 gene.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0081] Non-limiting examples of dysregulation of a MALT1 gene or a MALT1 protein are shown in Table B1 below. Table B1. MALT1 Protein Amino Acid Substitutions / Insertions / Deletions Amino Acid Position(s)Non-limiting ExemplaryNon-Limiting Exemplary MutationsMALT1 associated Cancers ra3United States Patent Application Publication US20130096021A1 4United States Patent Application Publication US20150320754A1

[0082] The term “CARD11-associated autoimmune disorder” as used herein refers to autoimmune disorders associated with or having a dysregulation of a CARD11 gene, a CARD11 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD11 gene, a CARD11 protein, or the expression or activity or level of any of the same described herein).

[0083] The term “CARD11-associated inflammatory disorder” as used herein refers to inflammatory disorders associated with or having a dysregulation of a CARD11 gene, a CARD11 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD11 gene, a CARD11 protein, or the expression or activity or level of any of the same described herein).

[0084] The term “CARD11-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a CARD11 gene, a CARD11 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD11 gene, a CARD11 protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a CARD11-associated cancer are described herein.

[0085] The phrase “dysregulation of a CARD11 gene, a CARD11 protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a CARD11 domain and a fusion partner, a mutation in a CARD11 gene that results in the expression of a CARD11 protein that includes a deletion of at least one amino acid as compared to a wild-type CARD11 protein, a mutation in a CARD11 gene that results in the expression of a CARD11 protein with one or more point mutations as compared to a wild-type CARD11Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) protein, a mutation in a CARD11 gene that results in the expression of a CARD11 protein with at least one inserted amino acid as compared to a wild-type CARD11 protein, a gene duplication that results in an increased level of CARD11 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 CARD11 protein in a cell), an alternative spliced version of a CARD11 mRNA that results in a CARD11 protein having a deletion of at least one amino acid in the CARD11 protein as compared to the wild-type CARD11 protein, or increased expression (e.g., increased levels) of a wild-type CARD11 protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a CARD11 gene, a CARD11 protein, or expression or activity, or level of any of the same, can be a mutation in a CARD11 gene that encodes a CARD11 protein that is constitutively active or has increased activity as compared to a protein encoded by a CARD11 gene that does not include the mutation. As a further example, an increased copy number of the CARD11 gene can result in overexpression of CARD11 protein. For example, a dysregulation of a CARD11 gene, a CARD11 protein, or expression or activity, or level of any of the same, can be the result of a gene or chromosome translocation which results in the expression of a fusion protein that contains a first portion of CARD11, and a second portion of a partner protein (i.e., that is not CARD11). In some examples, dysregulation of a CARD11 gene, a CARD11 protein, or expression or activity or level of any of the same can be a result of a gene translocation of one CARD11 gene with another non-CARD11 gene.

[0086] Non-limiting examples of dysregulation of a CARD11 gene or a CARD11 protein are shown in Table B2 below. Table B2. CARD11 Protein Amino Acid Substitutions / Insertions / Deletions Amino Acid Position(s) Non-limiting Exemplary Non-Limiting ExemplaryAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) CARD11 Protein Amino Acid Substitutions / Insertions / Deletions Amino Acid Position(s) Non-limiting Exemplary Non-Limiting Exemplary Mutations CARD11-associated Cancers

[0087] The term “CARD14-associated autoimmune disorder” as used herein refers to autoimmune disorders associated with or having a dysregulation of a CARD14 gene, a CARD14 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD14 gene, a CARD14 protein, or the expression or activity or level of any of the same described herein).

[0088] The term “CARD14-associated inflammatory disorder” as used herein refers to inflammatory disorders associated with or having a dysregulation of a CARD14 gene, a CARD14 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD14 gene, a CARD14 protein, or the expression or activity or level of any of the same described herein).

[0089] The term “CARD14-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a CARD14 gene, a CARD14 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD14 gene, a CARD14 protein, or the expression or activity or level of any of the same described herein).

[0090] The term “CARD10-associated autoimmune disorder” as used herein refers to autoimmune disorders associated with or having a dysregulation of a CARD10 gene, a CARD10 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD10 gene, a CARD10 protein, or the expression or activity or level of any of the same described herein).Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0091] The term “CARD10-associated inflammatory disorder” as used herein refers to inflammatory disorders associated with or having a dysregulation of a CARD10 gene, a CARD10 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD10 gene, a CARD10 protein, or the expression or activity or level of any of the same described herein).

[0092] The term “CARD10-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a CARD10 gene, a CARD10 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD10 gene, a CARD10 protein, or the expression or activity or level of any of the same described herein).

[0093] The phrase “dysregulation of a CARD10 gene, a CARD10 protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a CARD10 domain and a fusion partner, a mutation in a CARD10 gene that results in the expression of a CARD10 protein that includes a deletion of at least one amino acid as compared to a wild-type CARD10 protein, a mutation in a CARD10 gene that results in the expression of a CARD10 protein with one or more point mutations as compared to a wild-type CARD10 protein, a mutation in a CARD10 gene that results in the expression of a CARD10 protein with at least one inserted amino acid as compared to a wild-type CARD10 protein, a gene duplication that results in an increased level of CARD10 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 CARD10 protein in a cell), an alternative spliced version of a CARD10 mRNA that results in a CARD10 protein having a deletion of at least one amino acid in the CARD10 protein as compared to the wild-type CARD10 protein, or increased expression (e.g., increased levels) of a wild-type CARD10 protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a CARD10 gene, a CARD10 protein, or expression or activity, or level of any of the same, can be a mutation in a CARD10 gene that encodes a CARD10 protein that is constitutively active or has increased activity as compared to a protein encoded by a CARD10 gene that does not include the mutation. As a further example, an increased copy number of the CARD10 gene can result in overexpression of CARD10 protein. For example, a dysregulation of a CARD10 gene, a CARD10 protein, or expression or activity, or level of any of the same, can be the result of a gene or chromosome translocation which results in the expression of a fusion protein that contains a first portion of CARD10, and a second portion of a partner protein (i.e., that is not CARD10). In some examples, dysregulation of a CARD10 gene, a CARD10 protein, or expression or activity or level of any of the same can be a result of a gene translocation of one CARD10 gene with another non-CARD10 gene.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0094] The term “CARD9-associated autoimmune disorder” as used herein refers to autoimmune disorders associated with or having a dysregulation of a CARD9 gene, a CARD9 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD9 gene, a CARD9 protein, or the expression or activity or level of any of the same described herein).

[0095] The term “CARD9-associated inflammatory disorder” as used herein refers to inflammatory disorders associated with or having a dysregulation of a CARD9 gene, a CARD9 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD9 gene, a CARD9 protein, or the expression or activity or level of any of the same described herein).

[0096] The term “CARD9-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a CARD9 gene, a CARD9 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CARD9 gene, a CARD9 protein, or the expression or activity or level of any of the same described herein).

[0097] The phrase “dysregulation of a CARD9 gene, a CARD9 protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a CARD9 domain and a fusion partner, a mutation in a CARD9 gene that results in the expression of a CARD9 protein that includes a deletion of at least one amino acid as compared to a wild-type CARD9 protein, a mutation in a CARD9 gene that results in the expression of a CARD9 protein with one or more point mutations as compared to a wild-type CARD9 protein, a mutation in a CARD9 gene that results in the expression of a CARD9 protein with at least one inserted amino acid as compared to a 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), an alternative spliced version of a CARD9 mRNA that results in a CARD9 protein having a deletion of at least one amino acid in the CARD9 protein as compared to the wild-type CARD9 protein, or increased expression (e.g., increased levels) of a wild-type CARD9 protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a CARD9 gene, a CARD9 protein, or expression or activity, or level of any of the same, can be a mutation in a CARD9 gene that encodes a CARD9 protein that is constitutively active or has increased activity as compared to a protein encoded by a CARD9 gene that does not include the mutation. As a further example, an increased copy number of the CARD9 gene can result in overexpression of CARD9 protein. For example, a dysregulation of a CARD9 gene, a CARD9 protein, or expression or activity, or level of any of the same, can be the result of a gene or chromosome translocation which results in the expression of a fusion protein that contains a first portion of CARD9, and a second portion of a partner protein (i.e., that is not CARD9). In someAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) examples, dysregulation of a CARD9 gene, a CARD9 protein, or expression or activity or level of any of the same can be a result of a gene translocation of one CARD9 gene with another non-CARD9 gene.

[0098] The term “BCL10-associated autoimmune disorder” as used herein refers to autoimmune disorders associated with or having a dysregulation of a BCL10 gene, a BCL10 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a BCL10 gene, a BCL10 protein, or the expression or activity or level of any of the same described herein).

[0099] The term “BCL10-associated inflammatory disorder” as used herein refers to inflammatory disorders associated with or having a dysregulation of a BCL10 gene, a BCL10 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a BCL10 gene, a BCL10 protein, or the expression or activity or level of any of the same described herein).

[0100] The term “BCL10-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a BCL10 gene, a BCL10 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a BCL10 gene, a BCL10 protein, or the expression or activity or level of any of the same described herein).

[0101] The phrase “dysregulation of a BCL10 gene, a BCL10 protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a BCL10 domain and a fusion partner, a mutation in a BCL10 gene that results in the expression of a BCL10 protein that includes a deletion of at least one amino acid as compared to a wild-type BCL10 protein, a mutation in a BCL10 gene that results in the expression of a BCL10 protein with one or more point mutations as compared to a wild-type BCL10 protein, a mutation in a BCL10 gene that results in the expression of a BCL10 protein with at least one inserted amino acid as compared to a wild-type BCL10 protein, a gene duplication that results in an increased level of BCL10 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of BCL10 protein in a cell), an alternative spliced version of a BCL10 mRNA that results in a BCL10 protein having a deletion of at least one amino acid in the BCL10 protein as compared to the wild-type BCL10 protein, or increased expression (e.g., increased levels) of a wild-type BCL10 protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). For example, a dysregulation of a BCL10 gene, a BCL10 protein, or expression or activity, or level of any of the same, can be the result of a gene or chromosome translocation which results in the expression of a fusion protein that contains a first portion of BCL10, and a second portion of a partner protein (i.e., that is not BCL10). In some examples, dysregulation of a BCL10 gene, a BCL10 protein, or expression or activity or level of any of the same can be a result of a gene translocation of one BCL10 gene with another non-BCL10 gene.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0102] Non-limiting examples of dysregulation of a BCL10 gene or a BCL10 protein are shown in Table B3 below. Table B3. BCL10 Protein Amino Acid Substitutions / Insertions / Deletions Amino Acid Position(s) Non-limiting Exemplary Non-Limiting Exemplary Mutations BCL10 associated Cancers 1 2

[003] e term protease substrate-assoc ated cancer as used ere n re ers to cancers associated with or having a dysregulation of a gene, a protein, or the expression or activity or level of any (e.g., one or more) of the same associated with a MALT1 protease substrate. In some embodiments, a MALT1 protease substrate-associated cancer is selected from the group consisting of a BCL10-associatedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) cancer, an A20-associated cancer, a CYLD-associated cancer, a RelB-associated cancer, a Regnase 1- associated cancer, a roquin-1-associated cancer, a HOIL1-associated cancer, a NIK associated cancer, a LIMA1α-associated cancer, and combinations thereof. In some embodiments, a MALT1 protease substrate- associated cancer is selected from the group consisting of a BCL10-associated cancer, an A20-associated cancer, a CYLD-associated cancer, and combinations thereof. The cancers “associated” with a particular gene or protein described in this paragraph refer to cancers associated with or having a dysregulation of the particular gene, the particular protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of the particular gene, the particular protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of such cancers are described herein.

[0104] Non-limiting examples of dysregulation of an A20 gene or an A20 protein are shown in Table B4 below. Table B4. A20 Protein Amino Acid Substitutions / Insertions / Deletions Amino Acid Position(s) Non-limiting Exemplary Non-Limiting Exemplary A20- a2, . . .

[0105] The term “cancer associated with a component of the NF-κB pathway downstream of a CBM complex” as used herein refers to cancers associated with or having a dysregulation of a gene, a protein, or the expression or activity or level of any (e.g., one or more) of the same associated with a component of the NF-κB pathway downstream of a CBM complex. In some embodiments, a cancer associated with a component of the NF-κB pathway downstream of a CBM complex is selected from the group consisting of a TAK1-associated cancer, a TRAF6-associated cancer, a TAB1-associated cancer, a TAB2-associated cancer, a TAB3-associated cancer, a MKK7-associated cancer, an IKKα-associated cancer, an IKKβ- associated cancer, an IKKγ-associated cancer, an IkBα-associated cancer, a p50-associated cancer, a p65 (RelA)-associated cancer, a c-Rel-associated cancer, and combinations thereof. In some embodiments, a cancer associated with a component of the NF-κB pathway downstream of a CBM complex is an IKKγ- associated cancer. The cancers “associated” with a particular gene or protein described in this paragraphAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) refer to cancers associated with or having a dysregulation of the particular gene, the particular protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of the particular gene, the particular protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of such cancers are described herein.

[0106] The term “cancer associated with a component of the JNK pathway downstream of a CBM complex” as used herein refers to cancers associated with or having a dysregulation of a gene, a protein, or the expression or activity or level of any (e.g., one or more) of the same associated with a component of the JNK pathway downstream of a CBM complex. In some embodiments, a cancer associated with a component of the JNK pathway downstream of a CBM complex is selected from the group consisting of a JNK1- associated cancer, a JNK2-associated cancer, a JNK3-associated cancer, a MYD88 transcription factor- associated cancer, an AP-1 transcription factor-associated cancer, and combinations thereof. The cancers “associated” with a particular gene or protein described in this paragraph refer to cancers associated with or having a dysregulation of the particular gene, the particular protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of the particular gene, the particular protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of such cancers are described herein. Compounds of the Disclosure

[0107] In one aspect, the invention relates to a compound of formula (I): , or a pharmaceutically acceptable saltX is CH, CF, or N; Y is CH, CF, or N; R1is H, halo, or C1-C3 alkyl; R2is H, halo, C1-C3 alkyl;Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) R0, R3, and R4are defined as follows: (i) R0is H; R3is C1-C6 alkyl, C1-C6 haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6haloalkyl; and R4is C1-C6alkyl; or (ii) R0is H; and R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl or a 4-7 membered heterocyclyl; or (iii) R0and R3, together with the carbon atoms to which they are attached, form a C3-C7 cycloalkyl; and R4is C1-C6 alkyl; R5is H or halo; R6is H or halo; and R7and R8are defined as follows: (i) R7is C1-C6 alkyl; and R8is C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; or (ii) R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; provided that no more than one of X and Y is N.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0108] In some embodiments, the invention relates to a compound of formula (I), wherein the compound is of formula (I-1): , or a pharmaceutically acceptable salt

[0109] In some embodiments, to a compound of formula (I), wherein the compound is of formula (I-2a): , or a pharmaceutically acceptable saltAttorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0110] In some embodiments, the invention relates to a compound of formula (I), wherein the compound is of formula (I-2b): , or a pharmaceutically acceptable salt

[0111] In some embodiments, to a of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CH. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CF. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is N.

[0112] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein Y is CH. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein Y is CF. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein Y is N.

[0113] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CH and Y is CH. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CF and Y is CH. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is N and Y is CH. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CH and Y is CF. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CH and Y is N.

[0114] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R1is H.

[0115] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R2is F.

[0116] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R1is H and R2is F.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0117] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R0is H.

[0118] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R3is C1-C6alkyl, C1-C6haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6haloalkyl. In other embodiments, R3is C1-C6alkyl. In other embodiments, R3is C1-C6 haloalkyl. In other embodiments, R3is or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6 haloalkyl. In other embodiments, R3is or 4-7 membered heteroaryl, wherein said heteroaryl is substituted with 1 C1-C6 haloalkyl. In other embodiments, R3is or 5-membered heteroaryl, wherein said heteroaryl is substituted with 1 C1-C6 haloalkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein Inor (I-2b), wherein R4is C1-C6 alkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R4is CH3.

[0120] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl. In other embodiments, R3and R4, together with the carbon atom to which they are attached, form a C3-C4 cycloalkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R3and R4, together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl. In other embodiments, R3and R4, together with the carbon atom to which they are attached, form a cyclopropyl. In other embodiments, R3and R4, together with the carbon atom to which they are attached, form a cyclobutyl.

[0121] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R0and R3, together with the carbon atoms to which they are attached, form a C3-C7cycloalkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R0and R3, together with the carbon atoms to which they are attached, form a cyclobutyl.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0122] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R3is C1-C6alkyl and R4is C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R3is CH3 and R4is CH3. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R3is C1-C6haloalkyl and R4is C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R3is CF3 and R4is CH3. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R0and R3, together with the carbon atoms to which they are attached, form a cyclobutyl and R4is CH3.

[0123] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R1is H, R2is F, R3is C1-C6 alkyl, and R4is C1-C6 alkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R1is H, R2is F, R3is CH3, and R4is CH3. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R1is H, R2is F, R3is C1-C6 haloalkyl, and R4is C1-C6 alkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R1is H, R2is F, R3is CF3, and R4is CH3. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R1is H, R2is F, R0and R3, together with the carbon atoms to which they are attached, form a cyclobutyl, and R4is CH3.

[0124] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R5is halo. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R5is H or F. In other embodiments, R5is H. In other embodiments, R5is F.

[0125] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R6is H or halo. In other embodiments, R6is halo. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R6is H or F. In other embodiments, R6is H. In other embodiments, R6is F.

[0126] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R5is H and R6is H. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R5is H and R6is halo. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R5is H and R6is F. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R5is halo and R6is H. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R5is F and R6is H.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0127] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R7is C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R7is CH3.

[0128] In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R8is C3-C6cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo. In other embodiments, R8is C3-C6 cycloalkyl. In other embodiments, R8is 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo. In other embodiments, R8is 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R8is C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo. In other embodiments, R8is 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2oxo. In other embodiments, R8is 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R8,. In other embodiments, R8. In otheris, , , or (I-2b), wherein R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; and R6is H. In some embodiments, the invention relates to a compoundAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) of formula (I), (I-1), (I-2a), or (I-2b), wherein R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; and R6is H. In some embodiments, the invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; and R6is H.

[0130] In some embodiments, the invention relates to a compound of formula (I-A): ,or a pharmaceutically acceptable salt thereof, wherein: X is CH, CF, or N; Y is CH, CF, or N; R0, R3, and R4are defined as follows: (i) R0is H; R3is C1-C6 alkyl, C1-C6 haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6haloalkyl; and R4is C1-C6 alkyl; or (ii) R0is H; and R3and R4, together with the carbon atom to which they are attached, form a C3-C7cycloalkyl or a 4-7 membered heterocyclyl; or (iii) R0and R3, together with the carbon atoms to which they are attached, form a C3-C7cycloalkyl; and R4is C1-C6alkyl; R5is H or halo;Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) R6is H or halo; and R8is C3-C6cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; provided that no more than one of X and Y is N.

[0131] In some embodiments, the invention relates to a compound of formula (I-A), wherein the compound is of formula (I-A-1): , or a pharmaceutically acceptable salt

[0132] In some embodiments, the invention relates to a compound of formula (I-A), wherein the compound is of formula (I-A-2a): , or a pharmaceutically acceptable saltAttorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0133] In some embodiments, the invention relates to a compound of formula (I-A), wherein the compound is of formula (I-A-2b): , or a pharmaceutically acceptable salt

[0134] In some embodiments, to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein X is CH. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein X is CF. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein X is N.

[0135] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein Y is CH. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein Y is CF. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein Y is N.

[0136] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R0is H.

[0137] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R3is C1-C6alkyl, C1-C6haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6haloalkyl. In other embodiments, R3is C1-C6alkyl. In other embodiments, R3is C1-C6haloalkyl. In other embodiments, R3is or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6 haloalkyl. In other embodiments, R3is or 4-7 membered heteroaryl, wherein said heteroaryl is substituted with 1 C1-C6 haloalkyl. In other embodiments, R3is or 5-membered heteroaryl, wherein said heteroaryl is substituted with 1 C1-C6haloalkyl. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b),Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) other embodiments, R3is CH3. In other embodiments, R3is CF3.In other .

[0138] In some invention relates to a compound of formula (I-A), (I-A-1),(I-A-2a), or (I-A-2b), C6 alkyl. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R4is CH3.

[0139] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R3and R4, together with the carbon atom to which they are attached, form a C3-C4 cycloalkyl. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R3and R4, together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl. In other embodiments, R3and R4, together with the carbon atom to which they are attached, form a cyclopropyl. In other embodiments, R3and R4, together with the carbon atom to which they are attached, form a cyclobutyl.

[0140] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R0and R3, together with the carbon atoms to which they are attached, form a C3-C7 cycloalkyl. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R0and R3, together with the carbon atoms to which they are attached, form a cyclobutyl.

[0141] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R5is halo. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R5is H or F. In other embodiments, R5is H. In other embodiments, R5is F.

[0142] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R6is halo. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R6is H or F. In other embodiments, R6is H. In other embodiments, R6is F.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0143] In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R8is C3-C6cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo. In other embodiments, R8is C3-C6 cycloalkyl. In other embodiments, R8is 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R8is C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo. In other embodiments, R8is 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo. In some embodiments, the invention relates to a compound of formula (I-A), (I-A-1), (I-A-2a), or (I-A-2b), wherein R8,. In other embodiments, ., or a pharmaceutically acceptable saltAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) X is CH, CF, or N; Y is CH, CF, or N; R3and R4are defined as follows: (i) R3is C1-C6alkyl or C1-C6haloalkyl; and R4is C1-C6alkyl; or (ii) R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl or a 4-7 membered heterocyclyl; R5is H or halo; R6is H or halo; and R9and R10,together with the carbon atom to which they are attached, join together to form a 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; provided that no more than one of X and Y is N.

[0145] In some embodiments, the invention relates to a compound of formula (I-B), wherein the compound is of formula (I-B-1): , or a pharmaceutically acceptable saltAttorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0146] In some embodiments, the invention relates to a compound of formula (I-B), wherein the compound is of formula (I-B-2a): , or a pharmaceutically acceptable salt

[0147] In some embodiments, the invention relates to a compound of formula (I-B), wherein the compound is of formula (I-B-2b): , or a pharmaceutically acceptable salt

[0148] In some embodiments, the invention relates to a compound of formula (I-B), (I-B-1), (I-B-2a), or (I-B-2a), wherein X is CH.

[0149] In some embodiments, the invention relates to a compound of formula (I-B), (I-B-1), (I-B-2a), or (I-B-2a), wherein Y is CH.

[0150] In some embodiments, the invention relates to a compound of formula (I-B), (I-B-1), (I-B-2a), or (I-B-2a), wherein R3is C1-C6 alkyl. In some embodiments, the invention relates to a compound of formula (I-B), (I-B-1), (I-B-2a), or (I-B-2a), wherein R3is CH3.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0151] In some embodiments, the invention relates to a compound of formula (I-B), (I-B-1), (I-B-2a), or (I-B-2a), wherein R4is C1-C6alkyl. In some embodiments, the invention relates to a compound of formula (I-B), (I-B-1), (I-B-2a), or (I-B-2a), wherein R4is CH3.

[0152] In some embodiments, the invention relates to a compound of formula (I-B), (I-B-1), (I-B-2a), or (I-B-2a), wherein R5is H.

[0153] In some embodiments, the invention relates to a compound of formula (I-B), (I-B-1), (I-B-2a), or (I-B-2a), wherein R6is H.

[0154] In some embodiments, R9and R10, together with the carbon atom to which they are attached, join together to form a C3-C7 cycloalkyl. In other embodiments, R9and R10, together with the carbon atom to which they are attached, join together to form a 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo. In other embodiments, R9and R10, together with the carbon atom to which they are attached, join together to form a 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo. In some embodiments, the invention relates to a compound of formula (I-C), wherein R9and R10, together with the carbon atom to which they are attached, join together to form a C3-C7 cycloalkyl or 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo. In other embodiments, R9and R10, together with the carbon atom to which they are attached, join together to form a 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo. In other embodiments, R9and R10, together with the carbon atom to which they are attached, join together to form a 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo. In some embodiments, the invention relates to a compound of formula (I-C), wherein R9and R10, together with the carbon atom to which they are attached, join together to form a tetrahydropyranyl or 1,1-dioxo-tetrahydrothiopyranyl.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0155] In some embodiments, the invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A, i.e., the compound in non-salt form.

[0156] Table A. o- l- - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) - - ar 8- arAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) F o- l- - 8- -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) o- l- 8-Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) o- 8- - - - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) - - - o- l- -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) 8- - o- l- -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) - - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) o- 8- - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) o- az - - - - - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) o- - - - - - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) - '- - - - - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) )- )- - )- )- -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) )- 2 )- - - - )-Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) 8- )- o- a- H- - - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) o- a- H- - - - - o- a- H- - - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) 2- - - - - - - - - -Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) - - - - - 3- 2-Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) F F N F 3- 2- 3- 2-Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

[0157] As discussed herein, the invention provides compounds, and pharmaceutically acceptable salts thereof, that are inhibitors of MALT1, and thus the present compounds, and pharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions including, but not limited to cancers, autoimmune disorders, and inflammatory disorders. Accordingly, in another aspect of the invention, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents, as described herein.

[0158] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of a compound of this invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of MALT1.

[0159] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compound of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0160] As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasingAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0161] In another aspect, the invention features a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0162] In another aspect, the invention features a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles. Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0163] In another aspect, the invention features a method of inhibiting MALT1 in a subject, comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0164] In yet another aspect, the invention features a method of treating a cancer, an autoimmune disorder, or an inflammatory disorder in a subject, comprising administering to the subject an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0165] Some embodiments provide a method of treating an autoimmune disorder (e.g., a MALT1- associated autoimmune disorder) in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of the invention, 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). In some embodiments, the autoimmune disorder is rheumatoid arthritis. In some embodiments, the autoimmune disorder is multiple sclerosis.

[0166] Some embodiments provide a method of treating an inflammatory disorder (e.g., a MALT1- associated inflammatory disorder) in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the inflammatory disorder is chronic graft versus host disease (cGVHD).

[0167] Some embodiments provide a method of treating cancer (e.g., a MALT1-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. For example, provided herein are methods for treating a MALT1-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a MALT1 gene,Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) a MALT1 protease, or the expression or activity or level of any of the same in a sample from the subject; and b) administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a MALT1 gene, a MALT1 protease, or the expression or activity or level of any of the same includes one or more fusion proteins.

[0168] In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1- associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-associated cancer) is a lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), 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 neoplasms, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, mammary neoplasm, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-associated cancer) is selected from the group of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adolescents, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, unknown primary carcinoma, cardiac tumors, cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct cancer, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasms, head and neck neoplasms, CNS tumor, primary CNS tumor, heart cancer, hepatocellular cancer, histiocytosis, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma,Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) macroglobulinemia, malignant fibrous histiocytoma of bone, osteocarcinoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, neoplasms by site, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, lung neoplasm, pulmonary cancer, pulmonary neoplasms, respiratory tract neoplasms, bronchogenic carcinoma, bronchial neoplasms, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromosytoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colonic neoplasms, renal cell cancer, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, Spitz tumors, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis, unknown primary carcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms’ tumor.

[0169] In some embodiments, the cancer is a hematological cancer, such as a leukemia or a lymphoma. In some embodiments, a hematological cancer (e.g., hematological cancers that are MALT1-associated cancers) is selected from the group consisting of leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large- cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM). Additional examples of hematological cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer (e.g., the hematological cancer that is a MALT1-associated cancer) is AML or CMML.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0170] In some embodiments, the cancer is glioblastoma, chronic myelogenous leukemia, myeloid leukemia, or non-Hodgkin’s lymphoma.

[0171] In some embodiments, the cancer (e.g., the MALT1-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are MALT1-associated cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, small-cell lung carcinoma), 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.

[0172] In some embodiments, the cancer is selected from diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT lymphoma), chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), and an advanced solid tumor. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the cancer is mantle cell lymphoma (MCL). In some embodiments, the cancer is marginal zone B-cell lymphoma (MZL). In some embodiments, the cancer is mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the cancer is an advanced solid tumors.

[0173] In some embodiments, the subject is a human.

[0174] Compounds of the invention and pharmaceutically acceptable salts thereof are also useful for treating a MALT1-associated cancer. Compounds of the invention and pharmaceutically acceptable salts thereof are also useful for treating a MALT1-associated autoimmune disorder. Compounds of the invention and pharmaceutically acceptable salts thereof are also useful for treating a MALT1-associated inflammatory disease.

[0175] Accordingly, also provided herein is a method for treating a subject diagnosed with or identified as having a MALT1-associated cancer, e.g., any of the exemplary MALT1-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0176] Also provided herein is a method for treating a CBM complex pathway-associated cancer (such as any of those disclosed herein) in a subject in need thereof, including administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. AlsoAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) provided is a method for treating a cancer in a subject in need thereof, including (a) identifying the cancer as being a CBM complex pathway-associated cancer; and (b) administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0177] Identifying the cancer identifying the cancer in the subject as a CBM complex pathway- associated cancer can be performed by any appropriate method. In some embodiments, the step of identifying the cancer in the subject as a CBM complex pathway-associated cancer includes performing an assay to detect dysregulation in a CBM complex pathway-associated gene, a CBM complex pathway- associated protease protein, or expression or activity or level of any of the same in a sample from the subject. In some embodiments, the method further includes obtaining a sample from the subject (e.g., a biopsy sample). An assay can be any appropriate assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0178] Also provided herein is a method for treating a cancer in a subject in need thereof, including administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof to a subject identified as having a CBM complex pathway-associated cancer.

[0179] Also provided herein is a method of treating a MALT1-associated cancer in a subject, including administering to a subject identified or diagnosed as having a MALT1-associated cancer an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. Provided herein is also a method for treating cancer in a subject in need thereof, including: (a) determining that the cancer is associated with a dysregulation of a MALT1 gene, a MALT1 protease, or expression or activity or level of any of the same; and (b) administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0180] Determining that the cancer is associated with a dysregulation of a MALT1 gene, a MALT1 protease, or expression or activity or level of any of the same can be performed using any appropriate method. In some embodiments, the step of determining that the cancer in the subject is a MALT1-associated cancer includes performing an assay to detect dysregulation in a MALT1 gene, a MALT1 protease protein, or expression or activity or level of any of the same in a sample from the subject. In some embodiments, the method further includes obtaining a sample from the subject (e.g., a biopsy sample). An assay can be any appropriate assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0181] As described herein, a CBM complex pathway-associated cancer can be any appropriate CBM complex pathway-associated cancer (such as any of those described herein). In some embodiments, a CBMAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) complex pathway-associated cancer is selected from the group consisting of a CBM complex pathway cell surface receptor-associated cancer, a cancer associated with a signal transducer between a cell surface receptor and a CBM complex, a component of a CBM complex-associated cancer, a MALT1 protease substrate-associated cancer, a cancer associated with a component of the NF-κB pathway downstream of a CBM complex, a cancer associated with a component of the JNK pathway downstream of a CBM complex, and a combination thereof. In some embodiments, the CBM complex pathway cell surface receptor- associated cancer is selected from the group consisting of a CD28-associated cancer, a BCR-associated cancer, a HER1-associated cancer, a HER2-associated cancer, and combinations thereof. In some embodiments, the cancer associated with a signal transducer between a cell surface receptor and a CBM complex is a protein kinase C beta (PKCβ)-associated cancer, a protein kinase C theta (PCKθ)-associated cancer, or a combination thereof. In some embodiments, the component of a CBM complex-associated cancer is selected from the group consisting of a MALT1-associated cancer, a CARD11-associated cancer, a CARD14-associated cancer, a CARD10-associated cancer, a CARD9-associated cancer, a BCL10- associated cancer, and combinations thereof. In some embodiments, the component of a CBM complex- associated cancer is selected from the group consisting of a MALT1-associated cancer, a CARD11- associated cancer, a BCL10-associated cancer, and combinations thereof. See, e.g., Tables B1, B2, and B3 for exemplary dysregulations in MALT1, CARD11, and BCL10. In some embodiments, the MALT1 protease substrate-associated cancer is selected from the group consisting of a BCL10-associated cancer, an A20-associated cancer, a CYLD-associated cancer, a RelB-associated cancer, a Regnase 1-associated cancer, a roquin-1-associated cancer, a HOIL1-associated cancer, a NIK associated cancer, a LIMA1α- associated cancer, and a combination thereof. In some embodiments, the MALT1 protease substrate- associated cancer is selected from the group consisting of a BCL10-associated cancer, an A20-associated cancer, a CYLD-associated cancer, and combinations thereof. See, e.g., Tables B3 and B4 for exemplary dysregulations in BCL10 and A20. In some embodiments, the cancer associated with a component of the NF-κB pathway downstream of a CBM complex is selected from the group consisting of a TAK1-associated cancer, a TRAF6-associated cancer, a TAB1-associated cancer, a TAB2-associated cancer, a TAB3- associated cancer, a MKK7-associated cancer, an IKKα-associated cancer, an IKKβ-associated cancer, an IKKγ-associated cancer, an IkBα-associated cancer, a p50-associated cancer, a p65 (RelA)-associated cancer, a c-Rel-associated cancer, and combinations thereof. In some embodiments, the cancer associated with a component of the NF-κB pathway downstream of a CBM complex is an IKKγ-associated cancer. In some embodiments, the cancer associated with a component of the JNK pathway downstream of a CBM complex is selected from the group consisting of a JNK1-associated cancer, a JNK2-associated cancer, aAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) JNK3-associated cancer, a MYD88 transcription factor-associated cancer, an AP-1 transcription factor- associated cancer, and combinations thereof.

[0182] In some embodiments, the CBM complex pathway-associated cancer is a MALT1-associated cancer. A MALT1-associated cancer can have any appropriate dysregulation, such as any of those described herein. In some embodiments, the MALT1-associated cancer comprises an IAP2-MALT1 fusion. In some embodiments, the MALT1-associated cancer comprises an IGH-MALT1 fusion.

[0183] Also provided herein are methods of treating CBM complex pathway-associated diseases or disorders, autoimmune disorders, and inflammatory disorders. Accordingly, provided herein is a method for treating an autoimmune disorder in a subject in need thereof, including administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. Also provided herein is a method of treating a MALT1-associated autoimmune disorder in a subject, including administering to a subject identified or diagnosed as having a MALT1-associated autoimmune disorder an effective amount of a compound of the invention, 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, including: (a) determining that the autoimmune disorder is associated with a dysregulation of a MALT1 gene, a MALT1 protease, or expression or activity or level of any of the same; and (b) administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. Provided also herein is a method of treating a MALT1-associated autoimmune disorder in a subject, including administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof to a subject determined to have a MALT1-associated autoimmune disorder. In addition, provided herein is a method for treating an inflammatory disorder in a subject in need thereof, including administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In some cases, provided herein is a method of treating a MALT1- associated inflammatory disorder in a subject, including administering to a subject identified or diagnosed as having a MALT1-associated inflammatory disorder an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating an inflammatory disorder in a subject in need thereof, including: (a) determining that the inflammatory disorder is associated with a dysregulation of a MALT1 gene, a MALT1 protease, or expression or activity or level of any of the same; and (b) administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. Provided also herein is a method of treating a MALT1-associated inflammatory disorder in a subject, including administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof to a subject determined to have a MALT1- associated inflammatory disorder.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0184] Additionally provided herein is a method for treating a CBM complex pathway-associated disease or disorder in a subject in need thereof, including administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. Also provided is a method for treating a disease or disorder in a subject in need thereof, including: (a) identifying the cancer as being a CBM complex pathway-associated disease or disorder; and (b) administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In addition, provided herein is a method for treating a disease or disorder in a subject in need thereof, including: administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof to a subject identified as having a CBM complex pathway-associated disease or disorder.

[0185] A CBM complex pathway-associated disease or disorder can be any appropriate CBM complex pathway-associated disease or disorder, such as any of those described herein. In some embodiments, the CBM complex pathway-associated disease or disorder is an autoimmune disease. In some embodiments, the CBM complex pathway-associated disease or disorder is an inflammatory disease. In some embodiments, the CBM complex pathway-associated cancer is selected from the group consisting of a CBM complex pathway cell surface receptor-associated cancer, a disease or disorder associated with a signal transducer between a cell surface receptor and a CBM complex, a component of a CBM complex-associated cancer, a MALT1 protease substrate-associated cancer, a disease or disorder associated with a component of the NF-κB pathway downstream of a CBM complex, a disease or disorder associated with a component of the JNK pathway downstream of a CBM complex, and a combination thereof. In some embodiments, the CBM complex pathway-associated disease or disorder is a MALT1-associated disease or disorder.

[0186] In some cases, compounds of the invention, or a pharmaceutically acceptable salt thereof can be useful for inhibiting the processes of cells, such as inhibiting the proliferation of cells. Accordingly, provided herein is a method for inhibiting mammalian cell proliferation, including contacting the mammalian cell with a compound of the invention, or a pharmaceutically acceptable salt thereof. Also provided herein is a method for inhibiting CBM complex pathway activity in a mammalian cell, including contacting the mammalian cell with a compound of the invention, or a pharmaceutically acceptable salt thereof. Provided also herein is a method for inhibiting MALT1 protease activity in a mammalian cell, including contacting the mammalian cell with a compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. A mammalian cell can be any appropriate cell. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian CBM complex pathway- associated cancer cell. In some embodiments, the mammalian cancer cell is a mammalian MALT1-Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) associated cancer cell. In some embodiments, the mammalian cell has dysregulation of a MALT1 gene, a MALT1 protease protein, or expression or activity or level of any of the same. In some embodiments, the dysregulation of a MALT1 gene, a MALT1 protease protein, or expression or activity or level of any of the same is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0187] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting a MALT1 protease in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in an effective amount. For example, treatment of a subject with cancer (e.g., a MALT1-associated cancer such as a MALT1-associated brain or CNS cancer) can include administration (e.g., oral administration) of the compound to the subject. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor. For example, the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, the tumors listed in Louis, D.N. et al. Acta Neuropathol 131(6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the subject has previously been treated with another anticancer agent, e.g., another protease inhibitor (e.g., a compound that is not a compound of the invention). In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the subject has previously been treated with another anticancer agent, e.g., another protease inhibitor (e.g., a compound that is not a compound of the invention).

[0188] In some embodiments of any of the methods or uses described herein, an assay used to determine whether the subject has a dysregulation of a gene (e.g., a MALT1 gene), or a protein (e.g., a MALT1 protein), or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of a gene (e.g., a MALT1 gene), a protein (e.g., a MALT1 protein), or expression or activity or levels of any of the same. 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-associated cancer, a subject having one or more symptoms of aAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) MALT1-associated cancer, and / or a subject that has an increased risk of developing a MALT1-associated cancer).

[0189] Although the genetic basis of tumorigenesis may vary between different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During a metastatic cascade, the cancer cells lose growth inhibitory responses, undergo alterations in adhesiveness and produce enzymes that can degrade extracellular matrix components. This leads to detachment of tumor cells from the original tumor, infiltration into the circulation through newly formed vasculature, migration and extravasation of the tumor cells at favorable distant sites where they may form colonies.

[0190] Accordingly, also provided herein are methods for inhibiting, preventing, aiding in the prevention, or decreasing the symptoms of metastasis of a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Such methods can be used in the treatment of one or more of the cancers described herein. See, e.g., US Publication No. 2013 / 0029925; International Publication No. WO 2014 / 083567; and US Patent No. 8,568,998. See also, e.g., Hezam K et al., Rev Neurosci 2018 Jan 26;29:93-98; Gao L, et al., Pancreas 2015 Jan;44:134-143; Ding K et al., J Biol Chem 2014 Jun 6; 289:16057-71; and Amit M et al., Oncogene 2017 Jun 8; 36:3232- 3239. In some embodiments, the cancer is a MALT1-associated cancer. In some embodiments, the compound of the invention, 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.

[0191] The term “metastasis” is an art known term and means the formation of an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject, where the additional tumor includes the same or similar cancer cells as the primary tumor.

[0192] Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a MALT1-associated cancer that include: selecting, identifying, or diagnosing a subject as having a MALT1-associated cancer, and administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having a MALT1-associated cancer. Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a MALT1-associated cancer that includes administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof to a subject having a MALT1-associated cancer. The decrease in the risk of developing a metastasis or an additional metastasis in a subject having a MALT1-associated cancer can be compared to the risk ofAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) developing a metastasis or an additional metastasis in the subject prior to treatment, or as compared to a subject or a population of subjects having a similar or the same MALT1-associated cancer that has received no treatment or a different treatment.

[0193] The phrase “risk of developing a metastasis” means the risk that a subject having a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject over a set period of time, where the additional tumor includes the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing a metastasis in a subject having a cancer are described herein.

[0194] The phrase “risk of developing additional metastases” means the risk that a subject having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors include the same or similar cancer cells as the primary tumor) will develop one or more further tumors distant from the primary tumor, where the further tumors include the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastasis are described herein.

[0195] Some embodiments described herein provide methods of treating an autoimmune disorder (e.g., a MALT1-associated autoimmune disorder), such as rheumatoid arthritis, multiple sclerosis, and SLE, the method comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0196] Some embodiments described herein provide methods of treating an inflammatory disorder (e.g., a MALT1-associated autoimmune disorder), such as chronic graft versus host disease, the method comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0197] Also provided is a method for inhibiting MALT1 protease activity in a mammalian cell, comprising contacting the mammalian cell with a compound of the invention. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of the invention, 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 as described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell.

[0198] Also provided is a method for inhibiting MALT1 protease activity in a mammalian cell, comprising contacting the mammalian cell with a compound of the invention. In some embodiments, theAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of the invention, 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 as described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell. In some embodiments, the mammalian cell is a gastrointestinal mammalian cell.

[0199] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a MALT1 protease with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a MALT1 protease, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing the MALT1 protease.

[0200] Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo, the method comprising contacting a mammalian cell with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0201] A “MALT1 protease inhibitor” as defined herein includes any compound exhibiting MALT1 inhibition activity. In some embodiments, a MALT1 protease inhibitor is selective for a MALT1 protease. Exemplary MALT1 protease inhibitors can exhibit inhibition activity (IC50) against a MALT1 protease of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein. In some embodiments, a MALT1 protease inhibitor can exhibit inhibition activity (IC50) against a MALT1 protease of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.

[0202] As used herein, a “first MALT1 protease inhibitor” or “first MALT1 inhibitor” is a MALT1 protease inhibitor as defined herein, but which does not include a compound of the invention, or a pharmaceutically acceptable salt thereof as defined herein. As used herein, a “second MALT1 protease inhibitor” or a “second MALT1 inhibitor” is a MALT1 protease inhibitor as defined herein, but which does not include a compound of the invention, or a pharmaceutically acceptable salt thereof as defined herein. When both a first and a second MALT1 inhibitor are present in a method provided herein, the first and second MALT1 protease inhibitor are different.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0203] Exemplary first and second MALT1 protease inhibitors are described herein. In some embodiments, a first or second MALT1 protease inhibitor can be, for example, JNJ-67856633 or CTX-177.

[0204] In yet another aspect, the invention features a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition.

[0205] The phrase “effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a MALT1-associated disease or disorder (such as a MALT1-associated cancer), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the invention, or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

[0206] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0207] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting MALT1 in a subject.

[0208] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating cancer, an autoimmune disorder, or an inflammatory disorder.

[0209] Some embodiments provide a compound of the invention, 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) in a subject. In some embodiments, the autoimmune disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE). In some embodiments, the autoimmune disorder is rheumatoid arthritis. In some embodiments, the autoimmune disorder is multiple sclerosis.

[0210] Some embodiments provide a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating an inflammatory disorder (e.g., a MALT1-associated inflammatory disorder) in a subject. In some embodiments, the inflammatory disorder is chronic graft versus host disease (cGVHD).Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0211] Some embodiments provide a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating cancer (e.g., a MALT1- associated cancer) in a subject. In some embodiments, the dysregulation of a MALT1 gene, a MALT1 protease, or the expression or activity or level of any of the same includes one or more fusion proteins.

[0212] Accordingly, also provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating a subject diagnosed with or identified as having a MALT1-associated cancer, e.g., any of the exemplary MALT1-associated cancers disclosed herein.

[0213] Also provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating a CBM complex pathway-associated cancer (such as any of those disclosed herein) in a subject.

[0214] Also provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a cancer in a subject identified as having a CBM complex pathway-associated cancer.

[0215] Also provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a MALT1-associated cancer in a subject.

[0216] In some embodiments, the cancer is selected from diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT lymphoma), chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), and an advanced solid tumor. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the cancer is mantle cell lymphoma (MCL). In some embodiments, the cancer is marginal zone B-cell lymphoma (MZL). In some embodiments, the cancer is mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the cancer is an advanced solid tumors.

[0217] Also provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in methods of treating CBM complex pathway-associated diseases or disorders, autoimmune disorders, and inflammatory disorders in a subject. Accordingly, provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating an autoimmune disorder in a subject. Also providedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a MALT1-associated autoimmune disorder in a subject. Provided also herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a MALT1-associated autoimmune disorder in a subject. In addition, provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating an inflammatory disorder in a subject. In some cases, provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a MALT1-associated inflammatory disorder in a subject identified or diagnosed as having a MALT1-associated inflammatory disorder. Provided also herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a MALT1-associated inflammatory disorder in a subject determined to have a MALT1-associated inflammatory disorder.

[0218] Additionally provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a CBM complex pathway- associated disease or disorder in a subject. In addition, provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a disease or disorder in a subject identified as having a CBM complex pathway-associated disease or disorder.

[0219] Also provided herein is a compound of the invention, 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 the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting CBM complex pathway activity in a mammalian cell. Provided also herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting MALT1 protease activity in a mammalian cell. A mammalian cell can be any appropriate cell. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian CBM complex pathway-associated cancer cell. In some embodiments, the mammalian cancer cell is a mammalian MALT1-associated cancer cell. In some embodiments, the mammalian cell has dysregulation of a MALT1 gene, a MALT1 protease protein, or expression or activity or level of any of the same. In some embodiments, the dysregulation of a MALT1 gene, a MALT1 protease protein, or expression or activity or level of any of the same is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0220] Also provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in methods of inhibiting, preventing, aiding in the prevention,Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) or decreasing the symptoms of metastasis of a cancer in a subject. Such methods can be used in the treatment of one or more of the cancers described herein. See, e.g., US Publication No. 2013 / 0029925; International Publication No. WO 2014 / 083567; and US Patent No. 8,568,998. See also, e.g., Hezam K et al., Rev Neurosci 2018 Jan 26;29:93-98; Gao L, et al., Pancreas 2015 Jan;44:134-143; Ding K et al., J Biol Chem 2014 Jun 6; 289:16057-71; and Amit M et al., Oncogene 2017 Jun 8; 36:3232-3239. In some embodiments, the cancer is a MALT1-associated cancer. In some embodiments, the compound of the invention, 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.

[0221] Also provided are a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a MALT1-associated cancer. The decrease in the risk of developing a metastasis or an additional metastasis in a subject having a MALT1-associated cancer can be compared to the risk of developing a metastasis or an additional metastasis in the subject prior to treatment, or as compared to a subject or a population of subjects having a similar or the same MALT1-associated cancer that has received no treatment or a different treatment.

[0222] Some embodiments described herein provide a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in methods of treating an autoimmune disorder (e.g., a MALT1-associated autoimmune disorder), such as rheumatoid arthritis, multiple sclerosis, and SLE in a subject.

[0223] Some embodiments described herein provide a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in methods of treating an inflammatory disorder (e.g., a MALT1-associated autoimmune disorder), such as chronic graft versus host disease in a subject.

[0224] Also provided is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of 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 as described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell.

[0225] Also provided herein is a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting mammalian cell proliferation.

[0226] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method wherein the subject is treatedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. Manufacture of Medicaments

[0227] In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0228] In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in inhibiting MALT1 in a subject.

[0229] In yet another aspect, the invention provides the use of a compound of the invention, 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.

[0230] Some embodiments provide the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating an autoimmune disorder (e.g., a MALT1-associated autoimmune disorder) in a subject. In some embodiments, the autoimmune disorder is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE). In some embodiments, the autoimmune disorder is rheumatoid arthritis. In some embodiments, the autoimmune disorder is multiple sclerosis.

[0231] Some embodiments provide the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating an inflammatory disorder (e.g., a MALT1-associated inflammatory disorder) in a subject. In some embodiments, the inflammatory disorder is chronic graft versus host disease (cGVHD).

[0232] Some embodiments provide the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating cancer (e.g., a MALT1-associated cancer) in a subject. In some embodiments, the dysregulation of a MALT1 gene, a MALT1 protease, or the expression or activity or level of any of the same includes one or more fusion proteins.

[0233] Accordingly, also provided herein is the use of a compound of the invention, 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-associated cancer, e.g., any of the exemplary MALT1-associated cancers disclosed herein.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0234] Also provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating a CBM complex pathway-associated cancer (such as any of those disclosed herein) in a subject.

[0235] Also provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating a cancer in a subject identified as having a CBM complex pathway-associated cancer.

[0236] Also provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating a MALT1-associated cancer in a subject.

[0237] In some embodiments, the cancer is selected from diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT lymphoma), chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), and an advanced solid tumor. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the cancer is mantle cell lymphoma (MCL). In some embodiments, the cancer is marginal zone B-cell lymphoma (MZL). In some embodiments, the cancer is mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the cancer is an advanced solid tumors.

[0238] Also provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating CBM complex pathway-associated diseases or disorders, autoimmune disorders, and inflammatory disorders in a subject. Accordingly, provided herein is the use of a compound of the invention, 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 the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating a MALT1-associated autoimmune disorder in a subject. Provided also herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating a MALT1-associated autoimmune disorder in a subject. In addition, provided herein is the use of a compound of the invention, 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,Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating a MALT1- associated inflammatory disorder in a subject identified or diagnosed as having a MALT1-associated inflammatory disorder. Provided also herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or 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.

[0239] Additionally provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating a CBM complex pathway-associated disease or disorder in a subject. In addition, provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating a disease or disorder in a subject identified as having a CBM complex pathway-associated disease or disorder.

[0240] Also provided herein is the use of a compound of the invention, 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 the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting CBM complex pathway activity in a mammalian cell. Provided also herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting MALT1 protease activity in a mammalian cell. A mammalian cell can be any appropriate cell. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian CBM complex pathway-associated cancer cell. In some embodiments, the mammalian cancer cell is a mammalian MALT1-associated cancer cell. In some embodiments, the mammalian cell has dysregulation of a MALT1 gene, a MALT1 protease protein, or expression or activity or level of any of the same. In some embodiments, the dysregulation of a MALT1 gene, a MALT1 protease protein, or expression or activity or level of any of the same is an IAP2- MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0241] Also provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting, preventing, aiding in the prevention, or decreasing the symptoms of metastasis of a cancer in a subject. In some embodiments, the cancer is a MALT1-associated cancer. In some embodiments, the compound of the invention, or a pharmaceutically acceptable salt thereof is used in combination with anAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) additional therapy or another therapeutic agent, as described herein. For example, a first or second MALT1 protease inhibitor.

[0242] Also provided is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in decreasing the risk of developing a metastasis or an additional metastasis in a subject having a MALT1-associated cancer. The decrease in the risk of developing a metastasis or an additional metastasis in a subject having a MALT1- associated cancer can be compared to the risk of developing a metastasis or an additional metastasis in the subject prior to treatment, or as compared to a subject or a population of subjects having a similar or the same MALT1-associated cancer that has received no treatment or a different treatment.

[0243] Some embodiments described herein provide the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating an autoimmune disorder (e.g., a MALT1-associated autoimmune disorder), such as rheumatoid arthritis, multiple sclerosis, and SLE in a subject.

[0244] Some embodiments described herein provide the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in treating an inflammatory disorder (e.g., a MALT1-associated autoimmune disorder), such as chronic graft versus host disease in a subject.

[0245] Also provided is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, 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 as described herein. In some embodiments, the mammalian cancer cell is a MALT1-associated mammalian cancer cell.

[0246] Also provided herein is the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in inhibiting mammalian cell proliferation.

[0247] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0248] When employed as pharmaceuticals, compounds of the invention, including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions. TheseAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can 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.

[0249] Also provided herein are pharmaceutical compositions which contain, as the active ingredient, a compound of the invention or pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients. For example, a pharmaceutical composition prepared using a compound of the invention or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft 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.

[0250] Further provided herein are pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof as the active ingredient can be prepared by intimately mixing the compound of the invention, or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending upon theAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0251] 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 Pharmaceutical Society of Great Britain.

[0252] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

[0253] In preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be employed. Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Solid oral preparations can also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients can be added to increase solubility or preservation. Injectable suspensions or solutions can also be prepared utilizing aqueous carriers along with appropriate additives. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described herein.

[0254] The compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of the invention or a pharmaceutically acceptable salt thereof ) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0255] In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.

[0256] In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient.

[0257] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0258] The daily dosage of the compound of the invention or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg / kg to about 1000 mg / kg of body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 500 mg / kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 250 mg / kg of body weight per day, or any range therein. More preferably, from about 0.1 to about 100 mg / kg of body weight per day, or any range therein. In an example, the range can be from about 0.1 to about 50.0 mg / kg of body weight per day, or any amount or range therein. In another example, the range can be from about 0.1 to about 15.0 mg / kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg / kg of body weight per day, or any amount to range therein.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day or in a single daily dose.

[0259] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will be understood, therefore, that the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement of the disease condition. In addition, factors associated with the particular 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 dosages.

[0260] 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 compound provided herein can be administered in an amount of about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg.

[0261] One skilled in the art will recognize that both in vivo and in vitro trials using suitable, 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.

[0262] One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy subjects and / or those suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0263] Provided herein are pharmaceutical kits useful, for example, in the treatment of MALT1- associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Additional Therapeutic Agents

[0264] In the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other protease inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies.

[0265] For example, a surgery may be open surgery or minimally invasive surgery. Compounds of the invention, or a pharmaceutically acceptable salt thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of the invention, or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of the invention, or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of the invention, or a pharmaceutically acceptable salt thereof for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of the invention, or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0266] In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent), such as a first MALT1 inhibitor, a kinase inhibitor, immunotherapy, cell or gene therapy, or radiation (e.g., radioactive iodine). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a first MALT1 inhibitor or another protease inhibitor, immunotherapy, cell or gene therapy, or radiation (e.g., radioactive iodine). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is MALT1-protease inhibitor naïve. For example, the subject is naïve to treatment with a selective MALT1-protease inhibitor. In some embodiments, a subject is not MALT1-protease inhibitor naïve.

[0267] In some embodiments of any of the methods described herein, the compound of the invention, or a pharmaceutically acceptable salt thereof, is administered in combination with an effective amount ofAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic or immunomodulatory) agents. An additional therapy or therapeutic agent can be any appropriate additional therapy or therapeutic agent, such as any of those described herein.

[0268] Non-limiting examples of additional therapeutic agents include: other MALT1-targeted therapeutic agents (i.e. a first or second MALT1 protease inhibitor, e.g., JNJ-67856633 or CTX-177), other protease inhibitors, kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents such as BTK or EGFR inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., venetoclax or obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents (including antibody and cell-based immunotherapies, and antibody-drug conjugates) and radiotherapy.

[0269] In some embodiments, the compound of the invention, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of the invention, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order.

[0270] In some embodiments, the other MALT1-targeted therapeutic is another protease inhibitor exhibiting MALT1 inhibition activity. In some embodiments, the other MALT1-targeted therapeutic inhibitor is selective for a MALT1 protease. Exemplary MALT1 protease inhibitors can exhibit inhibition activity (IC50) against a MALT1 protease of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein. In some embodiments, a MALT1 protease inhibitors can exhibit inhibition activity (IC50) against a MALT1 protease of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.

[0271] Non-limiting examples of protease-targeted therapeutic agents (e.g., a first MALT1 inhibitor or a second MALT1 inhibitor) include JNJ-67856633 and CTX-177.

[0272] Non-limiting examples of multi-kinase inhibitors include alectinib (9-Ethyl-6,6-dimethyl-8-[4- (morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile); amuvatinib (MP470, HPK56) (N-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1- carbothioamide); apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl) phenyl-2-(4-picolyl)amino-3- Nicotinamide methanesulphonate); 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-Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one); fedratinib (SAR302503, TG101348) (N-(2-Methyl-2-propanyl)-3-{[5-methyl-2-({4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4- pyrimidinyl]amino}benzenesulfonamide); foretinib (XL880, EXEL-2880, GSK1363089, GSK089) (N1'- [3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]phenyl]-N1-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide); fostamantinib (R788) (2H-Pyrido[3,2-b]-1,4-oxazin- 3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4- [(phosphonooxy)methyl]-, sodium salt (1:2)); ilorasertib (ABT-348) (1-(4-(4-amino-7-(1-(2- hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea); lenvatinib (E7080, Lenvima) (4-[3-chloro-4- ( cyclopropylaminocarbonyl)aminophenoxy ]-7-methoxy-6- quinolinecarboxamide); motesanib (AMG 706) (N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin- 4-ylmethyl)amino]pyridine-3-carboxamide); nintedanib (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)- methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methyoxycarbonyl-2-indolinone); ponatinib (AP24534) (3-(2-Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1- yl)methyl]-3-(trifluoromethyl)phenyl]benzamide); PP242 (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, agerafenib) (1-(3-((6,7-dimethoxyquinazolin-4- yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea); semaxanib (SU5416) ((3Z)- 3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one); sitravatinib (MGCD516, MG516) (N-(3-Fluoro-4-{[2-(5-{[(2-methoxyethyl)amino]methyl}-2-pyridinyl)thieno[3,2-b]pyridin-7- yl]oxy}phenyl)-N’-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide); sorafenib (BAY 43-9006) (4-[4- [[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2- pyridinecarboxamide); vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4- yl)methoxy]quinazolin-4-amine); vatalanib (PTK787, PTK / ZK, ZK222584) (N-(4-chlorophenyl)-4- (pyridin-4-ylmethyl)phthalazin- 1-amine); AD-57 (N-[4-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]-N'-[3-(trifluoromethyl)phenyl]-urea); AD-80 (1-[4-(4-amino-1-propan-2- ylpyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea); AD-81 (1-(4-(4- amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea); ALW-II-41-27 (N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide); BPR1K871 (1-(3- chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)propoxy)quinazolin-4-yl)amino)ethyl)thiazol-2-yl)urea); CLM3 (1-phenethyl-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); EBI-907 (N-(2-chloro-3-Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) (1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]isoquinolin-7-yl)-4-fluorophenyl)-3-fluoropropane-1- sulfonamide); NVP-AST-487 (N-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-N'-[4-[[6- (methylamino)-4-pyrimidinyl]oxy]phenyl]-urea); NVP-BBT594 (BBT594) (5-((6-acetamidopyrimidin-4- yl)oxy)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide); PD173955 (6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one); PP2 (4-amino-5-(4-chlorophenyl)-7-(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)methylidene]-5,6-dimethoxy-1H-indol-2-one); SGI-7079 (3-[2-[[3-fluoro-4-(4-methyl-1- piperazinyl)phenyl]amino]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-benzeneacetonitrile); SPP86 (1- Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); SU4984 (4-[4-[(E)-(2-oxo-1H- indol-3-ylidene)methyl]phenyl]piperazine-1-carbaldehyde); sunitinb (SU11248) (N-(2- Diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxamide); TG101209 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1- yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide); Withaferin A ((4β,5β,6β,22R)-4,27- Dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-1,26-dione); XL-999 ((Z)-5-((1-ethylpiperidin-4- yl)amino)-3-((3-fluorophenyl)(5-methyl-1H-imidazol-2-yl)methylene)indolin-2-one); BPR1J373 (a 5- phenylthiazol-2-ylamine-pyriminide derivative); CG-806 (CG'806); DCC-2157; GTX-186; HG-6-63-01 ((E)-3-(2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)-4-methylbenzamide); SW-01 (Cyclobenzaprine hydrochloride); XMD15-44 (N- (4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3- ylethynyl)benzamide (generated from structure)); ITRI-305 (D0N5TB, DIB003599); BLU-667 ((1S,4R)- N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H- pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide); BLU6864; DS-5010; GSK3179106; GSK3352589; NMS-E668; TAS0286 / HM05; TPX0046; and N-(3-(2-(dimethylamino)ethoxy)-5- (trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide.

[0273] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeted therapeutic agents, include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, 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, Gö 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-Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]-urea, AZ623, AZ64, (S)-5-Chloro-N2-(1-(5- fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine, AZD7451, CEP- 751, CT327, sunitinib, GNF-8625, and (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2- b]pyridazin-3-yl)-[2,4'-bipyridin]-2'-yl)piperidin-4-ol.

[0274] In some embodiments, the additional therapeutic agent is a BRAF inhibitor. Non-limiting examples of a BRAF inhibitor include dabrafenib, vemurafenib (also called 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 a BRAF inhibitor are known in the art.

[0275] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor typrosine kinase inhibitor (EGFR). For example, EGFR inhibitors can include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0276] In some embodiments, the additional therapeutic agent is a Ras-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib), PI3K-Akt- mTOR-S6K pathway inhibitors (e.g., everolimus, rapamycin, perifosine, temsirolimus), and other kinase inhibitors, such as baricitinib, brigatinib, capmatinib, danusertib, ibrutinib, milciclib, quercetin, regorafenib, ruxolitinib, semaxanib, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736 ((R)-amino-N-[5,6-dihydro- 2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1Hpyrrolo[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).

[0277] In some embodiments, the additional therapeutic agent is a BTK inhibitor. Non-limiting examples of BTK inhibitors include ibrutinib, acalabrutinib, and zanubrutinib.

[0278] In some embodiments, the additional therapeutic agent is a Bcl-2 inhibitor. Non-limiting examples of Bcl-2 inhibitors include venetoclax, navitoclax, oblimersen, obatoclax, and AT-101.

[0279] 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.

[0280] In some embodiments, the additional therapeutic agent is a mTOR inhibitor. Non-limiting examples of mTOR inhibitors include everolimus, temsirolimus, and ridaforolimus.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0281] In some embodiments, the additional therapeutic agent is a HDAC inhibitor. Non-limiting examples of HDAC inhibitors include vorinostat, romidepsin, belinostat, chidamide, panobinostat, CXD101, and abexinostat.

[0282] 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.

[0283] In some embodiments, the additional therapeutic agent is a cytotoxic chemotherapeutic. Non- limiting example of cytotoxic chemotherapeutics include arsenic trioxide, bleomycin, bendamustine, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

[0284] In some embodiments, the additional therapeutic agent is an angiogenesis-targeted therapeutic. Non-limiting examples of angiogenesis-targeted therapies include lenalidomide, enzastaurine, aflibercept, and bevacizumab.

[0285] In some embodiments, an additional therapy or therapeutic agent can include a histidyl-tRNA synthetase (HRS) polypeptide or an expressible nucleotide that encodes the HRS polypeptide.

[0286] The term “immunotherapy” refers to an agent that modulates the immune system. In some embodiments, an immunotherapy can increase the expression and / or activity of a regulator of the immune system. In some embodiments, an immunotherapy can decrease the expression and / or activity of a regulator of the immune system. In some embodiments, an immunotherapy can recruit and / or enhance the activity of an immune cell.

[0287] In some embodiments, the immunotherapy is a cellular immunotherapy (e.g., adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101-108). In some embodiments, the cellular immunotherapy includes cells that express 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.

[0288] 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 isAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®), rituximab with human hyaluronidase (Rituxan HycelaTM), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG- 1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), avelumab (Bavencio®), necitumumab (Portrazza™), cirmtuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), lenzilumab, avelumab, spartalizumab, pembrolizumab, utomilumab, ublituximab, blinatumomab ganitumab, urelumab, pidilizumab, amatuximab, mosunetuzumab (BTCT4465A), CD20- TCB, RO7082859, XmAb13676, glofitamab, CD20-TDB, odronextamab (REGN1979), IGM-2323, BTCT4465A, AMG-562, or TTI-621.

[0289] In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM-1; Kadcyla®), mirvetuximab soravtansine (IMGN853), anetumab ravtansine, polatuzumab vedotine, loncastuximab tesirine (ADCT-402), camidanlumab tesirine (ADCT-301), or naratuximab emtansine (Debio 1562).

[0290] In some embodiments, the immunotherapy includes blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).

[0291] In some embodiments, the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

[0292] In some embodiments, the immunotherapy is a cytokine therapy. In some embodiments, the cytokine therapy is an interleukin 2 (IL-2) therapy, an interferon alpha (IFNα) therapy, a granulocyte colony stimulating factor (G-CSF) therapy, an interleukin 12 (IL-12) therapy, an interleukin 15 (IL-15) therapy, an interleukin 7 (IL-7) therapy or an erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNα therapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapy is filgrastim (Neupogen®).

[0293] In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the immunotherapy includes one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP- 675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumabAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®) or durvalumab (Imfinzi™).

[0294] In some embodiments, the immunotherapy is 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).

[0295] In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG) therapy.

[0296] In some embodiments, the immunotherapy is an oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC; Imlygic®).

[0297] In some embodiments, the immunotherapy is a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is Gardasil®, Gardasil9® or Cervarix®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®, Recombivax HB® or GI-13020 (Tarmogen®). In some embodiments, the cancer vaccine is Twinrix® or Pediarix®. In some embodiments, the cancer vaccine is BiovaxID®, Oncophage®, GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®, Rindopepimut®, CimaVax-EGF, lapuleucel-T (APC8024; Neuvenge™), GRNVAC1, GRNVAC2, GRN- 1201, hepcortespenlisimut-L (Hepko-V5), DCVAX®, SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac, or viagenpumatucel-L (HS-110).

[0298] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax™), 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 mammaglobin-A DNA vaccine (see, e.g., Kim et al. (2016) OncoImmunology 5(2): e1069940).

[0299] In some embodiments, immune-targeted agents are selected from aldesleukin, interferon alfa- 2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

[0300] In some embodiments, the additional therapy is radiotherapy. Non-limiting examples of radiotherapy include radioiodide therapy, external-beam radiation, and radium 223 therapy.

[0301] 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.

[0302] Additional kinase inhibitors include those described in, for example, U.S. Patent No. 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.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Publication No. US 2015 / 0018336; International Publication No. 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 2012 / 113774; WO 2015 / 191666; WO 2015 / 161277; WO 2015 / 161274; WO 2015 / 108992; WO 2015 / 061572; WO 2015 / 058129; WO 2015 / 057873; WO 2015 / 017528; WO / 2015 / 017533; WO 2014 / 160521; and WO 2014 / 011900, each of which is hereby incorporated by reference in its entirety.

[0303] In some embodiments, the subject was previously administered one or more standard of care therapies for a lymphoma. In some embodiments, the previously administered standard of care therapy is polatuzumab vedotine, selinexor, axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), bendamustine in combination with rituximab and polatuzumab vedotin, tafasitamab in combination with lenalidomide, or rituximab with human hyaluronidase (Rituxan Hycela).

[0304] In some embodiments, the subject is concomitantly receiving standard of care therapy for a lymphoma. In some embodiments, the standard of care therapy is polatuzumab vedotine, selinexor, axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), bendamustine in combination with rituximab and polatuzumab vedotin, tafasitamab in combination with lenalidomide, or rituximab with human hyaluronidase (Rituxan Hycela). Synthesis of the Compounds of the Invention

[0305] The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[0306] The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0307] Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1stEd., Oxford University Press, 2000; March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thEd., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997). Radiolabeled Analogs of the Compounds of the Invention

[0308] In another aspect, the invention relates to radiolabeled analogs of the compounds of the invention. As used herein, the term “radiolabeled analogs of the compounds of the invention” refers to compounds that are identical to the compounds of the invention, as described herein, including all embodiments thereof, except that one or more atoms has been replaced with a radioisotope of the atom present in the compounds of the invention.

[0309] As used herein, the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include3H,14C,32P,35S,18F,36Cl, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0310] The radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium (3H)- and / or carbon-14 (14C)-labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.

[0311] In another aspect, the invention relates to pharmaceutically acceptable salts of the radiolabeled analogs, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0312] In another aspect, the invention relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0313] In another aspect, the invention relates to methods of inhibiting MALT1 in a subject and methods of treating or lessening the severity of various diseases and disorders, including cancer, autoimmune disorders, and inflammatory disorders, in a subject comprising administering an effective amount of the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceuticalAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) compositions thereof, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0314] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0315] In another aspect, the invention relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0316] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the invention. ENUMERATED EMBODIMENTS

[0317] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds and methods of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[0318] 1. A compound of formula (I): , or a pharmaceutically acceptable saltX is CH, CF, or N; Y is CH, CF, or N;Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) R1is H, halo, or C1-C3alkyl; R2is H, halo, or C1-C3alkyl; R0, R3, and R4are defined as follows: (i) R0is H; R3is C1-C6alkyl, C1-C6haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6 haloalkyl; and R4is C1-C6 alkyl; or (ii) R0is H; and R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl or a 4-7 membered heterocyclyl; or (iii) R0and R3, together with the carbon atoms to which they are attached, form a C3-C7 cycloalkyl; and R4is C1-C6 alkyl; R5is H or halo; R6is H or halo; and R7and R8are defined as follows: (i) R7is C1-C6 alkyl; and R8is C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; or (ii) R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; provided that no more than one of X and Y is N.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0319] 2. The compound of clause 1, wherein the compound is of formula (I-1): , or a pharmaceutically acceptable salt

[0320] 3. The compound of or is of formula (I-2a): , or a pharmaceutically acceptable salt

[0321] 4. The compound of clause 1 or 2, wherein the compound is of formula (I-2b): ,Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) or a pharmaceutically acceptable salt thereof.

[0322] 5. The compound of any one of clauses 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0323] 6. The compound of any one of clauses 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is CF.

[0324] 7. The compound of any one of clauses 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0325] 8. The compound of any one of clauses 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

[0326] 9. The compound of any one of clauses 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is CF.

[0327] 10. The compound of any one of clauses 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is N.

[0328] 11. The compound of any one of clauses 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is H.

[0329] 12. The compound of any one of clauses 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2is F.

[0330] 13. The compound of any one of clauses 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3is C1-C6 alkyl, C1-C6 haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6 haloalkyl.

[0331] 14. The compound of clause 13, or a pharmaceutically acceptable salt thereof, wherein R3is .of any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R4is CH3.

[0333] 16. The compound of any one of clauses 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl.

[0334] 17. The compound of clause 16, wherein R3and R4, or a pharmaceutically acceptable salt thereof, together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0335] 18. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R0is H.

[0336] 19. The compound of any one of clauses 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R0and R3, together with the carbon atoms to which they are attached, form a C3-C7cycloalkyl.

[0337] 20. The compound of clause 19, wherein R0and R3, or a pharmaceutically acceptable salt thereof, together with the carbon atoms to which they are attached, form a cyclobutyl and R4is CH3.

[0338] 21. The compound of any one of clauses 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R5is H or F.

[0339] 22. The compound of any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R6is H or F.

[0340] 23. The compound of any one of clauses 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R7is C1-C6 alkyl.

[0341] 24. The compound of clause 23, wherein R7is CH3.

[0342] 25. The compound of any one of clauses 1 to 24, wherein R8is C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo.

[0343] 26. The compound of clause 25, or.27. The compound of any one of clauses 1 to 22, wherein R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0345] 28. The compound of clause 1, wherein the compound has formula (I-A): ,or a pharmaceutically acceptable salt thereof, wherein: X is CH, CF, or N; Y is CH, CF, or N; R0, R3, and R4are defined as follows: (i) R0is H; R3is C1-C6 alkyl, C1-C6 haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6 haloalkyl; and R4is C1-C6 alkyl; or (ii) R0is H; and R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl or a 4-7 membered heterocyclyl; or (iii) R0and R3, together with the carbon atoms to which they are attached, form a C3-C7cycloalkyl; and R4is C1-C6alkyl; R5is H or halo; R6is H or halo; and R8is C3-C6cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; and provided that no more than one of X and Y is N.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0346] 29. The compound of clause 28, wherein the compound is of formula (I-A-1): , or a pharmaceutically acceptable salt

[0347] 30. The compound of or compound is of formula (I-A-2a): , or a pharmaceutically acceptable salt

[0348] 31. The compound of clause 28 or 29, wherein the compound is of formula (I-A-2b): ,Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) or a pharmaceutically acceptable salt thereof.

[0349] 32. The compound of any one of clauses 28 to 31, or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0350] 33. The compound of any one of clauses 28 to 31, or a pharmaceutically acceptable salt thereof, wherein X is CF.

[0351] 34. The compound of any one of clauses 28 to 31, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0352] 35. The compound of any one of clauses 28 to 34, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

[0353] 36. The compound of any one of clauses 28 to 34, or a pharmaceutically acceptable salt thereof, wherein Y is CF.

[0354] 37. The compound of any one of clauses 28 to 34, or a pharmaceutically acceptable salt thereof, wherein Y is N.

[0355] 38. The compound of any one of clauses 28 to 37, or a pharmaceutically acceptable salt thereof, wherein R3is C1-C6 alkyl, C1-C6 haloalkyl, 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6 haloalkyl.

[0356] 39. The compound of clause 38, or a pharmaceutically acceptable salt thereof, wherein R3is .of any one of clauses 28 to 39, or a pharmaceutically acceptable salt thereof, wherein R4is CH3.

[0358] 41. The compound of any one of clauses 28 to 39, or a pharmaceutically acceptable salt thereof, wherein R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl.

[0359] 42. The compound of clause 41, wherein R3and R4, or a pharmaceutically acceptable salt thereof, together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl.

[0360] 43. The compound of any one of clauses 28 to 42, or a pharmaceutically acceptable salt thereof, wherein R0is H.

[0361] 44. The compound of any one of clauses 28 to 37, or a pharmaceutically acceptable salt thereof, wherein R0and R3, together with the carbon atoms to which they are attached, form a C3-C7 cycloalkyl.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0362] 45. The compound of clause 44, wherein R0and R3, or a pharmaceutically acceptable salt thereof, together with the carbon atoms to which they are attached, form a cyclobutyl and R4is CH3.

[0363] 46. The compound of any one of clauses 28 to 45, wherein R5is H or F.

[0364] 47. The compound of any one of clauses 28 to 46, wherein R6is H or F.

[0365] 48. The compound of any one of clauses 28 to 47, wherein R8is C3-C6cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo.

[0366] 49. The compound of clause 48, or.The compound of clause 1, wherein the compound has formula (I-B): or a pharmaceutically acceptable saltX is CH, CF, or N; Y is CH, CF, or N; R3and R4are defined as follows: (i) R3is C1-C6 alkyl or C1-C6 haloalkyl; and R4is C1-C6alkyl; or (ii) R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl or a 4-7 membered heterocyclyl; R5is H or halo;Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) R6is H or halo; and R9and R10, together with the carbon atom to which they are attached, join together to form a 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo provided that no more than one of X and Y is N.

[0368] 51. The compound of clause 50, wherein the compound is of formula (I-B-1): , or a pharmaceutically acceptable salt

[0369] 52. The compound of clause 50 or 51, wherein the compound is of formula (I-B-2a): , or a pharmaceutically acceptable saltAttorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0370] 53. The compound of clause 50 or 51, wherein the compound is of formula (I-B-2b): , or a pharmaceutically acceptable salt

[0371] 54. The compound of any one to or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0372] 55. The compound of any one of clauses 50 to 54, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

[0373] 56. The compound of any one of clauses 50 to 55, or a pharmaceutically acceptable salt thereof, wherein R3is C1-C6 alkyl.

[0374] 57. The compound of clause 56, or a pharmaceutically acceptable salt thereof, wherein R3is CH3.

[0375] 58. The compound of any one of clauses 50 to 57, or a pharmaceutically acceptable salt thereof, wherein R4is CH3.

[0376] 59. The compound of any one of clauses 50 to 58, or a pharmaceutically acceptable salt thereof, wherein R5is H.

[0377] 60. The compound of any one of clauses 50 to 58, or a pharmaceutically acceptable salt thereof, wherein R6is H.

[0378] 61. The compound of any one of clauses 50 to 60, or a pharmaceutically acceptable salt thereof, wherein R9and R10, together with the carbon atom to which they are attached, join together to form a 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 2 oxo.

[0379] 62. The compound of clause 61, wherein R9and R10, or a pharmaceutically acceptable salt thereof, together with the carbon atom to which they are attached, join together to form a tetrahydropyranyl or 1,1-dioxo-tetrahydrothiopyranyl.

[0380] 63. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0381] 64. The compound of any one of clauses 1 to 63, wherein the compound is in a non-salt form.

[0382] 65. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of clauses 1 to 63, or a pharmaceutically acceptable salt thereof, or the compound of clause 64 and one or more pharmaceutically acceptable carriers or vehicles.

[0383] 66. A pharmaceutical composition comprising the compound of any one of clauses 1 to 63, or a pharmaceutically acceptable salt thereof, or the compound of clause 64 and one or more pharmaceutically acceptable carriers or vehicles.

[0384] 67. A method of inhibiting MALT1 in a subject comprising administering to the subject the compound of any one of clauses 1 to 63, or a pharmaceutically acceptable salt thereof, the compound of clause 64, or the pharmaceutical composition of clause 65 or 66.

[0385] 68. A method of treating or lessening the severity in a subject of a disorder selected from a cancer, an autoimmune disorder, or an inflammatory disorder, comprising administering to the subject an effective amount of the compound of any one of clauses 1 to 63, or a pharmaceutically acceptable salt thereof, the compound of clause 64, or the pharmaceutical composition of clause 65 or 66.

[0386] 69. The method of clause 68, wherein the disorder is a cancer.

[0387] 70. The method of clause 69, wherein the cancer is a MALT1-associated cancer.

[0388] 71. The method of clause 69 or 70, wherein the cancer is selected from diffuse large B-cell lymphoma (DLBCL), activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT lymphoma), chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia (T-ALL), and an advanced solid tumor.

[0389] 72. The method of clause 68, wherein the disorder is an autoimmune disorder.

[0390] 73. The method of clause 72, wherein the autoimmune disorder is a MALT1-associated autoimmune disorder.

[0391] 74. The method of clause 72 or 73, wherein the autoimmune disorder is selected from multiple sclerosis (MS) and rheumatoid arthritis (RA).

[0392] 75. The method of clause 68, wherein the disorder is an inflammatory disorder.

[0393] 76. The method of clause 75, wherein the inflammatory disorder is a MALT1-associated inflammatory disorder.

[0394] 77. The method of clause 75 or 76, wherein the inflammatory disorder is chronic graft- versus-host disease (cGvHD).

[0395] 78. A method of treating or lessening the severity in a subject of a mature B-cell neoplasm, comprising administering to the subject an effective amount of the compound of any one of clauses 1 toAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) 63, or a pharmaceutically acceptable salt thereof, the compound of clause 64, or the pharmaceutical composition of clause 65 or 66.

[0396] 79. The method of any one of clauses 67 to 78, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

[0397] 80. Use of the compound of any one of clauses 1 to 63, or a pharmaceutically acceptable salt thereof, the compound of clause 64, or the pharmaceutical composition of clause 65 or 66, as a medicament.

[0398] 81. Use of the compound of any one of clauses 1 to 63, or a pharmaceutically acceptable salt thereof, the compound of clause 64, or the pharmaceutical composition of clause 65 or 66 in the manufacture of a medicament for the treatment of a cancer, an autoimmune disorder, or an inflammatory disorder. EXAMPLES

[0399] General methods. Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). Analytical TLC was generally performed using Sanpont precoated TLC plates, silica gel GF-254, layer thickness 0.25 mm. LC-MS was performed as described below.

[0400] LC-MS analysis was generally performed using a Shimadzu LCMS-2020 equipped with electrospray ionization in positive ion detection mode and a 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. The column was generally HALO a C1830*5.0 mm, 2.7 µm. Mobile phase A was water containing 0.05% TFA and mobile phase B was acetonitrile containing 0.05% TFA. Gradient elution was generally used, ranging from 5% mobile phase B to 100% over 2.0 min, hold 0.7 min, then reverting to 5% mobile phase B over 0.05 min and maintained for 0.25 min. The Column Oven (CTO-20AC) was operated at a temperature of 40.0 ℃. The flow rate was 1.5 mL / min, and the sample injection volume was 1 µl. PDA (SPD-M20A) detection was in the range 190-400 nm. The MS detector, which was configured with electrospray ionization as ionizable source; Acquisition mode: Scan; Nebulizing Gas Flow:1.5 L / min; Drying Gas Flow:15 L / min; Detector Voltage: Tuning Voltage ± 0.2 kv; DL Temperature: 250 ℃; Heat Block Temperature: 250 ℃; Scan Range: 90.00 - 900.00 m / z. ELSD (Alltech 3300) detector Parameters: Drift Tube Temperature:60 ± 5 ℃; N2Flow- Rate: 1.8 ± 0.2 L / min. In some instances, mobile phase gradients were specifically optimized for the individual compounds.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0401] GC-MS analysis was generally performed using a Shimadzu GCMS-QP2010 Ultra equipped with an FID and MS Detector. The MS detector was operated in an acquisition mode with the following parameters: 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.

[0402] Preparative HPLC purifications were generally performed using a Waters Auto purification system (2545-2767) equipped with a 2489 UV detector. The column was Waters C18, 19 x 150 mm, 5 μm. The mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.1%FA. Flow rates were maintained at 25 mL / min, the sample injection volume was 1200 μL, and the UV detector was used to measure intensity at two channels, 254 nm and 220 nm. In some instances, mobile phase gradients were specifically optimized for individual compounds.

[0403] In some instances, 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 (Regis technologies, Inc. ); CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) at different column sizes (50x4.6mm, 100x4.6mm, 150x4.6mm, 250x4.6mm, 50x3.0mm, 100x3.0mm) with noted percentage of either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as isocratic solvent systems. In other instrances, chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (%Et / Hex) or isopropanol in heptane (%IPA / Hep) as isocratic solvent systems.

[0404] Chiral preparative chromatography was conducted on one of Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.); (R,R)- Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc. ); CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) at different column size (250x20mm, 250x30mm, 250x50mm) with desired isocratic solvent systems identified on chiral analytical chromatography.

[0405] Reactions performed using microwave irradiation were generally carried out using an Initiator™ microwave reactor manufactured by Biotage.

[0406] Concentration of solutions was carried out using a rotary evaporator under reduced pressure.

[0407] Flash column chromatography was generally performed using a Biotage Flash Chromatography apparatus (Dyax Corp.) on silica gel (40-60 μM, 60 Å pore size) in pre-packed cartridges of the size noted.

[0408] 1H NMR spectra were acquired at 400 MHz in DMSO-d6, unless otherwise noted. Chemical shifts were reported in parts per million (ppm), using tetramethylsilane (TMS) as an internal reference inAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) DMSO-d6solutions, or residual CH3OH peak or TMS as an internal reference in CD3OD solutions. Coupling constants (J) were reported in hertz (Hz). Abbreviations

[0409] Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: Abbreviation Meaning NMR Nuclear magnetic resonance ESI-MS Electrospray mass spectrometry LC / MS Liquid chromatography-mass spectrometry UPLC Ultra performance liquid chromatography HPLC / MS / MS High performance liquid chromatography / tandem mass spectrometry IS Internal standard HPLC High performance liquid chromatography SFC Supercritical fluid chromatography ESI Electrospray ionization kg Kilogram g Grams mg Milligrams L Liter(s) mL Milliliters μL Microliters nL Nanoliters mol Mole mmol Millimoles hr, h Hours min Minutes mm Millimeters μm Micrometers nm Nanometer MHz Megahertz Hz Hertz N Normal (concentration) M Molar (concentration) mM Millimolar (concentration) μM Micromolar (concentration) ppm Parts per million % w / v Weight-volume concentration % w / w Weight-weight concentration Ac –C(O)CH3 AcOH or HOAc Acetic acid OAc –OC(O)CH3 aq Aqueous Cbz Benzyloxycarbonyl DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamideAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) Abbreviation Meaning EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc Ethyl acetate ether or Et2O Diethyl ether HOTT N,N,N',N'-Tetramethyl-S-(1-oxido-2-pyridyl)thiuronium hexafluorophosphate PE Petroleum ether IPA 2-propanol or isopropanol ms or MS mass spectrum MTBE methyl t-butylether PyBOP (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate Rt, rt, or RT retention time Brine saturated aq sodium chloride solution TFA trifluoroacetic acid THF Tetrahydrofuran FC flash chromatography LC liquid chromatography LCMS or LC-MS; liquid chromatography-mass spectrometry SFC supercritical fluid chromatography Boc or BOC t-butyloxycarbonyl DAST Diethylaminosulfur trifluoride DCM Dichloromethane DMA or DMAC Dimethylacetamide HFIP Hexafluoroisopropanol DMSO Dimethylsulfoxide DPPP 1,3-Bis(diphenylphosphino)propane m-CPBA 3-chloroperoxybenzoic acid Me Methyl MeOH Methanol TCFH N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate NMI N-methylimidazole NBS N-bromosuccinamide TLC thin layer chromatography

[0410] The following are representative procedures for the preparation of the compounds used in the following Examples, or which can be substituted for the compounds used in the following Examples which may not be commercially available.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0411] Intermediate 1: 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidine-6-carboxylic acid (INT-1) Method 1

[0413] A solution of 2,2-dimethylcyclopentanone (20 g, 178.3 mmol) in 1,1-dimethoxy-N,N- dimethylmethanamine (160 mL) was stirred for 24 h at 120 °C. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure to afford the title compound (15 g, crude) as yellow oil which was used directly in the next step. LC-MS: m / z 168 [M+H]+.

[0414] Step 2: 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine

[0415] To a stirred solution of 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one (7.45 g, 44.5 mmol) in toluene (150 mL) were added 3-fluoro-1H-pyrazol-5-amine (3.75 g, 37.1 mmol) and AcOH (15 mL) at room temperature. The resulting mixture was stirred at 90 °C for 5 h under nitrogen. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with water (100 mL). The pH was adjusted to 6~7 with sodium bicarbonate (sat., aq.). The resulting solution was extracted with ethyl acetate (2x 100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with EtOAc / PE (1:5) to give the title compound (3 g, 39% yield) as a yellow solid.1H NMR (400 MHz, Chloroform-d) δ: 8.37 (s, 1H), 6.18 (d, J = 4.8 Hz, 1H), 3.00 (t, J = 7.6 Hz, 2H), 2.13 (t, J = 7.6 Hz, 2H), 1.58 (s, 6H). LC-MS: m / z 206 [M+H]+.

[0416] Step 3: 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6- carbonitrile

[0417] To a stirred solution of 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidine (3 g, 14.6 mmol) in chlorobenzene (60 mL) were added (4R)-4-benzyl-2-[1-[(4R)-4-benzyl- 4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazole (636 mg, 1.8 mmol), acetoxycopper (359 mg, 2.9 mmol), N-fluorobenzenesulfonimide (6.91 g, 21.9 mmol), and TMSCN (7.25 g, 73.1 mmol). The mixture was stirred at room temperature for 16 h under nitrogen. The solvent was removed under vacuumAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) and the residue was applied onto a silica gel column and eluted with EtOAc / PE (1:5) to give the title compound (5.5 g, 33% yield) as a yellow solid. LC-MS: m / z 231 [M+H]+.

[0418] Step 4: 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6- carboxylic acid

[0419] To a 30 mL vial was added 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidine-6-carbonitrile (5.2 g, 22.6 mmol) in AcOH (52 mL) and HCl (12M, 52 mL). The resulting mixture was stirred at 100 °C for 1.5 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with water (300 mL) and the pH was adjusted to 5~6 with NaHCO3 (sat., aq.). The resulting solution was extracted with ethyl acetate (3x 200 mL), dried over anhydrous Sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with DCM / MeOH (10:1) to give the title compound (INT-1, 450 mg) as an off-white solid. LC-MS: m / z 250 [M+H]+. This product was used in next steps without further purification. Method 2

[0421] Diethyl malonate (200 g, 1.25 mol) and CH3CN (2000 mL) were added into a 5 L reactor. Caesium carbonate (489 g, 1.5 mol) was added at 25 °C in batches. Then, 3-chloro-2-methylprop-1-ene (135 g, 1.5 mol) was added at 25 °C. The temperature of the reaction mixture rose from 25 °C to 40 °C over 1 hour. The reaction mixture was stirred for 48 h at 25 °C. The reaction mixture was filtered, and the filter cake was washed DCM (500 mL). The filtrate was concentrated to give the crude title compound (260 g) as a light-yellow oil, which was used directly in the next step.

[0422] Step 2: Diethyl 2-(cyanomethyl)-2-(2-methylallyl)malonate

[0423] Diethyl 2-(2-methylallyl) malonate (200 g, 934 mmol) and THF (2000 mL) were added into a 5 L reactor. The mixture was cooled to 0 °C, and t-BuOK (125.6 g, 1120 mmol) was added in 5 batches (reaction solution was colorless). Then, 2-bromoacetonitrile (157.2 g, 1310 mmol) was added dropwise at 0 °C within 2 h. The reaction mixture was stirred for 1 h at room temperature. Activated carbon (200 g) was added at room temperature and it was stirred for 1 h. The mixture was filtered, and to the filtrate wasAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) added sat. aq. NH4Cl (1000 mL) and it was extracted with MTBE (2x 2000 mL). The combined organic layers were concentrated. MTBE (1000 mL) and activated carbon (200 g) were added and it was stirred for 1 h. The mixture was filtered, the filtrate dried over sodium sulfate and concentrated to give the crude title compound (254 g) as a yellow oil, which was used directly in the next step.

[0424] Step 3: Diethyl 3,3-dimethyl-4-oxocyclopentane-1,1-dicarboxylate

[0425] To a solution of diethyl 2-(cyanomethyl)-2-(2-methylallyl)malonate (160 g, 632.4 mmol) in HFIP / EtOH(1600 mL, 1:1) was added Fe(acac)3 (44.3 g, 126.6 mmol), followed by slow addition of PhSiH3 (204.9 g, 1.9 mol). The mixture was stirred at room temperature until no further gas evolution was observed and the temperature no longer increased. The mixture was stirred at 60 °C for 1 h. HCl(aq) (2M, 1600 mL) was added, and it was stirred for 2 h at 60 °C. The layers were separated, and the aqueous solution was extracted with DCM (2x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 10% to 20% EA in PE) to give the title compound as a light-yellow liquid (124.7 g, 77% yield).1H NMR (400 MHz, CDCl3) δ 4.29-4.21 (m, 4H), 2.99 (s, 2H), 2.53 (s, 2H), 1.31-1.25 (m, 6H), 1.08 (s, 6H).

[0426] Step 4: Diethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxocyclopentane-1,1- dicarboxylate

[0427] A solution of diethyl 3,3-dimethyl-4-oxocyclopentane-1,1-dicarboxylate (124.7g, 487.0 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1000 mL) was stirred for 16 h at 80 °C. The reaction mixture was then concentrated to obtain the crude title compound (160 g), which was used directly in the next step.

[0428] Step 5: Diethyl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidine-6,6-dicarboxylate

[0429] To a solution of crude diethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxocyclo pentane-1,1-dicarboxylate (160 g) in toluene (1000 mL) were added 5-fluoro-1H-pyrazol-3-amine (58.2 g, 582 mmol) and AcOH (100 mL). The mixture was stirred at 110 °C for 40 h. The mixture was concentrated to obtain the crude title compound (180 g), which was used directly in the next step.

[0430] Step 6: 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6- carboxylic acid

[0431] To crude diethyl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidine-6,6-dicarboxylate (180 g) was added HCl (6M, 1800 mL), and the mixture was stirred at 100 °C for 16h. The reaction mixture was poured into cold water (3600 mL), and it was extracted with EA (3x 1800 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered andAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) concentrated. The residue was slurried in EA:PE (1:1) to obtain the title compound (INT-1, 62 g, 51.5% over 3 steps) as a light-yellow solid. LC-MS: m / z 250.1 [M+H]+.

[0432] Intermediate 2: 1,3-dioxoisoindolin-2-yl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate (INT-2)

[0433] A mixture of[e]pyrazolo[1,5-a]pyrimidine- 6-carboxylic acid (INT-1, 100 mg, 401 μmol), 2-hydroxyisoindoline-1,3-dione (72 mg, 441 μmol), EDCI (85 mg, 441 μmol) and DMAP (2.5 mg, 20 μmol) in THF (2 mL) was stirred at 25 °C for 2 h. The reaction was quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (3x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 50% petroleum ether and 50% ethyl acetate as eluent to afford the title compound (INT-2, 120 mg, 68% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.94-8.04 (m, 4H), 6.62 (d, J = 4.8 Hz, 1H), 4.89-5.03 (m, 1H), 2.63-2.80 (m, 1H), 2.45-2.49 (m, 1H), 1.60 (s, 3H), 1.58 (s, 3H). LC-MS: m / z 395 [M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Method A1- - 6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N- ((S)-2,2,2-trifluoro-1-(4-((S)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide

[0435] The absolute stereochemistry of each example was not determined.

[0436] Step 1: (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (A1-1)

[0437] To a mixture of 1-(4-bromophenyl)-2,2,2-trifluoro-ethanone (50 g, 197.6 mmol) in THF (1000 mL) were added (R)-2-methylpropane-2-sulfinamide (29.9 g, 247.0 mmol) and titanium tetraisopropanolate (70.2 g, 247.0 mmol, 73.52 mL). The reaction mixture was stirred at 80 °C for 12 h. The mixture was cooled to 10 °C. To this mixture was added lithium trisec-butylboranuide (1M in THF, 250 mL) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 3 h. The reaction was quenched by the addition of ice water (1000 mL) and the mixture was warmed to 10 °C. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (5x 300 mL). The filtrate was concentrated under reducedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) pressure. The residue was purified by silica gel column chromatography eluted with DCM / EA (1:4) to afford the title compound (A1-1, 31 g, 83% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 8.40 Hz, 2 H), 7.58 (d, J = 8.40 Hz, 2 H), 6.47 (d, J = 9.60 Hz, 1 H), 5.27 (quin, J = 8.80 Hz, 1 H), 1.13 (s, 9 H). LC-MS: m / z 358 [M+H]+.

[0438] Step 2: (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2- sulfinamide (A1-2)

[0439] To a solution of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (24 g, 67.0 mmol) in 2-methyltetrahydrofuran (500 mL) was added LDA (2M in THF, 134.0 mmol) dropwise at -50 °C. The mixture was stirred at -50 °C for 1.5 h. Then, iodomethane (57.0 g, 401.99 mmol) was added at -50 °C. The mixture was stirred at 15 °C for 2 h. The mixture was cooled to -30 °C and quenched with sat. aq. NH4Cl (400 mL). Water (100 mL) was added, and the mixture was extracted with ethyl acetate (1000 mL). The organic layer was washed with brine (2x 200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with PE / EA (1:4) to afford the title compound (A1-2, 12 g, 45% yield) as a yellow oil. LC-MS: m / z 372 [M+H]+.

[0440] Step 3: Methyl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidine-6-carboxylate

[0441] A mixture of 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a] pyrimidine- 6-carboxylic acid (INT-1, 1.0 g, 4.0 mmol) and H2SO4 (0.5 mL) in MeOH (20 mL) was stirred at 60 °C for 16 h. The reaction was quenched by the addition of water (30 ml), and the resulting mixture was extracted with ethyl acetate (3x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.0 g, 94% yield) as a yellow solid. LC-MS: m / z 264 [M+H]+.

[0442] Step 4: Methyl 6-(4-((S)-1-(((R)-tert-butylsulfinyl)(methyl)amino)-2,2,2- trifluoroethyl)phenyl)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6- carboxylate

[0443] To a stirred solution of methyl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate (707 mg, 2.7 mmol) in toluene (10 mL) was added LHMDS (1 M, 2.7 mL) under nitrogen atmosphere. The mixture was stirred at 25 °C for 30 min. Pd2(dba)3(246 mg, 268 μmol), (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2- sulfinamide (A1-2, 1.0 g, 2.7 mmol) and t-Bu3P (1 M in toluene, 537 μL) were added, and the mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction was quenched by the addition of water (10 ml), and the resulting mixture was extracted with ethyl acetate (3x 10 mL). The combined organic layersAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 80% petroleum ether and 20% ethyl acetate as eluent to afford the title compound (520 mg, 34% yield) as a red solid. LC-MS: m / z 555 [M+H]+.

[0444] Step 5: 6-(4-((S)-1-(((R)-tert-butylsulfinyl)(methyl)amino)-2,2,2-trifluoroethyl) phenyl)-2- fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0445] To a stirred solution of methyl 6-(4-((S)-1-(((R)-tert-butylsulfinyl)(methyl)amino)-2,2,2- trifluoroethyl)phenyl)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6- carboxylate (580 mg, 1.1 mmol) in THF (20 mL) and water (20 mL) was added LiOH (75 mg, 3.1 mmol). The reaction mixture was stirred at 25 °C for 16 h. The pH was adjusted to 7-8 with 2N HCl, and the resulting mixture was extracted with ethyl acetate (3x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (200.0 mg, 88% yield) as a yellow solid. LC-MS: m / z 541 [M+H]+.

[0446] Step 6: (R)-N,2-dimethyl-N-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro- 6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)propane-2-sulfinamide

[0447] A solution of 6-(4-((S)-1-(((R)-tert-butylsulfinyl)(methyl)amino)-2,2,2-trifluoroethyl) phenyl)- 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (500 mg, 925 μmol) in NMP (5 mL) was stirred at 100 °C for 16 h. The reaction was quenched by the addition of water (50 ml), and the resulting mixture was extracted with ethyl acetate (3x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 80% petroleum ether and 20% ethyl acetate as eluent to afford the title compound (300 mg, 65% yield) as a white solid. LC-MS: m / z 497 [M+H]+.

[0448] Step 7: (1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethan-1-amine (A1-7)

[0449] A solution of (R)-N,2-dimethyl-N-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8- dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)propane-2-sulfinamide (400 mg, 805 μmol) in HCl (4M in EA, 20 mL) was stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 70% dichloromethane and 30% ethyl acetate as eluent to afford the title compound (A1-7, 230 mg, 72% yield) as a yellow solid. LC-MS: m / z 393 [M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0450] Step 8: N-methyl-N-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide

[0451] To a stirred solution of (1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethan-1-amine (A1-7, 230.0 mg, 586 μmol) in DCM (5 mL) was added NaH (112 mg, 2.3 mmol, 50% in mineral oil) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. 1,1-dioxothiane-4-carbonyl chloride (173 mg, 879 μmol) was added, and the mixture was stirred at 25 °C for 1 h. The reaction was quenched by the addition of water (10 ml), and the resulting mixture was extracted with DCM (3x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC using 50% dichloromethane and 50% ethyl acetate as eluent to give a product which was further purified by prep- HPLC to afford a mixture of diastereomers of the title compound (200 mg, 61% yield) as a white solid. LC- MS: m / z 553[M+H]+.

[0452] Step 9: Separation of diastereomers to obtain Example 1 and Example 2

[0453] 140 mg of N-methyl-N-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide were submitted to chiral HPLC purification (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 50% Mobile Phase B; Wave Length: 254 / 220nm nm; RT1(min): 19.355; RT2(min): 26.423; Sample Solvent: EtOH--HPLC; Injection Volume: 1.0 mL; Number of Runs: 7). The first eluting isomer was concentrated and lyophilized to afford Example 1 (54.5 mg) as a white solid. The second eluting isomer was concentrated and lyophilized to afford Example 2 (48.8 mg) as a white solid.

[0454] Example 1:1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.34-7.43 (m, 4H), 6.53-6.58 (m, 2H), 4.68 (t, J = 8.0 Hz, 1H), 3.09-3.32 (m, 5H), 2.91 (s, 3H), 2.59-2.65 (m, 1H), 1.97-2.15 (m, 5H), 1.66 (s, 3H), 1.51 (s, 3H). LC-MS: m / z 553.1 [M+H]+.

[0455] Example 2:1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.34-7.43 (m, 4H), 6.52-6.58 (m, 2H), 4.68 (t, J = 8.0 Hz, 1H), 3.09-3.32 (m, 5H), 2.91 (s, 3H), 2.59-2.65 (m, 1H), 1.97-2.15 (m, 5H), 1.66 (s, 3H), 1.51 (s, 3H). LC-MS: m / z 553.1 [M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Method A26H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)cyclopropanecarboxamide; N-methyl-N- ((S)-2,2,2-trifluoro-1-(4-((S)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidin-6-yl)phenyl)ethyl)cyclopropanecarboxamide

[0457] The absolute stereochemistry of each example was not determined.

[0458] Step 1: N-methyl-N-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)cyclopropanecarboxamide

[0459] To a stirred solution of (1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethan-1-amine (A1-7, 28 mg, 0.07 mmol) in DCM (1.5 mL) were added DIPEA (46 mg, 0.36 mmol) and cyclopropanecarbonyl chloride (15 mg, 0.14 mmol), and it was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (SiO2, PE / EA = 4 / 1) to afford a mixture of diastereomers of the title compound (20 mg, 61% yield) as a white solid. LCMS: m / z 461.1[M+H]+.

[0460] Step 2: Separation of diastereomers to obtain Example 3 and Example 4

[0461] N-methyl-N-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)cyclopropanecarboxamide (20 mg, 0.04 mmol) was separated by SFC (column: IG-34.6 x 100 mm, 3 um; eluent: CO2 / EtOH (1% NH3(7 M in MeOH)) = 75 / 25)) to afford Example 3 (RT: 1.213 min, 6.84 mg) and Example 4 (RT: 1.357 min, 6.31 mg) as white solids.

[0462] Example 3:1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.44-7.33 (m, 4H), 6.54 (d, J = 4.9 Hz, 2H), 4.66-4.70 (m, 1H), 3.01 (s, 2H), 2.68-2.59 (m, 2H), 2.09-1.94 (m, 2H), 1.66 (s, 3H), 1.50 (s, 3H), 0.89-0.81 (m, 4H). LC-MS: m / z 461.0 [M+H]+.

[0463] Example 4:1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.44-7.33 (m, 4H), 6.54 (d, J = 4.9 Hz, 2H), 4.66-4.70 (m, 1H), 3.01 (s, 2H), 2.68-2.59 (m, 2H), 2.10-1.95 (m, 2H), 1.66 (s, 3H), 1.50 (s, 3H), 0.90-0.80 (m, 4H). LC-MS: m / z 461.1 [M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Method A36H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide; N- methyl-N-((S)-2,2,2-trifluoro-1-(4-((S)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0465] The absolute stereochemistry of each example was not determined.

[0466] Step 1: N-methyl-N-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0467] To a stirred solution of (1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethan-1-amine (A1-7, 60 mg, 153 μmol) in DCM (5 mL) was added DIEA (40 mg, 306 μmol). Tetrahydro-2H-pyran-4-carbonyl chloride (46 mg, 306 μmol) was added at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction was quenched by the addition of water (10 mL), and the resulting mixture was extracted with DCM (3x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford a mixture of diastereomers of the title compound (40 mg, 51% yield) as an off-white solid. LC-MS: m / z 505[M+H]+.

[0468] Step 2: Separation of diastereomers to obtain Example 5 and Example 6

[0469] 40 mg of N-methyl-N-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide (20 mg, 0.04 mmol) were submitted to chiral HPLC purification (Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 10% Mobile Phase B; Wave Length: 254 / 220nm nm; RT1(min): 14.771; RT2(min): 17.241; Sample Solvent: EtOH--HPLC; Injection Volume: 0.3 mL; Number of Runs: 9). The first eluting isomer was concentrated and lyophilized to afford Example 5 (16 mg) as an off-white solid. The second eluting isomer was concentrated and lyophilized to afford Example 6 (17 mg, 20% yield) as an off-white solid.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0470] Example 5:1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.34-7.41 (m, 4H), 6.53-6.58 (m, 2H), 4.67-4.70 (m, 1H), 3.86-3.88 (m, 2H), 3.40-3.43 (m, 2H), 2.99-3.04 (m, 1H), 2.91 (s, 3H), 2.60-2.66 (m, 1H), 1.98-2.03 (m, 1H), 1.61-1.66 (m, 7H), 1.50 (s, 3H). LC-MS: m / z 505 [M+H]+.

[0471] Example 6:1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.34-7.41 (m, 4H), 6.54-6.61 (m, 2H), 4.67-4.70 (m, 1H), 3.86-3.88 (m, 2H), 3.40-3.43 (m, 2H), 2.99-3.04 (m, 1H), 2.91 (s, 3H), 2.60-2.66 (m, 1H), 2.01-2.03 (m, 1H), 1.61-1.66 (m, 7H), 1.60 (s, 3H). LC-MS: m / z 505 [M+H]+. Method A4

[0472] 6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)oxetane-3-carboxamide

[0473] Step 1: Oxetane-3-carbonyl chloride

[0474] A mixture of oxetane-3-carboxylic acid (200 mg, 1.96 mmol) and DMF (12 uL, 0.16 mmol) in SOCl2 (5 mL) was degassed with vacuum / nitrogen three times and stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude title compound (230 mg) as a yellow oil, which was directly used in the next step.

[0475] Step 2: Example 7

[0476] To a stirred solution of (1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethan-1-amine (A1-7, 95 mg, 242 μmol) in DCM (5 mL) was added DIEA (112 mg, 484 μmol). Oxetane-3-carbonyl chloride (76 mg, 484 μmol) was added at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction was quenched by the addition of water (10 mL), and the resulting mixture was extracted with DCM (3x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC using 30% petroleum ether and 70% ethyl acetate as eluent to give a crude product which was further purified by prep-HPLC to afford Example 7 (mixture of diastereomers, 3 mg, 3% yield) as an off-white solid.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0477] Example 7:1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.41 (d, J = 8 Hz, 2H), 7.35 (d, J = 8 Hz, 2H)，6.53(d, J = 4.8 Hz, 1H), 6.06 (s, 1H), 5.68 (s, 1H), 4.65-4.69 (m, 2H), 3.78-3.87 (m, 3H), 2.63-2.66 (m, 1H), 2.33 (s, 3H), 2.02-2.05 (m, 1H), 1.66 (s, 3H), 1.51 (s, 3H). LC-MS: m / z 477[M+H]+. Method A5dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide; N-methyl-N-((S)-2,2,2-trifluoro-1-(5-((R)-2-fluoro-8,8-dimethyl-7,8-dihydro- 6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide; N-methyl-N-((R)-2,2,2-trifluoro-1-(5-((R)-2-fluoro-8,8-dimethyl-7,8-dihydro- 6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide; N-methyl-N-((R)-2,2,2-trifluoro-1-(5-((S)-2-fluoro-8,8-dimethyl-7,8-dihydro- 6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide

[0479] The absolute stereochemistry of each example was not determined.

[0480] Step 1: (R)-N-((5-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

[0481] A mixture of 5-bromopicolinaldehyde (17 g, 91.4 mmol), (R)-2-methylpropane-2-sulfinamide (11.1 g, 91.4 mmol) and Ti(OiPr)4(26 g, 91.4 mmol) in THF (200 mL) was stirred at 80 °C for 2 h. The reaction mixture was cooled to 25 °C and quenched by the addition of water (500 ml). The resulting mixture was extracted with ethyl acetate (3x 800 mL). The combined organic layers were washed with brine (500Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 60% petroleum ether and 40% ethyl acetate as eluent to afford the title compound (20 g, 64% yield) as a white solid. LC-MS: m / z 289 [M+H]+.

[0482] Step 2: (R)-N-((S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide

[0483] A mixture of (R)-N-((5-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (800 mg, 2.8 mmol) and tetrabutylammonium difluorotriphenylsilicate (TBAT)(2.2 g, 4.1 mmol) in THF (20 mL) was stirred at 25 °C for 30 min. TMSCF3 (2.0 g, 13.7 mmol) was added at -78°C and it was stirred at 25 °C for 16 h. The reaction was quenched by the addition of water (50 ml), and the resulting mixture was extracted with ethyl acetate (3x 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 50% petroleum ether and 50% ethyl acetate as eluent to afford the title compound (600 mg, 55% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 2.4 Hz, 1H), 8.12-8.29 (m, 1H), 7.69 (d, J = 8.4 Hz, 1H), 6.08 (d, J = 8.8 Hz, 1H), 5.36-5.59 (m, 1H), 1.16 (s, 9H). LC-MS: m / z 359 [M+H]+.

[0484] Step 3: (S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-amine

[0485] A mixture of (R)-N-((S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (1 g, 2.8 mmol) in HCl (4M in dioxane, 15 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (1.2 g, 84% yield, 50% purity) as a white solid. LC-MS: m / z 255 [M+H]+.

[0486] Step 4: N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)formamide

[0487] A mixture of (S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-amine (1.2 g, 4.7 mmol) and formic acid (1 g, 20.8 mmol) in toluene (10 mL) was stirred at 110 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 50% petroleum ether and 50% ethyl acetate as eluent to afford a racemic mixture of the title compound (650 mg, 44% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 9.6 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H), 7.99-8.44 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 5.92-6.18 (m, 1H). LC-MS: m / z 283 [M+H]+.

[0488] Step 5: 1-(5-bromopyridin-2-yl)-2,2,2-trifluoro-N-methylethan-1-amine

[0489] A mixture of N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)formamide (690 mg, 2.4 mmol) and borane-methyl sulfide complex (188 mg, 2.4 mmol) in THF (15 mL) was stirred at 25 °C for 16 h. The reaction was quenched by the addition of water (30 mL) and the mixture extracted with ethyl acetate (3x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silicaAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) gel using 50% petroleum ether and 50% ethyl acetate as eluent to afford the title compound (90 mg, 12% yield) as a white solid. LC-MS: m / z 269 [M+H]+.

[0490] Step 6: N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran- 4-carboxamide 1,1-dioxide

[0491] To a mixture of 1-(5-bromopyridin-2-yl)-2,2,2-trifluoro-N-methylethan-1-amine (80 mg, 297 μmol) in DCM (10 mL) were added DIEA (115 mg, 892 μmol) and tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide (117 mg, 594.7 μmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched by the addition of water (10 ml), and the resulting mixture was extracted with DCM (3x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gelusing 80% petroleum ether and 20% ethyl acetate as eluent to afford the title compound (90 mg, 63% yield) as a white solid. LC-MS: m / z 429 [M+H]+.

[0492] Step 7: N-methyl-N-(2,2,2-trifluoro-1-(5-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[0493] A mixture of N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide (80 mg, 186 μmol), 1,3-dioxoisoindolin-2-yl 2-fluoro-8,8-dimethyl- 7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate (INT-2, 74 mg, 186 μmol), NiBr2(dtbpy) (10 mg, 19 μmol) and Hantzsch ester (95 mg, 373 μmol) in DMA (5 mL) was stirred at 25 °C for 2 h under irradiation with blue LED (450 nm) under nitrogen. The reaction was quenched by the addition of water (20 ml), and the resulting mixture was extracted with ethyl acetate (3x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on C18 column using 40% water (0.1% FA) and 60% acetonitrile as eluent to afford 180 mg of a crude product, which was further purified by prep- HPLC to afford a mixture of all stereoisomers of the title compound (28 mg, 26% yield) as a white solid. LC-MS: m / z 554 [M+H]+.

[0494] Step 8: Separation of stereoisomers to obtain Example 8, Example 9, Example 10 and Example 11

[0495] 30 mg of N-methyl-N-(2,2,2-trifluoro-1-(5-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (30 mg, 54 μmol) were submitted 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: DCM=1: 1--HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 25% Mobile Phase B; Wave Length:Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) 254 / 220nm nm; RT1(min): 13.251; RT2(min): 15.912; RT3(min): 18.491; RT4(min): 23.288; Sample Solvent: EtOH--HPLC; Injection Volume: 0.6 mL; Number of Runs: 4). The first eluting isomer was concentrated and lyophilized to afford Example 8 (4.2 mg, 14% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to afford Example 9 (4.0 mg, 13% yield) as a white solid. The third eluting isomer was concentrated and lyophilized to afford Example 10 (3.5 mg, 11% yield) as a white solid. The fourth eluting isomer was concentrated and lyophilized to afford Example 11 (3.7 mg, 12.2% yield) as a white solid.

[0496] Example 8:1H NMR (400 MHz, DMSO-d6) δ 8.61-8.71 (m, 1H), 8.22 (s, 1H), 7.75-7.87 (m, 1H), 7.35-7.53 (m, 1H), 6.48-6.69 (m, 2H), 4.65-4.92 (m, 1H), 3.16-3.31 (m, 2H), 3.05-3.16 (m, 2H), 3.04 (s, 3H), 2.60-2.72 (m, 2H), 1.91-2.18 (m, 5H), 1.68 (s, 3H), 1.51 (s, 3H). LC-MS: m / z 554 [M+H]+.

[0497] Example 9:1H NMR (400 MHz, DMSO-d6) δ 8.56-8.81 (m, 1H), 8.22 (s, 1H), 7.77-7.91 (m, 1H), 7.34-7.55 (m, 1H), 6.38-6.67 (m, 2H), 4.67-4.79 (m, 1H), 3.17-3.29 (m, 2H), 3.07-3.17 (m, 2H), 3.04 (s, 3H), 2.57-2.79 (m, 2H), 1.97-2.15 (m, 5H), 1.68 (s, 3H), 1.51 (s, 3H). LC-MS: m / z 554 [M+H]+.

[0498] Example 10:1H NMR (400 MHz, DMSO-d6) δ 8.56-8.81 (m, 1H), 8.22 (s, 1H), 7.72-7.99 (m, 1H), 7.25-7.58 (m, 1H), 6.48-6.64 (m, 2H), 4.62-4.84 (m, 1H), 3.19-3.30 (m, 2H), 3.09-3.17 (m, 2H), 3.04 (s, 3H), 2.56-2.71 (m, 2H), 1.85-2.21 (m, 5H), 1.68 (s, 3H), 1.51 (s, 3H).LC-MS: m / z 554 [M+H]+.

[0499] Example 11:1H NMR (400 MHz, DMSO-d6) δ 8.57-8.78 (m, 1H), 8.21 (s, 1H), 7.67-7.93 (m, 1H), 7.31-7.60 (m, 1H), 6.37-6.69 (m, 2H), 4.59-4.98 (m, 1H), 3.16-3.29 (m, 2H), 3.08-3.15 (m, 2H), 3.04 (s, 3H), 2.60-2.72 (m, 2H), 1.95-2.17 (m, 5H), 1.68 (s, 3H), 1.51 (s, 3H). LC-MS: m / z 554 [M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Method A67,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran- 4-carboxamide 1,1-dioxide; N-methyl-N-((S)-2,2,2-trifluoro-1-(3-fluoro-5-((R)-2-fluoro-8,8-dimethyl- 7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran- 4-carboxamide 1,1-dioxide

[0501] The absolute stereochemistry of each example was not determined.

[0502] Step 1: (R)-N-((5-bromo-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

[0503] To a stirred solution of 5-bromo-3-fluoro-pyridine-2-carbaldehyde (19 g, 93.1 mmol) in DCM (100 mL) were added (R)-2-methylpropane-2-sulfinamide (11.3 g, 93.1 mmol) and Cs2CO3 (36.4 g, 111.8 mmol). The reaction mixture was stirred at 25°C for 16 h. The reaction was quenched by the addition of water (200 mL), and the resulting mixture was extracted with DCM (3x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 80% PE and 20% EtOAc as eluent to afford the title compound (25 g, 87% yield) as a yellow solid. LC-MS: m / z 307 [M+H]+.

[0504] Step 2: (R)-N-[(1S)-1-(5-bromo-3-fluoro-2-pyridyl)-2,2,2-trifluoro-ethyl]-2-methyl-propane- 2-sulfinamide

[0505] To a stirred solution of (R)-N-((5-bromo-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2- sulfinamide (200 mg, 651 μmol) in THF (5 mL) was added tetramethylammonium fluoride (2.1 g, 22.8 mmol). The reaction mixture was stirred at 25°C for 15 min. TMSCF3 (3.24 g, 22.79 mmol) was addedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) dropwise at -78°C, and the mixture was stirred at -78°C for 1 h. The reaction was quenched by the addition of water (10 mL), and the resulting mixture was extracted with ethyl acetate (3x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 90% PE and 10% EtOAc as eluent to afford the title compound (135 mg, 55% yield) as a yellow solid. LC-MS: m / z 377 [M+H]+.

[0506] Step 3: (S)-1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine

[0507] A mixture of (R)-N-[(1S)-1-(5-bromo-3-fluoro-2-pyridyl)-2,2,2-trifluoro-ethyl]-2-methyl- propane-2-sulfinamide (1 g, 2.65 mmol) in HCl (4M in dioxane, 20 mL) was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford the crude title compound (1g), which was used in next step without further purification. LC-MS: m / z 273 [M+H]+.

[0508] Step 4: (S)-N-(1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)formamide

[0509] A mixture of (S)-1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-amine (1 g, 3.7 mmol) and formic acid (1 g, 22.0 mmol) in toluene (10 mL) was stirred at 110 °C for 2 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 60% PE and 40% EtOAc as eluent to afford the title compound (600 mg, 54% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.56 (d, J = 9.6 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.37-8.44 (m, 1H), 8.21 (s, 1H), 6.01-6.17 (m, 1H). LC-MS: m / z 301 [M+H]+.

[0510] Step 5: (S)-1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoro-N-methylethan-1-amine

[0511] A mixture of (S)-N-(1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)formamide (600 mg, 2.0 mmol) and borane-methyl sulfide complex (157 mg, 2.0 mmol) in THF (12 mL) was stirred at 25 °C for 2 h. The reaction was quenched by the addition of water (30 mL), and the mixture was extracted with ethyl acetate (3x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 80% petroleum ether and 20% ethyl acetate as eluent to afford the title compound (150 mg, 26% yield) as colorless oil. LC-MS: m / z 287 [M+H]+.

[0512] Step 6: (S)-N-(1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro- 2H-thiopyran-4-carboxamide 1,1-dioxide

[0513] To a mixture of (S)-1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoro-N-methylethan-1-amine (40 mg, 139 μmol) in DCM (2 mL) were added DIEA (54 mg, 418 μmol) and tetrahydro-2H-thiopyran-4- carbonyl chloride 1,1-dioxide (41 mg, 209 μmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of water (10 ml), and the resulting mixture was extracted with DCM (3x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 50% petroleumAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) ether and 50% ethyl acetate as eluent to obtain the title compound (20 mg, 29% yield) as a white solid. LC- MS: m / z 447 [M+H]+.

[0514] Step 7: Example 12 and Example 13

[0515] A mixture of (S)-N-(1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (140 mg, 313 μmol), 1,3-dioxoisoindolin-2-yl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate (INT-2, 186 mg, 469 μmol), NiBr2(dtbpy) (15 mg, 31 μmol) and Hantzsch ester (159 mg, 626.0 μmol) in DMA (5 mL) was stirred at 25 °C for 2 h under irradiation with blue LED (450 nm) under nitrogen. The reaction was quenched by the addition of water (20 ml), and the resulting mixture was extracted with ethyl acetate (3x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 95% petroleum ether and 5% ethyl acetate as eluent to obtain two diastereomers. The first eluting diastereomer was further purified with prep-HPLC to afford Example 12 (12.3 mg, 6% yield) as a white solid. The second eluting diastereomer was further purified with prep-HPLC to afford Example 13 (18.7 mg, 10% yield) as a white solid. Chiral SFC characterization (Column: (S,S)-Whelk-O1 4.6*50 mm, 3um; Mobile Phase A: CO2, Mobile Phase B: MeOH(0.1%DEA); Flow rate: 2 mL / min; Gradient: 10% to 50% Mobile Phase B in 2.0 min, hold 1.0 min at 50% Mobile Phase B; Column Temperature(℃): 35; Back Pressure(psi): 1500; Wave Length: 220 nm): Example 13 (RT1 = 1.49 min) and Example 12 (RT2 = 1.60 min).

[0516] Example 12:1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.25 (s, 1H), 7.82-7.91 (m, 1H), 6.72-6.94 (m, 1H), 6.55 (d, J = 4.8 Hz, 1H), 4.70-4.88 (m, 1H), 3.06-3.29 (m, 5H), 3.04 (s, 3H), 2.60-2.69 (m, 1H), 1.94-2.15 (m, 5H), 1.69 (s, 3H), 1.50 (s, 3H). LC-MS: m / z 572 [M+H]+.

[0517] Example 13: 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.25 (s, 1H), 7.73-7.90 (m, 1H), 6.71-6.94 (m, 1H), 6.55 (d, J = 5.2 Hz, 1H), 4.71-4.88 (m, 1H), 3.08-3.029 (m, 5H), 3.05 (s, 3H), 2.62-2.71 (m, 1H), 1.93-2.16 (m, 5H), 1.69 (s, 3H), 1.50 (s, 3H). LC-MS: m / z 572 [M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Method A7cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)-8-oxa-2-azaspiro[4.5]decan-1-one; 2-((S)- 2,2,2-trifluoro-1-(4-((S)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6- yl)phenyl)ethyl)-8-oxa-2-azaspiro[4.5]decan-1-one

[0519] The absolute stereochemistry of each example was not determined.

[0520] Step 1: (1S)-1-(4-bromophenyl)-2,2,2-trifluoro-ethanamine (A7-1)

[0521] A mixture of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (A1-1, 8 g, 22.33 mmol) and HCl (4M in MeOH, 78.16 mL) in MeOH (80 mL) was stirred for 2 h at 0 °C. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, using PE / THF (1:3) as eluent to afford 8 g of material, which was further purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (20% to 75% in 25 min); Detector: UV 254 nm) to obtain the title compound (A7-1, 4.7 g, 83% yield) as a light yellow solid. LC-MS: m / z 253.9 [M+H]+.

[0522] Step 2: Methyl 4-allyltetrahydro-2H-pyran-4-carboxylate

[0523] To a stirred mixture of methyl tetrahydro-2H-pyran-4-carboxylate (20 g, 14 mmol) in THF (200 mL) was added LDA (104 mL, 2.0 M in THF) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 30 min under nitrogen atmosphere.3-bromoprop-1-ene (25.0 g, 208 mmol) was added dropwise at -78 °C under nitrogen atmosphere, and it was stirred at -78 °C for 1 h. The mixture was allowed to warm to 0 °C and was acidified to pH~2 using HCl (10%) at 0 °C. The mixture was extracted with ethyl acetate (3x 800 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel columnAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) chromatography eluted with PE / THF (5:1) to afford the title compound (23 g, 72% yield) as a pale-yellow oil. GC-MS (ES) m / z: 184 [M].

[0524] Step 3: Methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate

[0525] To a stirred mixture of methyl 4-allyltetrahydro-2H-pyran-4-carboxylate (10 g, 54.2 mmol) and sodium periodate (26.7 g, 124 mmol) in isopropyl alcohol (200 mL) and water (200 mL) was added osmium tetroxide (1.38 g, 5.43 mmol). The resulting mixture was stirred at 20 °C for 6 h. The reaction was quenched by the addition of ice water (500 mL), and the mixture was extracted with ethyl acetate (3x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (9.0 g, 71% yield) as brown oil. GC-MS (ES) m / z: 186 [M].

[0526] Step 4: Methyl (S)-4-(2-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)ethyl)tetrahydro-2H- pyran-4-carboxylate

[0527] To a stirred mixture of (1S)-1-(4-bromophenyl)-2,2,2-trifluoro-ethanamine (A7-1, 500 mg, 1.97 mmol) in DCM (10 mL) was added methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.8 g, 9.8 mmol). The resulting mixture was stirred at 25 °C for 16 h. Sodium triacetoxyboranuide (625 mg, 2.9 mmol) was added in portions at 0 °C, and the resulting mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. The reaction was quenched by the addition of ice water (100 mL), and the mixture was extracted with ethyl acetate (3x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (1:1) to afford the title compound (500 mg, 45% yield) as a yellow oil. LC-MS: m / z 424 [M+H]+.

[0528] Step 5: (S)-4-(2-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)ethyl)tetrahydro-2H-pyran- 4-carboxylic acid

[0529] To a stirred mixture of methyl (S)-4-(2-((1-(4-bromophenyl)-2,2,2- trifluoroethyl)amino)ethyl)tetrahydro-2H-pyran-4-carboxylate (280 mg, 659 μmol) in MeOH (2 mL) and THF (2 mL) was added LiOH (158 mg, 6.6 mmol) in water (2 mL). The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography to afford the title compound (148 mg, 43% yield) as an off-white solid. LC-MS: m / z 410 [M+H]+.

[0530] Step 6: (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-8-oxa-2-azaspiro[4.5]decan-1-one

[0531] To a stirred mixture of (S)-4-(2-((1-(4-bromophenyl)-2,2,2- trifluoroethyl)amino)ethyl)tetrahydro-2H-pyran-4-carboxylic acid (240 mg, 584 μmol) in DMF (3.0 mL) were added HATU (332 mg, 876 μmol) and DIEA (151 mg, 1170 μmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched by the addition of ice water (30 mL). The mixture was extractedAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) with ethyl acetate (3x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / THF (1:1) to afford the title compound (160 mg, 59% yield) as a yellow oil. LC-MS: m / z 392 [M+H]+.

[0532] Step 7: 2-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)-8-oxa-2-azaspiro[4.5]decan-1-one

[0533] A mixture of (S)-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-8-oxa-2-azaspiro[4.5]decan-1- one (100 mg, 254 μmol), 1,3-dioxoisoindolin-2-yl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate (100 mg, 254 μmol), NiBr2(dtbpy) (12 mg, 25 μmol) and Hantzsch ester (129 mg, 509 μmol) in DMA (4 mL) was stirred at 25 °C for 2 h under irradiation with blue LED (450 nm) under nitrogen. The reaction mixture was quenched by the addition of water (20 ml). The resulting mixture was extracted with ethyl acetate (3x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford a mixture of diastereomers of the title compound (40 mg, 29% yield) as a white solid. LC-MS: m / z 517 [M+H]+.

[0534] Step 8: Separation of diastereomers to obtain Example 14 and Example 15

[0535] 40 mg of 2-((1S)-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)-8-oxa-2-azaspiro[4.5]decan-1-one was submitted to chiral HPLC purification (Column: CHIRAL ART Cellulose-SJ, 2x25 cm, 5 μm; Mobile Phase A: Hex--HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20mL / min; Gradient: isocratic 8% Mobile Phase B; Wave Length: 254 / 220nm nm; RT1(min): 16.921; RT2(min): 20.514; Sample Solvent: EtOH--HPLC; Injection Volume: 0.3 mL; Number of Runs: 6). The first eluting isomer was concentrated and lyophilized to afford Example 14 (21.9 mg, 16% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to afford Example 15 (20.2 mg, 15% yield) as a white solid.

[0536] Example 14:1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.38-7.43 (m, 4H), 6.54 (d, J = 4.9 Hz, 1H), 5.88-5.95 (m, 1H), 4.62-4.71 (m, 1H), 3.76-3.84 (m, 2H), 3.38-3.54 (m, 3H), 3.14-3.20 (m, 1H), 2.59-2.64 (m, 1H), 1.94-2.08 (m, 3H), 1.66-1.80 (m, 2H), 1.66 (s, 3H), 1.50 (s, 3H), 1.34-1.39 (m, 1H), 1.19-1.28 (m, 1H). LC-MS: m / z 517 [M+H]+.

[0537] Example 15:1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.38-7.44 (m, 4H), 6.54 (d, J = 4.9 Hz, 1H), 5.88-5.95 (m, 1H), 4.62-4.72 (m, 1H), 3.75-3.84 (m, 2H), 3.38-3.54 (m, 3H), 3.14-3.20 (m, 1H), 2.60-2.64 (m, 1H), 1.94-2.08 (m, 3H), 1.66-1.81 (m, 2H), 1.66 (s, 3H), 1.50 (s, 3H), 1.34-1.39 (m, 1H), 1.18-1.28 (m, 1H). LC-MS: m / z 517 [M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) Method A8

[0538] 7,8- dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide; N-methyl-N-((S)-2,2,2-trifluoro-1-(6-((S)-2-fluoro-8,8-dimethyl-7,8-dihydro- 6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide

[0539] The absolute stereochemistry of each example was not determined.

[0540] Step 1: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-ol

[0541] To a solution of 6-bromonicotinaldehyde (2 g, 10.7 mmol) in DME (30 mL) were added CsF (82 mg, 538 μmol) and trimethyl(trifluoromethyl)silane (2.3 g, 16.1 mmol). The reaction mixture was stirred at 0 °C for 16 h under nitrogen atmosphere. The reaction was quenched by the addition of water (100 ml). The resulting mixture was extracted with ethyl acetate (3x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was re- dissolved in DCM (30 ml) and TFA (10 mL) was added. The reaction mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. The reaction was quenched by the addition of water (100 ml), and the resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue wasAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) purified by column chromatography on silica gel using 50% petroleum ether and 50% ethyl acetate as eluent to afford the title compound (2.5 g, 91% yield) as a colorless oil. LC-MS: m / z 256 [M+H]+.

[0542] Step 2: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-one

[0543] To a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-ol (2.5 g, 9.8 mmol) in ethyl acetate (50 mL) was added IBX (8.2 g, 14.6 mmol). The resulting mixture was stirred at 80 °C for 16 h. The reaction was quenched with saturated aqueous NaHSO3 (100 mL). The resulting mixture was extracted with ethyl acetate (3x 100 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound (1.6 g, 64% yield) as a white solid. LC-MS: m / z 272 [M+H2O+1]+.

[0544] Step 3: (R)-N-((S)-1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide

[0545] To a mixture of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-one (2 g, 7.8 mmol) in THF (50 mL) were added (R)-2-methylpropane-2-sulfinamide (1.2 g, 9.5 mmol) and titanium tetraisopropanolate (5.6 g, 19.7 mmol). The reaction mixture was stirred at 80 °C for 12 h. The mixture was cooled to 10 °C to give a solution. Trisec-butylboranuide (1M, 12 mL) was added at -78 °C under nitrogen atmosphere, and it was stirred at -78 °C for 3 h. The reaction mixture was quenched by the addition of ice water (100 mL) and warmed to 10 °C. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford the title compound (1.1 g, 39% yield) as a white solid. LC-MS: m / z 359 [M+H]+.

[0546] Step 4: (R)-N-((S)-1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2- sulfinamide

[0547] To a solution of (R)-N-((S)-1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (600 mg, 1.6 mmol) in THF (20 mL) was added LHMDS (1 M, 2.0 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Iodomethane (1.2 g, 402.0 mmol) was added to the reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction was quenched with aqueous saturated ammonium chloride (40 mL). Water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (2x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford the title compound (270 mg, 43% yield) as a white solid. LC-MS: m / z 373 [M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0548] Step 5: (R)-N,2-dimethyl-N-((1S)-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro- 6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide

[0549] To a solution of (R)-N-((S)-1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-N,2- dimethylpropane-2-sulfinamide (50 mg, 134 μmol) in DMF (5 mL) were added (Ir[DF(CF3)PPY]2(DTBPY))PF6(1.5 mg, 1.3 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (5.4 mg, 20 μmol), NiCl2.glyme (2.9 mg, 13.4 μmol), 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5- a]pyrimidine-6-carboxylic acid (INT-1, 50.1 mg, 201 μmol) and Cs2CO3 (65.5 mg, 201 μmol). The reaction mixture was stirred at 25°C for 3 h under irradiation with blue LED (450 nm) under nitrogen. The reaction was quenched with saturated NaHCO3 (20 mL), and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (3x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 50% petroleum ether and 50% ethyl acetate as eluent to afford a mixture of diastereomers of the title compound (25 mg, 39% yield) as a yellow solid. LC-MS: m / z 498 [M+H]+.

[0550] Step 6: (1S)-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)-N-methylethan-1-amine

[0551] A solution of (R)-N,2-dimethyl-N-((1S)-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8- dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (25 mg, 50 μmol) in HCl (2 mL, 4M in 1,4-dioxane) was stirred at 25 °C for 1 h. The reaction mixture was cooled to 0 °C and quenched with saturated NaHCO3 (5 mL). Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (2x 10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford a mixture of diastereomers of the title compound (15 mg, 76% yield) as a yellow solid. LC-MS: m / z 394 [M+H]+.

[0552] Step 7: N-methyl-N-((1S)-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[0553] To a stirred solution of (1S)-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)-N-methylethan-1-amine (15 mg, 38 μmol) in DCM (3 mL) was added DIEA (15 mg, 114 μmol) at 0 °C. Tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide (23 mg, 114 μmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of water (10 ml). The resulting mixture was extracted with DCM (3x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford a mixture of diastereomers of the title compound (1.8 mg, 8% yield) as a white solid. LC-MS: m / z 554[M+H]+.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1)

[0554] Step 8: Separation of diastereomers to obtain Example 16 and Example 17

[0555] 22 mg of N-methyl-N-((1S)-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide were submitted to chiral HPLC purification (Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH: DCM=1:1--HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 30% Mobile Phase B; Wave Length: 254 / 220nm nm; RT1(min): 20.338; RT2(min): 24.724; Sample Solvent: EtOH--HPLC; Injection Volume: 0.5 mL; Number of Runs: 5). The first eluting isomer was concentrated and lyophilized to afford Example 17 (5.2 mg, 23% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to afford Example 16 (3.8 mg, 17% yield) as a white solid.

[0556] Example 17:1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 1.6 Hz, 1H), 8.32 (s, 1H), 7.85 (dd, J = 1.6, 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.59-6.66 (m, 1H), 6.53 (d, J = 4.8 Hz, 1H), 4.86 (t, J = 8.0 Hz, 1H), 3.09-3.32 (m, 5H), 2.94 (s, 3H), 2.60-2.67 (m, 1H), 2.22-2.27 (m, 1H), 1.91-2.11 (m, 4H), 1.62 (s, 3H), 1.54 (s, 3H). LC-MS: m / z 554 [M+H]+.

[0557] Example 16:1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 2.0 Hz, 1H), 8.32 (...

Claims

Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) CLAIMS What is claimed is:

1. A compound of formula (I): , or a pharmaceutically acceptable saltX is CH, CF, or N; Y is CH, CF, or N; R1is H, halo, or C1-C3alkyl; R2is H, halo, or C1-C3alkyl; R0, R3, and R4are defined as follows: (i) R0is H; R3is C1-C6alkyl, C1-C6haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6haloalkyl; and R4is C1-C6alkyl; or (ii) R0is H; and R3and R4, together with the carbon atom to which they are attached, form a C3-C7cycloalkyl or a 4-7 membered heterocyclyl; or (iii) R0and R3, together with the carbon atoms to which they are attached, form a C3-C7 cycloalkyl; and R4is C1-C6 alkyl; R5is H or halo;Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) R6is H or halo; and R7and R8are defined as follows: (i) R7is C1-C6 alkyl; and R8is C3-C6cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; or (ii) R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; provided that no more than one of X and Y is N.

2. The compound of claim 1, wherein the compound is of formula (I-1): , or a pharmaceutically acceptable saltAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) 3. The compound of claim 1 or 2, wherein the compound is of formula (I-2a): , or a pharmaceutically acceptable salt4. The compound of claim 1 or 2, wherein the compound is of formula (I-2b): , or a pharmaceutically acceptable salt5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is CH.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is CF.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is N.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is CF.

10. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is N.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is H.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R2is F.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3is C1-C6 alkyl, C1-C6 haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6 haloalkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R3is CH3, .of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R4is CH3.

16. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3and R4, together with the carbon atom to which they are attached, form a C3-C7cycloalkyl.

17. The compound of claim 16, wherein R3and R4, or a pharmaceutically acceptable salt thereof, together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R0is H.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) 19. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R0and R3, together with the carbon atoms to which they are attached, form a C3-C7cycloalkyl.

20. The compound of claim 19, wherein R0and R3, or a pharmaceutically acceptable salt thereof, together with the carbon atoms to which they are attached, form a cyclobutyl and R4is CH3.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R5is H or F.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R6is H or F.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R7is C1-C6 alkyl.

24. The compound of claim 23, wherein R7is CH3.

25. The compound of any one of claims 1 to 24, wherein R8is C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo.

26. The compound of claim 25, or.

27. The compound of any one of claims 1 to 22, wherein R7and R8, together with the atoms to which they are attached, form a 5-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) 28. The compound of claim 1, wherein the compound has formula (I-A): ,or a pharmaceutically acceptable salt thereof, wherein: X is CH, CF, or N; Y is CH, CF, or N; R0, R3, and R4are defined as follows: (i) R0is H; R3is C1-C6 alkyl, C1-C6 haloalkyl, or 4-7 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 C1-C6 haloalkyl; and R4is C1-C6 alkyl; or (ii) R0is H; and R3and R4, together with the carbon atom to which they are attached, form a C3-C7 cycloalkyl or a 4-7 membered heterocyclyl; or (iii) R0and R3, together with the carbon atoms to which they are attached, form a C3-C7 cycloalkyl; and R4is C1-C6 alkyl; R5is H or halo; R6is H or halo; and R8is C3-C6cycloalkyl or 4-7 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo; and provided that no more than one of X and Y is N.Attorney Docket No.: 94019-413314 (P30860-WO-PRO1) 29. The compound of claim 28, wherein the compound is of formula (I-A-1): , or a pharmaceutically acceptable salt30. The compound of claim 28 or 29, wherein the compound is of formula (I-A-2a): , or a pharmaceutically acceptable saltAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) 31. The compound of claim 28 or 29, wherein the compound is of formula (I-A-2b): , or a pharmaceutically acceptable salt32. The compound of claim 1, wherein the compound has formula (I-B): or a pharmaceutically acceptable saltX is CH, CF, or N; Y is CH, CF, or N; R3and R4are defined as follows: (i) R3is C1-C6alkyl or C1-C6haloalkyl; and R4is C1-C6alkyl; or (ii) R3and R4, together with the carbon atom to which they are attached, form a C3-C7cycloalkyl or a 4-7 membered heterocyclyl; R5is H or halo; R6is H or halo; andAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) R9and R10, together with the carbon atom to which they are attached, join together to form a 4-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 oxo provided that no more than one of X and Y is N.

33. The compound of claim 32, wherein the compound is of formula (I-B-1): , or a pharmaceutically acceptable salt34. The compound of claim 32 or 33, wherein the compound is of formula (I-B-2a): , or a pharmaceutically acceptable saltAttorney Docket No.: 94019-413314 (P30860-WO-PRO1) 35. The compound of claim 32 or 33, wherein the compound is of formula (I-B-2b): , or a pharmaceutically acceptable salt36. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1 to 36, wherein the compound is in a non-salt form.

38. A pharmaceutical composition comprising the compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, or the compound of claim 37 and one or more pharmaceutically acceptable carriers or vehicles.

39. A method of inhibiting MALT1 in a subject comprising administering to the subject the compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, the compound of claim 37, or the pharmaceutical composition of claim 38.

40. A method of treating or lessening the severity in a subject of a disorder selected from a cancer, an autoimmune disorder, or an inflammatory disorder, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, the compound of claim 37, or the pharmaceutical composition of claim 38.

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