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. Also described are pharmaceutical compositions comprising the compounds of Formula (I) and pharmaceutically acceptable salts thereof, as well as methods of using the compounds and compositions for the treatment of diseases such as cancer, autoimmune disorders, and inflammatory disorders.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 537,637, filed on September 11, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0003] This application relates to tricyclic and other polycyclic compounds that can be used to treat proliferative diseases such as cancer, as well as autoimmune diseases and inflammatory diseases. Background Technology

[0004] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is an intracellular protein that participates in lymphocyte proliferation via upstream signaling of NF-κB, controlling lymphocyte activation, survival, proliferation, and differentiation. Along with CARMA or CARD scaffold proteins (e.g., CARD11 (caspase recruitment domain family member 11, also known as CARMA1), CARD14 (caspase recruitment domain family member 14, also known as CARMA2), CARD10 (caspase recruitment domain family member 10, also known as CARMA3), or CARD9 (caspase recruitment domain family member 9)) and BCL10 (B-cell CLL / lymphoma 10), MALT1 is one of the three subunits of the CBM complex formed upon activation of cell surface antigen receptors. See Jaworski et al., Cell Mol Life Science 2016, 73, 459-473 and Julian and Thome. Frontiers in Immunology 2018, 9, 1927. MALT1 is known to mediate NF-κB signaling through at least two mechanisms: first, MALT1 acts as a scaffold protein, recruiting NF-κB signaling proteins such as TRAF6, TABs (e.g., TAB1, TAB2, TAB3), TAK1, and NEMO-IKKα / β; second, as a cysteine ​​protease, it cleaves and inactivates negative regulators of NF-κB signaling, such as RelB, A20, or CYLD. See Rosebeck et al., Science, 2011, 331, 468-472.

[0005] MALT1 protease activity has emerged as a potential therapeutic target, especially given the perceived importance of NF-κB and related pathways. Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoma typically characterized by NF-κB overactivation, and studies have shown that MALT1 protease inhibition can significantly suppress the growth of highly aggressive ABC-type DLBCL and promote its apoptosis. See Ferch U et al., J Exp Med 2009, 206, 2313-2320; See also Hailfinger S et al., Proc Natl Acad Sci USA 2009, 106, 19946-19951. Known peptide substrates for MALT1 or the fusion protein API2-MALT1 include A20, CYLD, BCL10, RelB, regnase-1, roquin-1, NIK, and LIMA1a. See Rebeaud et al., Nat Immunol 2008, 9, 272-281; See also Coornaert et al., Nat Immunol 20008, 9, 263-271; Staal et al., EMBO J 2011, 30, 1742-1752; Hailfinger et al., PNAS 2011, 108, 14596-14601; Jeltsch et al., Nat Immunol 2014, 15, 1079-1089; Uehata et al., Cell 2013, 153, 1036-1049; Nie et al., Nat Commun 2015, 6, 5908; and Baens et al., PLoS ONE 2014, 9, e103774. A general profile of MALT1 substrates is described in the following literature: Kasperkiewicz et al. Scientific Reports 8.1 (2018): 1-10.

[0006] In addition, several chromosomal translocations leading to constitutively active MALT1 have been identified in ABC-DLBCL, and the identification of the MALT1 fusion protein API2-MALT1 / IgH-MALT1 leading to NF-κB activation independent of upstream stimuli further highlights the importance of this protein in cancer and various diseases. SeeFarinha et al., J Clinical Oncology 2005, 23, 6370-6378. Furthermore, MALT1 has been shown to be associated with several different types of cancer, such as hematologic malignancies (e.g., mantle cell lymphoma), chronic lymphocytic leukemia (CLL), and solid tumors (e.g., 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 July; 24(13):7550-7562. MALT1, as an immunomodulatory protein, is also involved in innate and adaptive immunity and may have an impact on several inflammatory conditions, such as psoriasis, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, ulcerative colitis, and various types of allergic diseases caused by chronic inflammation. See Afofina et al., FEBS Journal 2015, DOI: 10.1111 / febs.13325; See also Lowes et al., Ann Review Immunology 2014, 32, 227-255; Jabara et al., J Allergy Clin Immunology 2013, 132, 151-158; Streubel et al., Clin Cancer Research 2004, 10, 476-480; and Liu et al., Oncotarget 2016, 1-14. Recent findings have also demonstrated the importance of MALT1 in controlling regulatory T cell (Treg) function and homeostasis. Studies are ongoing to confirm the potential of MALT1 inhibitors, alone or in combination with immune checkpoint mechanisms, for the treatment of patients with solid tumors. However, no MALT1 inhibitors are currently approved for therapeutic use. Summary of the Invention

[0007] Therefore, this paper provides a compound of formula (I): , (I) Or a pharmaceutically acceptable salt thereof, wherein X, Y, R 0 R 1 R 2 R 3 R 4 R5 R 6 R 7 and R 8 As defined in this article.

[0008] This article also provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0009] A method is also provided for treating a subject with a CBM complex pathway-related disease or condition, comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0010] A method for treating CBM complex pathway-related cancers in subjects with this need is also provided, the method comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0011] A method for treating a subject with MALT1-related cancer is also provided, comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein. In some respects, the subject has been identified or diagnosed with MALT1-related cancer.

[0012] A method for inhibiting metastasis in a subject requiring such treatment is also provided, the method comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0013] A method for treating an autoimmune disease in a subject with this need is also provided, comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0014] A method for treating a subject with MALT1-related autoimmune disease is also provided, comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein. In some aspects, the subject has been identified or diagnosed with MALT1-related autoimmune disease.

[0015] A method for treating inflammatory conditions in a subject with such need is also provided, comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein.

[0016] A method for treating a subject with MALT1-related inflammatory conditions is also provided, comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein. In some respects, the subject has been identified or diagnosed with MALT1-related inflammatory conditions.

[0017] A method for inhibiting the activity of the CBM complex pathway in a subject is also provided, the method comprising contacting mammalian cells with the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0018] A method for inhibiting the activity of the MALT1 protease in a subject is also provided, the method comprising contacting mammalian cells with the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0019] 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 pertains. This document describes methods and materials used in this disclosure; other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of any conflict, this specification (including definitions) shall prevail.

[0020] Other features and advantages of this disclosure will become apparent from the following detailed description, the accompanying drawings, and the claims. Detailed Implementation

[0021] Definition

[0022] For the purposes of this invention, chemical elements are identified according to the periodic table, CAS version, and the Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th edition, edited by Smith, MB, and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0023] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the described structure. Unless otherwise stated, compounds identified herein as a particular tautomer by name or structure are intended to include other tautomers.

[0024] As used herein, the term “compound of the invention” refers to the compound of formula (I) and all embodiments thereof (e.g., formulas (I-1), (I-2a), (I-2b), (IA), (IA-1), (IA-2a), (IA-2b), (IB), (IB-1), (IB-2a), (IB-2b), etc.), as described herein, and the compounds identified in Table A.

[0025] As described herein, the compounds of the present invention comprise multiple variable groups (e.g., X, Y, R). 0 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10 (etc.). Those skilled in the art will recognize that the combinations of groups contemplated in this invention are those combinations that result in the formation of stable or chemically viable compounds. In this context, the term "stable" means that a compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and preferably recovered, purified, and used for one or more purposes disclosed herein. In some embodiments, a stable or chemically viable compound is one that remains substantially unchanged when kept at a temperature of 40°C or lower for at least one week in the absence of moisture or other chemically reactive conditions.

[0026] As used herein, the term "tautomer" refers to a compound whose structure is significantly different in atomic arrangement but exists in readily and rapidly equilibrated state. It should be understood that the compounds provided herein can be described as different tautomers, and when a compound has a tautomer form, all tautomer forms are intended to be within the scope of this disclosure, and the naming of the compounds does not exclude any tautomer.

[0027] Unless otherwise stated, the compounds of this invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers) and double bond isomers (e.g., [missing information]) of compounds identified by the chemical names and chemical structures provided herein. Z )and( EConformational isomers and tautomers are also included. Additionally, single stereoisomers, double bond isomers, conformational isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers, are also within the scope of this invention. It should be understood that some compounds provided herein may contain one or more asymmetric centers and therefore can be prepared and isolated as mixtures of isomers (e.g., racemic mixtures) or as enantiomeric pure forms.

[0028] As used herein, in any chemical structure or formula, non-bold straight bonds connected to one or more stereocenters of a compound, such as

[0029] This indicates that the configuration of the one or more stereocenters is not specified. The compound may have any configuration or a mixture of configurations at the one or more stereocenters.

[0030] The term "halogenated" refers to one of the halogens in Group 17 of the periodic table. Specifically, this term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0031] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any degree of unsaturation, and having a specified number of carbon atoms, which are connected to the rest of the molecule by single bonds. For example, "C1-C6 alkyl" refers to an alkyl group having one to six carbon atoms. The term "C1-C6 alkyl" refers to a straight-chain or branched hydrocarbon chain containing one, two, three, four, five, or six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Similarly, C1-C3 alkyl is a straight-chain or branched hydrocarbon chain containing one, two, or three carbon atoms.

[0032] As used herein, the term "haloalkyl" refers to an alkyl group having a specified number of carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by a halogenated group. The term "C1-C6 haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom (e.g., fluorine, chlorine, bromine, and iodine) that is independently chosen each time it appears. The halogen atom can be present at any position on the hydrocarbon chain. Similarly, C1-C3 haloalkyl is a straight-chain or branched hydrocarbon chain containing one, two, or three carbon atoms substituted with at least one halogen atom. For example, C1-C3-haloalkyl can 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, and trifluoropropyl.

[0033] When valence is permissible Indicates a single or double bond. For example, .

[0034] As used herein, the term "amino" refers to the –NH2 group.

[0035] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated 3- to 10-membered monocyclic or bicyclic hydrocarbon group; wherein bicyclic systems include fused rings, spirocyclic (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 bicyclic[1.1.1]pentyl.

[0036] The term "heterocyclic group" refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic system that is not aromatic and has at least one heteroatom selected from N, O, and S within the ring. Bicyclic heterocyclic groups include fused ring systems, spirocyclic systems (optionally referred to as "spiroheterocyclic" groups), and bridged ring systems. Heterocyclic ring systems may include oxygen substitution at one or more C, N, or S ring members. Heterocyclic groups may be represented, for example, as "5-10 membered heterocyclic groups," which are ring systems containing 5, 6, 7, 8, 9, or 10 atoms, wherein at least one atom is a heteroatom. For example, one, two, or three heteroatoms may be present, optionally one or two. Heterocyclic groups may be bonded to the rest of the molecule via any carbon atom or via a heteroatom (such as nitrogen). Exemplary heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, aziridine, oxaziridine, 2-azirospiro[3.3]heptyl, pyrrolidine-2-one, sulfolane, isothiazolin S,S-dioxide and decahydronaphthyl.

[0037] As used in this article, the term "oxo" refers to the "=O" group attached to a carbon atom.

[0038] As used in this article, symbols It describes the connection points between an atom or part and a specified atom or group in the rest of the molecule.

[0039] The compounds of the present invention include their pharmaceutically acceptable salts. Additionally, the compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for the preparation and / or purification of the compounds of the present invention and / or for the isolation of enantiomers of the compounds of the present invention. Non-limiting examples of pharmaceutically acceptable salts of the compounds of the present invention include trifluoroacetates and hydrochlorides.

[0040] It will be further understood that the compounds of the present invention or their salts can be separated as solvates, and therefore any such solvates are included within the scope of this disclosure. For example, the compounds of the present invention and their salts can exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc.

[0041] The term "pharmaceutically acceptable" indicates that the compound or its salt or composition is chemically and / or toxicologically compatible with other components of the formulation and / or with subjects treated with said formulation.

[0042] Protecting groups can be temporary substituents that protect potentially reactive functional groups from unwanted chemical transformations. The choice of a specific protecting group used is entirely within the skill of a person skilled in the art. Many factors can determine the choice of protecting group, including but not limited to the functional group being protected, other functional groups present in the molecule, the reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, the tolerance of the functional group to the conditions required for removal of the protecting group, and the reaction conditions for the thermal decomposition of the compound presented herein. The field of protecting group chemistry has been reviewed (Greene, TW and Wuts, PGM). Protective Groups in Organic Synthesis ,2.sup. Edited by Wiley: New York, 1991).

[0043] The nitrogen protecting group can be any temporary substituent that protects the amine moiety from undesirable chemical transformations. Examples of the moiety formed when such a protecting group is bonded to an amine include, but are not limited to, allylamine, benzylamine (e.g., benzylamine, ... To Methoxybenzylamine, 2,4-dimethoxybenzylamine, and triphenylmethylamine), acetamide, trichloroacetamide, trifluoroacetamide, pent-4-enamide, phthalimide, carbamates (e.g., methyl carbamate, carbamate) tert Butyl ester, benzyl carbamate, allyl carbamate, 2,2,2-trichloroethyl carbamate and 9-fluorenyl methyl carbamate), imines and sulfonamides (benzenesulfonamide, To Toluenesulfonamide and To Nitrobenzenesulfonamide).

[0044] The oxygen protecting group can be any temporary substituent that protects the hydroxyl moiety from undesirable chemical transformations. Examples of the moiety formed when such a protecting group is bonded to the hydroxyl group include, but are not limited to, esters (e.g., acetyl groups, etc.). tert Butyl carbonyl and benzoyl), benzyl (e.g., benzyl, p-methoxybenzyl and 2,4-dimethoxybenzyl and triphenylmethyl), carbonates (e.g. methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate and benzyl carbonate), ketals, and acetals, as well as ethers.

[0045] In the specification and claims, unless otherwise stated, any atom not specifically designated as a particular isotope in any compound of the invention is intended to represent any stable isotope of a particular element. In instances where an atom is not specifically designated as a particular isotope in any compound of the invention, no effort is made to enrich that atom with that particular isotope, and therefore those skilled in the art will understand that such an atom may exist with an isotopic composition approximating the natural abundance of the designated element.

[0046] As used herein, the term “stable” when referring to an isotope means that it is unknown whether the isotope will undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes whose decay modes have not been identified in the following literature: VS Shirley & CM Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0047] As used herein in the specification and claims, “H” means hydrogen and includes any stable isotope of hydrogen, i.e. 1 H and D. In the example, when an atom is designated as “H”, no effort is made to enrich that atom with a specific hydrogen isotope, and therefore those skilled in the art will understand that such a hydrogen atom may exist with a natural abundance isotopic composition similar to that of hydrogen.

[0048] As used in this article, " 1 "H" refers to protium. When an atom in a compound of the present invention or a pharmaceutically acceptable salt thereof is designated as protium, protium is present at the designated location at a natural abundance concentration of at least protium.

[0049] As used in this article, “D”, “d” and “ 2 "H" refers to deuterium.

[0050] In some embodiments, the compounds of the present invention and their pharmaceutically acceptable salts comprise constituent atoms of a naturally abundant isotopic composition approximating the specified elements.

[0051] In some embodiments, the compounds of the present invention and their pharmaceutically acceptable salts comprise one or more atoms whose atomic mass or mass number differs from that of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts). Examples of commercially available stable isotopes suitable for use in the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, such as… 2 H, 13 C 15 N、18 O、 17 O and 31 P.

[0052] Isotope-labeled compounds and salts can be used in a variety of beneficial ways, including as pharmaceuticals. In some embodiments, the isotope-labeled compounds and salts are deuterium (…). 2 Marked with H). Deuterium ( 2 H)-labeled compounds and salts are useful in treatment, compared with non-H) 2 H-labeled compounds have potential therapeutic advantages compared to unlabeled compounds and salts. Generally, due to the kinetic isotope effect described below, deuterium (H-labeled compounds) exhibits greater therapeutic benefits compared to unlabeled compounds and salts. 2 H)-labeled compounds and salts can exhibit higher metabolic stability. Higher metabolic stability directly translates to increased in vivo half-life or lower dosage, which in most cases will represent a preferred embodiment of the invention. Isotope-labeled compounds and salts can generally be prepared by performing the procedures disclosed in the synthetic schemes, examples, and related descriptions, replacing non-isotope-labeled reactants with readily available isotope-labeled reactants.

[0053] deuterium( 2 H)-labeled compounds and salts can have their oxidative metabolic rates controlled by first-order kinetic isotope effects. These effects are changes in chemical reaction rates caused by isotopic nuclear exchange, which in turn is caused by changes in the ground-state energy of the covalent bonds involved in the reaction. Exchange of heavier isotopes typically leads to a decrease in the ground-state energy of the chemical bonds, and thus a reduction in the rate-limiting bond breaking. If bond breaking occurs in or near a saddle point region along a multi-product reaction coordinate system, the product distribution can be significantly altered. For example, if deuterium is bonded to a carbon atom at a non-exchangeable position, a typical rate difference is k. H / k D = 2-7. For further discussion, please refer to SL Harbeson and RD Tung. Deuterium In Drug Discovery and Development , Ann. Rep.Med. Chem. 2011, 46, 403-417, the entire contents of which are incorporated herein by reference.

[0054] The concentration of an isotope (e.g., deuterium) at a given position in an isotopically labeled compound or a pharmaceutically acceptable salt of the present invention can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" means the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of that isotope.

[0055] For illustrative purposes, this document provides general methods for preparing the compounds and key intermediates. For a more detailed description of each reaction step, please refer to the Examples section below. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of this invention. Although specific starting materials and reagents are described in the embodiments and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified using conventional chemical methods well known to those skilled in the art according to this disclosure.

[0056] The ability of the selected compounds to act as MALT1 inhibitors can be demonstrated by the biological assays described in this paper. 50 The values ​​are shown in Table 1.

[0057] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used to treat diseases and conditions that can be treated with MALT1 inhibitors, such as MALT1-related cancers, including blood cancers and solid tumors, MALT1-related autoimmune diseases, and MALT1-related inflammatory diseases.

[0058] As used herein, the term "treat" refers to a therapeutic or mitigating measure. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial relief of symptoms associated with the disease or condition, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or reduction of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean extended survival compared to expected survival without treatment.

[0059] 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 a disease or condition to be treated and / or prevented.

[0060] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof may be used to prevent diseases and conditions as defined herein (e.g., autoimmune diseases, inflammatory conditions, and cancer). As used herein, the term “prevention” means complete or partial prevention of the onset, recurrence, or spread of a disease or condition as described herein, or its symptoms.

[0061] Signal transduction via the NF-κB pathway is involved in many cancers. See, for exampleStaudt, Cold SpringHarbor Perspectives in Biology 2.6 (2010): a000109; Xia et al. Cancer Immunol. Res. 2.9 (2014): 823-830; Xia et al. OncoTargets and Therapy 11 (2018): 2063. NF-κB is a family of transcription factors including p50, p52, p65 (RelA), RelB, and c-Rel, which can bind to κB enhancer elements as various homodimers to induce transcription of many genes. Upon activation of certain cell surface receptors (e.g., CD28, BCR, HER1 (also known as EGFR (epidermal growth factor receptor) and ERBB1) or HER2 (also known as HER2 / neu or ERBB2)), the CBM complex is formed via CARD or CARMA proteins, possibly through phosphorylation of protein kinase C (e.g., protein kinase Cβ or protein kinase Cθ) and recruitment of the BCL10-MALT1 complex. See, for example Xia et al. OncoTargets and Therapy 11 (2018): 2063, Shi and Sun. Mol. Immunol. 68.2 (2015): 546-557, Xia et al. Cancer Immunol. Res. 2.9 (2014): 823-830, and Pan, Mol. CancerRes. 14.1 (2016): 93-102.

[0062] As described above, the CBM complex can function as a scaffold protein in the activation of the NF-κB pathway. Upon formation, the CBM complex can activate the IKK complex (e.g., IKKγ (also known as NEMO), IKKα, and IKKβ), possibly through the ubiquitination of MALT1 (e.g., K63-linked ubiquitination), which induces the recruitment, ubiquitination (e.g., K63-linked ubiquitination), and degradation of IKKγ, thereby releasing IKKα and IKKβ to phosphorylate IκB, leading to IκB ubiquitination (e.g., K48-linked ubiquitination) and degradation, thus releasing NF-κB transcription factors (typically NF-κB1 isoforms: p50-RelA and p50-cRel) into the nucleus. This cascade reaction may be mediated by the ubiquitin ligase TRAF6 (tumor necrosis factor receptor (TNFR)-associated factor 6). The CBM complex may also affect NF-κB signaling through other protein complexes, such as TAB1 / 2-TAK and the linear ubiquitin chain assembly complex (LUBAC). See, for exampleIsraël, Cold Spring Harbor Perspectives in Biology 2.3 (2010): a000158; Xia et al. OncoTargets and Therapy 11 (2018): 2063; Julian, Front. Immunol. 9 (2018): 1927. MALT1 can also activate the JNK pathway (also known as the JNK / AP-1 pathway), although there is relatively little research in this area. See, for example , Julian, Front. Immunol. 9(2018): 1927, and Wang et al., Oncogenesis 6.7 (2017): e365-e365.

[0063] In addition, MALT1 possesses cysteine ​​protease activity. Unrestricted examples of wild-type MALT1 substrates include BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, and HOIL1. Furthermore, the API2-MALT1 fusion protein (also known as cIAP2; the N-terminus of apoptosis inhibitor 2) has been shown to cleave NIK and LIMA1α. MALT1 cleavage of BCL10 is thought to lead to BCL10-independent NF-κB activation. By cleaving A20 (TNFα-inducible protein 3), MALT1 can reduce the negative regulation of the NF-κB pathway, as A20 is a deubiquitinating enzyme that has been suggested to reduce MALT1 ubiquitination, thereby reducing the recruitment and activation of the IKK complex. CYLD (CYLD lysine 63 deubiquitinase) is a deubiquitinating enzyme, and by cleaving this enzyme, MALT1 is believed to increase signaling via the NF-κB and / or JNK pathways. Cleavage of RelB typically alleviates the negative regulation of the NF-κB pathway because RelB forms a transcriptionally inactive complex with RelA and c-Rel. Cleavage of HOIL1 (also known as RBCK1) is believed to alleviate the negative regulation of NF-κB, as HOIL1 is thought to reduce linear ubiquitination. MALT1 can also be autoprocessed to promote signaling via the NF-κB pathway through a mechanism not yet fully understood. Cleavage of NIK (NF-κB-inducible kinase) generates the c-terminal fragment of NIK, which is resistant to proteasome degradation, thereby increasing non-canonical NF-κB signaling. Cleavage of LIMA1α (LIM domain and actin-binding protein 1) reduces the tumor-suppressive properties of this protein, and the remaining fragment is believed to have oncogenic properties and enhance 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 thought to lead to the stabilization of mRNAs containing cytokines, chemokines, and co-stimulatory proteins such as ICOS, OX40, and TNF. This activity may be independent of MALT1 activity in the NF-κB and JNK pathways. See for exampleAfonina 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 Julian, Front. Immunol. 9 (2018): 1927. MALT1 is also involved in oncogenic BCR signaling in ibrutinib-responsive cell lines and biopsy samples, coordinated by a multi-protein supercomplex (hereinafter referred to as the My-T-BCR supercomplex) formed by MYD88, TLR9, and BCR. The My-T-BCR supercomplex co-localizes with mTOR on lysosomes, where it drives survival-promoting NF-κB and mTOR signaling. See Phelan et al., Nature, August 2018; 560(7718):387-391.

[0064] Therefore, inhibition of MALT1 can provide beneficial effects for many types of conditions associated with abnormal signaling in the NF-κB or JNK pathways. For example, inhibiting MALT1 can reduce flux through the NF-κB or JNK pathways caused by one or more of the following: (1) Inactivated tumor suppressor genes. Non-restricted examples of tumor suppressor genes that can be inactivated include BRCA1 and p53 (e.g., p53 H61L or I123T). See, for example Sau et al. Cell Stem Cell 19.1 (2016): 52-65, Xia et al. Cancer Immunol. Res. 2.9 (2014): 823-830, Johansson et al. Oncotarget 7.38 (2016): 62627.

[0065] (2) Dysregulated cell surface receptors. Non-restrictive examples of cell surface receptors include HER1 and HER2. See, for example, Xia et al. Cancer Immunol. Res. 2.9 (2014): 823-830, and Pan, Mol. CancerRes.14.1 (2016): 93-102.

[0066] (3) Imbalance of one or more components of the CBM complex. Non-limiting examples of components of the CBM complex include MALT1, CARD11, CARD14, CARD10, CARD9 and BCL10.

[0067] (4) Dysregulation of one or more MALT1 protease substrates (e.g., wild-type MALT1 protease or dysregulated MALT1 protease). Non-limiting examples of MALT1 protease substrates include BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, HOIL1, NIK, and LIMA1α.

[0068] (5) Dysregulation of one or more components of the NF-κB pathway downstream of the CBM complex. Non-limiting examples of components of the NF-κB pathway downstream of the CBM complex include TRAF6, IKKα, IKKβ, IKKγ (also known as NEMO), IkBα, p50, p52, p65 (RelA), RelB and c-Rel.

[0069] (6) Dysregulation of one or more components of the JNK pathway downstream of the CBM complex. Non-restricted examples of components of the JNK pathway downstream of the CBM complex include JNK1 (mitogen-activated protein kinase 8), JNK2 (mitogen-activated protein kinase 9), JNK3 (mitogen-activated protein kinase 10), or AP-1 transcription factors (e.g., heterodimers of any of the c-Fos, c-Jun, ATF, or JDP families).

[0070] (7) Dysregulation of one or more fusion proteins caused by chromosomal translocation of the MALT1 gene. Non-limiting examples include the cIAP-MALT1 fusion protein.

[0071] (8) Imbalance of one or more components of the My-T-BCR supercomplex. Non-limiting examples of components of the My-T-BCR supercomplex include MYD88, TLR9 and mTOR.

[0072] As used herein, the term "CBM complex pathway" encompasses genes, transcripts, and proteins in signal transduction pathways that include CBM. For example, many aspects of the NF-κB pathway are part of the CBM complex pathway. The CBM complex pathway may include, for example, cell surface receptors (e.g., CD28, BCR, HER1, and HER2), signal transducers between cell surface receptors and the CBM complex (e.g., protein kinase Cβ or protein kinase Cθ), components of the CBM complex (e.g., MALT1, CARD11, CARD14, CARD10, CARD9, or BCL10), substrates of the MALT1 protease (e.g., BCL10, A20, CYLD, RelB, Regnase 1, roquin-1, HOIL1, NIK, and LIMA1α), and components of the downstream NF-κB pathway of the CBM complex (e.g., TAK1, TRAF6, TAB1, TAB2, TAB3, MKK7, IKKα, IKKβ, IKKγ, IkBα, p50, and p65). (RelA) or c-Rel), components of the JNK pathway downstream of the CBM complex (e.g., JNK1, JNK2, JNK3 or AP-1 transcription factors) or components of the My-T-BCR supercomplex (e.g., MYD88, TLR9 or mTOR).

[0073] As used herein, the term "CBM complex pathway-related disease or condition" refers to a disease or condition associated with or having a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of a gene, protein, or any of the CBM complex pathway, as described herein) in the CBM complex pathway. Non-limiting examples of CBM complex pathway-related diseases or conditions include, for example, CBM-related primary immunodeficiency diseases, autoimmune diseases, multiple sclerosis, colitis, psoriasis, and cancer. See, for example McGuire et al., J. Neuroinflamm. 11.1(2014): 1-12; Lu et al., Front. Immunol. 9 (2018): 2078; Jaworski et al., EMBO J. 33.23(2014): 2765-2781. Non-limiting examples of diseases or conditions related to the CBM complex pathway include MALT1-related diseases or conditions, such as MALT1-related cancers, MALT1-related autoimmune diseases, and MALT1-related inflammatory diseases.

[0074] As used herein, the term "CBM complex pathway-associated autoimmune disease" refers to an autoimmune disease associated with or having a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of CBM complex pathway genes, CBM complex pathway proteins, or any of them, e.g., one or more) of these genes, proteins, or any of them. Non-limiting examples of CBM complex pathway-associated autoimmune diseases are described herein.

[0075] As used herein, the term "CBM complex pathway-associated inflammatory condition" refers to an inflammatory condition associated with or having dysregulation (e.g., any type of dysregulation of the expression, activity, or level of CBM complex pathway genes, CBM complex pathway proteins, or any of them, e.g., one or more) of these genes, proteins, or any of them. Non-limiting examples of CBM complex pathway-associated inflammatory conditions are described herein.

[0076] In some embodiments, CBM complex pathway-related diseases or conditions are CBM complex pathway-related cancers, such as CBM complex pathway cell surface receptor-related cancers (e.g., CD28-related cancers, BCR-related cancers, HER1-related cancers, or HER2-related cancers), cancers related to signal transduction mechanisms between cell surface receptors and the CBM complex (e.g., protein kinase Cβ (PKCβ)-related cancers or protein kinase Cθ (PCKθ)-related cancers), components of CBM complex-related cancers (e.g., MALT1-related cancers, CARD11-related cancers, CARD14-related cancers, CARD10-related cancers, CARD9-related cancers, or BCL10-related cancers), and MALT1 protease substrate-related cancers (e.g., BCL10-related cancers, A20-related cancers, CYLD-related cancers, RelB-related cancers, Regnase-related cancers). Cancers associated with CBM complexes include: 1-related cancers, roquin-1-related cancers, HOIL1-related cancers, NIK-related cancers, or LIMA1α-related cancers; cancers associated with components of the NF-κB pathway downstream of the CBM complex (e.g., TAK1-related cancers, TRAF6-related cancers, TAB1-related cancers, TAB2-related cancers, TAB3-related cancers, MKK7-related cancers, IKKα-related cancers, IKKβ-related cancers, IKKγ-related cancers, IkBα-related cancers, p50-related cancers, p65 (RelA)-related cancers, or c-Rel-related cancers); cancers associated with components of the JNK pathway downstream of the CBM complex (e.g., JNK1-related cancers, JNK2-related cancers, JNK3-related cancers, or AP-1 transcription factor-related cancers); MYD88-related cancers, or combinations thereof.

[0077] In some embodiments, dysregulation can be a dysregulation that results in abnormal activation of the expression, activity, or level of a gene, protein, or any of them. Activation can occur through any suitable mechanism, including but not limited to gene amplification, activation mutations, activation translocations, transcriptional activation, epigenetic alterations, and / or overexpression of the protein product of an oncogene. In some embodiments, dysregulation can be a dysregulation that results in abnormal inactivation of the expression, activity, or level of a gene, protein, or any of them. Inactivation can occur through any suitable mechanism, including but not limited to gene deletion, inactivation mutations, inactivation translocations, transcriptional silencing, epigenetic alterations, and degradation of the mRNA and / or protein product of a gene. Generally, as used herein, dysregulation (whether activation or inactivation) is a dysregulation that results in increased signal transduction via the NF-κB or JNK signaling pathway.

[0078] The term "wildtype" describes nucleic acids (e.g., the MALT1 gene or MALT1 mRNA) or proteins (e.g., the MALT1 protein) found in subjects who do not have a disease or condition related to nucleic acids or proteins (e.g., the MALT1 gene, MALT1 mRNA, or MALT1 protein) (and optionally do not have an increased risk of having a disease or condition related to nucleic acids or proteins and / or are not suspected of having a disease or condition related to nucleic acids or proteins), or from cells or tissues of subjects who do not have a disease or condition related to nucleic acids or proteins (e.g., MALT1-related cancer, autoimmune disease, or inflammatory disease) (and optionally do not have an increased risk of having a disease or condition related to nucleic acids or proteins and / or are not suspected of having a disease or condition related to nucleic acids or proteins).

[0079] In some embodiments, the subject has been identified or diagnosed with cancer that has dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or any of them (CBM complex pathway-related cancer) (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has cancer that is resistant to one or more prior therapies. In some embodiments, the subject has a tumor that is positive for dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). The subject may be a subject with a tumor that is positive for dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or any of them (e.g., identified as positive using a regulatory-approved (e.g., FDA-approved) assay or kit). The subject may be a subject whose tumor has dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or both (e.g., in cases where the tumor is identified using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has a tumor resistant to one or more prior therapies. In some embodiments, the subject is suspected of having CBM complex pathway-related cancer. In some embodiments, the subject has a suspected tumor resistant to one or more prior therapies. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression, activity, or level of a CBM complex pathway-related gene (e.g., the MALT1 gene), a CBM complex pathway-related protein (e.g., the MALT1 protein), or either of these (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 prior therapies. In some embodiments, the subject has been identified or diagnosed with cancer that has been determined based on histological examination to be associated with dysregulation of the expression, activity, or level of CBM complex pathway-related genes (e.g., the MALT1 gene), CBM complex pathway-related proteins (e.g., the MALT1 protein), or any of them (CBM complex pathway-related cancer).

[0080] In some embodiments, the subject has been identified or diagnosed with an autoimmune disease (CBM pathway-associated autoimmune disease) having dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject is suspected of having a CBM complex pathway-associated autoimmune disease. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subjects are pediatric subjects. In some embodiments, the subjects have been identified or diagnosed with an autoimmune disease that has been determined based on histological examination to be associated with dysregulation of the expression, activity, or level of CBM complex pathway-related genes (e.g., the MALT1 gene), CBM complex pathway-related proteins (e.g., the MALT1 protein), or any of them (CBM complex pathway-related autoimmune disease).

[0081] In some embodiments, the subject has been identified or diagnosed with an inflammatory condition (CBM pathway-associated inflammation) having dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some embodiments, the subject is suspected of having CBM complex pathway-associated inflammation. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression, activity, or level of a CBM complex pathway-associated gene (e.g., the MALT1 gene), a CBM complex pathway-associated protein (e.g., the MALT1 protein), or any of them (and optionally, the clinical 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 with an inflammatory condition that has been determined based on histological examination to be associated with dysregulation of the expression, activity, or level of CBM complex pathway-related genes (e.g., the MALT1 gene), CBM complex pathway-related proteins (e.g., the MALT1 protein), or any of them (CBM complex pathway-related inflammatory condition).

[0082] As used herein, the term "CBM complex pathway cell surface receptor-associated cancer" refers to cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any of these (e.g., one or more), said dysregulation being associated with a CBM complex pathway cell surface receptor. In some embodiments, CBM complex pathway cell surface receptor-associated cancer is selected from the group consisting of: CD28-associated cancer, BCR-associated cancer, HER1-associated cancer, HER2-associated cancer, and combinations thereof.

[0083] As used in this article, the term " "Related cancers" refers to cancers associated with... Gene, The expression, activity, or level of a protein or any of them (e.g., one or more) are associated with or dysregulated (e.g., as described herein). Gene, Cancer of any type of dysregulation of the expression, activity, or level of a protein or any of these proteins, wherein " "Refers to the specific CBM complex pathway gene or protein described herein. In some embodiments," The relevant cancers were selected from the following groups: CD28-related cancers, BCR-related cancers, HER1-related cancers, HER2-related cancers, PKCβ-related cancers, PKCθ-related cancers, MALT1-related cancers, CARD11-related cancers, CARD14-related cancers, A20-related cancers, CYLD-related cancers, RelB-related cancers, HOIL1-related cancers, NIK-related cancers, Regnase 1-related cancers, LIMA1α-related cancers, roquin-1-related cancers, TRAF6-related cancers, TAK1-related cancers, TAB1-related cancers, TAB2-related cancers, TAB3-related cancers, MKK7-related cancers, IKKα-related cancers, IKKβ-related cancers, IKKγ-related cancers, IkBα-related cancers, p50-related cancers, p65-related cancers, c-Rel-related cancers, JNK1-related cancers, JNK2-related cancers, JNK3-related cancers, MYD88 transcription factor-related cancers, and AP-1 transcription factor-related cancers. In some embodiments, The associated cancers are CD28-related cancers. In some embodiments, The associated cancers are BCR-related cancers. In some embodiments, The associated cancers are HER1-related cancers. In some embodiments, The associated cancers are HER2-related cancers. In some embodiments, The associated cancer is PKCβ-related cancer. In some embodiments, The associated cancer is PKCθ-related cancer. In some embodiments, The associated cancers are MALT1-related cancers. In some embodiments, The associated cancers are CARD11-related cancers. In some embodiments, The associated cancers are CARD14-related cancers. In some embodiments, The associated cancers are A20-related cancers. In some embodiments, The associated cancers are CYLD-related cancers. In some embodiments, The associated cancers are RelB-related cancers. In some embodiments, The associated cancers are HOIL1-related cancers. In some embodiments, The associated cancers are NIK-related cancers. In some embodiments, The associated cancers are Regnase 1-related cancers. In some embodiments, The associated cancers are LIMA1α-related cancers. In some embodiments, The associated cancers are roquin-1-related cancers. In some embodiments, The associated cancers are TRAF6-related cancers. In some embodiments, The associated cancers are TAK1-related cancers. In some embodiments, The associated cancers are TAB1-related cancers. In some embodiments, The associated cancer is TAB2-related cancer. In some embodiments, The associated cancers are TAB3-related cancers. In some embodiments, The associated cancers are MKK7-related cancers and IKKα-related cancers. In some embodiments, The associated cancers are IKKβ-related cancers. In some embodiments, The associated cancer is IKKγ-related cancer. In some embodiments, The associated cancers are IkBα-related cancers. In some embodiments, The associated cancers are p50-related cancers. In some embodiments, The associated cancers are p65-related cancers. In some embodiments, The associated cancer is c-Rel-related cancer. In some embodiments, The associated cancers are JNK1-related cancers. In some embodiments, The associated cancers are JNK2-related cancers. In some embodiments, The associated cancers are JNK3-related cancers. In some embodiments, The associated cancers are AP-1 transcription factor-related cancers. In some embodiments, The associated cancer is MYD88 transcription factor-related cancer.

[0084] A disease or condition “associated with” a specific gene or protein described herein refers to a disease or condition that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the specific gene, protein, or any of the specific proteins described herein) in relation to or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the specific gene, protein, or any of the specific proteins described herein). Non-limiting examples of such diseases or conditions are described herein. Similarly, a cancer “associated with” a specific gene or protein described herein refers to a cancer that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the specific gene, protein, or any of the specific proteins described herein) in relation to or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the specific gene, protein, or any of the specific proteins described herein). Non-limiting examples of such cancers are described herein.

[0085] As used herein, the term "cancer associated with a signal transducer between cell surface receptors and the CBM complex" refers to cancer associated with or having an dysregulation of the expression, activity, or level of a gene, protein, or any one or more thereof, said dysregulation being associated with a signal transducer between cell surface receptors and the CBM complex. In some embodiments, cancer associated with a signal transducer between cell surface receptors and the CBM complex is selected from the group consisting of PKCβ-associated cancers, PCKθ-associated cancers, and combinations thereof. Cancer "associated" with a specific gene or protein described in this paragraph refers to cancer associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any one thereof described herein) related to the expression, activity, or level of that specific gene, protein, or any one thereof. Non-limiting examples of such cancers are described herein.

[0086] As used herein, the term "component of CBM complex-associated cancer" refers to cancer associated with or having an dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more), said dysregulation being associated with a component of the CBM complex. In some embodiments, the component of CBM complex-associated cancer is selected from the group consisting of: MALT1-associated cancer, CARD11-associated cancer, CARD14-associated cancer, CARD10-associated cancer, CARD9-associated cancer, BCL10-associated cancer, and combinations thereof. In some embodiments, the CBM complex-associated cancer is selected from the group consisting of: MALT1-associated cancer, CARD11-associated cancer, BCL10-associated cancer, and combinations thereof. Cancer "associated" with a specific gene or protein described in this paragraph refers to cancer associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein) being associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein). Non-limiting examples of such cancers are described herein.

[0087] As used herein, the term "MALT1-associated autoimmune disease" refers to an autoimmune disease associated with or having dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any of them (e.g., one or more)). Non-limiting examples of MALT1-associated autoimmune diseases are described herein.

[0088] As used herein, the term "MALT1-associated inflammatory condition" refers to an inflammatory condition associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any of them (e.g., one or more)). Non-limiting examples of MALT1-associated inflammatory conditions are described herein.

[0089] As used herein, the term "MALT1-related cancer" refers to cancer associated with or dysregulated (e.g., any type of dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein (also referred to herein as MALT1 protease protein or MALT1 protease), or any of them (e.g., one or more). Non-limiting examples of MALT1-related cancers are described herein.

[0090] The phrase "dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein, or either of them" refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type MALT1 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a MALT1 protease domain and a fusion chaperone; mutation in the MALT1 gene causing expression of MALT1 protein containing at least one amino acid deletion compared to wild-type MALT1 protein; mutation in the MALT1 gene causing expression of MALT1 protein with one or more point mutations compared to wild-type MALT1 protein; mutation in the MALT1 gene causing expression of MALT1 protein with at least one inserted amino acid compared to wild-type MALT1 protein; gene duplication causing elevated MALT1 protein levels in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated MALT1 protein levels in cells). Alternative splicing of mRNA resulting in a MALT1 protein with at least one amino acid deletion compared to the wild-type MALT1 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulation of autocrine / paracrine signaling. As another example, dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein, or either thereof can be a mutation in the MALT1 gene encoding the MALT1 protein, which is constitutively active or has increased activity compared to a protein encoded by a non-mutated MALT1 gene. As yet another example, an increased copy number of the MALT1 gene can cause overexpression of the MALT1 protease. For example, dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein, or either thereof can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first portion of MALT1 (which includes a functional protease domain) and a second portion of a chaperone protein (i.e., not MALT1). In some instances, dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protein, or either of them can be the result of a gene translocation between a MALT1 gene and another non-MALT1 gene.

[0091] Non-restrictive examples of MALT1 gene or MALT1 protein dysregulation are shown in Table B1 below.

[0092] Table B1.

[0093] 1 US Patent 10,711,036

[0094] 2 US Patent Application Publication US20190160045A1

[0095] 3 US Patent Application Publication US20130096021A1

[0096] 4 US Patent Application Publication US20150320754A1

[0097] As used herein, the term “CARD11-associated autoimmune disease” refers to an autoimmune disease that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them, as described herein) of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them.

[0098] As used herein, the term “CARD11-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them, as described herein) with respect to or with respect to the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them.

[0099] As used herein, the term “CARD11-related cancer” refers to cancer that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or any of them, e.g., one or more) of the CARD11 gene, CARD11 protein, or any of them as described herein. Non-limiting examples of CARD11-related cancers are described herein.

[0100] The phrase “dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or either of them” refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type CARD11 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a CARD11 domain and a fusion chaperone; mutation in the CARD11 gene causing expression of a CARD11 protein containing at least one amino acid deletion compared to wild-type CARD11 protein; mutation in the CARD11 gene causing expression of a CARD11 protein with one or more point mutations compared to wild-type CARD11 protein; mutation in the CARD11 gene causing expression of a CARD11 protein with at least one inserted amino acid compared to wild-type CARD11 protein; gene duplication causing elevated levels of CARD11 protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of CARD11 protein in cells). Alternative splicing forms of mRNA that result in a CARD11 protein with at least one amino acid deletion compared to the wild-type CARD11 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, dysregulation of the expression, activity, or level of the CARD11 gene, the CARD11 protein, or either thereof can be a mutation in the CARD11 gene encoding the CARD11 protein, which is constitutively active or has increased activity compared to a protein encoded by a CARD11 gene without the mutation. As yet another example, an increased copy number of the CARD11 gene can cause overexpression of the CARD11 protein. For example, dysregulation of the expression, activity, or level of the CARD11 gene, the CARD11 protein, or either thereof can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first portion of CARD11 and a second portion of a chaperone protein (i.e., not CARD11). In some instances, dysregulation of the expression, activity, or level of the CARD11 gene, CARD11 protein, or either of them can be the result of a gene translocation between a CARD11 gene and another non-CARD11 gene.

[0101] Non-restrictive examples of CARD11 gene or CARD11 protein dysregulation are shown in Table B2 below.

[0102] Table B2.

[0103] 1Wu et al., Oncotarget 7.25 (2016): 38180.

[0104] 2 Watt et al. The American Journal of Pathology 185.9 (2015): 2354-2363.

[0105] As used herein, the term “CARD14-associated autoimmune disease” refers to an autoimmune disease that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them, as described herein) of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them.

[0106] As used herein, the term “CARD14-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them, as described herein) of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them.

[0107] As used herein, the term “CARD14-associated cancer” refers to cancer that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them, as described herein) of the expression, activity, or level of the CARD14 gene, CARD14 protein, or any of them.

[0108] As used herein, the term “CARD10-associated autoimmune disease” refers to an autoimmune disease that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them, as described herein) of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them.

[0109] As used herein, the term “CARD10-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them, as described herein) of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them.

[0110] As used herein, the term “CARD10-associated cancer” refers to cancer that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them, as described herein) of the expression, activity, or level of the CARD10 gene, CARD10 protein, or any of them.

[0111] The phrase "dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or either of these" refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type CARD10 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a CARD10 domain and a fusion chaperone; mutation in the CARD10 gene causing expression of a CARD10 protein with at least one amino acid deletion compared to wild-type CARD10 protein; mutation in the CARD10 gene causing expression of a CARD10 protein with one or more point mutations compared to wild-type CARD10 protein; mutation in the CARD10 gene causing expression of a CARD10 protein with at least one inserted amino acid compared to wild-type CARD10 protein; gene duplication causing elevated levels of CARD10 protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of CARD10 protein in cells). Alternative splicing forms of mRNA that result in a CARD10 protein with at least one amino acid deletion compared to the wild-type CARD10 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, dysregulation of the expression, activity, or level of the CARD10 gene, the CARD10 protein, or either thereof can be a mutation in the CARD10 gene encoding the CARD10 protein, which is constitutively active or has increased activity compared to a protein encoded by a CARD10 gene without the mutation. As yet another example, an increased copy number of the CARD10 gene can cause overexpression of the CARD10 protein. For example, dysregulation of the expression, activity, or level of the CARD10 gene, the CARD10 protein, or either thereof can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion of CARD10 and a second portion of a chaperone protein (i.e., not CARD10). In some instances, dysregulation of the expression, activity, or level of the CARD10 gene, CARD10 protein, or either of them can be the result of a gene translocation between a CARD10 gene and another non-CARD10 gene.

[0112] As used herein, the term “CARD9-associated autoimmune disease” refers to an autoimmune disease that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein) of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them.

[0113] As used herein, the term “CARD9-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein) that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein).

[0114] As used herein, the term “CARD9-related cancer” refers to cancer that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them, as described herein) of the expression, activity, or level of the CARD9 gene, CARD9 protein, or any of them.

[0115] The phrase "dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or either of these" refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type CARD9 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a CARD9 domain and a fusion chaperone; mutation in the CARD9 gene causing expression of a CARD9 protein containing at least one amino acid deletion compared to wild-type CARD9; mutation in the CARD9 gene causing expression of a CARD9 protein with one or more point mutations compared to wild-type CARD9; mutation in the CARD9 gene causing expression of a CARD9 protein with at least one inserted amino acid compared to wild-type CARD9; gene duplication causing elevated levels of CARD9 protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of CARD9 protein in cells). Alternative splicing of mRNA resulting in a CARD9 protein with at least one amino acid deletion compared to the wild-type CARD9 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling. As another example, dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or either thereof can be a mutation in the CARD9 gene encoding the CARD9 protein, which is constitutively active or has increased activity compared to a protein encoded by a CARD9 gene without the mutation. As yet another example, an increased copy number of the CARD9 gene can cause overexpression of the CARD9 protein. For example, dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or either thereof can be the result of a gene or chromosomal translocation that causes the expression of a fusion protein containing a first part of CARD9 and a second part of a chaperone protein (i.e., not CARD9). In some instances, dysregulation of the expression, activity, or level of the CARD9 gene, CARD9 protein, or either of them can be the result of a gene translocation between a CARD9 gene and another non-CARD9 gene.

[0116] As used herein, the term “BCL10-associated autoimmune disease” refers to an autoimmune disease that is associated with or has a dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them, as described herein) of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them.

[0117] As used herein, the term “BCL10-associated inflammatory condition” refers to an inflammatory condition that is associated with or has an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them, as described herein) of the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them.

[0118] As used herein, the term “BCL10-associated cancer” refers to cancer that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them, as described herein) with respect to or with an imbalance (e.g., any type of imbalance in the expression, activity, or level of the BCL10 gene, BCL10 protein, or any of them, as described herein).

[0119] The phrase “dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or either of them” refers to (e.g., compared to control non-cancer cells) a gene mutation of the wild-type BCL10 protein in mammalian cells (e.g., chromosomal translocation causing expression of a fusion protein containing a BCL10 domain and a fusion chaperone; mutation in the BCL10 gene causing expression of a BCL10 protein with at least one amino acid deletion compared to wild-type BCL10 protein; mutation in the BCL10 gene causing expression of a BCL10 protein with one or more point mutations compared to wild-type BCL10 protein; mutation in the BCL10 gene causing expression of a BCL10 protein with at least one inserted amino acid compared to wild-type BCL10 protein; gene duplication causing elevated levels of BCL10 protein in cells; or mutation in regulatory sequences (e.g., promoters and / or enhancers) causing elevated levels of BCL10 protein in cells). Alternative splicing forms of mRNA that result in a BCL10 protein with at least one amino acid deletion compared to the wild-type BCL10 protein; or increased expression (e.g., elevated levels) due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling. For example, dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or either thereof can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion of BCL10 and a second portion of a chaperone protein (i.e., not BCL10). In some instances, dysregulation of the expression, activity, or level of the BCL10 gene, BCL10 protein, or either thereof can be the result of a gene translocation of a BCL10 gene to another non-BCL10 gene.

[0120] Non-restrictive examples of BCL10 gene or BCL10 protein dysregulation are shown in Table B3 below.

[0121] Table B3.

[0122] 1 Willis et al. Cell 96.1 (1999): 35-45.

[0123] 2 Zhang et al., Nature Genetics 22.1 (1999): 63-68.

[0124] As used herein, the term "MALT1 protease substrate-associated cancer" refers to cancer associated with or having an dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more), said dysregulation being associated with a MALT1 protease substrate. In some embodiments, MALT1 protease substrate-associated cancer is selected from the group consisting of: BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, RelB-associated cancer, Regnase 1-associated cancer, roquin-1-associated cancer, HOIL1-associated cancer, NIK-associated cancer, LIMA1α-associated cancer, and combinations thereof. In some embodiments, MALT1 protease substrate-associated cancer is selected from the group consisting of: BCL10-associated cancer, A20-associated cancer, CYLD-associated cancer, and combinations thereof. Cancer "associated" with a specific gene or protein described in this paragraph refers to cancer associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein) being associated with or having an dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein). This article describes a non-limiting example of this type of cancer.

[0125] Non-restrictive examples of A20 gene or A20 protein dysregulation are shown in Table B4 below.

[0126] Table B4.

[0127] 1 Johansson et al. Oncotarget 7.38 (2016): 62627.

[0128] 2 Novak et al. Blood 113.20 (2009): 4918-4921.

[0129] As used herein, the term "cancer associated with a component of the NF-κB pathway downstream of the CBM complex" refers to cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any of these (e.g., one or more), said dysregulation being associated with a component of the NF-κB pathway downstream of the CBM complex. In some embodiments, cancers associated with a component of the NF-κB pathway downstream of the CBM complex are selected from the group consisting of: TAK1-associated cancers, TRAF6-associated cancers, TAB1-associated cancers, TAB2-associated cancers, TAB3-associated cancers, MKK7-associated cancers, IKKα-associated cancers, IKKβ-associated cancers, IKKγ-associated cancers, IkBα-associated cancers, p50-associated cancers, p65 (RelA)-associated cancers, c-Rel-associated cancers, and combinations thereof. In some embodiments, cancers associated with a component of the NF-κB pathway downstream of the CBM complex are IKKγ-associated cancers. Cancer “associated with” a particular gene or protein described in this paragraph refers to cancer that is associated with or has an imbalance (e.g., any type of imbalance in the expression, activity, or level of the particular gene, protein, or any of them described herein) with the expression or activity or level of the particular gene, protein, or any of them. Non-limiting examples of such cancers are described herein.

[0130] As used herein, the term "cancer associated with a component of the JNK pathway downstream of the CBM complex" refers to cancer associated with or having dysregulation of the expression, activity, or level of a gene, protein, or any of them (e.g., one or more), said dysregulation being associated with a component of the JNK pathway downstream of the CBM complex. In some embodiments, cancers associated with a component of the JNK pathway downstream of the CBM complex are selected from the group consisting of: JNK1-associated cancers, JNK2-associated cancers, JNK3-associated cancers, MYD88 transcription factor-associated cancers, AP-1 transcription factor-associated cancers, and combinations thereof. Cancer "associated" with a specific gene or protein described in this paragraph refers to cancer associated with or having dysregulation (e.g., any type of dysregulation of the expression, activity, or level of the specific gene, protein, or any of them described herein) associated with or having dysregulation of the expression, activity, or level of that specific gene, protein, or any of them. Non-limiting examples of such cancers are described herein.

[0131] Compounds of the present disclosure

[0132] In one aspect, the present invention relates to a compound of formula (I): , (I) Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 1 It is H, halogenated, or C1-C3 alkyl; R 2 It is H, halogenated, or C1-C3 alkyl; R 0 R 3 and R 4 The definition is as follows: (i)R 0 It is H; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 0 It is H; and R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; or (iii)R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups; and R 4 It is a C1-C6 alkyl group; R 5 It is H or halogenated; R 6 It is H or halogenated; and R 7 and R 8 The definition is as follows: (i)R 7 It is a C1-C6 alkyl group; and R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups; or (ii)R 7 and R 8 Together with the atoms to which they are attached, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygen groups; The premise is that at most one of X and Y is N.

[0133] In some embodiments, the present invention relates to a compound of formula (I), wherein the compound has formula (I-1): , (I-1) Or its pharmaceutically acceptable salt.

[0134] In some embodiments, the present invention relates to a compound of formula (I), wherein the compound has formula (I-2a): , (I-2a) Or its pharmaceutically acceptable salt.

[0135] In some embodiments, the present invention relates to a compound of formula (I), wherein the compound has formula (I-2b): , (I-2b) Or its pharmaceutically acceptable salt.

[0136] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CH. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CF. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is N.

[0137] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein Y is CH. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein Y is CF. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein Y is N.

[0138] In some embodiments, the present 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 present 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 present 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 present 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 present invention relates to a compound of formula (I), (I-1), (I-2a), or (I-2b), wherein X is CH and Y is N.

[0139] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 1 It is H.

[0140] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 2 It is F.

[0141] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 1 It is H and R 2 It is F.

[0142] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 0 It is H.

[0143] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 3 It is a C1-C6 alkyl, C1-C6 haloalkyl, or 4-7 heteroaryl, wherein the heteroaryl is optionally substituted with one C1-C6 haloalkyl group. In other embodiments, R 3 It is a C1-C6 alkyl group. In other embodiments, R 3 It is a C1-C6 haloalkyl group. In other embodiments, R 3 It is a 4-7 membered heteroaryl group, wherein the heteroaryl group is optionally substituted with one C1-C6 haloalkyl group. In other embodiments, R 3 It is a 4-7 membered heteroaryl group, wherein the heteroaryl group is substituted by one C1-C6 haloalkyl group. In other embodiments, R 3 It is a 5-membered heteroaryl group, wherein the heteroaryl group is substituted by one C1-C6 haloalkyl group. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 3 Is it CH3, CF3 or In other embodiments, R 3 It is CH3. In other embodiments, R 3 It is CF3. In other embodiments, R 3 yes .

[0144] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 4It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 4 It is CH3.

[0145] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups. In other embodiments, R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C4 cycloalkyl groups. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 3 and R 4 Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups. In other embodiments, R 3 and R 4 Together with the carbon atoms they are attached to, they form cyclopropyl groups. In other embodiments, R 3 and R 4 Together with the carbon atoms they are attached to, they form cyclobutyl groups.

[0146] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 0 and R 3 Together with the carbon atoms to which they are attached, they form C3-C7 cycloalkyl groups. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 0 and R 3 Together with the carbon atoms they are attached to, they form cyclobutyl groups.

[0147] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 3 It is a C1-C6 alkyl group, and R 4 It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 3 It is CH3, and R 4 It is CH3. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 3 It is a C1-C6 haloalkyl group, and R 4It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 3 It is CF3, and R 4 It is CH3. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 0 and R 3 Together with the carbon atoms they are attached to, they form cyclobutyl groups, and R 4 It is CH3.

[0148] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 1 It is H, R 2 It is F, R 3 It is a C1-C6 alkyl group, and R 4 It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 1 It is H, R 2 It is F, R 3 It is CH3, and R 4 It is CH3. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 1 It is H, R 2 It is F, R 3 It is a C1-C6 haloalkyl group, and R 4 It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 1 It is H, R 2 It is F, R 3 It is CF3, and R 4 It is CH3. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 1 It is H, R 2 It is F, R 0 and R 3 Together with the carbon atoms they are attached to, they form cyclobutyl groups, and R 4 It is CH3.

[0149] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 5It is halogenated. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 5 It is H or F. In other embodiments, R 5 It is H. In other embodiments, R 5 It is F.

[0150] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 6 It is H or halogenated. In other embodiments, R 6 It is halogenated. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 6 It is H or F. In other embodiments, R 6 It is H. In other embodiments, R 6 It is F.

[0151] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 5 It is H and R 6 It is H. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 5 It is H and R 6 It is halogenated. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 5 It is H and R 6 It is F. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 5 It is halogenated and R 6 It is H. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 5 It is F and R 6 It is H.

[0152] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 7 It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 7 It is CH3.

[0153] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups. In other embodiments, R 8 It is a C3-C6 cycloalkyl group. In other embodiments, R 8 It is a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups. In other embodiments, R 8 It is a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with two oxygen groups. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups. In other embodiments, R 8 It is a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups. In other embodiments, R 8 It is a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with two oxygen groups. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 8 yes , , , or In other embodiments, R 8 yes In other embodiments, R 8 yes In other embodiments, R 8 yes In other embodiments, R 8 yes In other embodiments, R 8 yes .

[0154] In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 7 and R 8 Together with the atoms to which they are attached, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with 1-2 oxygen atoms. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 7 and R 8Together with the atoms they are attached to, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygen atoms; and R 6 It is H. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 7 and R 8 Together with the atoms they are attached to, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygen atoms; and R 6 It is H. In some embodiments, the present invention relates to a compound of formula (I), (I-1), (I-2a) or (I-2b), wherein R 7 and R 8 Together with the atoms they are attached to, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygen atoms; and R 6 It is H.

[0155] In some embodiments, the present invention relates to a compound of formula (IA): , (IA) Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 0 R 3 and R 4 The definition is as follows: (i)R 0 It is H; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 0 It is H; and R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; or (iii)R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups; and R 4 It is a C1-C6 alkyl group; R 5 It is H or halogenated; R 6 It is H or halogenated; and R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1-2 oxygen groups; The premise is that at most one of X and Y is N.

[0156] In some embodiments, the present invention relates to a compound of formula (IA), wherein the compound has formula (IA-1): , (IA-1) Or its pharmaceutically acceptable salt.

[0157] In some embodiments, the present invention relates to a compound of formula (IA), wherein the compound has formula (IA-2a): , (IA-2a) Or its pharmaceutically acceptable salt.

[0158] In some embodiments, the present invention relates to a compound of formula (IA), wherein the compound has formula (IA-2b): , (IA-2b) Or its pharmaceutically acceptable salt.

[0159] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein X is CH. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein X is CF. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein X is N.

[0160] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein Y is CH. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein Y is CF. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein Y is N.

[0161] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 0It is H.

[0162] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 3 It is a C1-C6 alkyl, C1-C6 haloalkyl, or 4-7 heteroaryl, wherein the heteroaryl is optionally substituted with one C1-C6 haloalkyl group. In other embodiments, R 3 It is a C1-C6 alkyl group. In other embodiments, R 3 It is a C1-C6 haloalkyl group. In other embodiments, R 3 It is a 4-7 membered heteroaryl group, wherein the heteroaryl group is optionally substituted with one C1-C6 haloalkyl group. In other embodiments, R 3 It is a 4-7 membered heteroaryl group, wherein the heteroaryl group is substituted by one C1-C6 haloalkyl group. In other embodiments, R 3 It is a 5-membered heteroaryl group, wherein the heteroaryl group is substituted with one C1-C6 haloalkyl group. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a) or (IA-2b), wherein R 3 Is it CH3, CF3 or In other embodiments, R 3 It is CH3. In other embodiments, R 3 It is CF3. In other embodiments, R 3 yes .

[0163] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 4 It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a) or (IA-2b), wherein R 4 It is CH3.

[0164] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 3 and R 4 Together with the carbon atoms to which they are attached, they form C3-C7 cycloalkyl groups. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 3 and R 4Together with the carbon atoms to which they are attached, they form C3-C4 cycloalkyl groups. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a) or (IA-2b), wherein R 3 and R 4 Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups. In other embodiments, R 3 and R 4 Together with the carbon atoms they are attached to, they form cyclopropyl groups. In other embodiments, R 3 and R 4 Together with the carbon atoms they are attached to, they form cyclobutyl groups.

[0165] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 0 and R 3 Together with the carbon atoms to which they are attached, they form C3-C7 cycloalkyl groups. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 0 and R 3 Together with the carbon atoms they are attached to, they form cyclobutyl groups.

[0166] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 5 It is halogenated. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a) or (IA-2b), wherein R 5 It is H or F. In other embodiments, R 5 It is H. In other embodiments, R 5 It is F.

[0167] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 6 It is halogenated. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a) or (IA-2b), wherein R 6 It is H or F. In other embodiments, R 6 It is H. In other embodiments, R 6 It is F.

[0168] In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a), or (IA-2b), wherein R 8It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with two oxygen groups. In other embodiments, R 8 It is a C3-C6 cycloalkyl group. In other embodiments, R 8 It is a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with two oxygen groups. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a) or (IA-2b), wherein R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with two oxygen groups. In other embodiments, R 8 It is a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with two oxygen groups. In some embodiments, the present invention relates to a compound of formula (IA), (IA-1), (IA-2a) or (IA-2b), wherein R 8 yes , , , or In other embodiments, R 8 yes In other embodiments, R 8 yes In other embodiments, R 8 yes In other embodiments, R 8 yes In other embodiments, R 8 yes .

[0169] In some embodiments, the present invention relates to a compound of formula (IB): , (IB) Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 3 and R 4 The definition is as follows: (i)R 3 It is a C1-C6 alkyl or a C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; R 5It is H or halogenated; R 6 It is H or halogenated; and R 9 and R 10 They are linked together with the carbon atoms to which they are attached to form 4-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygen atoms; The premise is that at most one of X and Y is N.

[0170] In some embodiments, the present invention relates to a compound of formula (IB), wherein the compound has formula (IB-1): , (IB-1) Or its pharmaceutically acceptable salt.

[0171] In some embodiments, the present invention relates to a compound of formula (IB), wherein the compound has formula (IB-2a): , (IB-2a) Or its pharmaceutically acceptable salt.

[0172] In some embodiments, the present invention relates to a compound of formula (IB), wherein the compound has formula (IB-2b): , (IB-2b) Or its pharmaceutically acceptable salt.

[0173] In some embodiments, the present invention relates to a compound of formula (IB), (IB-1), (IB-2a) or (IB-2a), wherein X is CH.

[0174] In some embodiments, the present invention relates to a compound of formula (IB), (IB-1), (IB-2a) or (IB-2a), wherein Y is CH.

[0175] In some embodiments, the present invention relates to a compound of formula (IB), (IB-1), (IB-2a), or (IB-2a), wherein R 3 It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (IB), (IB-1), (IB-2a), or (IB-2a), wherein R 3 It is CH3.

[0176] In some embodiments, the present invention relates to a compound of formula (IB), (IB-1), (IB-2a), or (IB-2a), wherein R 4 It is a C1-C6 alkyl group. In some embodiments, the present invention relates to a compound of formula (IB), (IB-1), (IB-2a), or (IB-2a), wherein R 4 It is CH3.

[0177] In some embodiments, the present invention relates to a compound of formula (IB), (IB-1), (IB-2a), or (IB-2a), wherein R 5 It is H.

[0178] In some embodiments, the present invention relates to a compound of formula (IB), (IB-1), (IB-2a), or (IB-2a), wherein R 6 It is H.

[0179] In some embodiments, R 9 and R 10 They are linked together with the carbon atoms to which they are attached to form C3-C7 cycloalkyl groups. In other embodiments, R 9 and R 10 They are linked together with the carbon atoms to form 4-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with 1-2 oxygen atoms. In other embodiments, R 9 and R 10 They are linked together with the carbon atoms to form 4-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with two oxygen atoms. In some embodiments, the present invention relates to a compound of formula (IC), wherein R 9 and R 10 They are linked together with the carbon atoms to form C3-C7 cycloalkyl or 4-6 membered heterocyclic groups, wherein the heterocyclic group is optionally substituted with 1-2 oxygen atoms. In other embodiments, R 9 and R 10 They are linked together with the carbon atoms to form 4-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with 1-2 oxygen atoms. In other embodiments, R 9 and R 10 They are linked together with the carbon atoms to form 4-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with two oxygen atoms. In some embodiments, the present invention relates to a compound of formula (IC), wherein R 9 and R 10 They are linked together with the carbon atoms to form tetrahydropyranyl or 1,1-dioxo-tetrahydrothiaranyl.

[0180] In some embodiments, the present invention relates to a compound selected from Table A or a pharmaceutically acceptable salt thereof. In other embodiments, the present invention relates to a compound selected from Table A, i.e., a compound in a non-salt form.

[0181] Table A.

[0182] Salts, compositions, uses, formulations, administrations, and additives

[0183] Pharmaceutically acceptable salts and compositions

[0184] As discussed herein, the present invention provides compounds as MALT1 inhibitors and pharmaceutically acceptable salts thereof, and therefore the compounds and pharmaceutically acceptable salts thereof can be used to treat diseases, conditions, and illnesses including, but not limited to, cancer, autoimmune diseases, and inflammatory diseases. Accordingly, in another aspect of the invention, pharmaceutical compositions are provided, wherein such compositions comprise compounds as described herein or pharmaceutically acceptable salts thereof, and optionally comprise pharmaceutically acceptable carriers, adjuvants, or mediators. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents as described herein.

[0185] As used herein, the term "pharmaceutically acceptable salt" means salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit-risk ratio. "Pharmaceutically acceptable salts" of the compounds of this invention include any non-toxic salt that, upon administration to a recipient, can directly or indirectly provide the compound of this invention or its inhibitory metabolites or residues. Salts may be in pure form, in mixtures with one or more other substances (e.g., solutions, suspensions, or colloids), or in hydrated, solvated, or cocrystal form. As used herein, the term "inhibitory metabolites or residues" means that the metabolites or residues are also inhibitors of MALT1.

[0186] Pharmaceutically acceptable salts are well known in the field. For example, SM Berge et al ,exist J. Pharmaceutical Sciences Pharmaceutically acceptable salts are described in detail in , 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by reacting amino groups 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, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0187] As described herein, pharmaceutically acceptable compositions of the present invention may further comprise pharmaceutically acceptable carriers, adjuvants, or mediators, which, as used herein, include any and all solvents, diluents or other liquid mediators, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., provided they are suitable for the desired specific dosage form. Remington's Pharmaceutical Sciences, 16th Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of the present invention, for example, by producing any undesirable biological effects or interacting in other harmful ways with any other component of the pharmaceutically acceptable composition, its use is considered within the scope of the present invention. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, or potassium sorbate), mixtures of metaglycerides 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, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, 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 astragalus gum; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; ethylene glycol; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions, and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition (at the discretion of the formulator).

[0188] In another aspect, the present invention is characterized by a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0189] In another aspect, the present invention is characterized by 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 mediators.

[0190] Uses of compounds and pharmaceutically acceptable salts and compositions

[0191] In another aspect, the present invention is characterized by a method for inhibiting MALT1 in a subject, the method comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0192] In another aspect, the present invention is characterized by a method of treating a subject with cancer, an autoimmune disease, or an inflammatory disease, the method comprising administering to the subject an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0193] Some embodiments provide a method of treating an autoimmune disease (e.g., MALT1-related autoimmune disease) in a subject requiring such treatment, the method comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE). In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is multiple sclerosis.

[0194] Some embodiments provide a method of treating an inflammatory condition (e.g., MALT1-related inflammatory condition) in a subject requiring such treatment, the method comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the inflammatory condition is chronic graft-versus-host disease (cGVHD).

[0195] Some embodiments provide methods for treating cancer (e.g., MALT1-related cancer) in a subject requiring such treatment, the method comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. For example, this document provides a method for treating MALT1-related cancer in a subject requiring such treatment, the method comprising: a) detecting dysregulation of the expression or activity or level of the MALT1 gene, MALT1 protease, or any of therein in a sample from said subject; and b) administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of the expression or activity or level of the MALT1 gene, MALT1 protease, or any of therein comprises one or more fusion proteins.

[0196] In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is a blood cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma (e.g., sporadic medullary thyroid carcinoma or hereditary medullary thyroid carcinoma), differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland tumor, lung adenocarcinoma, bronchioloalveolar lung cancer, type 2A or 2B multiple endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast cancer, breast adenoma, breast tumor, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, inflammatory myofibroblastoma, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., MALT1-related cancer) is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma. Lymphoma, carcinoid tumor, unknown primary cancer, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, tumors by location, tumors, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct cancer, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma Sarcoma, extracranial germ cell tumors, gonadal extragerminal tumors, extrahepatic bile duct carcinoma, ocular cancer, fallopian tube cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, glioma, pilocytoma, hairy cell leukemia, head and neck cancer, thoracic tumors, head and neck tumors, CNS tumors, primary CNS tumors, heart disease, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis.Cellhistiocytosis), laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, tumors by location, tumors, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung cancer, lung tumors, respiratory tract tumors. Bronchial cancer, bronchial tumors, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleural pulmonary blastoma, pregnancy-related breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon tumor, renal cell carcinoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome Syndrome), skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis, unknown primary cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0197] In some embodiments, the cancer is a blood cancer, such as leukemia or lymphoma. In some embodiments, blood cancers (e.g., blood cancers as MALT1-related cancers) are selected from the group consisting of: leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also known as Hodgkin lymphoma), and myeloma, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), lymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplastic syndromes (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDS), myelodysplastic syndromes (MPD), and multiple myeloma (MM). Other examples of blood cancers include myelodysplastic disorders (MPDs) such as polycythemia vera (PV), essential thrombocytopenic purpura (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, blood cancers (e.g., blood cancers as MALT1-related cancers) are AML or CMML.

[0198] In some embodiments, the cancer is glioblastoma, chronic myeloid leukemia, granulocytic leukemia, or non-Hodgkin's lymphoma.

[0199] In some embodiments, the cancer (e.g., MALT1-related cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are MALT1-related cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal carcinoma, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, neuroblastoma, and melanoma. See, e g Jiang et al., Cancer Research 2011, 71, 2183-2192; See also Pan et al., Mol CancerRes 2016, 14, 93-102 and Penas et al., Blood 2010, 115, 2214-2219.

[0200] 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 advanced solid tumors. 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 large 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 advanced solid tumors.

[0201] In some embodiments, the subject is a human being.

[0202] The compounds of the present invention and their pharmaceutically acceptable salts can also be used to treat MALT1-related cancers. The compounds of the present invention and their pharmaceutically acceptable salts can also be used to treat MALT1-related autoimmune diseases. The compounds of the present invention and their pharmaceutically acceptable salts can also be used to treat MALT1-related inflammatory diseases.

[0203] Therefore, this document also provides a method for treating a subject diagnosed with or identified as having MALT1-related cancer (e.g., any exemplary MALT1-related cancer disclosed herein), the method comprising administering to the subject an effective amount of a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0204] This document also provides a method for treating a subject with CBM complex pathway-related cancer (such as any cancer disclosed herein) in the presence of such a subject, the method comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. A method for treating a subject with such a subject with cancer is also provided, comprising (a) identifying the cancer as a CBM complex pathway-related cancer; and (b) administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0205] Identifying a subject's cancer as CBM complex pathway-related cancer can be performed by any suitable method. In some embodiments, the step of identifying a subject's cancer as CBM complex pathway-related cancer includes performing an assay to detect dysregulation of the expression, activity, or level of a CBM complex pathway-related gene, a CBM complex pathway-related protease protein, or either of these in a sample from the subject. In some embodiments, the method further includes obtaining a sample from the subject (e.g., a biopsy sample). The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence in situ hybridization (FISH).

[0206] Furthermore, this article provides a method for treating cancer in a subject with this need, the method comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to the subject identified as having a CBM complex pathway-related cancer.

[0207] This document also provides a method for treating MALT1-related cancer in a subject, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject identified or diagnosed with MALT1-related cancer. This document also provides a method for treating cancer in a subject with this need, comprising: (a) determining that the cancer is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of therein; and (b) administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to the subject.

[0208] Determining whether the cancer is associated with an dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of them can be performed using any suitable method. In some embodiments, the step of determining that the subject's cancer is a MALT1-related cancer includes performing an assay to detect an dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease protein, or any of them in a sample from the subject. In some embodiments, the method further includes obtaining a sample (e.g., a biopsy sample) from the subject. The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence in situ hybridization (FISH).

[0209] As described herein, CBM complex pathway-related cancers can be any suitable CBM complex pathway-related cancer (as described herein). In some embodiments, CBM complex pathway-related cancers are selected from the group consisting of: CBM complex pathway cell surface receptor-related cancers, cancers associated with signal transducers between cell surface receptors and the CBM complex, components of CBM complex-related cancers, MALT1 protease substrate-related cancers, cancers associated with components of the NF-κB pathway downstream of the CBM complex, cancers associated with components of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, CBM complex pathway cell surface receptor-related cancers are selected from the group consisting of: CD28-related cancers, BCR-related cancers, HER1-related cancers, HER2-related cancers, and combinations thereof. In some embodiments, cancers associated with signal transducers between cell surface receptors and the CBM complex are protein kinase Cβ (PKCβ)-related cancers, protein kinase Cθ (PCKθ)-related cancers, or combinations thereof. In some embodiments, the components of CBM complex-related cancers are selected from the group consisting of: MALT1-related cancers, CARD11-related cancers, CARD14-related cancers, CARD10-related cancers, CARD9-related cancers, BCL10-related cancers, and combinations thereof. For exemplary dysregulations in MALT1, CARD11, and BCL10, see, for example, Tables B1, B2, and B3. In some embodiments, MALT1 protease substrate-related cancers are selected from the group consisting of: BCL10-related cancers, A20-related cancers, CYLD-related cancers, RelB-related cancers, Regnase 1-related cancers, roquin-1-related cancers, HOIL1-related cancers, NIK-related cancers, LIMA1α-related cancers, and combinations thereof. In some embodiments, MALT1 protease substrate-related cancers are selected from the group consisting of: BCL10-related cancers, A20-related cancers, CYLD-related cancers, and combinations thereof. For exemplary dysregulations in BCL10 and A20, see, for example, Tables B3 and B4. In some embodiments, cancers associated with components of the NF-κB pathway downstream of the CBM complex are selected from the group consisting of: TAK1-associated cancers, TRAF6-associated cancers, TAB1-associated cancers, TAB2-associated cancers, TAB3-associated cancers, MKK7-associated cancers, IKKα-associated cancers, IKKβ-associated cancers, IKKγ-associated cancers, IkBα-associated cancers, p50-associated cancers, p65 (RelA)-associated cancers, c-Rel-associated cancers, and combinations thereof.In some embodiments, cancers associated with components of the NF-κB pathway downstream of the CBM complex are IKKγ-related cancers. In some embodiments, cancers associated with components of the JNK pathway downstream of the CBM complex are selected from the group consisting of: JNK1-related cancers, JNK2-related cancers, JNK3-related cancers, MYD88 transcription factor-related cancers, AP-1 transcription factor-related cancers, and combinations thereof.

[0210] In some embodiments, CBM complex pathway-associated cancers are MALT1-associated cancers. MALT1-associated cancers may have any suitable dysregulation, such as any of the dysregulations described herein. In some embodiments, MALT1-associated cancers include IAP2-MALT1 fusions. In some embodiments, MALT1-associated cancers include IGH-MALT1 fusions.

[0211] This document also provides methods for treating CBM complex pathway-related diseases or conditions, autoimmune conditions, and inflammatory conditions. Therefore, this document provides a method for treating an autoimmune condition in a subject with this need, comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. This document also provides a method for treating a subject with MALT1-related autoimmune disease, comprising administering to a subject identified or diagnosed with MALT1-related autoimmune disease an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. In some cases, this document provides a method for treating an autoimmune disease in a subject with this need, comprising: (a) determining that the autoimmune disease is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of therein; and (b) administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. This document also provides a method for treating a subject with MALT1-related autoimmune disease, comprising administering to a subject identified as having MALT1-related autoimmune disease an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. Furthermore, this document provides a method for treating an inflammatory condition in a subject with this need, the method comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. In some cases, this document provides a method for treating MALT1-related inflammatory conditions in a subject, the method comprising administering to a subject identified or diagnosed with MALT1-related inflammatory conditions an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. This document also provides a method for treating an inflammatory condition in a subject with this need, comprising: (a) determining that the inflammatory condition is associated with dysregulation of the expression, activity, or level of the MALT1 gene, MALT1 protease, or any of thereto; and (b) administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. This document also provides a method for treating MALT1-related inflammatory conditions in a subject, the method comprising administering to a subject identified as having MALT1-related inflammatory conditions an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0212] This document also provides a method for treating a CBM complex pathway-related disease or condition in a subject with this need, the method comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. A method for treating a disease or condition in a subject with this need is also provided, comprising: (a) identifying the cancer as a CBM complex pathway-related disease or condition; and (b) administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. Furthermore, this document provides a method for treating a disease or condition in a subject with this need, the method comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject identified as having a CBM complex pathway-related disease or condition.

[0213] CBM complex pathway-related diseases or conditions can be any suitable CBM complex pathway-related disease or condition, as described herein. In some embodiments, CBM complex pathway-related diseases or conditions are autoimmune diseases. In some embodiments, CBM complex pathway-related diseases or conditions are inflammatory conditions. In some embodiments, the CBM complex pathway-related cancers are selected from the group consisting of: CBM complex pathway cell surface receptor-related cancers, diseases or conditions related to signal transduction mechanisms between cell surface receptors and the CBM complex, components of CBM complex-related cancers, MALT1 protease substrate-related cancers, diseases or conditions related to components of the NF-κB pathway downstream of the CBM complex, diseases or conditions related to components of the JNK pathway downstream of the CBM complex, and combinations thereof. In some embodiments, CBM complex pathway-related diseases or conditions are MALT1-related diseases or conditions.

[0214] In some cases, the compounds of the present invention or pharmaceutically acceptable salts thereof can be used to inhibit cellular processes, such as inhibiting cell proliferation. Therefore, this document provides a method for inhibiting mammalian cell proliferation, the method comprising contacting mammalian cells with the compounds of the present invention or pharmaceutically acceptable salts thereof. This document also provides a method for inhibiting CBM complex pathway activity in mammalian cells, the method comprising contacting mammalian cells with the compounds of the present invention or pharmaceutically acceptable salts thereof. This document further provides a method for inhibiting MALT1 protease activity in mammalian cells, the method comprising contacting mammalian cells with the compounds of the present invention or pharmaceutically acceptable salts thereof. In some embodiments, contact occurs... In vivo In some embodiments, contact occurs In vitroMammalian cells can be any suitable cell type. In some embodiments, mammalian cells are mammalian immune cells. In some embodiments, mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are mammalian CBM complex pathway-associated cancer cells. In some embodiments, the mammalian cancer cells are mammalian MALT1-associated cancer cells. In some embodiments, the mammalian cells exhibit dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of these. In some embodiments, dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of these is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0215] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) permeability. Such compounds are capable of crossing the blood-brain barrier and inhibiting the 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., MALT1-related cancers, such as MALT1-related brain cancer or CNS cancer) may comprise administration (e.g., oral administration) of the compound to said subject. In some such embodiments, the compounds provided herein can be used to treat primary or metastatic brain tumors. For example, said compounds can be used to treat one or more gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglioma, ependymoma and mixed glioma, meningioma, medulloblastoma, intracranial ganglion glioma, schwannomas / neurilemmomas, and craniopharyngiomas (see, for example, tumors listed in the following literature: Louis, DN et al.). Acta Neuropathol 131(6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the subject has been previously treated with another anticancer agent, such as another protease inhibitor (e.g., a compound not of the present invention). In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the subject has been previously treated with another anticancer agent, such as another protease inhibitor (e.g., a compound not of the present invention).

[0216] In some embodiments of any of the methods or uses described herein, an assay for determining whether a subject has an dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them, using a sample from a subject, may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, FISH separation analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment. The assay may utilize other detection methods known in the art to detect dysregulation of the expression, activity, or level of a gene (e.g., the MALT1 gene), a protein (e.g., the MALT1 protein), or any of them. In some embodiments, the sample is a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having MALT1-related cancer, a subject with one or more symptoms of MALT1-related cancer, and / or a subject at increased risk of developing MALT1-related cancer.

[0217] Although the genetic basis of tumorigenesis may differ between different types of cancer, the cellular and molecular mechanisms required for metastasis appear to be similar for all types of solid tumors. In the metastatic cascade, cancer cells lose their growth-inhibiting responses, undergo adhesive alterations, and produce enzymes that can degrade components of the extracellular matrix. This leads to the separation of tumor cells from the original tumor, their infiltration into the circulatory system via newly formed vascular systems, and their migration and extravasation at favorable distal sites where colonies may form.

[0218] Therefore, this document also provides a method for inhibiting, preventing, aiding in the prevention of, or alleviating metastatic symptoms of cancer in a subject with such need, the method comprising administering to the subject an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Such methods can be used to treat one or more cancers described herein. See, for example U.S. Publication No. 2013 / 0029925; International Publication No. WO 2014 / 083567; and U.S. Patent No. 8,568,998. See also, for example, Hezam K et al. Rev Neurosci January 26, 2018; 29:93-98; Gao L et al. Pancreas January 2015; 44:134-143; Ding K et al. J Biol Chem June 6, 2014; 289:16057-71; and Amit M et al., OncogeneJune 8, 2017; 36:3232-3239. In some embodiments, the cancer is MALT1-related cancer. In some embodiments, as described herein, the compounds of the present invention or pharmaceutically acceptable salts thereof are used in combination with other therapies or another therapeutic agent. For example, a first or second MALT1 protease inhibitor.

[0219] The term “metastasis” is a term known in the art and refers to the formation of an additional tumor (e.g., a solid tumor) in a subject at a site distant from the primary tumor, wherein the additional tumor contains cancer cells that are the same as or similar to the primary tumor.

[0220] A method for reducing the risk of metastasis or further metastasis in a subject with MALT1-related cancer is also provided, the method comprising: selecting, identifying, or diagnosing a subject with MALT1-related cancer, and administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to the selected, identified, or diagnosed subject with MALT1-related cancer. A method for reducing the risk of metastasis or further metastasis in a subject with MALT1-related cancer is also provided, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to the subject with MALT1-related cancer. The reduction in the risk of metastasis or further metastasis in a subject with MALT1-related cancer can be compared to the risk of metastasis or further metastasis in a subject before treatment, or to a subject or group of subjects with similar or identical MALT1-related cancer who have not received any treatment or have received different treatments.

[0221] The phrase "risk of metastasis" refers to the risk that a subject with a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from the primary tumor within a specified time period, wherein the additional tumor contains cancer cells that are the same as or similar to the primary tumor. This article describes methods for reducing the risk of metastasis in subjects with cancer.

[0222] The phrase "risk of additional metastasis" refers to the risk that a subject with a primary tumor and one or more additional tumors at sites distant from the primary tumor (wherein the additional tumors contain cancer cells identical or similar to the primary tumor) will develop one or more additional tumors distant from the primary tumor, wherein the additional tumors contain cancer cells identical or similar to the primary tumor. This article describes methods for reducing the risk of additional metastasis.

[0223] Some embodiments described herein provide methods for treating autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and SLE (e.g., MALT1-related autoimmune diseases), comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need.

[0224] Some embodiments described herein provide methods for treating inflammatory conditions such as chronic graft-versus-host disease (e.g., MALT1-related autoimmune diseases), comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need.

[0225] A method for inhibiting the activity of the MALT1 protease in mammalian cells is also provided, the method comprising contacting mammalian cells with the compounds of the present invention. In some embodiments, contact is In vitro In some embodiments, contact is In vivo In some embodiments, contact is In vivo The method comprises administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject having mammalian cells with MALT1 protease activity. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer described herein. In some embodiments, the mammalian cancer cells are MALT1-associated mammalian cancer cells.

[0226] A method for inhibiting the activity of the MALT1 protease in mammalian cells is also provided, the method comprising contacting mammalian cells with the compounds of the present invention. In some embodiments, contact is In vitro In some embodiments, contact is In vivo In some embodiments, contact is In vivo The method comprises administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal having mammalian cells with MALT1 protease activity. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer described herein. In some embodiments, the mammalian cancer cells are MALT1-associated mammalian cancer cells. In some embodiments, the mammalian cells are gastrointestinal mammalian cells.

[0227] As used herein, the term "contact" refers to... In vitro System or In vivoThe instructions in the system are grouped together. For example, “contacting” the MALT1 protease with the compound provided herein includes administering the compound provided herein to a subject (such as a human) who has the MALT1 protease, and, for example, introducing the compound provided herein into a sample containing mammalian cells or a purified formulation containing the MALT1 protease.

[0228] This article also provides a method for... In vitro or In vivo A method for inhibiting mammalian cell proliferation, the method comprising contacting mammalian cells with an effective amount of a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0229] As defined herein, “MALT1 protease inhibitor” includes any compound exhibiting MALT1 inhibitory activity. In some embodiments, the MALT1 protease inhibitor is selective for the MALT1 protease. Exemplary MALT1 protease inhibitors may exhibit inhibitory activity (IC50) of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM against the MALT1 protease. 50 As measured in the assays described herein. In some embodiments, the MALT1 protease inhibitor may exhibit inhibitory activity (IC50) against the MALT1 protease of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM. 50 (as measured in the measurements provided herein).

[0230] As used herein, a “first MALT1 protease inhibitor” or “first MALT1 inhibitor” is a MALT1 protease inhibitor as defined herein, but does not contain a compound of the present invention as defined herein or a pharmaceutically acceptable salt thereof. As used herein, a “second MALT1 protease inhibitor” or “second MALT1 inhibitor” is a MALT1 protease inhibitor as defined herein, but does not contain a compound of the present invention as defined herein or a pharmaceutically acceptable salt thereof. When both first and second MALT1 inhibitors are present in the methods provided herein, the first and second MALT1 protease inhibitors are distinct.

[0231] This document describes exemplary first and second MALT1 protease inhibitors. In some embodiments, the first or second MALT1 protease inhibitor may be, for example, JNJ-67856633 or CTX-177.

[0232] In another aspect, the invention is characterized by a method in which a subject is treated with one or more additional therapeutic agents, which are administered concurrently with, before or after treatment with an effective amount of a compound, a pharmaceutically acceptable salt or a pharmaceutical composition.

[0233] The phrase “effective amount” means an amount of compound which, when administered to a subject requiring such treatment, is sufficient to (i) treat a MALT1-related disease or condition (such as MALT1-related cancer); (ii) alleviate, improve, or eliminate one or more symptoms of a particular disease, symptom, or condition; or (iii) delay the onset of one or more symptoms of a particular disease, symptom, or condition described herein. The amount of the compound of the invention or a pharmaceutically acceptable salt thereof corresponding to this amount will vary depending on factors such as the specific compound, the disease condition and its severity, and the identity of the subject requiring treatment (e.g., weight), but can still be conventionally determined by those skilled in the art.

[0234] Compounds, pharmaceutically acceptable salts, and compositions for use

[0235] In another aspect, the present invention is characterized by the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof, which are used as medicines.

[0236] In another aspect, the present invention is characterized by the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof in a method of inhibiting MALT1 in a subject.

[0237] In another aspect, the present invention is characterized by the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof in methods of treating cancer, autoimmune diseases or inflammatory diseases.

[0238] Some embodiments provide compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating a subject with an autoimmune disease (e.g., MALT1-related autoimmune disease). In some embodiments, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE). In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is multiple sclerosis.

[0239] Some embodiments provide compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating a subject with an inflammatory condition (e.g., MALT1-associated inflammatory condition). In some embodiments, the inflammatory condition is chronic graft-versus-host disease (cGVHD).

[0240] Some embodiments provide compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating a subject with cancer (e.g., MALT1-related cancer). In some embodiments, dysregulation of the expression or activity or level of the MALT1 gene, the MALT1 protease, or any of them comprises one or more fusion proteins.

[0241] Therefore, this document also provides compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in methods of treating subjects who have been diagnosed with or identified as having MALT1-related cancer (e.g., any of the exemplary MALT1-related cancers disclosed herein).

[0242] This document also provides compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in methods of treating subjects with CBM complex pathway-related cancers, such as any of those disclosed herein.

[0243] This document also provides compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in a method of treating cancer in a subject identified as having a cancer associated with the CBM complex pathway.

[0244] This document also provides compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in methods of treating subjects with MALT1-related cancer.

[0245] 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 advanced solid tumors. 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 large 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 advanced solid tumors.

[0246] This document also provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating subjects with CBM complex pathway-related diseases or conditions, autoimmune conditions, and inflammatory conditions. Therefore, this document provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating subjects with autoimmune conditions. This document also provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating subjects with MALT1-related autoimmune conditions. This document also provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating subjects with MALT1-related autoimmune conditions. Additionally, this document provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating subjects with inflammatory conditions. In some cases, this document provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating subjects with MALT1-related inflammatory conditions. This document also provides compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in a method of treating MALT1-related inflammatory conditions in a subject identified as having MALT1-related inflammatory conditions.

[0247] This document further provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating subjects with CBM complex pathway-related diseases or conditions. Additionally, this document provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating subjects identified as having CBM complex pathway-related diseases or conditions.

[0248] This document also provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of inhibiting mammalian cell proliferation. This document also provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of inhibiting CBM complex pathway activity in mammalian cells. This document also provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of inhibiting MALT1 protease activity in mammalian cells. Mammalian cells can be any suitable cell type. In some embodiments, mammalian cells are mammalian immune cells. In some embodiments, mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are mammalian CBM complex pathway-associated cancer cells. In some embodiments, the mammalian cancer cells are mammalian MALT1-associated cancer cells. In some embodiments, the mammalian cells have dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them. In some embodiments, dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0249] This document also provides compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of inhibiting, preventing, aiding in the prevention of, or alleviating symptoms of cancer metastasis in a subject. Such methods may be used to treat one or more cancers described herein. See, for example U.S. Publication No. 2013 / 0029925; International Publication No. WO 2014 / 083567; and U.S. Patent No. 8,568,998. See also, for example, Hezam K et al. Rev Neurosci January 26, 2018; 29:93-98; Gao L et al. Pancreas January 2015; 44:134-143; Ding K et al. J Biol Chem June 6, 2014; 289:16057-71; and Amit M et al., Oncogene June 8, 2017; 36:3232-3239. In some embodiments, the cancer is MALT1-related cancer. In some embodiments, as described herein, the compounds of the present invention or pharmaceutically acceptable salts thereof are used in combination with other therapies or another therapeutic agent. For example, a first or second MALT1 protease inhibitor.

[0250] Also provided are compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of reducing the risk of metastasis or additional metastasis in subjects with MALT1-related cancer. The reduction in the risk of metastasis or additional metastasis in subjects with MALT1-related cancer can be compared to the risk of metastasis or additional metastasis in subjects before treatment, or to subjects or groups of subjects with similar or identical MALT1-related cancer who have not received any treatment or have received different treatments.

[0251] Some embodiments described herein provide compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in methods of treating subjects with autoimmune conditions (e.g., MALT1-related autoimmune conditions), such as rheumatoid arthritis, multiple sclerosis, and SLE.

[0252] Some embodiments described herein provide compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in methods of treating a subject with an inflammatory condition (e.g., MALT1-associated autoimmune disease), such as chronic graft-versus-host disease.

[0253] Also provided are compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of inhibiting MALT1 protease activity in mammalian cells. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer described herein. In some embodiments, the mammalian cancer cells are MALT1-associated mammalian cancer cells.

[0254] This document also provides compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for use in methods of inhibiting mammalian cell proliferation.

[0255] In another aspect, the invention is characterized by the use of the compound of the invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof in a method of treating a subject with one or more additional therapeutic agents administered concurrently with, before or after treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition.

[0256] Manufacture of drugs

[0257] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof for the manufacture of a medicament.

[0258] In another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the manufacture of a medicament for use in inhibiting MALT1 in a subject.

[0259] In another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the manufacture of a medicament for use in treating a subject with cancer, an autoimmune disease, or an inflammatory condition.

[0260] Some embodiments provide the use of the compounds of the present invention, their pharmaceutically acceptable salts, or pharmaceutical compositions in the manufacture of a medicament for use in treating a subject with an autoimmune disease (e.g., MALT1-related autoimmune disease). In some embodiments, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (SLE). In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is multiple sclerosis.

[0261] Some embodiments provide the use of the compounds of the present invention, their pharmaceutically acceptable salts, or pharmaceutical compositions in the manufacture of a medicament for use in treating an inflammatory condition (e.g., MALT1-associated inflammatory condition) in a subject. In some embodiments, the inflammatory condition is chronic graft-versus-host disease (cGVHD).

[0262] Some embodiments provide for the use of the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in treating a subject's cancer (e.g., MALT1-related cancer). In some embodiments, dysregulation of the expression or activity or level of the MALT1 gene, the MALT1 protease, or either thereof comprises one or more fusion proteins.

[0263] Therefore, this document also provides for the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the manufacture of a medicament for use in treating a subject diagnosed with or identified as having MALT1-related cancer (e.g., any of the exemplary MALT1-related cancers disclosed herein).

[0264] This document also provides for the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for use in treating subjects with CBM complex pathway-related cancers, such as any of those disclosed herein.

[0265] This document also provides the use of the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in treating a subject identified as having a cancer associated with the CBM complex pathway.

[0266] This document also provides the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the manufacture of a medicament for use in treating subjects with MALT1-related cancer.

[0267] 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 advanced solid tumors. 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 large 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 advanced solid tumors.

[0268] This document also provides the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for use in treating subjects with CBM complex pathway-related diseases or conditions, autoimmune diseases, and inflammatory diseases. Therefore, this document provides the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for treating subjects with autoimmune diseases. This document also provides the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for treating subjects with MALT1-related autoimmune diseases. This document also provides the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for treating subjects with MALT1-related autoimmune diseases. Furthermore, this document provides the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for treating subjects with inflammatory diseases. In some cases, this document provides the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for treating subjects identified as or diagnosed with MALT1-related inflammatory diseases. This document also provides the use of the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in treating MALT1-related inflammatory conditions in subjects diagnosed with MALT1-related inflammatory conditions.

[0269] This document further provides for the use of the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in treating a subject with a CBM complex pathway-related disease or condition. Additionally, this document provides for the use of the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for treating a subject identified as having a CBM complex pathway-related disease or condition.

[0270] This document also provides for the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in inhibiting mammalian cell proliferation. This document also provides for the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in inhibiting CBM complex pathway activity in mammalian cells. This document also provides for the use of compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in inhibiting MALT1 protease activity in mammalian cells. Mammalian cells can be any suitable cell type. In some embodiments, mammalian cells are mammalian immune cells. In some embodiments, mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are mammalian CBM complex pathway-associated cancer cells. In some embodiments, the mammalian cancer cells are mammalian MALT1-associated cancer cells. In some embodiments, the mammalian cells have dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them. In some embodiments, dysregulation of the expression, activity, or level of the MALT1 gene, the MALT1 protease protein, or any of them is an IAP2-MALT1 fusion, an IGH-MALT1 fusion, or a combination thereof.

[0271] This document also provides for the use of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the manufacture of a medicament for use in inhibiting, preventing, aiding in the prevention of, or alleviating metastatic symptoms of cancer in a subject. In some embodiments, the cancer is MALT1-related cancer. In some embodiments, as described herein, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used in combination with additional therapies or another therapeutic agent. For example, a first or second MALT1 protease inhibitor.

[0272] Also provided is the use of the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in reducing the risk of metastasis or additional metastasis in subjects with MALT1-related cancer. The reduction in the risk of metastasis or additional metastasis in subjects with MALT1-related cancer can be compared to the risk of metastasis or additional metastasis in subjects before treatment, or to subjects or groups of subjects with similar or identical MALT1-related cancer who have not received any treatment or have received different treatments.

[0273] Some embodiments described herein provide for the use of compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the manufacture of medicaments for use in treating subjects with autoimmune diseases (e.g., MALT1-related autoimmune diseases), such as rheumatoid arthritis, multiple sclerosis, and SLE.

[0274] Some embodiments described herein provide for the use of the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for use in treating inflammatory conditions (e.g., MALT1-related autoimmune conditions) in subjects, such as chronic graft-versus-host disease.

[0275] Also provided is the use of the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for use in inhibiting the activity of the MALT1 protease in mammalian cells. In some embodiments, the mammalian cells are mammalian immune cells. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer described herein. In some embodiments, the mammalian cancer cells are MALT1-associated mammalian cancer cells.

[0276] This document also provides the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the manufacture of medicaments for use in inhibiting mammalian cell proliferation.

[0277] In another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered concurrently with, before, or after treatment with the compound or pharmaceutical composition.

[0278] Administration of compounds, pharmaceutically acceptable salts, and compositions

[0279] When used as a medicine, the compounds of the present invention (including their pharmaceutically acceptable salts) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in ways well known in the pharmaceutical industry and can be administered via a variety of routes, depending on whether local or systemic treatment is desired and depending on the site of treatment. Administration can be local (including transdermal, epidermal, ophthalmic, and mucosal administration, including intranasal, vaginal, and rectal delivery), pulmonary administration (… For example It can be administered by inhalation or blowing in of powder or aerosol, including through a nebulizer; intratracheal or intranasal; or orally or parenterally. Oral administration can include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenterally administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion administration; or intracranial administration. For example Intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for topical application may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous, powdered, or oily bases, thickeners, etc., may be necessary or desirable.

[0280] This document also provides pharmaceutical compositions comprising a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable excipients. For example, pharmaceutical compositions prepared using the compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is suitable for topical application. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in a carrier, for example, in the form of capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material, which can act as a mordant, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, capsules, 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 gelatin capsules and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated into tablets or capsules.

[0281] This document further provides pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. Pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof as active ingredients can be prepared by thoroughly mixing the compounds of the present invention or pharmaceutically acceptable salts thereof with a drug carrier according to conventional pharmaceutical compounding techniques. Depending on the desired route of administration ( For example (Oral, parenteral), the carrier can take various forms. In some embodiments, the composition is a solid oral composition.

[0282] 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. The Handbook of Pharmaceutical Excipients It can be found in ( ) ).

[0283] Methods for preparing pharmaceutical compositions have been described in numerous publications, such as those edited by Lieberman et al. Pharmaceutical Dosage Forms: Tablets, 2nd Edition, Revised and Expanded Volumes 1-3; edited by Avis et al. Pharmaceutical Dosage Forms: Parenteral Medications Volumes 1-2; and edited by Lieberman et al. Pharmaceutical Dosage Forms: Disperse Systems Volumes 1-2; published by Marcel Dekker, Inc.

[0284] When preparing compositions for oral dosage forms, any conventional pharmaceutical medium can be used. Therefore, suitable carriers and additives for liquid oral dosage forms such as suspensions, elixirs, and solutions include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.; for solid oral dosage forms such as powders, capsules, and tablets, suitable carriers and additives include starch, sugars, diluents, granulators, lubricants, binders, disintegrants, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium oleate), sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Solid oral dosage forms can also be coated or enteric-coated with substances such as sugars to modulate the main absorption sites. For parenteral administration, the carrier will typically consist of sterile water, and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions can also be prepared using aqueous carriers and appropriate additives. The pharmaceutical compositions described in this article per dose unit ( For exampleThe tablets, capsules, powders, injections, teaspoons, etc. will contain a certain amount of the active ingredient necessary to deliver the effective dose as described herein.

[0285] Compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into unit dosage forms, each dose containing about 5 mg to about 1,000 mg (1 g) of the active ingredient, more typically about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other subjects, each unit containing a predetermined amount of the active material (…). Namely The predetermined amount of active material (the compound of the present invention or a pharmaceutically acceptable salt thereof) is calculated to produce the desired therapeutic effect and is combined with a suitable pharmaceutical excipient.

[0286] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of an active ingredient. Those skilled in the art will understand 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 an active ingredient.

[0287] In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of the active ingredient. Those skilled in the art will understand 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.

[0288] In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of an active ingredient. Those skilled in the art will understand that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of an active ingredient.

[0289] The daily dose of the compounds of the present invention or pharmaceutically acceptable salts thereof may vary within a wide range or any range thereof from 1.0 mg to 10,000 mg or higher per adult per day. For oral administration, the composition is preferably provided in tablet form 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 mg of the active ingredient for symptomatic dose adjustment in treated subjects. An effective amount of the drug is typically provided at a dose level of about 0.1 mg / kg to about 1000 mg / kg body weight per day (or any range thereof). Preferably, the range is about 0.5 mg / kg to about 500 mg / kg body weight per day (or any range thereof). More preferably, about 1.0 mg / kg to about 250 mg / kg body weight per day (or any range thereof). More preferably, the dosage is from about 0.1 mg / kg to about 100 mg / kg body weight daily, or any range thereof. In one example, the range may be from about 0.1 mg / kg to about 50.0 mg / kg body weight daily, or any amount or range thereof. In another example, the range may be from about 0.1 mg / kg to about 15.0 mg / kg body weight daily, or any range thereof. In yet another example, the range may be from about 0.5 mg / kg to about 7.5 mg / kg body weight daily, or any range thereof. Pharmaceutical compositions containing the compounds of the present invention or pharmaceutically acceptable salts thereof may be administered in a regimen of 1 to 4 times daily or as a single daily dose.

[0290] Active compounds can be effective over a wide dose range and are typically administered at pharmaceutically effective amounts. Those skilled in the art can readily determine the optimal dose to be administered. Therefore, it should be understood that the amount of compound actually administered will generally be determined by a physician and will vary depending on relevant circumstances, including the mode of administration, the compound actually administered, the strength of the formulation, the condition being treated, and the progression of the disease condition. Additionally, factors relevant to the specific subject being treated (including subject response, age, weight, diet, time of administration, and severity of the subject's symptoms) will necessitate dose adjustments.

[0291] In some embodiments, the compounds provided herein may be administered in amounts ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein may be administered in amounts ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg.

[0292] Those skilled in the art will recognize that the use of suitable, known and generally accepted cell and / or animal models In vivo Experiment and In vitro Both trials predicted the ability of the tested compounds to treat or prevent a given ailment.

[0293] Those skilled in the art will further recognize that human clinical trials, including first-in-human trials, dose-range trials, and efficacy trials, can be conducted in healthy subjects and / or subjects with a given condition, based on methods known in the clinical and medical fields.

[0294] This document provides pharmaceutical kits for treating, for example, MALT1-related diseases or conditions (such as cancer), comprising one or more containers containing a pharmaceutical composition comprising an effective amount of the compounds provided herein. As will be apparent to those skilled in the art, such kits may further comprise one or more of a variety of conventional pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, additional containers, etc., if desired. The kit may also include instructions (as inserts or as labels) indicating the amount of the component to be administered, instructions for administration, and / or instructions for mixing the components.

[0295] Additional therapeutic agents

[0296] In the field of medical oncology, common practice is to treat each subject with cancer using a combination of different forms of therapy. In medical oncology, in addition to the compositions provided herein, one or more other components of such combination therapies or treatments may be, for example, surgical procedures, radiation therapy, and chemotherapy agents, such as other protease inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies.

[0297] For example, the surgery can be open surgery or minimally invasive surgery. Therefore, the compounds of the present invention or pharmaceutically acceptable salts thereof can also be used as adjuvants in cancer treatment, i.e., they can be used in combination with one or more other therapies or therapeutic agents (e.g., chemotherapeutic agents acting through the same or different mechanisms of action). In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof may be administered prior to the administration of other therapeutic agents or other therapies. For example, one or more doses of the compounds of the present invention or pharmaceutically acceptable salts thereof may be administered to a subject in need over a period of time, and then the tumor may be at least partially removed. In some embodiments, treatment with one or more doses of the compounds of the present invention or pharmaceutically acceptable salts thereof to reduce tumor size (e.g., tumor burden) prior to at least partial removal of the tumor. In some embodiments, one or more doses of the compounds of the present invention or pharmaceutically acceptable salts thereof may be administered to a subject in need over a period of time and in one or more rounds of radiotherapy. In some embodiments, treatment with one or more doses of the compounds of the present invention or pharmaceutically acceptable salts thereof to reduce tumor size (e.g., tumor burden) prior to one or more rounds of radiotherapy.

[0298] In some embodiments, the subject has refractory cancer (e.g., locally advanced or metastatic tumor) that is intolerant to standard therapy (e.g., chemotherapy), such as a first MALT1 inhibitor, a kinase inhibitor, immunotherapy, cell or gene therapy, or radiation therapy (e.g., radioactive iodine). In some embodiments, the subject has refractory cancer (e.g., locally advanced or metastatic tumor) that is intolerant to prior therapy (e.g., chemotherapy, such as a first MALT1 inhibitor or another protease inhibitor, immunotherapy, cell or gene therapy, or radiation therapy (e.g., radioactive iodine). In some embodiments, the subject has cancer for which there is no standard therapy (e.g., locally advanced or metastatic tumor). In some embodiments, the subject has not used a MALT1 protease inhibitor. For example, the subject has not been treated with a selective MALT1 protease inhibitor. In some embodiments, the subject has used a MALT1 protease inhibitor.

[0299] 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 of at least one additional therapeutic agent selected from one or more other therapies or therapeutic agents (e.g., chemotherapeutic agents or immunomodulators). The additional therapy or therapeutic agent can be any suitable additional therapy or therapeutic agent, as described herein.

[0300] Other non-limiting examples of therapeutic agents include: other MALT1-targeting agents (i.e., first or second MALT1 protease inhibitors, such as JNJ-67856633 or CTX-177), other protease inhibitors, kinase inhibitors (e.g., receptor tyrosine kinase-targeting agents, such as BTK or EGFR inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways (e.g., venetoclax or obataclax); cytotoxic chemotherapy drugs, angiogenesis-targeting therapies, immune-targeting agents (including antibody- and cell-based immunotherapies and antibody-drug conjugates), and radiation therapy.

[0301] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, along with other therapeutic agents, are administered simultaneously in individual doses. In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, along with other therapeutic agents, are administered sequentially in individual doses in any order.

[0302] In some embodiments, other MALT1-targeting therapeutic agents are other protease inhibitors that exhibit MALT1 inhibitory activity. In some embodiments, other MALT1-targeting therapeutic agents are selective for the MALT1 protease. Exemplary MALT1 protease inhibitors may exhibit inhibitory activity (IC50) against the 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. 50 As measured in the assays described herein. In some embodiments, the MALT1 protease inhibitor may exhibit inhibitory activity (IC50) against the MALT1 protease of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM. 50 ), as measured in the determinations provided herein.

[0303] Non-limiting examples of protease-targeting therapeutic agents (e.g., a first or second MALT1 inhibitor) include JNJ-67856633 and CTX-177.

[0304] 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-carboxynitrile); amovatinib (MP470, HPK56) (N-(1,3-benzodioxo-5-ylmethyl)-4-([1]benzofurano[3,2-d]pyrimidin-4-yl)piperazine-1-thiocarboxamide); apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl)phenyl-2-(4-pyridinylmethyl)amino-3-nicotinamide methanesulfonate); cabozantinib (Cometriq) XL-184) (N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); Dovirtinib (TKI258; GFKI-258; CHIR-258) ((3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-yl]quinoline-2-one); Famitinib (5-[2-(diethylamino)ethyl]-2-[(Z) )-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one; Fizzotinib (SAR302503, TG101348) (N-(2-methyl-2-propyl)-3-{[5-methyl-2-({4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4-pyrimidinyl]amino}benzenesulfonamide); Furetinib (XL880, EXEL-2880, G SK1363089, GSK089) (N1'-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); Foutantinib (R788) (2H-pyrido[3,2-b]-1,4-oxazine-3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl -4-[(phosphonoyloxy)methyl]-, sodium salt (1:2)); iloratinib (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-quinoline carboxamide); motsebenzini (AMG 706) (N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridin-3-carboxamide);Nintedanib (3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolone); Ponatinib (AP24534) (3-(2-imidazo[1,2-b]pyridazin-3-ethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl) [Phenylacetylbenzamide]); PP242 (Tocinib) (2-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-indole-5-ol); Quizatinib (1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazo-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, agrafenib) (1-(3-((6,7-dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)urea); smasani ( SU5416 ((3Z)-3-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-1,3-dihydro-2H-indol-2-one); cetirizine (MGCD516, MG516) (N-(3-fluoro-4-{[2-(5-{[(2-methoxyethyl)amino]methyl}-2-pyridyl)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); Vandertanil (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine); Vatalani (PTK787, PTK / ZK, ZK222584) (N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazine-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-propyl-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)thiazolyl)urea); CLM3 (1-phenethyl-N-(1-phenethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); EBI-907 (N-(2-chloro-3-(1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]isoquinoline-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)dihydroindole-1-carboxamide); PD173955 (6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylthioanilino)pyrido[2,3-d]pyrimidin-7-one); PP2 (4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidin); PZ-1 (N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1Hbenzo[d]imidazol-1-yl)phenyl)acetamide); RPI-1 (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one; (3E)-3-[(4-hydroxyphenyl)methylene]-5,6-dimethoxy-1H-indol-2-one); SGI-7079 (3-[2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenylacetonitrile); SPP86 (1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine); SU4984 (4-[4-[(E)-(2-oxo-1H-indol-3-ylidene)methyl]phenyl]piperazin-1-carboxaldehyde);Sunitinib (SU11248) (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indole-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); Solanine A ((4β,5β,6β,22R)-4,27-dihydroxy-5,6:22,26-diepoxyergoster-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)indololin-2-one); BPR1J373 (5-phenylthiazol-2-ylamine-pyrimidine derivative); CG-806 (CG'806); DCC-2157; GTX-186; HG-6-63-01 ((E)-3-(2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide); SW-01 (cyclobenzalin hydrochloride); XMD15-44 (N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridin-3-ylethynyl)benzamide (derived from the structure)); ITRI-305 (D0N5TB, DIB003599); BLU-667 ((1S,4R)-N-((S)-1-( 6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide); BLU6864; DS-5010; GSK3179106; GSK3352589; NMS-E668; TAS0286 / HM05; TPX0046; and N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide;

[0305] Non-limiting examples of receptor tyrosine kinase (e.g., Trk) targeted therapies include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, and letatinib. estaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, l-((3S,4R)-4-(3-fluorophenyl)-l-(2-methoxyethyl)pyrrolidine-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-l-phenyl-lH-pyrazole-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-pyrrolo-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]-urea, AZ623, AZ64, ( S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-2,4-diamine, AZD7451, CEP-751, CT327, sunitinib, GNF-8625, and (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)-[2,4'-dipyridin]-2'-yl)piperidin-4-ol.

[0306] In some embodiments, an additional therapeutic agent is a BRAF inhibitor. Non-limiting examples of BRAF inhibitors include: dabrafenib, vemurafenib (also known as RG7204 or PLX4032), sorafenib tosylate, PLX-4720, GDC-0879, BMS-908662 (Bristol-Meyers Squibb), LGX818 (Novartis), PLX3603 (Hofmann-LaRoche), RAF265 (Novartis), RO5185426 (Hofmann-LaRoche), and GSK2118436 (GlaxoSmithKline). Further examples of BRAF inhibitors are known in the art.

[0307] In some embodiments, an additional therapeutic agent is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors may include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0308] In some embodiments, additional therapeutic agents are 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, and temsirolimus), and other kinase inhibitors such as baricitinib. Citinib, Brigatinib, Capmatinib, Danusertib, Ibrutinib, Milciclib, Quercetin, Regorafenib, Ruxolitinib, Smasani, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736 ((R)-amino-NN-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepine-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).

[0309] In some embodiments, the additional therapeutic agent is a BTK inhibitor. Non-limiting examples of BTK inhibitors include ibrutinib, acalabrutinib, and zanubrutinib.

[0310] In some embodiments, the additional therapeutic agent is a Bcl-2 inhibitor. Non-limiting examples of Bcl-2 inhibitors include venetoclax, navitoclax, oblimersen, octopok, and AT-101.

[0311] 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.

[0312] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. Non-limiting examples of mTOR inhibitors include everolimus, tesimolimus, and ridaforolimus.

[0313] In some embodiments, the additional therapeutic agent is an HDAC inhibitor. Non-limiting examples of HDAC inhibitors include vorinostat, romidepsin, belinostat, chidamide, panobinostat, CXD101, and abexinostat.

[0314] In some embodiments, an 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.

[0315] In some embodiments, an additional therapeutic agent is cytotoxic chemotherapy. In some embodiments, cytotoxic chemotherapy includes arsenic trioxide, bleomycin, bendamustine, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, and mitomycin C. C), oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

[0316] In some embodiments, the additional therapeutic agent is an angiogenesis-targeting therapeutic agent. Non-limiting examples of angiogenesis-targeting therapies include lenalidomide, enzastaurine, aflibercept, and bevacizumab.

[0317] In some embodiments, additional therapies or therapeutic agents may comprise a histidine-tRNA synthetase (HRS) polypeptide or an expressible nucleotide encoding an HRS polypeptide.

[0318] The term "immunotherapy" refers to agents that modulate the immune system. In some embodiments, immunotherapy may increase the expression and / or activity of immune system modulators. In some embodiments, immunotherapy may decrease the expression and / or activity of immune system modulators. In some embodiments, immunotherapy may recruit and / or enhance the activity of immune cells.

[0319] In some embodiments, the immunotherapy is a cellular immunotherapy (e.g., adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101-108). In some embodiments, the cellular immunotherapy comprises cells expressing a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is 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.

[0320] In some embodiments, immunotherapy is antibody therapy (e.g., monoclonal antibodies, conjugated antibodies, or bispecific antibodies). In some embodiments, antibody therapy includes bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®), and rituximab containing human hyaluronidase (Rituxan Hycela). TM), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), trimelimab (CP-675, 206), ramucirumab (Cyramza®), ublituximab (TG-1101), Panitumumab (Vectibix®), Elotuzumab (Empliciti™), Avelumab (Bavencio®), Nexituzumab (Portrazza™), Cimutuzumab (UC-961), Ibritumomab (Zevalin®), Ixatuximab (SAR650984), Nimotuzumab, Fresolimumab (GC1008), Lirilumab (INN), Mogamulizumab (Poteligeo®), Ficlatuzumab (AV-299), Denosumab (Xgeva®), lenzilumab, acitumab, spartalizumab, pembrolizumab, utomilumab, blinatumomab, ganitumab, urelumab, pildizumab, amatuximab, mosunetuzumab (BTCT4465A), CD20-TCB, RO7082859, XmAb13676, glofitamab, CD20-TDB, odronextamab (REGN1979), IGM-2323, BTCT4465A, AMG-562, or TTI-621.

[0321] 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), anetumabravtansine, polatuzumab vedotine, loncastuximab tesirine (ADCT-402), or camidanlumab tesirine. (ADCT-301) or Naratuximab emtansine (Debio 1562).

[0322] In some embodiments, immunotherapy includes blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).

[0323] In some embodiments, the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

[0324] In some embodiments, immunotherapy is cytokine therapy. In some embodiments, cytokine therapy is interleukin-2 (IL-2) therapy, interferon-alpha (IFNα) therapy, granulocyte colony-stimulating factor (G-CSF) therapy, interleukin-12 (IL-12) therapy, interleukin-15 (IL-15) therapy, interleukin-7 (IL-7) therapy, or erythropoietin-alpha (EPO) therapy. In some embodiments, IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, IFNα therapy is IntronA® (Roferon-A®). In some embodiments, G-CSF therapy is filgrastim (Neupogen®).

[0325] In some embodiments, immunotherapy is an immune checkpoint inhibitor. In some embodiments, 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 trimemumab (CP-675, 206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), acitumab (Bavencio®), or durvalumab (Imfinzi™).

[0326] In some embodiments, the immunotherapy is an mRNA-based immunotherapy. In some embodiments, the mRNA-based immunotherapy is CV9104 (see, for example, Rausch et al. (2014) Human Vaccin Immunother 10(11):3146-52; and Kubler et al. (2015) J. Immunother Cancer 3:26).

[0327] In some embodiments, immunotherapy is Bacillus Calmette-Guerin (BCG) therapy.

[0328] In some embodiments, the immunotherapy is oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC; Imlygic®).

[0329] 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).

[0330] 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, for example, Ott et al. (2017) Nature 547: 217-221; Sahin et al. (2017) Nature 547: 222-226). In some embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA-based vaccine is a lactoglobulin-A DNA vaccine (see, for example, Kim et al. (2016) OncoImmunology 5(2): e1069940).

[0331] In some embodiments, the immune targeting agent is selected from interleukin, interferon α-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

[0332] In some embodiments, an additional therapy is radiation therapy. Non-limiting examples of radiation therapy include radioactive iodine therapy, external beam radiation, and radium-223 therapy.

[0333] In some embodiments, additional therapeutic agents are GSK-3368715, PF-06821497, ceralasertib; AZD6738, BI-894999, MAK-683, AZD-6738, taminadenant, TAK-981, MIK-665, or danvatirsen.

[0334] Other kinase inhibitors include those described in the following patents: for example, U.S. Patent Nos. 7,514,446; 7,863,289; 8,026,247; 8,501,756; 8,552,002; 8815,901; 8912,204; 9,260,437; 9,273,051; U.S. Publication No. US2015 / 0018336; International Publication Nos. WO 2007 / 002325; WO 2007 / 002433; WO 2008 / 080001; WO2008 / 079906; WO 2008 / 079903; WO 2008 / 079909; WO 2008 / 080015; WO 2009 / 007748; WO2009 / 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 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 incorporated herein by reference in its entirety.

[0335] In some embodiments, the subject has previously been treated with one or more standard of care therapies for lymphoma. In some embodiments, the previously treated standard of care therapies are vetin-polotuluzumab, celiniso, akilenza (Yescarta), tesalenza (Kymriah), a combination of bendamustine with rituximab and vetin-polotuluzumab, a combination of tanxitosumab with lenalidomide, or a combination of rituximab with human hyaluronidase (Rituxan Hycela).

[0336] In some embodiments, the subject also received standard care therapy for lymphoma. In some embodiments, standard care therapy is vetin-polotuluzumab, celiniso, akirenzab (Yescarta), tesalenzab (Kymriah), a combination of bendamustine with rituximab and vetin-polotuluzumab, a combination of tanxitoumab with lenalidomide, or a combination of rituximab with human hyaluronidase (Rituxan Hycela).

[0337] Synthesis of the compounds of the present invention

[0338] The compounds (including their salts) presented herein can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes.

[0339] The reactions used to prepare the compounds presented herein can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent can be used at the temperature at which the reaction is carried out (…). For example The solvent (ranging from its freezing point to its boiling point) is substantially non-reactive with the starting material (reactant), intermediate, or product. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, those skilled in the art can select a suitable solvent for that specific reaction step.

[0340] The preparation of the compounds presented herein may 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 those skilled in the art. The chemistry of protecting groups can be found, for example, in the following literature: Protecting Group Chemistry , 1st edition, OxfordUniversity Press, 2000; March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 5th edition, Wiley-Interscience Publication, 2001; and Petrussion, S. et al “ Protecting Groups in Carbohydrate Chemistry “ J. Chem. Educ., 74(11), 1297 (1997).

[0341] Radioactively labeled analogs of the compounds of the present invention

[0342] In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention. As used herein, the term "radiolabeled analogue of the compounds of the present invention" refers to a compound that is identical to the compounds of the present invention described herein, except that one or more atoms have been replaced by a radioactive isotope of an atom present in the compounds of the present invention, including all embodiments thereof.

[0343] As used herein, the term "radioactive isotope" refers to an isotope of an element known to undergo spontaneous radioactive decay. Examples of radioactive isotopes include... 3 H, 14 C 32 P, 35 S, 18 F, 36 Cl et al. and isotopes whose decay patterns were identified in the following literature: VSShirley & CMLederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0344] Radiolabeled analogues can be used in a variety of beneficial ways, including various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 ( 14 C) Labeled compounds can be used for various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0345] In another aspect, the present invention relates to pharmaceutically acceptable salts of radiolabeled analogs according to any embodiment described herein in conjunction with the compounds of the invention.

[0346] In another aspect, the present invention relates to pharmaceutical compositions comprising a radiolabeled analogue or a pharmaceutically acceptable salt thereof, according to any embodiment described herein in conjunction with the compounds of the present invention, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0347] In another aspect, the present invention relates to methods for inhibiting MALT1 in subjects and methods for treating or reducing the severity of various diseases and conditions in subjects, including cancer, autoimmune diseases and inflammatory diseases, comprising administering an effective amount of a radiolabeled analogue according to any embodiment of the compounds described herein in conjunction with the present invention, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof.

[0348] In another aspect, the present invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof for use in any embodiment described herein in conjunction with the compounds of the present invention.

[0349] In another aspect, the present invention relates to the use of radiolabeled analogues or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in the manufacture of medicines, according to any embodiment described herein in conjunction with the compounds of the invention.

[0350] In another respect, radiolabeled analogs, their pharmaceutically acceptable salts, and their pharmaceutical compositions may be used in combination therapies according to any of the embodiments described herein in conjunction with the compounds of the present invention.

[0351] Listed Examples

[0352] Further embodiments, features, and advantages of this disclosure will become apparent from the following detailed description and from thorough practice of this disclosure. The compounds and methods of this disclosure may be described as embodiments as listed in any of the following enumerated terms. It should be understood that any embodiment described herein may be used in conjunction with any other embodiment described herein, provided that such embodiments do not contradict each other.

[0353] 1. A compound of formula (I): , (I) Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 1 It is H, halogenated, or C1-C3 alkyl; R 2 It is H, halogenated, or C1-C3 alkyl; R 0 R 3 and R 4 The definition is as follows: (i)R 0 It is H; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 0 It is H; and R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; or (iii)R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups; and R 4 It is a C1-C6 alkyl group; R 5 It is H or halogenated; R 6 It is H or halogenated; and R 7 and R 8 The definition is as follows: (i)R 7 It is a C1-C6 alkyl group; and R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups; or (ii)R 7 and R 8 Together with the atoms to which they are attached, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygen groups; The premise is that at most one of X and Y is N.

[0354] 2. The compound according to Clause 1, wherein the compound has the formula (I-1): , (I-1) Or its pharmaceutically acceptable salt.

[0355] 3. The compound according to clause 1 or 2, wherein the compound has formula (I-2a): , (I-2a) Or its pharmaceutically acceptable salt.

[0356] 4. The compound according to clause 1 or 2, wherein the compound has the formula (I-2b): , (I-2b) Or its pharmaceutically acceptable salt.

[0357] 5. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 4, wherein X is CH.

[0358] 6. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 4, wherein X is CF.

[0359] 7. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 4, wherein X is N.

[0360] 8. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 7, wherein Y is CH.

[0361] 9. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 7, wherein Y is CF.

[0362] 10. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 7, wherein Y is N.

[0363] 11. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 10, wherein R 1 It is H.

[0364] 12. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 11, wherein R 2 It is F.

[0365] 13. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 12, wherein R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl.

[0366] 14. The compound or a pharmaceutically acceptable salt thereof as described in Clause 13, wherein R 3 Is it CH3, CF3 or .

[0367] 15. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 14, wherein R 4 It is CH3.

[0368] 16. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 12, wherein R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups.

[0369] 17. The compound according to Clause 16, wherein R 3 and R 4Or, or their pharmaceutically acceptable salts, together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl.

[0370] 18. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 17, wherein R 0 It is H.

[0371] 19. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 12, wherein R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups.

[0372] 20. The compound according to Clause 19, wherein R 0 and R 3 Or, or a pharmaceutically acceptable salt thereof, together with the carbon atom to which they are attached, form a cyclobutyl group, and R 4 It is CH3.

[0373] 21. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 20, wherein R 5 It is H or F.

[0374] 22. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 21, wherein R 6 It is H or F.

[0375] 23. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 22, wherein R 7 It is a C1-C6 alkyl group.

[0376] 24. The compound according to clause 23, wherein R 7 It is CH3.

[0377] 25. The compound according to any one of clauses 1 to 24, wherein R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups.

[0378] 26. The compound according to clause 25, wherein R 8 yes , , , or .

[0379] 27. The compound according to any one of clauses 1 to 22, wherein R 7 and R 8Together with the atoms to which they are attached, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygens.

[0380] 28. The compound according to Clause 1, wherein the compound has the formula (IA): , (IA) Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 0 R 3 and R 4 The definition is as follows: (i)R 0 It is H; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 0 It is H; and R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; or (iii)R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups; and R 4 It is a C1-C6 alkyl group; R 5 It is H or halogenated; R 6 It is H or halogenated; and R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups; and The premise is that at most one of X and Y is N.

[0381] 29. The compound according to Clause 28, wherein the compound has the formula (IA-1): , (IA-1) Or its pharmaceutically acceptable salt.

[0382] 30. The compound according to clause 28 or 29, wherein the compound has the formula (IA-2a): , (IA-2a) Or its pharmaceutically acceptable salt.

[0383] 31. The compound according to clause 28 or 29, wherein the compound has the formula (IA-2b): , (IA-2b) Or its pharmaceutically acceptable salt.

[0384] 32. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 31, wherein X is CH.

[0385] 33. A compound or a pharmaceutically acceptable salt thereof pursuant to any one of clauses 28 to 31, wherein X is CF.

[0386] 34. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 31, wherein X is N.

[0387] 35. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 34, wherein Y is CH.

[0388] 36. A compound or a pharmaceutically acceptable salt thereof pursuant to any one of clauses 28 to 34, wherein Y is CF.

[0389] 37. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 34, wherein Y is N.

[0390] 38. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 37, wherein R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl.

[0391] 39. A compound or a pharmaceutically acceptable salt thereof as described in Clause 38, wherein R 3 Is it CH3, CF3 or .

[0392] 40. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 39, wherein R 4 It is CH3.

[0393] 41. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 39, wherein R3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups.

[0394] 42. The compound according to clause 41, wherein R 3 and R 4 Or, or their pharmaceutically acceptable salts, together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl.

[0395] 43. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 42, wherein R 0 It is H.

[0396] 44. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 28 to 37, wherein R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups.

[0397] 45. The compound according to clause 44, wherein R 0 and R 3 Or, or a pharmaceutically acceptable salt thereof, together with the carbon atom to which they are attached, form a cyclobutyl group, and R 4 It is CH3.

[0398] 46. ​​The compound according to any one of clauses 28 to 45, wherein R 5 It can be H or F.

[0399] 47. The compound according to any one of clauses 28 to 46, wherein R 6 It can be H or F.

[0400] 48. The compound according to any one of clauses 28 to 47, wherein R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with two oxygen groups.

[0401] 49. The compound according to clause 48, wherein R 8 yes , , , or .

[0402] 50. The compound according to Clause 1, wherein the compound has the formula (IB):

[0403] (IB)

[0404] Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 3 and R 4 The definition is as follows: (i)R 3 It is a C1-C6 alkyl or a C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; R 5 It is H or halogenated; R 6 It is H or halogenated; and R 9 and R 10 These atoms are linked together with the carbon atoms to form 4-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with 1-2 oxygen atoms. The premise is that at most one of X and Y is N.

[0405] 51. The compound according to clause 50, wherein the compound has the formula (IB-1): , (IB-1) Or its pharmaceutically acceptable salt.

[0406] 52. The compound according to clause 50 or 51, wherein the compound has the formula (IB-2a): , (IB-2a) Or its pharmaceutically acceptable salt.

[0407] 53. The compound according to clause 50 or 51, wherein the compound has the formula (IB-2b): , (IB-2b) Or its pharmaceutically acceptable salt.

[0408] 54. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 50 to 53, wherein X is CH.

[0409] 55. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 50 to 54, wherein Y is CH.

[0410] 56. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 50 to 55, wherein R 3 It is a C1-C6 alkyl group.

[0411] 57. A compound or a pharmaceutically acceptable salt thereof as described in Clause 56, wherein R 3 It is CH3.

[0412] 58. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 50 to 57, wherein R 4 It is CH3.

[0413] 59. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 50 to 58, wherein R 5 It is H.

[0414] 60. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 50 to 58, wherein R 6 It is H.

[0415] 61. A compound or a pharmaceutically acceptable salt thereof according to any one of clauses 50 to 60, wherein R 9 and R 10 They are linked together with the carbon atoms to form 4-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 2 oxygen atoms.

[0416] 62. The compound according to clause 61, wherein R 9 and R 10 Or, or a pharmaceutically acceptable salt thereof, linked together with the carbon atom to which they are attached to form tetrahydropyranyl or 1,1-dioxo-tetrahydrothiaranyl.

[0417] 63. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

[0418] 64. The compound according to any one of clauses 1 to 63, wherein the compound is in a non-salt form.

[0419] 65. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 63, or a compound according to clause 64, and one or more pharmaceutically acceptable carriers or mediators.

[0420] 66. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 63 or a pharmaceutically acceptable salt thereof, or a compound according to clause 64 and one or more pharmaceutically acceptable carriers or mediators.

[0421] 67. A method for inhibiting MALT1 in a subject, the method comprising administering to the subject a compound according to any one of clauses 1 to 63 or a pharmaceutically acceptable salt thereof, a compound according to clause 64, or a pharmaceutical composition according to clauses 65 or 66.

[0422] 68. A method for treating or reducing the severity of a condition in a subject selected from cancer, autoimmune diseases, or inflammatory diseases, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of clauses 1 to 63, a compound according to clause 64, or a pharmaceutical composition according to clauses 65 or 66.

[0423] 69. The method described in Article 68, wherein the condition is cancer.

[0424] 70. The method described in Clause 69, wherein the cancer is a MALT1-related cancer.

[0425] 71. The method described in accordance with 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 advanced solid tumors.

[0426] 72. The method described in Clause 68, wherein the condition is an autoimmune condition.

[0427] 73. The method described in accordance with Clause 72, wherein the autoimmune disease is a MALT1-associated autoimmune disease.

[0428] 74. The method according to clause 72 or 73, wherein the autoimmune disease is selected from multiple sclerosis (MS) and rheumatoid arthritis (RA).

[0429] 75. The method described in Clause 68, wherein the condition is an inflammatory condition.

[0430] 76. The method described in accordance with Clause 75, wherein the inflammatory condition is a MALT1-related inflammatory condition.

[0431] 77. The method described in accordance with clause 75 or 76, wherein the inflammatory condition is chronic graft-versus-host disease (cGvHD).

[0432] 78. A method of treating or reducing the severity of a mature B-cell tumor in a subject, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Clauses 1 to 63, a compound according to Clause 64, or a pharmaceutical composition according to Clauses 65 or 66.

[0433] 79. The method according to any one of clauses 67 to 78, wherein the subject is treated with one or more additional therapeutic agents, which are administered concurrently with, before, or after treatment with a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition.

[0434] 80. Use as a medicament by any one of the compounds of any one of Clauses 1 to 63 or a pharmaceutically acceptable salt thereof, a compound of Clause 64 or a pharmaceutical composition of Clause 65 or 66.

[0435] 81. Use of any compound of any one of Clauses 1 to 63 or a pharmaceutically acceptable salt thereof, a compound of Clause 64 or a pharmaceutical composition of Clause 65 or 66 in the manufacture of a medicament for the treatment of cancer, an autoimmune disease or an inflammatory disease.

[0436] Example

[0437] General Methods. Reactions sensitive to moisture or air are carried out under nitrogen or argon atmosphere using anhydrous solvents and reagents. Reaction progress is determined by analysis of thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). TLC analysis is typically performed using Sanpont pre-coated TLC plates, silica gel GF-254, with a layer thickness of 0.25 mm. LC-MS is performed as described below.

[0438] LC-MS analysis is typically performed using a Shimadzu LCMS-2020 and 20ADXR pump equipped with electrospray ionization and positive ion detection mode, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS 2020 MS detector. The column is typically a HALO a C2000. 18 30 5.0 mm, 2.7 µm. Mobile phase A is water containing 0.05% TFA, and mobile phase B is acetonitrile containing 0.05% TFA. Gradient elution is typically used, ranging from 5% mobile phase B to 100% in 2.0 min, holding for 0.7 min, then returning to 5% mobile phase B in 0.05 min and holding for 0.25 min. The column oven (CTO-20AC) is operated at 40.0 °C. The flow rate is 1.5 mL / min, and the injection volume is 1 µL. The PDA (SPD-M20A) detection range is 190–400 nm. MS detector, equipped with electrospray ionization as the ionizable source; acquisition mode: scan; atomized gas flow rate: 1.5 L / min; dry gas flow rate: 15 L / min; detector voltage: tuned voltage ±0.2 kV; DL temperature: 250℃; heating block temperature: 250℃; scan range: 90.00-900.00 m / z. ELSD (Alltech 3300) detector parameters: drift tube temperature: 60±5℃; N2 flow rate: 1.8 ± 0.2 L / min. In some cases, the mobile phase gradient is specifically optimized for individual compounds.

[0439] GC-MS analysis was typically performed using a Shimadzu GCMS-QP2010 Ultra equipped with an FID and MS detector. The MS detector was operated in acquisition mode with the following parameters: start time: 2.00 min; end time: 9.00 min; ACQ mode: scan; event time: 0.30 s; scan rate: 2000; start m / z: 50.00; end m / z: 550.00; ion source temperature: 200.00 °C; interface temperature: 250.00 °C; solvent cut-off time: 2.00 min.

[0440] Preparative HPLC purification is typically performed using a Waters automated purification system (2545-2767) equipped with a 2489 UV detector. The column is a Waters C10 column. 18 The mobile phase consisted of 19 x 150 mm, 5 μm. The mobile phase was a mixture of acetonitrile (5-95%) in water containing 0.1% FA. The flow rate was maintained at 25 mL / min, the injection volume was 1200 µL, and the intensity at both 254 nm and 220 nm channels was measured using a UV detector. In some cases, the mobile phase gradient was specifically optimized for individual compounds.

[0441] In some cases, in 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 Chiral analysis was performed on one of the following columns: a Whelk-O1 column (Regis Technologies, Inc.); or a CHIRAL Cellulose-SB, SC, or SA column (YMC Co., Ltd.) with different column sizes (50x4.6 mm, 100x4.6 mm, 150x4.6 mm, 250x4.6 mm, 50x3.0 mm, 100x3.0 mm) using the recorded percentages of ethanol (%Et / Hex) or isopropanol (%IPA / Hex) in hexane as the solvent system. In some cases, chiral analysis was performed on one of the following columns: a Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ column (250x4.6 mm) (Daicel Chemical Industries, Ltd.) using the recorded percentages of ethanol / hexane (%Et / Hex) or isopropanol / heptane (%IPA / Hep) as the solvent system.

[0442] On 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 Chiral preparative chromatography was performed on one of the following columns: )-Whelk-O1 column (Registechnologies, Inc.); CHIRAL Cellulose-SB, SC, SA column (YMC Co., Ltd.) with different column sizes (250x20mm, 250x30mm, 250x50mm), wherein the required isocratic solvent system was determined in the chiral analytical chromatography.

[0443] Reactions involving microwave irradiation are typically carried out using the Initiator™ microwave reactor manufactured by Biotage.

[0444] The solution was concentrated under reduced pressure using a rotary evaporator.

[0445] Rapid column chromatography is typically performed using Biotage rapid chromatography equipment (Dyax Corp.) on pre-packed cartridges of this size in silica gel (40-60 μM, 60 Å pore size).

[0446] Unless otherwise stated, 1¹H NMR spectra were acquired at 400 MHz in DMSO-d6. Chemical shifts were reported in parts per million (ppm) using tetramethylsilane (TMS) as an internal control in DMSO-d6 solution, or using the residual CH₃OH peak or TMS as an internal control in CD₃OD solution. Coupling constants (J) were reported in Hertz (Hz).

[0447] abbreviation

[0448] Unless otherwise stated or the context otherwise requires, the following abbreviations shall be understood to have the following meanings:

[0449] The following are representative procedures for preparing the compounds used in the examples below, or procedures that may replace compounds that may not be commercially available and used in the examples below.

[0450] Intermediate 1: 2-Fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (INT-1)

[0451] Method 1

[0452] Step 1: 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one

[0453] A solution of 2,2-dimethylcyclopentanone (20 g, 178.3 mmol) in 1,1-dimethoxy-N,N-dimethylmethylamine (160 mL) was stirred at 120 °C for 24 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give the title compound (15 g, crude product) as a yellow oil, which was used directly in the next step. LC-MS: m / z 168 [M+H] + .

[0454] Step 2: 2-Fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine

[0455] 3-Fluoro-1H-pyrazole-5-amine (3.75 g, 37.1 mmol) and AcOH (15 mL) were added to a stirred solution of 5-((dimethylamino)methylene)-2,2-dimethylcyclopentan-1-one (7.45 g, 44.5 mmol) in toluene (150 mL) at room temperature. The resulting mixture was stirred at 90 °C under nitrogen for 5 hours. The mixture was cooled 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 (saturated, aqueous solution). The resulting solution was extracted with ethyl acetate (2 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was fed onto a silica gel column and eluted with EtOAc / PE (1:5) to give the title compound (3 g, 39% yield) as a yellow solid. 1 HNMR (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] + .

[0456] Step 3: 2-Fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxynitrile

[0457] Add (4 g) to a stirred solution of 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine (3 g, 14.6 mmol) in chlorobenzene (60 mL) R )-4-benzyl-2-[1-[(4 R [-4-benzyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5-dihydrooxazol (636 mg, 1.8 mmol), copper acetoxy (359 mg, 2.9 mmol), N-fluorobenzenesulfonamide (6.91 g, 21.9 mmol), and TMSCN (7.25 g, 73.1 mmol). The mixture was stirred under nitrogen at room temperature for 16 hours. The solvent was removed under vacuum, and the residue was applied to a silica gel column and eluted with EtOAc / PE (1:5) to give the title compound as a yellow solid (5.5 g, 33% yield). LC-MS: m / z 231 [M+H] + .

[0458] Step 4: 2-Fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0459] AcOH (52 mL) and HCl (12 M, 52 mL) containing 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxynitrile (5.2 g, 22.6 mmol) were added to a 30 mL vial. The resulting mixture was stirred at 100 °C for 1.5 h. The mixture was cooled 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 (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3 x 200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with DCM / MeOH (10:1) to give the title compound (INT-1, 450 mg) as a grayish-white solid. LC-MS: m / z 250 [M+H] + This product is used in the next step without further purification.

[0460] Method 2

[0461] Step 1: Diethyl 2-(2-methylallyl)malonate

[0462] Diethyl malonate (200 g, 1.25 mol) and CH3CN (2000 mL) were added to a 5 L reactor. Cesium carbonate (489 g, 1.5 mol) was added in portions at 25 °C. Then, 3-chloro-2-methylprop-1-ene (135 g, 1.5 mol) was added at 25 °C. The temperature of the reaction mixture was increased from 25 °C to 40 °C over 1 hour. The reaction mixture was stirred at 25 °C for 48 hours. The reaction mixture was filtered, and the filter cake was washed with DCM (500 mL). The filtrate was concentrated to give a crude title compound (260 g) as a pale yellow oil, which was used directly in the next step.

[0463] Step 2: Diethyl 2-(cyanomethyl)-2-(2-methylallyl)malonate

[0464] Diethyl 2-(2-methylallyl)malonate (200 g, 934 mmol) and THF (2000 mL) were added to a 5 L reactor. The mixture was cooled to 0 °C and added in 5 batches. t-BuOK (125.6 g, 1120 mmol) (reaction solution colorless). Then, 2-bromoacetonitrile (157.2 g, 1310 mmol) was added dropwise over 2 hours at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. Activated carbon (200 g) was added at room temperature and stirred for 1 hour. The mixture was filtered, and saturated NH4Cl aqueous solution (1000 mL) was added to the filtrate, which was then extracted with MTBE (2 x 2000 mL). The combined organic layers were concentrated. MTBE (1000 mL) and activated carbon (200 g) were added and stirred for 1 hour. The mixture was filtered, the filtrate was dried over sodium sulfate and concentrated to give a crude title compound (254 g) as a yellow oil, which was used directly in the next step.

[0465] Step 3: Diethyl 3,3-dimethyl-4-oxocyclopentane-1,1-dicarboxylate

[0466] Fe(acac)3 (44.3 g, 126.6 mmol) was added to a solution of diethyl 2-(cyanomethyl)-2-(2-methylallyl)malonate (160 g, 632.4 mmol) in HFIP / EtOH (1600 mL, 1:1), followed by the slow addition of PhSiH3 (204.9 g, 1.9 mol). The mixture was stirred at room temperature until no further gas release was observed and the temperature no longer increased. The mixture was stirred at 60 °C for 1 hour. HCl (aqueous solution) (2 M, 1600 mL) was added, and the mixture was stirred at 60 °C for 2 hours. The layers were separated, and the aqueous solution was extracted with DCM (2 x 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 (eluting with 10% to 20% EA in PE) to give the title compound (124.7 g, 77% yield) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0467] Step 4: Diethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxocyclopentane-1,1-dicarboxylate

[0468] A solution of diethyl 3,3-dimethyl-4-oxocyclopentane-1,1-dicarboxylate (124.7 g, 487.0 mmol) in 1,1-dimethoxy-N,N-dimethylmethylamine (1000 mL) was stirred at 80 °C for 16 hours. The reaction mixture was then concentrated to give crude title compound (160 g), which was used directly in the next step.

[0469] Step 5: Diethyl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6,6-dicarboxylic acid

[0470] To a solution of crude 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxocyclopentane-1,1-dicarboxylate (160 g) in toluene (1000 mL), 5-fluoro-1H-pyrazole-3-amine (58.2 g, 582 mmol) and AcOH (100 mL) were added. The mixture was stirred at 110 °C for 40 hours. The mixture was concentrated to give crude title compound (180 g), which was used directly in the next step.

[0471] Step 6: 2-Fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0472] HCl (6 M, 1800 mL) was added to crude 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6,6-dicarboxylic acid diethyl ester (180 g), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into cold water (3600 mL) and extracted with EA (3 x 1800 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried in EA:PE (1:1) to give the title compound as a pale yellow solid (INT-1, 62 g, 51.5% yield in 3 steps). LC-MS: m / z 250.1 [M+H] + .

[0473] Intermediate 2: 1,3-dioxoisoindoline-2-yl-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate (INT-2)

[0474] A mixture of 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[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 adding water (10 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% petroleum ether and 50% ethyl acetate as eluents to give the title compound (INT-2, 120 mg, 68% yield) as a white solid. 1 H 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] + .

[0475] Method A1

[0476] Examples 1 and 2: N-methyl-N-(( S )-2,2,2-trifluoro-1-(4-(( R )-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-thiaran-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-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0477] The absolute stereochemistry of each instance is undetermined.

[0478] Step 1: ( R )-N-(( S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (A1-1)

[0479] Add ( ) to a mixture of 1-(4-bromophenyl)-2,2,2-trifluoro-ethyl ketone (50 g, 197.6 mmol) in THF (1000 mL) R 2-Methylpropane-2-sulfinamide (29.9 g, 247.0 mmol) and tetraisopropyl titanate (70.2 g, 247.0 mmol, 73.52 mL). The reaction mixture was stirred at 80 °C for 12 hours. The mixture was cooled to 10 °C. Trisec-butylborohydride (1 M in THF, 250 mL) was added to the mixture at -78 °C under a nitrogen atmosphere. The mixture was stirred at -78 °C for 3 hours. The reaction was quenched by adding 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 (5 x 300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / EA (1:4) to give 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 = 8.40Hz, 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] + .

[0480] Step 2: ( R )-N-(( S )-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (A1-2)

[0481] At -50℃, towards ( R )-N-(( SLDA (2M in THF, 134.0 mmol) was added dropwise to a solution of 2-methyltetrahydrofuran (500 mL) containing 2-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (24 g, 67.0 mmol). 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 a saturated aqueous solution of 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 (2 x 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, eluting with PE / EA (1:4) to give the title compound (A1-2, 12 g, 45% yield) as a yellow oil. LC-MS: m / z 372 [M+H] + .

[0482] Step 3: Methyl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate

[0483] A mixture of 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[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 adding water (30 mL), and the resulting mixture was extracted with ethyl acetate (3 x 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] + .

[0484] Step 4: 6-(4-(( S )-1-((( R )- tert Butylsulfinyl(methyl)amino)-2,2,2-trifluoroethyl)phenyl)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid methyl ester

[0485] Under a nitrogen atmosphere, LHMDS (1 M, 2.7 mL) was added to a stirred solution of methyl 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate (707 mg, 2.7 mmol) in toluene (10 mL). The mixture was stirred at 25 °C for 30 minutes. Pd2(dba)3 (246 mg, 268 μmol) was added. 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) was added, and the mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction was quenched by adding water (10 mL), and the resulting mixture was extracted with ethyl acetate (3 x 10 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 silica gel column chromatography using 80% petroleum ether and 20% ethyl acetate as eluents to give the title compound (520 mg, 34% yield) as a red solid. LC-MS: m / z 555 [M+H] + .

[0486] 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-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0487] To 6-(4-(( S )-1-((( R )- tertMethyl butylsulfinyl(methyl)amino)-2,2,2-trifluoroethyl)phenyl)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidine-6-carboxylate (580 mg, 1.1 mmol) was reacted with LiOH (75 mg, 3.1 mmol) in a stirred solution of THF (20 mL) and water (20 mL). 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 (3 x 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 as a yellow solid (200.0 mg, 88% yield). LC-MS: m / z 541 [M+H] + .

[0488] Step 6: ( R )-N,2-dimethyl-N-((1 S )-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)propane-2-sulfinamide

[0489] 6-(4-(( S )-1-((( R )- tert A solution of butylsulfinyl(methyl)amino)-2,2,2-trifluoroethyl)phenyl)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[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 adding water (50 mL), and the resulting mixture was extracted with ethyl acetate (3 x 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 silica gel column chromatography using 80% petroleum ether and 20% ethyl acetate as eluents to give the title compound (300 mg, 65% yield) as a white solid. LC-MS: m / z 497 [M+H] + .

[0490] Step 7: (1) S )-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethane-1-amine (A1-7)

[0491] Will( R)-N,2-dimethyl-N-((1 S A solution of 2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)propane-2-sulfinamide (400 mg, 805 μmol) in HCl (4 M in EA, 20 mL) was stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 70% dichloromethane and 30% ethyl acetate as eluents to give the title compound (A1-7, 230 mg, 72% yield) as a yellow solid. LC-MS: m / z 393 [M+H] + .

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

[0493] At 0℃ towards (1 S 2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethane-1-amine (A1-7, 230.0 mg, 586 μmol) was added to a stirred solution of DCM (5 mL) with NaH (112 mg, 2.3 mmol, 50% in mineral oil). The mixture was stirred at 25 °C for 0.5 h. 1,1-dioxane-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 adding water (10 mL), and the resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC using 50% dichloromethane and 50% ethyl acetate as eluents to obtain the product, which was further purified by preparative HPLC to give a mixture of diastereomers of the title compound as a white solid (200 mg, 61% yield). LC-MS: m / z 553 [M+H] + .

[0494] Step 9: Separate the diastereomers to obtain Example 1 and Example 2

[0495] 140 mg of N-methyl-N-((1 S1,1-dioxide of 2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-thiaran-4-carboxamide was purified by chiral HPLC (column: CHIRALPAK IG, 2). 25 cm, 5 μm; Mobile phase A: Hex (0.1% FA)--HPLC, Mobile phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 50% isocratic mobile phase B; Wavelength: 254 / 220 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 give Example 1 (54.5 mg) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 2 (48.8 mg) as a white solid.

[0496] Example 1: 1 H NMR (400 MHz, DMSO- d 6) 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 / z553.1 [M+H] + .

[0497] Example 2: 1 H NMR (400 MHz, DMSO- d 6) 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 / z553.1 [M+H] + .

[0498] Method A2

[0499] Examples 3 and 4: N-methyl-N-(( S )-2,2,2-trifluoro-1-(4-(( R )-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)cyclopropaneamide; N-methyl-N-(( S )-2,2,2-trifluoro-1-(4-(( S 2-Fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)cyclopropylformamide

[0500] The absolute stereochemistry of each instance is undetermined.

[0501] Step 1: N-methyl-N-((1) S )-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6) H -Cyclopenta[ e ]pyrazolo[1,5- a ]pyrimidin-6-yl)phenyl)ethyl)cyclopropionamide

[0502] To (1) S 2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethane-1-amine (A1-7, 28 mg, 0.07 mmol) was added to a stirred solution in DCM (1.5 mL) with DIPEA (46 mg, 0.36 mmol) and cyclopropaneformyl chloride (15 mg, 0.14 mmol) and stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (SiO2, PE / EA = 4 / 1) to give a mixture of diastereomers of the title compound as a white solid (20 mg, 61% yield). LCMS: m / z 461.1 [M+H] + .

[0503] Step 2: Separate the diastereomers to obtain Examples 3 and 4.

[0504] N-methyl-N-((1 S )-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6) H -Cyclopenta[e ]pyrazolo[1,5- a Pyrimidin-6-yl)phenyl)ethyl)cyclopropanecarboxamide (20 mg, 0.04 mmol) was separated by SFC (column: IG-3 4.6 x 100 mm, 3 μm; eluent: CO2 / EtOH (1% NH3 (7 M in MeOH)) = 75 / 25) to give Example 3 (RT: 1.213 min, 6.84 mg) and Example 4 (RT: 1.357 min, 6.31 mg) as white solids.

[0505] Example 3: 1 H NMR (400 MHz, DMSO- d 6) 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 / z461.0 [M+H] + .

[0506] Example 4: 1 H NMR (400 MHz, DMSO- d 6) 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 / z461.1 [M+H] + .

[0507] Method A3

[0508] Examples 5 and 6: N-methyl-N-(( S )-2,2,2-trifluoro-1-(4-(( R)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[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-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0509] The absolute stereochemistry of each instance is undetermined.

[0510] Step 1: N-methyl-N-((1) S )-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6) H -Cyclopenta[ e ]pyrazolo[1,5- a Pyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide

[0511] To (1) S 2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethane-1-amine (Al-7, 60 mg, 153 μmol) was added to a stirred solution of DIEA (40 mg, 306 μmol) in DCM (5 mL). 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 adding water (10 mL), and the resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a mixture of diastereomers of the title compound as a grayish-white solid (40 mg, 51% yield). LC-MS: m / z 505 [M+H] + .

[0512] Step 2: Separate the diastereomers to obtain Examples 5 and 6.

[0513] 40 mg of N-methyl-N-((1 S )-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6) H -Cyclopenta[ e ]pyrazolo[1,5- aPyrimidin-6-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide (20 mg, 0.04 mmol) was purified by chiral HPLC (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: 20 mL / min; Gradient: 10% isocratic mobile phase B; Wavelength: 254 / 220 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 give Example 5 (16 mg) as a grayish-white solid. The second eluting isomer was concentrated and lyophilized to give Example 6 (17 mg, 20% yield) as a grayish-white solid.

[0514] Example 5: 1 H NMR (400 MHz, DMSO- d 6) 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] + .

[0515] Example 6: 1 H NMR (400 MHz, DMSO- d 6) 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] + .

[0516] Method A4

[0517] Example 7: N-methyl-N-((1 S )-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)oxetane-3-carboxamide

[0518] Step 1: Oxybutane-3-carbonyl chloride

[0519] The mixture of oxetane-3-carboxylic acid (200 mg, 1.96 mmol) and DMF (12 μL, 0.16 mmol) in SOCl2 (5 mL) was degassed three times under vacuum / nitrogen and stirred at 80 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude title compound (230 mg) as a yellow oil, which was used directly in the next step.

[0520] Step 2: Example 7

[0521] To (1) S 2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-N-methylethane-1-amine (Al-7, 95 mg, 242 μmol) was added to a stirred solution in DCM (5 mL) with DIEA (112 mg, 484 μmol). Oxycyclobutane-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 adding water (10 mL), and the resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC using 30% petroleum ether and 70% ethyl acetate as eluents to obtain a crude product, which was further purified by preparative HPLC to obtain Example 7 (a mixture of diastereomers, 3 mg, 3% yield) as a grayish-white solid.

[0522] Example 7: 1 H NMR (400 MHz, DMSO- d 6) 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] + .

[0523] Method A5

[0524] Examples 8, 9, 10, 11: N-methyl-N-(( S )-2,2,2-trifluoro-1-(5-(( S )-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiaran-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-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiaran-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-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiaran-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-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0525] The absolute stereochemistry of each instance is undetermined.

[0526] Step 1: ( R )-N-((5-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

[0527] 5-bromopyridinecarboxaldehyde (17 g, 91.4 mmol) was added at 80 °C. R A mixture of 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 for 2 hours. The reaction mixture was cooled to 25 °C and quenched by adding water (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 800 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 60% petroleum ether and 40% ethyl acetate as eluents to give the title compound (20 g, 64% yield) as a white solid. LC-MS: m / z 289 [M+H] + .

[0528] Step 2: ( R )-N-(( S )-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide

[0529] At 25℃, ( R A mixture of 5-((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 for 30 min. TMSCF3 (2.0 g, 13.7 mmol) was added at -78 °C and the mixture was stirred at 25 °C for 16 h. The reaction was quenched by adding water (50 mL), and the resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% petroleum ether and 50% ethyl acetate as eluents to give the title compound (600 mg, 55% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ8.78 (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] + .

[0530] Step 3: ( S 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethane-1-amine

[0531] At 25℃, ( R )-N-(( S A mixture of 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (1 g, 2.8 mmol) in HCl (4 M in dioxane, 15 mL) was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (1.2 g, 84% yield, 50% purity). LC-MS: m / z 255 [M+H] + .

[0532] Step 4: N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)formamide

[0533] At 110℃ ( S A mixture of 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethane-1-amine (1.2 g, 4.7 mmol) and formic acid (1 g, 20.8 mmol) in toluene (10 mL) was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% petroleum ether and 50% ethyl acetate as eluents to give a racemic mixture of the title compound as a white solid (650 mg, 44% yield). 1 H 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] + .

[0534] Step 5: 1-(5-bromopyridin-2-yl)-2,2,2-trifluoro-N-methylethane-1-amine

[0535] A mixture of N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)formamide (690 mg, 2.4 mmol) and borane-dimethyl sulfide complex (188 mg, 2.4 mmol) in THF (15 mL) was stirred for 16 hours at 25 °C. The reaction was quenched by adding water (30 mL) and the mixture was extracted with ethyl acetate (3 x 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 silica gel column chromatography using 50% petroleum ether and 50% ethyl acetate as eluents to give the title compound (90 mg, 12% yield) as a white solid. LC-MS: m / z 269 [M+H] + .

[0536] Step 6: N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0537] DIEA (115 mg, 892 μmol) and tetrahydro-2H-thiaran-4-carbonyl chloride 1,1-dioxide (117 mg, 594.7 μmol) were added to a mixture of 1-(5-bromopyridin-2-yl)-2,2,2-trifluoro-N-methylethane-1-amine (80 mg, 297 μmol) in DCM (10 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched by adding water (10 mL), and the resulting mixture was extracted with DCM (3 x 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 silica gel column chromatography using 80% petroleum ether and 20% ethyl acetate as eluents to give the title compound as a white solid (90 mg, 63% yield). LC-MS: m / z 429 [M+H] + .

[0538] Step 7: N-methyl-N-(2,2,2-trifluoro-1-(5-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0539] A mixture of N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide (80 mg, 186 μmol), 1,3-dioxoisoindoline-2-yl-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[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 for 2 h under a blue LED (450 nm) at 25 °C under nitrogen atmosphere. The reaction was quenched by adding water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography on a C18 column using 40% water (0.1% FA) and 60% acetonitrile as eluent to give 180 mg of crude product. This crude product was further purified by preparative HPLC to give a mixture of all stereoisomers of the title compound as a white solid (28 mg, 26% yield). LC-MS: m / z 554 [M+H] + .

[0540] Step 8: Separate the stereoisomers to obtain Examples 8, 9, 10 and 11.

[0541] 30 mg of N-methyl-N-(2,2,2-trifluoro-1-(5-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide (30 mg, 54 μmol) was purified by chiral HPLC (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: 20 mL / min; Gradient: isocratic 25% mobile phase B; Wavelength: 254 / 220 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 give Example 8 (4.2 mg, 14% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 9 (4.0 mg, 13% yield) as a white solid. The third eluting isomer was concentrated and lyophilized to give Example 10 (3.5 mg, 11% yield) as a white solid. The fourth eluting isomer was concentrated and lyophilized to give Example 11 (3.7 mg, 12.2% yield) as a white solid.

[0542] Example 8: 1 H 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] + .

[0543] Example 9: 11H 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] + .

[0544] Example 10: 1 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] + .

[0545] Example 11: 1 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] + .

[0546] Method A6

[0547] Examples 12 and 13: N-methyl-N-(( S )-2,2,2-trifluoro-1-(3-fluoro-5-(( S )-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiaran-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-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0548] The absolute stereochemistry of each instance is undetermined.

[0549] Step 1: ( R )-N-((5-bromo-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

[0550] Add ( ) to a stirred solution of 5-bromo-3-fluoro-pyridine-2-carboxaldehyde (19 g, 93.1 mmol) in DCM (100 mL) 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 adding water (200 mL), and the resulting mixture was extracted with DCM (3 x 200 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 using 80% PE and 20% EtOAc as eluents to give the title compound (25 g, 87% yield) as a yellow solid. LC-MS: m / z 307 [M+H] + .

[0551] Step 2: ( R )-N-[(1 S )-1-(5-bromo-3-fluoro-2-pyridyl)-2,2,2-trifluoro-ethyl]-2-methyl-propane-2-sulfinamide

[0552] Towards( R200 mg (651 μmol) of 5-bromo-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (200 mg, 651 μmol) was added to a stirred solution of THF (5 mL) with 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 added dropwise at -78 °C, and the mixture was stirred at -78 °C for 1 h. The reaction was quenched by adding water (10 mL), and the resulting mixture was extracted with ethyl acetate (3 x 10 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 using 90% PE and 10% EtOAc as eluents to give the title compound (135 mg, 55% yield) as a yellow solid. LC-MS: m / z 377 [M+H] + .

[0553] Step 3: ( S 1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethane-1-amine

[0554] At 25℃, ( R )-N-[(1 S A mixture of 1-(5-bromo-3-fluoro-2-pyridyl)-2,2,2-trifluoro-ethyl]-2-methyl-propane-2-sulfinamide (1 g, 2.65 mmol) in HCl (4 M in dioxane, 20 mL) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give the crude title compound (1 g), which was used in the next step without further purification. LC-MS: m / z 273 [M+H] + .

[0555] Step 4: ( S )-N-(1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)formamide

[0556] At 110℃ ( S A mixture of 1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethane-1-amine (1 g, 3.7 mmol) and formic acid (1 g, 22.0 mmol) in toluene (10 mL) was stirred for 2 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 60% PE and 40% EtOAc as eluents to give the title compound (600 mg, 54% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ9.56 (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] + .

[0557] Step 5: ( S 1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoro-N-methylethane-1-amine

[0558] At 25℃, ( S A mixture of 1-N-(1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)formamide (600 mg, 2.0 mmol) and borane-dimethyl sulfide complex (157 mg, 2.0 mmol) in THF (12 mL) was stirred for 2 hours. The reaction was quenched by adding water (30 mL) and the mixture was extracted with ethyl acetate (3 x 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 using 80% petroleum ether and 20% ethyl acetate as eluents to give the title compound (150 mg, 26% yield) as a colorless oil. LC-MS: m / z 287 [M+H] + .

[0559] Step 6: ( S )-N-(1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0560] Towards( S DIEA (54 mg, 418 μmol) and tetrahydro-2H-thiaran-4-carbonyl chloride 1,1-dioxide (41 mg, 209 μmol) were added to a mixture of 1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoro-N-methylethane-1-amine (40 mg, 139 μmol) in DCM (2 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding water (10 mL), and the resulting mixture was extracted with DCM (3 x 20 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 using 50% petroleum ether and 50% ethyl acetate as eluents to obtain the title compound as a white solid (20 mg, 29% yield). LC-MS: m / z 447 [M+H] +.

[0561] Step 7: Examples 12 and 13

[0562] Under nitrogen atmosphere at 25°C, ( S A mixture of 1,1-(1-(5-bromo-3-fluoropyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide (140 mg, 313 μmol), 1,3-dioxoisoindoline-2-yl-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[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 for 2 h under blue LED (450 nm) irradiation. The reaction was quenched by adding water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 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 using 95% petroleum ether and 5% ethyl acetate as eluents to give two diastereomers. The first eluted diastereomer was further purified by preparative HPLC to give Example 12 (12.3 mg, 6% yield) as a white solid. The second eluted diastereomer was further purified by preparative HPLC to give Example 13 (18.7 mg, 10% yield) as a white solid. Chiral SFC characterization (column: (S,S)-Whelk-O1 4.6) 50 mm, 3 μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% DEA); Flow rate: 2 mL / min; Gradient: from 10% to 50% mobile phase B in 2.0 min, held at 50% mobile phase B for 1.0 min; Column temperature (°C): 35; Back pressure (psi): 1500; Wavelength: 220 nm: Example 13 (RT1 = 1.49 min) and Example 12 (RT2 = 1.60 min).

[0563] Example 12: 1 H 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] + .

[0564] 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, δ ) 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] + .

[0565] Method A7

[0566] Examples 14 and 15: 2-(( S )-2,2,2-trifluoro-1-(4-(( R )-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)-8-oxa-2-azaspiro[4,5]decane-1-one; 2-(( S )-2,2,2-trifluoro-1-(4-(( S )-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)-8-oxa-2-azaspiro[4,5]decane-1-one

[0567] The absolute stereochemistry of each instance is undetermined.

[0568] Step 1: (1 S 1-(4-bromophenyl)-2,2,2-trifluoroethylamine (A7-1)

[0569] At 0℃, ( R )-N-(( SA mixture of 1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (A1-1, 8 g, 22.33 mmol) and HCl (4 M in MeOH, 78.16 mL) in MeOH (80 mL) was stirred for 2 hours. 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 give 8 g of material, which was further purified by reversed-phase rapid chromatography (column, C18 silica gel; mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (20% to 75% within 25 min); detector: UV 254 nm) to give the title compound (A7-1, 4.7 g, 83% yield) as a pale yellow solid. LC-MS: m / z 253.9 [M+H] + .

[0570] Step 2: Methyl 4-allyltetrahydro-2H-pyran-4-carboxylate

[0571] LDA (104 mL, 2.0 M in THF) was added dropwise to a stirred mixture of methyl tetrahydro-2H-pyran-4-carboxylate (20 g, 14 mmol) in THF (200 mL) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 30 min. 3-Bromoprop-1-ene (25.0 g, 208 mmol) was added dropwise at -78 °C under a nitrogen atmosphere, and the mixture was stirred at -78 °C for 1 h. The mixture was warmed to 0 °C and acidified to pH 2 at 0 °C using HCl (10%). The mixture was extracted with ethyl acetate (3 x 800 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, eluting with PE / THF (5:1) to give the title compound (23 g, 72% yield) as a pale yellow oil. GC-MS (ES) m / z: 184 [M].

[0572] Step 3: Methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate

[0573] Osmium tetroxide (1.38 g, 5.43 mmol) was added 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 isopropanol (200 mL) and water (200 mL). The resulting mixture was stirred at 20 °C for 6 h. The reaction was quenched by adding ice water (500 mL), and the mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (9.0 g, 71% yield) as a brown oil. GC-MS (ES) m / z: 186 [M].

[0574] Step 4: ( S methyl 4-(2-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)ethyl)tetrahydro-2H-pyran-4-carboxylate

[0575] To (1) S 1-(4-bromophenyl)-2,2,2-trifluoroethylamine (A7-1, 500 Mg, 1.97 mmol) was added to a stirred mixture in DCM (10 mL) along with 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 triacetoxyborohydride (625 mg, 2.9 mmol) was added in portions at 0 °C, and the mixture was stirred at 25 °C for 16 h under a nitrogen atmosphere. The reaction was quenched by adding ice water (100 mL), and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / THF (1:1) to give the title compound (500 mg, 45% yield) as a yellow oil. LC-MS: m / z 424 [M+H] + .

[0576] Step 5: ( S )-4-(2-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)ethyl)tetrahydro-2H-pyran-4-carboxylic acid

[0577] Towards( SMethyl 4-(2-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)ethyl)tetrahydro-2H-pyran-4-carboxylate (280 mg, 659 μmol) was reacted with a mixture of LiOH (158 mg, 6.6 mmol) in water (2 mL) and stirred in MeOH (2 mL) and THF (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 reversed-phase rapid chromatography to give the title compound (148 mg, 43% yield) as a grayish-white solid. LC-MS: m / z 410 [M+H] + .

[0578] Step 6: ( S )-2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-8-oxa-2-azaspiro[4.5]decane-1-one

[0579] Towards( S HATU (332 mg, 876 μmol) and DIEA (151 mg, 1170 μmol) were added to a stirred mixture of 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). The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched by adding ice water (30 mL). The mixture was extracted with ethyl acetate (3 x 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, eluting with PE / THF (1:1) to give the title compound (160 mg, 59% yield) as a yellow oil. LC-MS: m / z 392 [M+H] + .

[0580] Step 7: 2-((1) S )-2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)-8-oxa-2-azaspiro[4,5]decane-1-one

[0581] Under nitrogen atmosphere at 25°C, ( SA mixture of 2-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-8-oxa-2-azaspiro[4.5]decane-1-one (100 mg, 254 μmol), 1,3-dioxoisoindoline-2-yl-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[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 for 2 h under blue LED (450 nm) irradiation. The reaction mixture was quenched by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a mixture of diastereomers of the title compound as a white solid (40 mg, 29% yield). LC-MS: m / z 517 [M+H] + .

[0582] Step 8: Separate the diastereomers to obtain Examples 14 and 15.

[0583] 40 mg 2-((1 S Chiral HPLC purification of 2,2,2-trifluoro-1-(4-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)ethyl)-8-oxa-2-azaspiro[4.5]decane-1-one was performed (column: CHIRAL ART Cellulose-SJ, 2x25 cm, 5 μm; mobile phase A: Hex--HPLC, mobile phase B: EtOH: DCM=1: 1-HPLC; flow rate: 20 mL / min; gradient: isocratic 8% mobile phase B; wavelength: 254 / 220 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 give Example 14 (21.9 mg, 16% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 15 (20.2 mg, 15% yield) as a white solid.

[0584] 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] + .

[0585] Example 15: 1 H 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] + .

[0586] Method A8

[0587] Examples 16 and 17: N-methyl-N-(( S )-2,2,2-trifluoro-1-(6-(( R)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiaran-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-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0588] The absolute stereochemistry of each instance is undetermined.

[0589] Step 1: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethane-1-ol

[0590] CsF (82 mg, 538 μmol) and trimethyl(trifluoromethyl)silane (2.3 g, 16.1 mmol) were added to a solution of 6-bromonicaraldehyde (2 g, 10.7 mmol) in DME (30 mL). The reaction mixture was stirred at 0 °C for 16 h under a nitrogen atmosphere. The reaction was quenched by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was redissolved in DCM (30 mL) and TFA (10 mL) was added. The reaction mixture was stirred at 25 °C for 16 h under a nitrogen atmosphere. The reaction was quenched by adding 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 was purified by silica gel column chromatography using 50% petroleum ether and 50% ethyl acetate as eluents to give the title compound (2.5 g, 91% yield) as a colorless oil. LC-MS: m / z 256 [M+H] + .

[0591] Step 2: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethane-1-one

[0592] IBX (8.2 g, 14.6 mmol) was added to a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethane-1-ol (2.5 g, 9.8 mmol) in ethyl acetate (50 mL). The resulting mixture was stirred at 80 °C for 16 h. The reaction was quenched with saturated aqueous NaHSO3 solution (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 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 preparative HPLC to give the title compound (1.6 g, 64% yield) as a white solid. LC-MS: m / z 272 [M+H2O+1] + .

[0593] Step 3: ( R )-N-(( S )-1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide

[0594] Add ( ) to a mixture of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethane-1-one (2 g, 7.8 mmol) in THF (50 mL) R 2-Methylpropane-2-sulfinamide (1.2 g, 9.5 mmol) and tetraisopropyl titanate (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 obtain a solution. Tri-sec-butylborohydride (1 M, 12 mL) was added at -78 °C under a nitrogen atmosphere, and the mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched by adding ice water (100 mL) and warmed to 10 °C. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography to give the title compound (1.1 g, 39% yield) as a white solid. LC-MS: m / z 359 [M+H] + .

[0595] Step 4: ( R )-N-(( S )-1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide

[0596] At 0℃, towards ( R )-N-(( S1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.6 mmol) was added dropwise to a solution of THF (20 mL) with LHMDS (1 M, 2.0 mL). The mixture was stirred at 0 °C for 0.5 h. Iodimethane (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 a saturated aqueous solution of 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 (2 x 20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography to give the title compound (270 mg, 43% yield) as a white solid. LC-MS: m / z 373 [M+H] + .

[0597] Step 5: ( R )-N,2-dimethyl-N-((1 S )-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide

[0598] Towards( R )-N-(( S )-1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (50 mg, 134 μmol) was added to a solution of (Ir[DF(CF3)PPY]2(DTBPY))PF6 (1.5 mg, 1.3 μmol) and 4,4'-di tertButyl-2,2'-bipyridine (5.4 mg, 20 μmol), NiCl2 glycol dimethyl ether (2.9 mg, 13.4 μmol), 2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[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 nitrogen atmosphere and irradiation with a blue LED (450 nm). 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 (3 x 20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% petroleum ether and 50% ethyl acetate as eluents to give a mixture of diastereomers of the title compound as a yellow solid (25 mg, 39% yield). LC-MS: m / z 498 [M+H] + .

[0599] Step 6: (1) S )-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)-N-methylethane-1-amine

[0600] At 25℃, ( R )-N,2-dimethyl-N-((1 S A solution of 2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (25 mg, 50 μmol) in HCl (2 mL, 4 M in 1,4-dioxane solution) was stirred for 1 hour. 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 (2 x 10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a mixture of diastereomers of the title compound as a yellow solid (15 mg, 76% yield). LC-MS: m / z 394 [M+H] + .

[0601] Step 7: N-methyl-N-((1) S)-2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0602] At 0℃ towards (1 S 2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)-N-methylethane-1-amine (15 mg, 38 μmol) was added to a stirred solution of DIEA (15 mg, 114 μmol) in DCM (3 mL). Tetrahydro-2H-thiaran-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 adding water (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a mixture of diastereomers of the title compound as a white solid (1.8 mg, 8% yield). LC-MS: m / z 554 [M+H] + .

[0603] Step 8: Separate the diastereomers to obtain Examples 16 and 17.

[0604] 22 mg of N-methyl-N-((1 S 1,1-dioxide of 2,2,2-trifluoro-1-(6-(2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide was purified by chiral HPLC (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: 20 mL / min; Gradient: 30% isocratic mobile phase B; Wavelength: 254 / 220 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 give Example 17 (5.2 mg, 23% yield) as a white solid. The second eluting isomer was concentrated and lyophilized to give Example 16 (3.8 mg, 17% yield) as a white solid.

[0605] Example 17: 1 H NMR (400 MHz, DMSO- d 6) 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] + .

[0606] Example 16: 1 H NMR (400 MHz, DMSO- d 6) δ 8.51 (d, J = 2.0 Hz, 1H), 8.32 (s,1H), 7.85 (dd, J = 2.0, 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.59-6.66 (m,1H), 6.52 (d, J = 5.2 Hz, 1H), 4.86 (t, J = 8.0 Hz, 1H), 3.09-3.32 (m, 5H), 2.94 (s, 3H), 2.60-2.68 (m, 1H), 2.22-2.27 (m, 1H), 1.91-2.08 (m, 4H), 1.62(s, 3H), 1.54(s, 3H) LC-MS: m / z 554 [M+H] + .

[0607] Method A9

[0608] Examples 18 and 19: N-methyl-N-(( S )-2,2,2-trifluoro-1-(5-fluoro-6-(( S)-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide; N-methyl-N-(( S )-2,2,2-trifluoro-1-(5-fluoro-6-(( R )-2-fluoro-8,8-dimethyl-7,8-dihydro-6H-cyclopentano[e]pyrazolo[1,5-a]pyrimidin-6-yl)pyridin-3-yl)ethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide

[0609] The absolute stereochemistry of each instance is undetermined.

[0610] Step 1: ( R )-N-((6-chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide

[0611] Add ( ) to the stirred mixture of 6-chloro-5-fluoronicotinaldehyde (7.0 g, 43.9 mmol) in DCM (100 mL) R 2-Methylpropane-2-sulfinamide (6.4 g, 52.6 mmol) and Cs₂CO₃ (42.9 g, 131.6 mmol). The resulting mixture was stirred at 25 °C for 3 h under a nitrogen atmosphere. The reaction was quenched by adding water (1.0 L), and the resulting mixture was extracted with DCM (3 x 1.0 L). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% PE and 50% EtOAc as eluents to give the title compound (10.0 g, 82% yield) as a white solid. LC-MS: m / z 263 [M+H] + .

[0612] Step 2: ( R )-N-(( S )-1-(6-chloro-5-fluoropyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide

[0613] Towards( RTetrabutylammonium difluorotriphenylsilicate (61.6 g, 114.2 mmol) was added dropwise to a stirred mixture of 10.0 g (38.1 mmol) of 6-chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide in THF (90.0 mL). The resulting mixture was stirred at 25 °C for 0.5 h under a nitrogen atmosphere. The mixture was cooled to -78 °C. TMSCF3 (16.2 g, 114.2 mmol) was added dropwise, and the resulting mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere. The mixture was warmed to room temperature and the reaction was quenched by adding water (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 500 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 using 60% PE and 40% EtOAc as eluents to give the title compound as...

Claims

1. A compound of formula (I): ， (I) Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 1 It is H, halogenated, or C1-C3 alkyl; R 2 It is H, halogenated, or C1-C3 alkyl; R 0 R 3 and R 4 The definition is as follows: (i)R 0 It is H; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 0 It is H; and R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; or (iii)R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups; and R 4 It is a C1-C6 alkyl group; R 5 It is H or halogenated; R 6 It is H or halogenated; and R 7 and R 8 The definition is as follows: (i)R 7 It is a C1-C6 alkyl group; and R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups; or (ii)R 7 and R 8 Together with the atoms to which they are attached, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygen groups; The premise is that at most one of X and Y is N.

2. The compound according to claim 1, wherein the compound has the formula (I-1): ， (I-1) Or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2, wherein the compound has formula (I-2a): ， (I-2a) Or its pharmaceutically acceptable salt.

4. The compound according to claim 1 or 2, wherein the compound has the formula (I-2b): ， (I-2b) Or its pharmaceutically acceptable salt.

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

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

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

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

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

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

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

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 2 It is F.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 3 Is it CH3, CF3 or .

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 4 It is CH3.

16. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups.

17. The compound according to claim 16, wherein R 3 and R 4 Or, or their pharmaceutically acceptable salts, together with the carbon atoms to which they are attached, form cyclopropyl or cyclobutyl.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 0 It is H.

19. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups.

20. The compound according to claim 19, wherein R 0 and R 3 Or, or a pharmaceutically acceptable salt thereof, together with the carbon atom to which they are attached, form a cyclobutyl group, and R 4 It is CH3.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 It is H or F.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 6 It is H or F.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 7 It is a C1-C6 alkyl group.

24. The compound according to claim 23, wherein R 7 It is CH3.

25. The compound according to any one of claims 1 to 24, wherein R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups.

26. The compound according to claim 25, wherein R 8 yes , , , or .

27. The compound according to any one of claims 1 to 22, wherein R 7 and R 8 Together with the atoms to which they are attached, they form 5-12 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-2 oxygens.

28. The compound according to claim 1, wherein the compound has the formula (IA): ， (IA) Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 0 R 3 and R 4 The definition is as follows: (i)R 0 It is H; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a 4-7 heteroaryl, wherein the heteroaryl is optionally substituted by one C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 0 It is H; and R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; or (iii)R 0 and R 3 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups; and R 4 It is a C1-C6 alkyl group; R 5 It is H or halogenated; R 6 It is H or halogenated; and R 8 It is a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1-2 oxygen groups; and The premise is that at most one of X and Y is N.

29. The compound according to claim 28, wherein the compound has the formula (IA-1): ， (IA-1) Or its pharmaceutically acceptable salt.

30. The compound according to claim 28 or 29, wherein the compound has the formula (IA-2a): ， (IA-2a) Or its pharmaceutically acceptable salt.

31. The compound according to claim 28 or 29, wherein the compound has the formula (IA-2b): ， (IA-2b) Or its pharmaceutically acceptable salt.

32. The compound according to claim 1, wherein the compound has the formula (IB): (IB) Or its pharmaceutically acceptable salt, wherein: X is CH, CF, or N; Y is CH, CF, or N; R 3 and R 4 The definition is as follows: (i)R 3 It is a C1-C6 alkyl or a C1-C6 haloalkyl; and R 4 It is a C1-C6 alkyl group; or (ii)R 3 and R 4 Together with the carbon atoms they are attached to, they form C3-C7 cycloalkyl groups or 4-7 membered heterocyclic groups; R 5 It is H or halogenated; R 6 It is H or halogenated; and R 9 and R 10 These atoms are linked together with the carbon atoms to form 4-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with 1-2 oxygen atoms. The premise is that at most one of X and Y is N.

33. The compound according to claim 32, wherein the compound has the formula (IB-1): ， (IB-1) Or its pharmaceutically acceptable salt.

34. The compound according to claim 32 or 33, wherein the compound has the formula (IB-2a): ， (IB-2a) Or its pharmaceutically acceptable salt.

35. The compound according to claim 32 or 33, wherein the compound has the formula (IB-2b): ， (IB-2b) Or its pharmaceutically acceptable salt.

36. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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