Combination therapy using a malt1 inhibitor and a BTK inhibitor

Abstract

The present disclosure is directed to a combination therapy comprising an inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein and an inhibitor of BTK, and methods of use thereof.

Description

[0001] COMBINATION THERAPY USING A MALT1 INHIBITOR AND A BTK INHIBITOR TECHNICAL FIELD The present disclosure is directed to a combination therapy comprising an inhibitor of mucosa- associated lymphoid tissue lymphoma translocation protein and an inhibitor of a BTK inhibitor, and methods of use thereof. BACKGROUND MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and has been shown to play a critical role in different types of lymphoma, including activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). MALT1 is the only human paracaspase that transduces signals from the B cell receptor (BCR) and T cell receptor (TCR). MALT1 is the active subunit of the CBM complex which is formed upon receptor activation. The “CBM complex” consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B-cell CLL / Lymphoma 10), and MALT1. MALT1 affects NF-κB signaling by two mechanisms: firstly, MALT1 functions as a scaffolding protein and recruits NF-κB signaling proteins such as TRAF6, TAB-TAKl or ΝΕΜΟ-ΙΚΚα / β; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NF- κB signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the FKB transcription factor complex and activation of FKB signaling. Non-Hodgkin lymphoma represents a diverse set of diseases, of which more than 60 subtypes have been identified. Worldwide, DLBCL represents the most common subtype of NHL, accounting for 30% to 40% of all newly diagnosed cases. DLBCL typically presents as an aggressive lymphoma, evolving over months and resulting in symptomatic disease that is fatal without treatment (Ibid). Constitutive activation of NF-κB signaling is the hallmark of ABC-DLBCL (Diffuse Large B Cell Lymphoma of the Activated B Cell-like subtype), the more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% of lymphoma cases while ABC-DLBCL comprises approximately 40% of DLBCL. NF-κB pathway activation is driven by mutations of signaling components, such as CD79A / B, CARD11, MYD88 or A20, in ABC-DLBCL patients. Outcomes in DLBCL have improved dramatically over the last decade with the addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R CHOP). This regimen remains the current standard of care. However, R CHOP treatment fails in about 30% to 50% of patients with DLBCL. Less than half of these patients can be cured with stem cell transplantation, and those who are not cured will typically die from their disease. Since the best chance for cure is front-line treatment, there have been many attempts to improve upon R CHOP but so far, these treatments have failed to significantly improve outcomes. Recently, several studies have explored the addition of targeted agents to R CHOP in front-line treatment. Promising signs of activity in some of these studies encourage the further exploration of combinations that may improve cure rate of targeted agents in select patients. Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective. Follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) and Waldenström macroglobulinemia (WM) are considered largely incurable lymphomas that require therapies throughout the course of disease. Currently, there are limited lines of therapy available for these diseases, and treatments are needed that avoid the use of cytotoxic chemotherapy. The use of BTK inhibitors, for example Ibrutinib, provides clinical proof-of-concept that inhibiting NFΚB signaling in ABC-DLBCL is efficacious. MALT1 is downstream of BTK in the NFKB signaling pathway and a MALT1 inhibitor could target ABC-DLBCL patients not responding to Ibrutinib, mainly patients with CARD11 mutations, as well as treat patients that acquired resistance to Ibrutinib. Small molecule tool compound inhibitors of MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL. Interestingly, covalent catalytic site and allosteric inhibitors of MALT1 protease function have been described, suggesting that inhibitors of this protease may be useful as pharmaceutical agents. The chromosomal translocation creating the API2 -MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa-associated lymphoid tissue) lymphoma. API2 -MALT1 is a potent activator of the NF^B pathway. API2-MALT1 mimics ligand-bound TNF receptor and promotes TRAF2-dependent ubiquitination of RIP1 which acts as a scaffold for activating canonical NF^B signaling. Furthermore, API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NF^B-inducing kinase (NIK) thereby activating the non-canonical FKB pathway. In addition to lymphomas, MALT1 has been shown to play a critical role in innate and adaptive immunity. MALT1 protease inhibitor can attenuate disease onset and progression of mouse experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. Mice expressing catalytically inactive MALT1 mutant showed loss of marginal zone B cells and B1B cells and general immune deficiency characterized as decreased T and B cell activation and proliferation. However, those mice also developed spontaneous multi-organ autoimmune inflammation at the age of 9 to 10 weeks. It is still poorly understood why MALT1 protease dead knock-in mice show a break of tolerance while conventional MALT1 KO mice do not. One hypothesis suggests the unbalanced immune homeostasis in MALT1 protease dead knock-in mice may be caused by incomplete deficiency in T and B cell but severe deficiency of immunoregulatory cells. Similarly, MALT deficiency in humans has been associated with combined immunodeficiency disorder. Given the difference between genetic mutation and pharmacological inhibition, a phenotype of MALT1 protease dead knock-in mice might not resemble that of patients treated with MALT1 protease inhibitors. A reduction of immunosuppressive T cells by MALT1 protease inhibition may be beneficial to cancer patients by potentially increasing antitumor immunity. Thus, MALT1 inhibitors may provide a therapeutic benefit to patients suffering from cancer and / or immunological diseases. MALT1 inhibition can be effective in the treatment of ABC DLBCL and other DLBCL subtypes, MALT lymphoma, as well as CLL, MCL, and WM tumors, including tumors that are resistant to a Bruton tyrosine kinase inhibitor (BTKi). In addition, MALT1 inhibitors used together with a BTKi may provide a therapeutic benefit to patients suffering from cancers and / or immunological diseases. Nagel et al. determined that “[c]ombined inhibition of BTK by Ibrutinib and MALT1 by S-Mepazine additively impaired MALT1 cleavage activity and expression of NF-κB pro-survival factors. Thereby, combinatorial Ibrutinib and S- Mepazine treatment enhanced killing of CD79 mutant ABC DLBCL cells.” Nagel et al., Oncotarget 2015, 6, 42232-42242 at Abstract. Specifically, Nagel et al. observed that “[i]n contrast to the synergistic effects observed for instance by the combination of BTK and PI3K-AKT inhibitors

[0024] , BTK and MALT1 co-treatment yielded additive effects on MALT1 activity and killing of CD79 mutant ABC DLBCL cells. It confirms that both inhibitors are primarily targeting pathological BCR- NFκB signaling.” Nagel et al., Oncotarget 2015, 6, 42239-42240. However, while BTK inhibitor ibrutinib has shown beneficial anti-tumor effects in many B cell malignancies, resistance may occur necessitating the development of further combination therapies to improve anti-tumor activity. SUMMARY A first aspect of the present disclosure is directed to a method of treating cancer or an immunological disease in a subject in need thereof. This method involves administering to the subject a combination therapy comprising: (i) (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide having the following structure of Formula (I): , therapy is administered in an amount effective to treat the cancer or immunological disease in the subject. Another aspect of the present disclosure is an inhibitor of MALT1 for use in the treatment of cancer or an immunological disease, comprising administering an inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) having the structure of Formula (I) (I) , and an inhibitor of BTK. Unless otherwise indicated or clear from the context, all references to the structure of Formula (I), Compound 3, the MALT inhibitor, and (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)- 7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N- ((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide (‘Compound 3’ or ‘the MALT1 inhibitor’), in the context of this invention, might also refer to the pharmaceutically acceptable salts and solvates (including hydrates) thereof including any subgroup thereof or any combination of pharmaceutically acceptable salts and solvates thereof, even if not explicitly referred to, and are included in the scope of the present invention. Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with an inhibitor of BTK. Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with an inhibitor of BTK for use in the treatment of cancer or an immunological disease . Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in the treatment of cancer or an immunological disease, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide is used in combination with an inhibitor of BTK. Another aspect of the present disclosure is a combination comprising (1S,3R)-3-(4-((R)-2- chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and an inhibitor of BTK for use in the treatment of cancer or an immunological disease. Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and an inhibitor of BTK for use in the treatment of cancer or an immunological disease. Another aspect of the present disclosure is a combination comprising (1S,3R)-3-(4-((R)-2- chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and an inhibitor of BTK. Another aspect of the present disclosure is a combination therapy comprising (1S,3R)-3-(4- ((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin- 6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and an inhibitor of BTK for use in the treatment of cancer or an immunological disease. Another aspect of the present disclosure is a combination therapy comprising (1S,3R)-3-(4- ((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin- 6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and an inhibitor of BTK. Another aspect of the present disclosure is the use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide in the manufacture of a medicament for use in treating cancer or an immunological disease, wherein the medicament is for co-administration with an inhibitor of BTK. Another aspect of the present disclosure is the use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide in the manufacture of a medicament for treating cancer or an immunological disease, wherein the medicament is to be administered in combination with an inhibitor of BTK. Another aspect of the present disclosure is the use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for the manufacture of a medicament for the treatment of cancer or an immunological disease in a subject, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide (the MALT1 inhibitor) is adapted to be administrable to the subject in combination with an inhibitor of BTK, wherein the MALT1 inhibitor and the inhibitor of BTK are formulated and adapted to be administrable to the subject in separate compositions, and wherein the MALT1 inhibitor is in form of oral dosage. Another aspect of the present disclosure is the use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for the manufacture of a medicament for the treatment of cancer or an immunological disease in a subject, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide (the MALT1 inhibitor) is adapted to be administrable to the subject in combination with an inhibitor of BTK, wherein the MALT1 inhibitor and the inhibitor of BTK are administered in amounts that are therapeutically effective together, and wherein the MALT1 inhibitor and the inhibitor of BTK are administered together in a single dosage form or in separate dosage forms. Another aspect of the present disclosure is the use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide in combination with an inhibitor of BTK, for use in the treatment of cancer or an immunological disease . Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in co- administration with an inhibitor of BTK, for use in the treatment of cancer or an immunological disease . Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in co- administration with an inhibitor of BTK. Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co- administered with an inhibitor of BTK, for use in the treatment of cancer or an immunological disease . Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co- administered with an inhibitor of BTK. Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for co- administration with an inhibitor of BTK, for use in the treatment of cancer or an immunological disease . Another aspect of the present disclosure is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for co- administration with an inhibitor of BTK. Another aspect of the present disclosure is an inhibitor of BTK for use in the treatment of cancer or an immunological disease , comprising administering an inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) having the structure of Formula (I) (I) , and the inhibitor of BTK. In to the previous aspect, comprises a method as described in any of any one of the other embodiments and clauses described in this application. In particular, the inhibitor of BTK for use according to the previous aspects in this paragraph, comprises any one of the other limitations as described in any one of the other embodiments and clauses described in this application. Another aspect of the present disclosure is an inhibitor of BTK for use in combination with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide. Another aspect of the present disclosure is an inhibitor of BTK for use in combination with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in the treatment of cancer or an immunological disease. Another aspect of the present disclosure is an inhibitor of BTK for use in the treatment of cancer or an immunological disease, wherein the BTK inhibitor is used in combination with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide. Another aspect of the present disclosure is the use of a BTK inhibitor in the manufacture of a medicament for use in treating cancer or an immunological disease, wherein the medicament is for co-administration with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide. Another aspect of the present disclosure is the use of an inhibitor of BTK in the manufacture of a medicament for treating cancer or an immunological disease, wherein the medicament is to be administered in combination with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide. Another aspect of the present disclosure is the use of a BTK inhibitor for the manufacture of a medicament for the treatment of cancer or an immunological disease in a subject, wherein the BTK inhibitor is adapted to be administrable to the subject in combination with (1S,3R)-3-(4-((R)-2-chloro- 8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide (the MALT1 inhibitor), wherein the MALT1 inhibitor and the inhibitor of BTK are formulated and adapted to be administrable to the subject in separate compositions, and wherein the MALT1 inhibitor is in form of oral dosage. Another aspect of the present disclosure is the use of a BTK inhibitor for the manufacture of a medicament for the treatment of cancer or an immunological disease in a subject in need thereof, wherein the BTK inhibitor is adapted to be administrable to the subject in combination with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide (the MALT1 inhibitor), wherein the MALT1 inhibitor and the inhibitor of BTK are administered in amounts that are therapeutically effective together, and wherein the MALT1 inhibitor and the inhibitor of BTK are administered together in a single dosage form or in separate dosage forms. Another aspect of the present disclosure is the use of a BTK inhibitor in combination with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide, for use in the treatment of cancer or an immunological disease . Another aspect of the present disclosure is a BTK inhibitor for use in co-administration with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide, for use in the treatment of cancer or an immunological disease . Another aspect of the present disclosure is a BTK inhibitor for use in co-administration with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide. Another aspect of the present disclosure is a BTK inhibitor which is to be co-administered with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide, for use in the treatment of cancer or an immunological disease. Another aspect of the present disclosure is a BTK inhibitor which is to be co-administered with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide. Another aspect of the present disclosure is a BTK inhibitor for co-administration with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide, for use in the treatment of cancer or an immunological disease . Another aspect of the present disclosure is a BTK inhibitor for co-administration with (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide. In certain embodiments, the BTK inhibitor has the structure of Formula P-(II) (Compound B) Compound B The compound of Formula P-(II) (Compound B) is also known as N-((1R,2S)-2- acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8- triazaacenaphthylene-2-carboxamide. In some cases the compound of Formula P-(II) is also represented by the structure below: . All embodiments described herein for a method of treating, are also applicable to the other aspects listed hereabove or subgroups thereof. A further aspect of the present disclosure relates to a method of reducing levels of regulatory T cells in a subject having cancer or an immunological disease. This method involves administering, to said subject having the cancer or immunological disease, a combination therapy comprising: (i) Compound 3 and (ii) an inhibitor of BTK. In accordance with this method, the combination therapy is administered in an amount effective to reduce regulatory T cell levels in the subject relative to the levels of regulatory T cells in the subject prior to said administering. In an embodiment, the aspects and embodiments described herein or subgroups thereof are for use in the treatment of cancer or an immunological disease, whereby levels of regulatory T cells in the subject are reduced. In an embodiment, the aspects and embodiments described herein or subgroups thereof are for use in the treatment of cancer or an immunological disease, whereby levels of regulatory T cells in the subject, relative to the levels of regulatory T cells in the subject prior to administration or treatment, are reduced. In an embodiment, the aspects and embodiments described herein or subgroups thereof are for use in reducing levels of regulatory T cells in the subject. In an embodiment, the aspects and embodiments described herein or subgroups thereof are for use in reducing levels of regulatory T cells in the subject relative to the levels of regulatory T cells in the subject prior to administration or treatment. In an embodiment, the aspects and embodiments described herein or subgroups thereof are for use in reducing levels of regulatory T cells. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1: TMD8 cells were incubated with the indicated drug combination concentrations of Compound 3 and BTKi for 8 days in singlicate. Data from 3 independent experiments were pooled and analyzed. Combination effect is represented by the contour plot (Highest Single Agent (HSA) model). FIGURE 2: REC-1 cells were incubated with the indicated drug combination concentrations of Compound 3 and BTKi for 8 days in singlicate. Data from 3 independent experiments were pooled and analyzed. Combination effect is represented by the contour plot (Highest Single Agent (HSA) model). FIGURE 3: TMD8 cells were incubated with the indicated drug combination concentrations of Compound 3 and BTKi for 8 days in singlicate. Data from 3 independent experiments were pooled and analyzed. Combination effect is represented by the contour plot (generalized LOEWE model). FIGURE 4: REC-1 cells were incubated with the indicated drug combination concentrations of Compound 3 and BTKi for 8 days in singlicate. Data from 3 independent experiments were pooled and analyzed. Combination effect is represented by the contour plot (generalized LOEWE model). FIGURE 5: Effect of compound 3 and BTKi monotherapy in TMD8 cells. Data from 3 independent experiments were pooled and analyzed. FIGURE 6: Effect of compound 3 and BTKi monotherapy in REC-1 cells. Data from 3 independent experiments were pooled and analyzed. DETAILED DESCRIPTION The disclosure may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. It is to be appreciated that certain features of the disclosed compositions and methods which are, for clarity, described herein in the context of separate aspects, may also be provided in combination in a single aspect. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination. It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (for example, bodies of the appended claims) are generally intended as “open” terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to aspects containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (for example, “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of "two recitations," without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Compound 3 is (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide having the following structure of Formula (I): . Unless all references to the structure of Formula (I), Compound 3, the MALT inhibitor, and (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide (‘Compound 3’ or ‘the MALT1 inhibitor’), in the context of this invention, might also refer to the pharmaceutically acceptable salts and solvates (including hydrates) thereof including any subgroup thereof or any combination of pharmaceutically acceptable salts and solvates thereof, even if not explicitly referred to, and are included in the scope of the present invention. As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 component refers to groups having 1, 2, or 3 components. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 components, and so forth. Various of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications. Various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art, each of which is also intended to be encompassed by the disclosed aspect. The term “about” as used herein when immediately preceding a numerical value means a range of plus or minus 10% of that value, for example, “about 50” means 45 to 55, “about 25,000” means 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. An aspect of the present disclosure is directed to a method of treating cancer or an immunological disease in a subject in need thereof. The method involves administering to the subject a combination therapy comprising: (i) (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide having the following structure of Formula (I): , therapy is administered in an amount effective to treat the cancer or immunological disease in the subject. As used herein, “treating” or “treatment” of any disease, more specifically a cancer or immunological disease, refers, in some embodiments, to ameliorating the disease (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In other embodiments, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In further embodiments, “treating” or “treatment” refers to modulating the disease, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In other embodiments, “treating” or “treatment” refers to delaying the onset of the disease or recurrence of the disease. A further aspect of the present disclosure relates to a method of reducing levels of regulatory T cells in a subject having cancer or an immunological disease. This method involves administering, to said subject having the cancer or immunological disease, a combination therapy comprising: (i) Compound 3, and (ii) an inhibitor of BTK, where the combination therapy is administered to the subject in an amount effective to reduce regulatory T cell levels in the subject relative to the levels of regulatory T cells in the subject prior to said administering. As referred to herein, the terms “regulatory T cell” or “Treg” refer to T cells that suppress an abnormal or excessive immune response and play a role in immune tolerance. Regulatory T cells are typically transcription factor Foxp3-positive CD4+T cells and can also include transcription factor Foxp3- negative regulatory T cells that are IL-10-producing CD4+T cells. In some embodiments of the methods disclosed herein, administration of the combination therapy achieves at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more reduction in the amount of regulatory T cells in the subject relative to the levels of regulatory T cells in the subject prior to the administering step. Subjects suitable for treatment in accordance with the methods disclosed herein have cancer or an immunological disease. In particular cancer. The cancer may be a lymphoma, a leukemia, a carcinoma, a sarcoma, or any other known cancer . As referred to herein, a “lymphoma” is a malignant neoplasm originating from lymphocytes; a “leukemia” is a class of hematological malignancies of bone marrow cells in which immortal clones of immature blood cells multiply at the expense of normal blood cells; a “carcinoma” is a malignant tumor that occurs in epithelial tissue and may infiltrate local tissues or produce metastases; and a “sarcoma” is a cancer arising from mesenchymal tissue such as muscle or bone, which may affect the bones, bladder, kidneys, liver, lungs, parotids, and spleen. Lymphomas suitable for treatment in accordance with the methods disclosed herein include, without limitation, non-Hodgkin’s lymphoma (NHL (including B-cell NHL)), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma (MZL), T-cell lymphoma, Hodgkin’s lymphoma, small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, and Burkitt’s lymphoma. In some embodiments, the cancer is a B-Cell lymphoma. B-cell lymphomas suitable for treatment in accordance with the methods disclosed herein include, without limitation, a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt’s lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). DLBCL is an aggressive (fast-growing) NHL that affects B-lymphocytes and which can develop in the lymph nodes or in “extranodal sites” (areas outside the lymph nodes) such as the gastrointestinal tract, testes, thyroid, skin, breast, bone, brain, or essentially any organ of the body. In some embodiments, the diffuse large B-cell lymphoma (DLBCL) treated in accordance with the methods and compositions disclosed herein is activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL, or non- GCB-DLBCL. In particular the DLBCL is non-GCB-DLBCL. In particular the cancer is non-GCB- DLBCL. In some embodiments the cancer is a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, or primary intraocular lymphoma. In some embodiments, the cancer to be treated is a leukemia. Leukemias suitable for treatment in accordance with the methods disclosed herein include, without limitation, chronic lymphocytic leukemia (CLL), lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia and multiple myeloma. In an embodiment, the cancer to be treated in accordance with the methods as disclosed herein may include, without limitation, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer, non-small-cell lung cancer, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head & neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, Chronic graft versus host disease, and gastrointestinal stromal tumor. In an embodiment, the cancer to be treated in accordance with the methods as disclosed herein may include, without limitation, non-Hodgkin’s lymphoma (NHL (including B-cell NHL)), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head & neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, primary and secondary central nervous system lymphoma, transformed follicular lymphoma, diseases / cancer caused by API2-MALT1 fusion, and GIST (gastrointestinal stromal tumor). In an embodiment, the immunological diseaseses may include, without limitation, autoimmune and inflammatory disorders, e.g. sepsis-related acute lung injury (ALI), acute respiratory distress syndrome (ARDS), arthritis, rheumatoid arthritis (RA), psoriatic arthritis (PsA), inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjorgen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis. In particular, the immunological disease is selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD). Suitable subjects to be treated in accordance with the methods and compositions disclosed herein include, without limitation, mammalian subject. Exemplary mammalian subjects include, without limitation, humans, non-human primates, dogs, cats, rodents (e.g., mouse, rat, guinea pig), horses, cattle and cows, sheep, and pigs. In some embodiments, the subject is a human subject. The terms “human,” “patient,” and “subject” are used interchangeably herein. Where stereochemistry is specified by bonds which are shown as solid wedged or hashed wedged bonds, hashed or bold bonds, then that stereoisomer is so specified and defined. It will be clear for a skilled person that a hashed bond and a bold bond on a 1,3-disubstituted cyclobutyl moiety as shown below: , whereby X1and X2represent substituents, indicate that the substituents on the cyclobutyl moiety have trans-configuration. The stereodescriptor label “R” or “(R)” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the stereodescriptor label “S” or “(S)” means that the stereocenter is purely of the S-configuration. The term “pharmaceutically acceptable” refers to a compound of the disclosure that has been approved or is approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. For use in medicine, salts of a compound of the disclosure refer to non-toxic “pharmaceutically acceptable salts.” The compounds herein may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The examples of the present disclosure demonstrate that administering Compound 3 as disclosed herein in combination with an inhibitor of BTK is effective to synergistically increase anti-tumor activity. In accordance with the methods disclosed herein, an inhibitor of BTK inhibitor is administered in combination with the MALT1 inhibitor (Compound 3). In one embodiment, the BTK inhibitor is ibrutinib (1-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one). In another embodiment, the BTK inhibitor is Roche BTKi RN486. In yet another embodiment, the BTK inhibitor is acalabrutinib (4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N- pyridin-2-ylbenzamide). In yet another embodiment, the BTK inhibitor is zanubrutinib ((S)-7-(1- acryloylpiperidin-4-yl)-2-(4 phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3- carboxamide). In yet another embodiment, the BTK inhibitor is pirtobrutinib (5-amino-3-(4-((5- fluoro-2-methoxybenzamido)methyl)phenyl)-1-((2S)-1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4- carboxamide). Other BTK inhibitors that may be used in combination with the MALT1 inhibitor (Compound 3) are CT-1530, DTRMWXHS-12, spebrutinib besylate, vecabrutinib, evobrutinib, tirabrutinib, fenebrutinib, poseltinib, BMS-986142, ARQ- 531, LOU-064, PRN-1008, ABBV-599, AC-058, BIIB-068, BMS-986l95, HWH-486, PRN-2246, TAK-020, GDC-0834, BMX-IN-l, RN486, SNS-062, LFM-A13, and PCI-32765. In another embodiment, the BTK inhibitor is Compound B also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo- 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide. In another embodiment, the BTK inhibitor is Compound B also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo- 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide, and the cancer is a B-cell lymphoma. In another embodiment, the BTK inhibitor is Compound B also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo- 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide, and the cancer is a B-cell lymphoma wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. In another embodiment, the BTK inhibitor is Compound B also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo- 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide, and the cancer is a B-cell lymphoma wherein the B-cell lymphoma is DLBCL. In another embodiment, the BTK inhibitor is Compound B also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo- 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide, and the cancer is a B-cell lymphoma wherein the B-cell lymphoma is activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL or non-GCB-DLBCL. In another embodiment, the BTK inhibitor is Compound B also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo- 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide, and the cancer is a B-cell lymphoma wherein the B-cell lymphoma is non-GCB-DLBCL. In another embodiment, the BTK inhibitor is Compound B also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo- 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide, and the DLBCL is non-GCB- DLBCL. N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro- 3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide may be prepared, for example, as described in Example 298 of WO 2018 / 103060, WO 2017 / 100662, US 2017 / 0283430, and US 2019 / 0276471, which are incorporated herein by reference. It will be clear that in the context of this invention, references to any of the BTKi inhibitors listed above (e.g. Compound B), might also refer to the pharmaceutically acceptable salts and solvates (including hydrates) thereof including any subgroup thereof or any combination of pharmaceutically acceptable salts and solvates thereof, even if not explicitly referred to. Thus for example, unless otherwise indicated or clear from the context, all references to Compound B, the structure of Compound B, and N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4- methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide, in the context of this invention, might also refer to the pharmaceutically acceptable salts and solvates (including hydrates) thereof including any subgroup thereof or any combination of pharmaceutically acceptable salts and solvates thereof, even if not explicitly referred to. In particular, Compound B is a hydrate. In particular, Compound B is a dihydrate. The terms “administer” and “administration” have their usual and ordinary meaning in the art of treating a patient with a drug. The term “co-administration” and “co-administer” as used herein refer to administering two drugs to a patient in such a manner and with such timing that both drugs reside in the patient's body at the same time. The coadministration may be concurrently or sequentially in time, and the co-administered drugs may be administered to a patient at the same time, or separately but near in time, or on the same day, or otherwise in a way that results in substantial overlap of the residence periods for the respective drugs in the body. In an embodiment of the methods disclosed herein, Compound 3 and the BTK inhibitor may be administered concurrently or sequentially. In an embodiment, Compound 3 and the BTK inhibitor may be administered concurrently or sequentially. In an embodiment of the methods disclosed herein, Compound 3 and the BTK inhibitor may be administered in a combined dosage form or in separate dosage forms. In an embodiment, Compound 3 and the BTK inhibitor may be administered in a combined dosage form or in separate dosage forms. In an embodiment of the methods according to the disclosure, a therapeutically effective amount of (a) pharmaceutical agent(s) according to the disclosure (i.e., Compound 3 and the BTK inhibitor) is administered to a subject suffering from or diagnosed as having cancer or immunological disease. In an embodiment, a therapeutically effective amount of (a) pharmaceutical agent(s) according to the disclosure (i.e., Compound 3 and the BTK inhibitor) is administered to a subject suffering from or diagnosed as having cancer or immunological disease. A "therapeutically effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in patients in need of such treatment for the designated cancer. In the embodiments described herein the Compound 3 and the inhibitor of BTK may be administered in amounts that are therapeutically effective together. In an embodiment of the methods disclosed herein, administering the combination therapy achieves a synergistic effect on tumor growth inhibition as compared to administering the MALT1 inhibitor (Compound 3) or the BTK inhibitor alone. In an embodiment, the method of the present disclosure involves treating diffuse large B-cell lymphoma (DLBCL) in a subject. In some embodiments, the DLBCL is relapsed or refractory DLBCL. In an embodiment, the method of the present disclosure involves treating mantle cell lymphoma (MCL) in a subject. In some embodiments, the MCL is relapsed or refractory MCL. In an embodiment, the method of the present disclosure involves treating follicular lymphoma (FL) in a subject. In some embodiments, the FL is relapsed or refractory FL. In an embodiment, the method of the present disclosure involves treating transformed follicular lymphoma (tFL) in a subject. In some embodiments, the tFL is relapsed or refractory tFL. In an embodiment, the method of the present disclosure involves treating marginal zone lymphoma (MZL) in a subject. In some embodiments, the MZL is relapsed or refractory MZL. In an embodiment, the method of the present disclosure involves treating chronic lymphocytic leukemia (CLL) in a subject. In some embodiments, the CLL is relapsed or refractory CLL. In an embodiment, the method of the present disclosure involves treating small lymphocytic lymphoma (SLL) in a subject. In some embodiments, the SLL is relapsed or refractory SLL. In an embodiment, the method of the present disclosure involves treating Waldenström macroglobulinemia (WM) in a subject. In some embodiments, the WM is relapsed or refractory WM. In an embodiment, the method of the present disclosure involves treating MALT lymphoma in a subject. In some embodiments, the MALT lymphoma is relapsed or refractory MALT lymphoma. In an embodiment, the method of the present disclosure involves treating relapsed / refractory GCB- DLBCL. In an embodiment, the method of the present disclosure involves treating relapsed / refractory non-GCB-DLBCL. In an embodiment, the method of the present disclosure involves treating relapsed / refractory ABC-DLBCL. In an embodiment, the method of the present disclosure involves treating Burkitt lymphoma in a subject. In an embodiment, the method of the present disclosure involves treating hairy cell leukemia in a subject. In an embodiment, the method of the present disclosure involves treating primary central nervous system lymphoma in a subject. In an embodiment, the method of the present disclosure involves treating primary intraocular lymphoma in a subject. In an embodiment, the method of the present disclosure involves reducing levels of regulatory T cells in a subject having cancer or an immunological disease. In an embodiment, the subject has cancer. In an embodiment, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is relapsed or refractory DLBCL. In an embodiment, the cancer is mantle cell lymphoma (MCL). In some embodiments, the MCL is relapsed or refractory MCL. In an embodiment, the cancer is follicular lymphoma (FL). In some embodiments, the FL is relapsed or refractory FL. In an embodiment, the cancer is transformed follicular lymphoma (tFL). In some embodiments, the tFL is relapsed or refractory tFL. In an embodiment, the cancer is marginal zone lymphoma (MZL). In some embodiments, the MZL is relapsed or refractory MZL. In an embodiment, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the CLL is relapsed or refractory CLL. In an embodiment, the cancer is small lymphocytic lymphoma (SLL). In some embodiments, the SLL is relapsed or refractory SLL. In an embodiment, the cancer is Waldenström macroglobulinemia (WM). In some embodiments, the WM is relapsed or refractory WM. In an embodiment, the cancer is MALT lymphoma. In some embodiments, the MALT lymphoma is relapsed or refractory MALT lymphoma. In an embodiment, the cancer is relapsed / refractory GCB-DLBCL. In an embodiment, the cancer is relapsed / refractory non-GCB-DLBCL. In an embodiment, the cancer is relapsed / refractory ABC- DLBCL. In an embodiment, the cancer is Burkitt lymphoma. In an embodiment, the cancer is hairy cell leukemia. In an embodiment, the cancer is primary central nervous system lymphoma. In an embodiment, the cancer is primary intraocular lymphoma. In an embodiment, the cancer involves reducing levels of regulatory T cells. In an alternate embodiment, the cancer is selected from non-Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. In yet another embodiment of the invention, the cancer is lymphoma. In another embodiment of the invention, the cancer is the activated B cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). In another embodiment of the invention, the cancer is germinal center B cell like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL). In another embodiment of the invention, the cancer is non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL). In an additional embodiment of the invention, the cancer is chronic lymphocytic leukemia (CLL). In another embodiment, the cancer small lymphocytic lymphoma (SLL). In another embodiment of the invention, the lymphoma is MALT lymphoma. In another embodiment of the invention, the cancer is Waldenström macroglobulinemia (WM). In yet another embodiment, the cancer is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa- associated lymphoid tissue (MALT) lymphoma. In an alternate embodiment, the cancer is non-Hodgkin’s lymphoma (NHL). In a further embodiment, the non-Hodgkin’s lymphoma (NHL) is B-cell NHL. In yet another embodiment, the cancer is primary and secondary central nervous system lymphoma, transformed follicular lymphoma, or API2-MALT1 fusion dependent disease. In another embodiment of the invention, the cancer (cancer or immunological disease (such as any of the cancers listed above)) is relapsed or refractory to prior treatment. In another embodiment of the invention, the subject has cancer (such as any of the cancers mentioned above) and the subject has received prior treatment with a Bruton tyrosine kinase inhibitor (BTKi). In some embodiments, the subject may have received at least two prior lines of therapy, including a BTK inhibitor, prior to administration of Compound 3 and Compound B. In some embodiments, the subject may have received Ibrutinib prior to administration of Compound 3 and Compound B. In some embodiments, the subject may have received first line chemotherapy and at least one subsequent line of systemic therapy, including autologous stem cell transplantation (autoSCT), prior to administration of Compound 3 and Compound B. In some embodiments, the subject may have received at least two prior lines of systemic therapy, including a standard anti CD20 antibody, prior to administration of Compound 3 and Compound B. In some embodiments, the subject may have received at least two prior lines of systemic therapy, prior to administration of Compound 3 and Compound B. In some embodiments, the subject may have received at least two prior lines of therapy, including a BTK inhibitor, prior to administration of Compound 3 and a BTK inhibitor. In some embodiments, the subject may have received Ibrutinib prior to administration of Compound 3 and a BTK inhibitor. In some embodiments, the subject may have received first line chemotherapy and at least one subsequent line of systemic therapy, including autologous stem cell transplantation (autoSCT), prior to administration of Compound 3 and a BTK inhibitor. In some embodiments, the subject may have received at least two prior lines of systemic therapy, including a standard anti CD20 antibody, prior to administration of Compound 3 and and a BTK inhibitor. In some embodiments, the subject may have received at least two prior lines of systemic therapy, prior to administration of Compound 3 and a BTK inhibitor. In another embodiment of the invention, the subject has cancer (such as any of the cancers mentioned above) and the subject has received prior treatment with a Bruton tyrosine kinase inhibitor (BTKi). In an alternate embodiment of the invention, the subject has cancer (such as any of the cancers mentioned above) and the subject is relapsed or refractory to prior treatment with a Bruton tyrosine kinase inhibitor (BTKi). Another aspect of the present application is directed to a combination therapeutic comprising: (i) (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide having the following structure of Formula (I): , In an embodiment, the BTK inhibitor may be N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl- 4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide (Compound B). For example, in one embodiment, the combination therapeutic includes Compound 3 and N-((1R,2S)- 2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia- 3,5,8-triazaacenaphthylene-2-carboxamide (Compound B) In some embodiments Compound 3 and the BTK inhibitor are formulated together in a single pharmaceutical composition. In other embodiments of the combination therapeutic of the present disclosure, Compound 3 and the BTK inhibitor are formulated as separate pharmaceutical compositions. The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments. Likewise, the invention is not limited to any particular preferred embodiments described here. According to an embodiment, the invention provides combination therapeutics of Compound 3 and an inhibitor of BTK as described herein. According to an embodiment, the invention provides combination therapeutics of Compound 3 and an inhibitor of BTK as described herein for use as a medicament. According to an embodiment, the invention provides combination therapeutics of Compound 3 and an inhibitor of BTK as described herein for use in therapy. According to an embodiment, the invention provides combination therapeutics of Compound 3 and an inhibitor of BTK as described herein for the manufacture of a medicament. According to an embodiment, the invention provides combination therapeutics of Compound 3 and an inhibitor of BTK as described herein for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein. According to an embodiment, the invention provides combinations of Compound 3 and an inhibitor of BTK as described herein for use in the treatment, of cancers or immunological diseases as described herein. For example, the invention provides a combination therapy comprising: (i) Compound 3, and (ii) an inhibitor of BTK for use in the treatment of cancer or an immunological disease , comprising administering the combination therapy, wherein the combination therapy is administered to the subject in an amount effective to treat the cancer or immunological disease in the subject. For example, the invention provides Compound 3, for use in the treatment of cancer or an immunological disease , comprising administering Compound 3, and an inhibitor of BTK, wherein the therapy is administered to the subject in an amount effective to treat the cancer or immunological disease in the subject. For example, the invention provides an inhibitor of BTK for use in the treatment of cancer or an immunological disease , comprising administering Compound 3, and the inhibitor of BTK, wherein the therapy is administered to the subject in an amount effective to treat the cancer or immunological disease in the subject. According to an embodiment, the invention provides combinations of Compound 3, and an inhibitor of BTK as described herein for use in reducing levels of regulatory T cells. For example, the invention provides a combination therapy comprising: (i) Compound 3, and (ii) an inhibitor of BTK for use in a method of reducing levels of regulatory T cells in a subject having cancer or an immunological disease, said method comprising administering to said subject the combination therapy, wherein the combination therapy is administered to the subject in an amount effective to reduce regulatory T cell levels in the subject relative to the levels of regulatory T cells in the subject prior to said administering. For example, the invention provides Compound 3, for use in a method of reducing levels of regulatory T cells in a subject having cancer or an immunological disease, said method comprising administering to said subject Compound 3, and an inhibitor of BTK, wherein the therapy is administered to the subject in an amount effective to reduce regulatory T cell levels in the subject relative to the levels of regulatory T cells in the subject prior to said administering. For example, the invention provides an inhibitor of BTK for use in a method of reducing levels of regulatory T cells in a subject having cancer or an immunological disease, said method comprising administering to said subject Compound 3, and the inhibitor of BTK, wherein the therapy is administered to the subject in an amount effective to reduce regulatory T cell levels in the subject relative to the levels of regulatory T cells in the subject prior to said administering. According to an embodiment, the invention provides combinations of Compound 3 and an inhibitor of BTK as described herein for use in the treatment, of cancers or immunological diseases as described herein, by reducing levels of regulatory T cells. According to an embodiment, the invention provides combinations of Compound 3 and an inhibitor of BTK as described herein for use in the treatment of a B-cell lymphoma, including but not limited to diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. All embodiments described herein “for use in a method of treating”, are also applicable “for use in treating” or “for use in the treatment of”. All embodiments described herein for “a method of treating”, are also applicable “for use in treating” or “for use in the treatment of”. All embodiments described herein for “a method of treating cancer or immunological disease”, are also applicable “for use in treating said cancer or immunological disease” or “for use in the treatment of said cancer or immunological disease”. All embodiments described herein for methods of reducing levels of regulatory T cells in a subject having cancer or an immunological disease, are also applicable for use in reducing levels of regulatory T cells. All embodiments described herein for use in treating cancer or an immunological disease, are also applicable for methods of treating said cancer or immunological disease. All embodiments described herein for methods of treating cancer or an immunological disease, are also applicable for use in a method of treating said cancer or immunological disease. All embodiments described herein for methods of reducing levels of regulatory T cells in a subject having cancer or an immunological disease, are also applicable for use in a method of reducing levels of regulatory T cells in a subject having cancer or an immunological disease. All embodiments described herein for methods of reducing levels of regulatory T cells in a subject having cancer or an immunological disease, are also applicable for use in a method of reducing levels of regulatory T cells. All embodiments described herein for use in a method of treating cancer or an immunological disease, are also applicable for methods of treating said cancer or immunological disease. All embodiments described herein for use in treating cancer or an immunological disease, are also applicable for methods of treating said cancer or immunological disease. EXAMPLES The following examples of the invention are to further illustrate the nature of the invention. It is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. It should be understood that the following examples do not limit the invention and that the scope of the invention is to be determined by the appended claims. Example – Synthesis of MALT1 inhibitors Methods for preparing the intermediates and Compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods. Abbreviation Meaning ACN or CH3CN acetonitrile AcOH acetic acid Aq or aq. aqueous 2-(Dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’-triisopropyl- BrettPhos 1,1’-biphenyl [2-(Dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’-triisopropyl- BrettPhos Pd G3 1,1’-biphenyl]palladium(II) methanesulfonate Bu butyl Abbreviation Meaning Celite®diatomaceous earth Co Compound Co. No. Compound Number DCM dichloromethane CHCl3Chloroform DIBAL-H Diisobutylaluminium hydride DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMF-DMA N,N-Dimethylformamide dimethyl acetal equiv equivalent(s) Et3N or TEA triethylamine EtOAc ethyl acetate EtOH ethanol h hour(s) HCl Hydrochloric acid HPLC high performance liquid chromatography iPrNH2isopropylamine K2CO3Potassium carbonate LAH, LiAlH4Lithium Aluminium Hydride LC Liquid chromatography LCMS Liquid chromatography- Mass spectrometry Me methyl MeI methyl iodide MeMgBr Methyl magnesium bromide MeOH methanol MP melting point Abbreviation Meaning MgSO4magnesium sulphate MW molecular weight µW microwaves N2nitrogen NaH sodium hydride NaHCO3sodium bicarbonate NH4Cl ammonium chloride NH4HCO3Ammonium bicarbonate PCC Pyridinium chloro chromate PE Petroleum ether Quant. quantitative rac racemic rel- relative stereochemistry RP reversed phase Rochelle's salt Potassium sodium tartrate tetrahydrate RT room temperature Rt Retention time SFC supercritical fluid chromatography Sat or sat. saturated t-BuOH or tBuOH tert-butanol (tert-butyl alcohol) TBAF tetra-N-butylammonium fluoride TEA triethylamine TEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl, 2,2,6,6-Tetramethyl-1- piperidinyloxy, free radical TFA trifluoroacetic acid THF tetrahydrofuran Preparation of intermediates For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below. Intermediate 1 was placed ethyl 2-(benzylamino)acetate (550 g, 2.85 mol, 1.00 equiv), CHCl3 (5.5 L), TEA (576 g, 5.70 mmol, 2.00 equiv). Propanoyl chloride (290 g, 3.13 mol, 1.10 equiv) in CHCl3 (300 mL) was added dropwise at 0 °C. The mixture was stirred for 1 h at 25 °C. The mixture was poured into H2O (6 L). The resulting solution was extracted with DCM (2x 2 L). The organic layers were combined, dried over anhydrous MgSO4, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 1:2) to give Intermediate 1 (561 g, 79% yield) as a light-yellow oil. Intermediate 2 Intermediate 1 (561 g, 2.25 mol, 1.00 equiv) in THF (2 L) was added dropwise at 75 °C to a mixture of NaH (108 g, 2.70 mol, 1.20 equiv, 60%) and THF (10 L). After 12 h at 75 °C, the reaction was cooled to 20 °C, water (100 mL) was added, and the mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: MeOH / DCM 1:30) to give Intermediate 2 (231 g, 50% yield) as an off-white solid. Intermediate 3 1.14 mol, 1.00 equiv, 60%) was added portionwise at 0 °C to Intermediate 2 (231 g, 1.14 mol, 1.00 equiv) in DMF (4.6 L). The mixture was stirred for 0.5 h at 25 °C. 5- (Trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (457 g, 1.14 mol, 1.00 equiv) was added to the mixture at -55 °C. The mixture was gradually warmed up to 25 °C and stirred for 1 h. The mixture was poured into a mixture of ice / water (10 L) and extracted with EtOAc (2x 5 L). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 1:4) to give Intermediate 3 (275 g, 89% yield) as a light-yellow oil. Intermediate 4 g, mol, 4.00 equiv) was added at 0 °C to a mixture of Intermediate 3 (275 g, 1.01 mol, 1.00 equiv) in THF (5.5 L). The mixture was warmed up to 80 °C and stirred at this temperature for 15 h. The mixture was cooled to 0 °C, and were added 154 g of water, 154 g of aqueous of NaOH solution (10%), and 154 g of H2O. The mixture was stirred for 30 min at 25 °C and the precipitate was filtered off. The filtrate was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: MeOH / DCM 1:50) to give Intermediate 4 (204 g, 78% yield) as a colorless oil. Intermediate 5 HCl (787 mL, 1 M) and Pd / C (8.37 g, 78.7 mmol, 0.10 equiv) were added to a solution of Intermediate 4 (204 g, 787 mmol, 1.00 equiv) in EtOH (2 L). The mixture was degassed and flushed with hydrogen. The mixture was stirred for 18 h at 25 °C under an atmosphere of hydrogen (balloon). Then was added HCl (787 mL, 1 M) and the mixture was stirred for 30 min at 25 °C. The solid was filtered out and the filtrate was concentrated under vacuum to give Intermediate 5 (106 g, 66% yield; as a HCl salt, number of equivalents not determined) as a yellow solid which was used without further purifications. Intermediate 6 dicarbonate (169 g, 773 mmol, 1.50 equiv) was added to a mixture of Intermediate 5 (106 g, 515 mmol, 1.00 equiv), THF (2 L), and TEA (2089 g, 2.06 mol, 4.00 equiv). The flask was stirred for 2 h at 25 °C. The mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 1:4) to give Intermediate 6 (134 g, 96% yield) as a white solid. Intermediate 7 A mixture of Intermediate 6 (134 g, 0.496 mol, 1.00 equiv), DCM (2.6 L), PCC (534 g, 2.48 mol, 5.00 equiv) and silica gel (268 g, 4.46 mol, 9.00 equiv) was stirred for 12 h at 40 °C. The mixture was concentrated under vacuum and the resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 1:10) to give Intermediate 7 (79 g, 60% yield) as a white solid. Intermediate 8 g, 296 mmol, 1.00 equiv) and DMF-DMA (790 mL) were stirred for 1 h at 35 °C. The mixture was concentrated to give Intermediate 8 (100 g, crude) as a light-yellow oil which was used without any further purification. Intermediate 9 8 (100 g, 310 mmol, 1.00 equiv), 5-chloro-2H-pyrazol-3-amine [CAS: 916211-79-5] (36.5 g, 310 mmol, 1.00 equiv), toluene (1 L) and AcOH (100 mL) was stirred for 15 h at 95 °C. The reaction was cooled to 25 °C and concentrated under vacuum. NaHCO3 (1000 mL) was added to the mixture, and the resulting solution was extracted with EtOAc (2x 1 L). The organic layers were combined, dried over anhydrous MgSO4, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc / PE 15:85) to give Intermediate 9 (39.7 g, 34% yield) as a yellow oil. Intermediate 10 A mixture of Intermediate 9 (39.7 g, 105 mmol, 1.00 equiv), DCM (400 mL) and TFA (80 mL) was stirred for 1 h at 25 °C. The mixture was concentrated under vacuum and NaHCO3(500 mL) was added. The resulting mixture was extracted with DCM (3x300 mL). The organic layers were combined, dried over anhydrous MgSO4,and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc:PE (1:1). This resulted in 2- chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine (Intermediate 10, [CAS: 2661482-67-1], 15.2 g, 51% yield) as a yellow solid. Intermediate 11 and 12 Intermediate 10 (5.0 g) was separated in enantiomers via chiral SFC, using as stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2 to provide two fractions as follows: Fraction 1: Intermediate 11 (2.35 g, 47% yield) Fraction 2: Intermediate 12 (2.35 g, 47% yield) Intermediate 13 To a cooled (0 °C) suspension of NaH (60% in mineral oil, 2.59 g, 64.85 mmol) in THF (100 mL) was added triethylphosphonopropionate (13.9 mL, 64.85 mmol) dropwise. The reaction was stirred for 30 minutes, then a solution of 4-bromobenzaldehyde [1122-91-4] (10.0 g, 54.0 mmol) in THF (20 mL) was added dropwise, keeping the internal temperature between 0 °C and 5 °C. The mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with a saturated aqueous solution of NH4Cl (60 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane / EtOAc up to 90 / 10). The fractions containing compound were combined and concentrated in vacuo to give Intermediate 13 (12.3 g, 84% yield) as a colorless oil. Intermediate 14 of Intermediate 13 (12.3 g, 45.7 mmol) in dry THF (230 mL) under nitrogen, was added DIBAL-H (1M in THF, 115 mL, 115 mmol) dropwise. The mixture was then allowed to slowly warm up to RT and stirred for 1 h. The reaction was cooled down to 0 °C, diluted with EtOAc (100 mL) and quenched with a saturated aqueous solution of Rochelle's salt (250 mL). After stirring for 1 h, the reaction was allowed to warm up to RT, the organic layer was separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give Intermediate 14 (9.8 g, 94% yield) as a white solid. Intermediate 15 14 (8.70 g, 38.3 mmol) and imidazole (3.13 g, 46.0 mmol) in DCM (100 mL) pre-cooled to 0 °C, was added triisopropylsilyl chloride (9.0 mL, 42.1 mmol) dropwise. The mixture was allowed to warm up to RT and stirred for 16 h. The mixture was diluted with water (100 mL) and DCM (100 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography over silica gel (eluent: heptane / DCM up to 90 / 10) to obtain Intermediate 15 (14 g, 95% yield) as a colorless oil. Intermediate 16 In a 20 mL pressure tube charged with Intermediate 15 (1.15 g, 3.0 mmol) and tetrabutylammonium bromide (48.3 mg, 0.15 mmol), were added toluene (6 mL) and (bromodifluoromethyl)trimethylsilane (1.4 mL, 9 mmol). The reaction was stirred at 110 °C for 6 h. Six identical reactions were run in parallel and combined before work-up and purification. The reactions were cooled down to RT, each diluted with water (10-15 mL), EtOAc (20-25 mL), and combined. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (50 mL), cooled to 0 °C and TBAF (1M in THF, 27 mL, 27 mmol) was added. The reaction was allowed to warm up to RT and stirred for 1 h. Volatiles were removed under reduced pressure and the residue was diluted with water (50 mL) and EtOAc (100 mL). The aqueous layer was separated, and the organic layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane / EtOAc 70 / 30) to obtain Intermediate 16 (4.6 g, 92% yield) as a yellowish oil. Intermediate 17 16 (3.81 g, 13.75 mmol) in water / MeCN (87 mL / 87 mL), were added TEMPO (1.07 g, 6.87 mmol), (Diacetoxyiodo)benzene (13.29 g, 41.25 mmol) and NaHCO3 (2.89 g, 34.37 mmol). The mixture was stirred for 6 h at RT, the mixture was diluted with water, and aq HCl (1 M) was added until the pH reached approximately 2. EtOAc was added and the organic layer was separated.The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated. The product was stirred in diisopropyl ether and filtered. The filtrate was evaporated and stirred in heptane to obtain a precipitate that was filtered and dried over anhydrous MgSO4 to give Intermediate 17 (3.46 g, 86% yield) as white solid. Intermediate 18 To a mixture of Intermediate 17 (200.0 mg, 0.687 mmol) and N-[(Dimethylamino)-1H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (522.5 mg, 1.37 mmol) and N,N-Diethylethanamine (0.38 mL, 2.75 mmol) in MeCN (5.2 mL) was added 3- (methylsulfonyl)cyclobutan-1-amine hydrochloride [2639792-63-3] (205.0 mg, 1.37 mmol). The reaction was stirred at RT for 1 h. The reaction was diluted with EtOAc and water. The water layer was separated, and the acqueouse phase was extracted with EtOAc. The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: MeOH / DCM 0 to 7%) to give Intermediate 18 (264 mg, 91% yield) as a white solid. Intermediate 19 an analogous reaction protocol as Intermediate 18, starting from trans-3-methylsulfonylcyclobutylamine hydrochloride [1408075-97-7] (1.25 g, 6.73 mmol) instead of 3-(methylsulfonyl)cyclobutan-1-amine hydrochloride [2639792-63-3] to give Intermediate 19 (1.16 g, 73% yield) as a light-yellow solid. Compound 1 A pressure tube was charged with Intermediate 19 (175 mg, 0.41 mmol), Intermediate 11 (126.11 mg, 0.46 mmol), BrettPhos Pd G3 (37.57 mg, 0.041 mmol), BrettPhos (22.24 mg, 0.041 mmol), Cs2CO3(202.53 mg, 0.62 mmol), and 1,4-dioxane (4.05 mL). The mixture was degassed, then stirred at 60 °C for 8 h. The reaction was cooled down to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the crude was purified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 30x150mm, Mobile phase: 0.25% NH4HCO3solution in water, CH3CN) to obtain Compound 1 as a yellow solid (147 mg, 58% yield).1H NMR (CHLOROFORM-d, 400 MHz) δ ppm: 8.29 - 8.25 (m, 1H), 7.26 - 7.23 (m, 1H), 7.18 - 7.06 (m, 2H), 6.70 (s, 1H), 6.08 (d, J=6.2 Hz, 1H), 4.55 (sxt, J=7.6 Hz, 1H), 4.25 (d, J=12.3 Hz, 1H), 4.06 (d, J=11.7 Hz, 1H), 3.80 (tt, J=4.6, 9.5 Hz, 1H), 3.62 (d, J=15.6 Hz, 1H), 3.04 - 2.90 (m, 2H), 2.87 (s, 3H), 2.70 - 2.60 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H). Compound 2 and Compound 3 Compound 1 (147 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide two fractions as follows: Fraction 1: Compound 2 (61 mg, 24% yield starting from intermediate 19)1H NMR (CHLOROFORM-d, 400 MHz) δ ppm: 8.26 (d, J=1.3 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.15 (d, J=11.9 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.71 (s, 1H), 6.08 (br d, J=6.4 Hz, 1H), 4.55 (sxt, J=7.6 Hz, 1H), 4.26 (d, J=10.5 Hz, 1H), 4.06 (d, J=11.4 Hz, 1H), 3.79 (tt, J=4.7, 9.5 Hz, 1H), 3.64 - 3.59 (m, 1H), 3.00 - 2.92 (m, 2H), 2.87 (s, 3H), 2.70 - 2.61 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H). Fraction 2: Compound 3 (63 mg, 25% yield starting from intermediate 19)1H NMR (CHLOROFORM-d, 400 MHz) δ ppm: 8.26 (d, J=1.3 Hz, 1H), 7.25 - 7.05 (m, 3H), 6.70 (s, 1H), 6.06 (d, J=6.2Hz, 1H), 4.59 - 4.50 (m, 1H), 4.24 (d, J=10.5 Hz, 1H), 4.06 (d, J=11.5 Hz, 1H), 3.83 - 3.75 (m, 1H), 3.61 (d, J=16.0 Hz, 1H), 2.99 - 2.92 (m, 2H), 2.86 (s, 3H), 2.69 - 2.60 (m, 2H), 1.99 (s, 3H), 1.24 (s, 3H).1H NMR spectra were recorded on Bruker Avance III 400MHz and Avance NEO 400MHz spectrometers. CHLOROFORM-d was used as solvent, unless otherwise mentioned. The chemical shifts are expressed in ppm relative to tetramethylsilane. Analytical Analysis The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g., scanning range, dwell time…) to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]- (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]-, etc…). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane / silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica. LCMS methods are set out in Table 1, with flow expressed in mL / min, column temperature (T) in °C, run time in minutes. ‘ACN' refers to acetonitrile. Table 1: Methods used for LCMS analysis of compounds. Flow Method Run Instrument column mobile phase gradient ------- Code time Col T From 100% A: 10mM A to Waters: Acquity®Waters :BEH NH 5% A in 4HCO3 0.6 1 UPLC®- (1.7µm, in 95% H2O + 2.10min, and SQD 2.1*100mm) 5% CH3CN to 0 ------- 3.5 DAD % A in 0 55 B: CH .9min, 3CN to 5% A in 0.5min Flow Method Run Instrument column mobile phase gradient ------- Code time Col T From 100% A: 10mM A to Waters: Acquity®Waters :BEH CH 5% A in 3COONH4 2.10min 0.6 3 UPLC®- (1.7µm, in 95% H2O + , ------- 3.5 DAD and SQD 2.1*100mm) 5% CH3CN to 0% A in 5 CH3CN 0.9 5 B: min, to 5% A in 0.5min LCMS results for Compounds 1-3 are set out in Table 2, wherein Rtmeans retention time (in minutes); [M+H]+means the protonated mass of the compound; method refers to the method used for LCMS analysis of compounds; No. means number. Table 2: LCMS results. Compound LCMS results No. 1 confirms the MW, Rt: 2.10, [M+H]+: 618.3, Method: 1 2 confirms the MW, Rt: 2.10, [M+H]+: 618.3, Method: 3 3 confirms the MW, Rt: 2.10, [M+H]+: 618.3, Method: 3 Example – Pharmacological analysis of MALT1 inhibitors Biological Examples In vitro assays include assays that determine cell morphology, protein expression, and / or the cytotoxicity, enzyme inhibitory activity, and / or the subsequent functional consequences of treatment of cells with compounds of the invention. Alternate or additional in vitro assays may be used to quantitate the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor / target molecule complex and determining the amount of radiolabel bound. Alternatively or additionally, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of exemplary systems for assaying compounds described herein as MALT1 inhibitors are set forth in the Biological Examples below. Such assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner can appreciate that modifications can be made to conventional assays to develop equivalent or other assays that can be employed to comparably assess activity or otherwise characterize compounds and / or compositions as described herein. In Vitro Assays Biological Example 1 MALT1 Biochemical Protease Assay MALT1 protease activity was assessed in an in vitro assay using a tetrapeptide as substrate and full- length MALT1 protein (Strep-MALT1(1-824)-His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched, fluorescent substrate for the MALT1 protease (SM Biochemicals). Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 µM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM dithiothreitol (DTT), 1 mM ethylenediaminetetraacetic acid (EDTA), 0.05% bovine serum albumin (BSA) and 1.5% dimethyl sulfoxide (DMSO). Test compounds were spotted at 50 nL in 100% DMSO per well of a black 384-Proxiplate (Perkin Elmer). Test compound concentrations ranged from 30 µM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC). High control (HC) values were generated using the reaction with enzyme but no compound treatment. Compounds were pre-incubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently, and fluorescence was measured in Labsystems fluoroskan at excitation 355 nm and emission 460 nm to determine time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured. For IC50calculations, timepoint 0 was subtracted from the 4 h timepoint to correct for any potential autofluorescence of the compounds. The enzyme reaction was linear during the 4 h incubation period. Characterization of the substrate Ac-LRSR-AMC determined the Michaelis constant KMat 200 µM. IC50values were calculated using the following formula (Z prime should be >0.5): LC = Median of the low control values = Low control: Reaction without enzyme HC = Median of the High control values = High Control: Reaction with enzyme %Effect = 100-[((sample-LC) / (HC-LC)) x 100] %Control = (sample / HC) x 100 %Controlmin = ((sample-LC) / (HC-LC)) x 100 A best-fit curve was fitted by a minimum sum of squares method to the plot of %Controlmin vs. compound concentration. From this an IC50value (inhibitory concentration causing 50 % inhibition) can be obtained. An estimate of the slope of the plot in terms of the Hill coefficient was also obtained. IC50Calculation: yi= LB + UB – LB 1 +10(h*(pCONCi-pIC50))with y = estimated response UB = upper bound LB = lower bound h = Hill slope of curve CONC = concentration Used in “Lexis Dose Response Curve Fitting” Version 1.0. Resultant data are shown in Table 3. Table 3: IC50values for Compounds 1-3. MALT1_Biochemical Compound activity (Ac-LRSR- Number AMC) IC50 (µM) 1 0.033 2 0.081 3 0.014 Biological Example 2 GloSensor reporter MALT1-mediated cleavage In Jurkat Cells MALT1 GloSensorTMis a split luciferase reporter, which utilizes a genetically modified form of firefly luciferase (CP UltraGlo) split into 2 distinct domains by insertion of a RelB MALT1 cleavage site sequence PRLVSRGA. MALT1-induced cleavage allows for a conformational change that reestablishes a functional luciferase protein resulting in luminescence, and hence luciferase activity would be a surrogate of endogenous MALT1 protease activity. Jurkat MALT1 GloSensorTMwere generated by electroporation and selected and maintained in the presence of 0.5 mg / mL Geneticin. MALT1 protease is basally inactive in Jurkat cells and can be activated by treatment with PMA / Ionomycin. Small molecule MALT1 inhibitors added prior to PMA / Ionomycin addition prevent MALT1 protease activation and, therefore, the cleavage of the MALT1 GloSensor split luciferase reporter in a dose-dependent manner. Jurkat MALT1 GloSensorTMcells were maintained in complete RPMI 1640 media containing 10% fetal bovine serum, 10mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 100 units / mL of penicillin, 100 µg / mL of streptomycin and 0.5 mg / mL Geneticin. Prior to the assay, compounds were made 2.5-fold serial dilutions in DMSO. 100 nL of of test compounds were spotted per well of 384-well plates (Perkin Elmer, catalogue number 6007688). Jurkat cells were harvested by centrifuge at 1200 RPM for 5 min and suspended in fresh complete RPMI 1640 media with 2% GloSensor™ cAMP Reagent and preincubated for 45-60 minutes at 37 °C in a 5% CO2incubator. A volume of 50 uL of preincubated Jurkat MALT1 GloSensorTMcells (1 x 105cells) were seeded in each well of 384-well plate. Next, a volume 2 µL of diluted PMA / Ionomycin (2.5 mg / mL / 25 µM respectively, Sigma, catalogue number P1585 and 407953) in DMSO were added to each well. After incubation at 37 °C in 5% CO2incubator for 4 h, luminescence was measured on the Envision (Perkin Elmer) at 37 °C. IC50values were calculated using SmartFit in GeneData Screener®: where: x = concentration y = activity S0 = activity at bottom plateau of curve Sinf = activity at top plateau of curve S50 = inflection point, halfway between S0 and Sinf h = Hill slope of curve Resultant data are shown in Table 4. Table 4: IC50values for Compounds 1-3. Compound Jurkat MALT1 GloSensor^ Number IC50 (µM) 1 0.0055 2 0.033 3 0.0035 Biological Example 3 Human IL-6 / IL-10 Mesoscale Assay OCI-Ly3 cells were propagated in RPMI-1640 (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 1% PenStrep (Sigma Aldrich). Cell passage number should not exceed 30. Cells should be kept between 0.5 – 1.5 million cells per mL during culturing. For the Mesoscale assay, 100,000 OCI-Ly3 cells were seeded per well into black-colored 96-well plates with clear bottom (Corning®#3904) and test compounds were added in 9 dilution steps (1:2) ranging from 15 µM to 58.6 nM (final DMSO concentration 0.3%). DMSO control wells were used to determine the maximum signal (High Control (HC)). Treatment with reference compounds at an appropriate dose served as positive control for MALT1 inhibition and was used to determine the maximum inhibition (Low Control (LC)). Compounds and cells were incubated for 24 h at 37 °C and 5% CO2 (assay volume is 150 µL). After 24 h of incubation 50 µL of the supernatant was transferred to an MSD plate (V-Plex Proinflammation Panel 1 (human) kit, Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room temperature. Following incubation, plates were washed 3x with phosphate-buffered saline (PBS) + 0.05% Tween-20 and 25 µL detection antibody solution (IL-6 & IL-10 antibodies in diluent 3 (MSD)) was added per well followed by 2 h of incubation with vigorous shaking (600 rpm) at room temperature. After 3x washes with PBS + 0.05% Tween-20, plates were incubated with 150 µL 2x Read Buffer T and read on SECTOR imager. Resultant data are shown in Table 5 (‘Cpd No.’ means Compound Number, ‘Int’ means intermediate, ‘n.d.’ means not determined). Table 5: IC50data for Compounds 1-3. Human IL6 Human IL10 Mesoscale Compound Mesoscale assay assay (OCI-Ly3) Number (OCI-Ly3) IC50 (µM) IC50 (µM) 1 0.0095 0.0098 2 0.074 0.052 3 0.019 0.017 Biological Example 4 Proliferation Assays OCI-Ly3 cells were propagated in RPMI-1640 with Glutamax (ThermoFisher) supplemented with 10% heat inactivated fetal bovine serum (ThermoFisher). Cells should be kept between 0.2 – 1.5 million cells per mL and passed every 3-4 days during culturing. OCI-Ly7 cells were propagated in IMDM (ThermoFisher) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 µg / mL Gentamycin. Cells should be kept between 0.15 – 3 million cells per mL and passed every 3-4 days during culturing. Cell passage numbers should not exceed 20. To assess anti-proliferative effects, 450 nL of test compounds were spotted per well of U-bottom 96- well plates (Corning®, #3975).500 OCI-Ly3 or OCI-Ly7 cells were seeded in 150 µL media per well and incubated for 8 days at 37 °C and 5% CO2. Cell plating numbers were chosen based on growth curves to ensure linear cell growth. After 8 days of incubation, 100 µL of the plated cells were resuspended up and down by pipette and transferred to a flat bottom black plate (Corning®, #3904). 50 µL CellTiterGLO reagent (Promega) were added to each well and luminescence was measured on Envision (Perkin Elmer) after 10 minutes shaking at 300 rpm followed by 10 minutes of incubation at room temperature in the dark. IC50values were calculated using SmartFit in GeneData Screener®: where: x = concentration y = activity S0 = activity at bottom plateau of curve Sinf= activity at top plateau of curve S50= inflection point, halfway between S0 and Sinf h = Hill slope of curve Resultant data are shown in Table 6. Table 6: IC50data for Compounds 1-3. Anti- Anti- Compound proliferation: proliferation: Number OCI-Ly3 OCI-Ly7 IC50 (µM) IC50 (µM) 1 0.19 3.96 2 0.29 not determined 3 0.042 5.25 Example – In vitro combinations Materials and Methods Cell lines All cell lines were cultured at 37°C, 5% CO2 in the complete culture medium described below, and all were validated as mycoplasma negative. Cell line (mutational Histology Complete culture medium status) TMD8 DLBCL RPMI 1640 with GlutaMAX, 10% HI-FBS REC-1 MCL RPMI 1640 with GlutaMAX, 10% HI-FBS DLBCL, diffuse large B-cell lymphoma; FBS, fetal bovine serum; HI, heat inactivated; MCL, mantle cell lymphoma; RPMI, Roswell Park Memorial Institute. Combination Proliferation Assay of Compound 3 with Compound B ABC-DLBCL (TMD8) and MCL (REC-1) cell lines were harvested by centrifugation at 200×g for 5 minutes at room temperature (RT), then counted after dilution with Trypan Blue using a Countess II Cell Counter. Cells were diluted to the appropriate concentration for each cell line in complete culture medium. Then, 150 μL / well were seeded in 96-well round-bottom ultra-low attachment plates and exposed to a concentration range of Compound 3 (7-point serial dilution range of 10 μM to 0.86 nM) and BTKi (6-point serial dilution range of 2 μM to 0.17 nM). The DMSO content was normalized to 0.2%. Compounds were spotted using a Tecan D300e instrument. Cell seeding numbers were chosen based on growth curves to ensure linear growth throughout the experiment: TMD8 (800 cells / well) and REC-1 (800 cells / well). Cells were incubated for 8 days at 37°C, 5% CO2. Viability at the end of the experiment was determined by adding 50 μL of CellTiter-Glo to 100 μL of cells in a new 96-well flat-bottom black plate. Plates were incubated at RT for 10 minutes in the dark and centrifuged at 200×g for 2 minutes. Luminescence was read on an Envision 7 (PerkinElmer). The experiment was performed 3 times for each cell line. The monotherapy data were modeled using a 4-parameter logistic regression with a common baseline being estimated for both monotherapies and individual estimates for the remaining 3 parameters. Additionally, the lower asymptote was constraint to be ≥0. These 4-parameter logistic regression models were subsequently used to predict the expected effect of the combination under generalized Loewe, and Highest Single Agent (HSA) null models. The observed combination effects were evaluated using the Biochemically Intuitive Generalized Loewe Model R package, which measures the evidence of synergy in the data, in the presence of variability, against certain null models derived from the monotherapies. In a second step, hypothesis tests at 5% significance level were performed that basically contrast the observed readouts of the combination experiments with those predicted from the null model derived from the monotherapies where both highest single agent and generalized Loewe were assessed for these studies. For the estimation of the standard error, a linear mean-variance trend was assumed, and 5,000 iterations were used for bootstrapping the variance covariance matrix of the observed combination effects. All analyses were performed in R Version 4.2.2 and BIGL R Version 1.6.8. Example – In Vitro Combinations of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)- 7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N- ((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide (Compound 3) with N- ((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro- 3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide (Compound B) The effect of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide (Compound 3) in combination with N- ((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H- 1-thia-3,5,8-triazaacenaphthylene-2-carboxamide (Compound B) was determined in proliferation assays using the TMD8 and REC-1 cell lines. Experiments were carried out 3 times independently. Synergistic effects were observed in the CD79b-mutant ABC-DLBCL cell line TMD8 and in the MCL cell line REC-1, which are sensitive to both agents in monotherapy (Figure 5 and 6). Statistically significant synergy was observed using both the Highest Single Agent (HAS) (see Figure 1 and 2) and generalized Loewe (see Figure 3 and 4) analysis methods. BTKi in Figures 1-6 corresponds with N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4- oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide (Compound B).

[0002] The invention also provides the following numbered embodiments. 1. A method of treating cancer or an immunological disease in a subject in need thereof, said method comprising administering to said subject a combination therapy comprising: (i) (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide having the following structure of Formula (I): , to embodiment 1, wherein the method is for treating cancer. 2. The method according to embodiment 1b, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 3. The method according to embodiment 1b, wherein the cancer is a B-cell lymphoma. 4. The method according to embodiment 3, wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 5. The method according to embodiment 4, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL or non-GCB-DLBCL. 6. The method according to any one of embodiments 1–5, wherein the BTK inhibitor is Compound B. 7. The method according to any one of embodiments 1–6, wherein (1S,3R)-3-(4- ((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin- 6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and said BTK inhibitor are administered concurrently. 8. The method according to any one of embodiments 1–6, wherein (1S,3R)-3-(4- ((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin- 6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and said BTK inhibitor are administered sequentially. 9. The method according to any one of embodiments 1–6, wherein (1S,3R)-3-(4- ((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin- 6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and the BTK inhibitor are administered in a combined dosage form. 10. The method according to any one of embodiments 1–6, wherein (1S,3R)-3-(4- ((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin- 6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and the BTK inhibitor are administered in separate dosage forms. 11. The method according to any one of embodiments 1–10, wherein the subject is a human subject. 12. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with an inhibitor of BTK. 13. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to embodiment 12 for use in the treatment of cancer or an immunological disease. 13b. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to embodiment 12 for use in the treatment of cancer 14. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor, for use in the treatment of cancer according to embodiment 13b, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 15. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor, for use in the treatment of cancer according to embodiment 13b, wherein the cancer is a B- cell lymphoma. 16. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to embodiment 15 wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 17. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to embodiment 16, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL or non-GCB-DLBCL. 18. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to any one of embodiments 12–17, wherein the BTK inhibitor is Compound B. 19. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to any one of embodiments 12-18, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently. 20. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to any one of embodiments 12-18, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially. 21. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to any one of embodiments 12-18, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in a combined dosage form. 22. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to any one of embodiments 12-18, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms. 23. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in combination with a BTK inhibitor according to any one of embodiments 12-22, in a human subject. 24. A combination comprising (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and an inhibitor of BTK. 25. The combination according to embodiment 24 for use in the treatment of cancer or an immunological disease . 25b. The combination according to embodiment 24 for use in the treatment of cancer. 26. The combination for use in the treatment of cancer according to embodiment 25b, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 27. The combination for use in the treatment of cancer according to embodiment 25b, wherein the cancer is a B-cell lymphoma. 28. The combination according to embodiment 27 wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 29. The combination according to embodiment 28, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL or non-GCB-DLBCL.

[0003] 30. The combination according to any one of embodiments 24–29, wherein the BTK inhibitor is Compound B. 31. The combination according to any one of embodiments 24-30, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently. 32. The combination according to any one of embodiments 24-30, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially. 33. The combination according to any one of embodiments 24-30, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in a combined dosage form. 34. The combination according to any one of embodiments 24-30, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms. 35. The combination according to any one of embodiments 24-34, in a human subject. 36. The combination according to any one of embodiments 24-35 wherein the combination is a combination therapy. 37. Use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide in the manufacture of a medicament for treating cancer or an immunological disease, wherein the medicament is for co-administration with an inhibitor of BTK. 37b. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 37 for treating cancer. 38. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 37b, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 39. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 37b, wherein the cancer is a B-cell lymphoma. 40. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 39, wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 41. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 40, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B- cell (GCB)-DLBCL or non-GCB-DLBCL. 42. The use of the inhibitor of according to any one of embodiments 37–41, wherein the BTK inhibitor is Compound B. 43. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 37-42, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently. 44. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 37-42, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially. 45. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 37-42, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in a combined dosage form. 46. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 37-42, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms. 47. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 37-46, in a human subject. 48. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with an inhibitor of BTK. 49. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to embodiment 48 for use in the treatment of cancer or an immunological disease . 49b. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to embodiment 48 for use in the treatment of cancer. 50. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor for use in the treatment of cancer according to embodiment 49b, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 51. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor, for use in the treatment of cancer according to embodiment 49b, wherein the cancer is a B- cell lymphoma. 52. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to embodiment 51 wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 53. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to embodiment 52, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL or non-GCB-DLBCL. 54. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to any one of embodiments 48–53, wherein the BTK inhibitor is Compound B. 55. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to any one of embodiments 48-54, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently. 56. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to any one of embodiments 48-54, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially. 57. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to any one of embodiments 48-54, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in a combined dosage form. 58. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to any one of embodiments 48-54, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms. 59. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for (use in) co-administration with a BTK inhibitor according to any one of embodiments 48-58, in a human subject. 60. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with an inhibitor of BTK. 61. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to embodiment 60 for use in the treatment of cancer or an immunological disease . 61b. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to embodiment 60 for use in the treatment of cancer. 62. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor for use in the treatment of cancer according to embodiment 61b, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 63. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor, for use in the treatment of cancer according to embodiment 61b, wherein the cancer is a B-cell lymphoma. 64. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to embodiment 63 wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 65. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to embodiment 64, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL or non-GCB-DLBCL. 66. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to any one of embodiments 60–65, wherein the BTK inhibitor is Compound B. 67. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to any one of embodiments 60-66, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently. 68. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to any one of embodiments 60-66, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially. 69. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to any one of embodiments 60-66, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in a combined dosage form. 70. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to any one of embodiments 60-66, wherein (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms. 71. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide which is to be co-administered with a BTK inhibitor according to any one of embodiments 60-70, in a human subject. 72. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in the treatment of cancer or an immunological disease, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide is used in combination with an inhibitor of BTK. 73. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to embodiment 72 in the treatment of cancer. 74. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to embodiment 73, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 75. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to embodiment 73, wherein the cancer is a B-cell lymphoma. 76. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to embodiment 75 wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 77. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to embodiment 76, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL or non-GCB-DLBCL. 78. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of embodiments 72–77, wherein the BTK inhibitor is B. 79. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of embodiments 72-78, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently. 80. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of embodiments 72-78, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially. 81. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of embodiments 72-78, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in a combined dosage form. 82. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of embodiments 72-78, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms. 83. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of embodiments 72-82, in a human subject. 84. Use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide in the manufacture of a medicament for treating cancer or an immunological disease, wherein the medicament is to be administered to the subject in combination with an inhibitor of BTK . 85. Use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for the manufacture of a medicament for the treatment of cancer or an immunological disease in a subject, wherein (1S,3R)-3-(4-((R)-2- chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide (the MALT1 inhibitor) is adapted to be administrable to the subject in combination with an inhibitor of BTK , wherein the MALT1 inhibitor and the inhibitor of BTK are formulated and adapted to be administrable to the subject in separate compositions, and wherein the MALT1 inhibitor is in form of oral dosage. 86. Use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro- 6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for the manufacture of a medicament for the treatment of cancer or an immunological disease in a subject, wherein (1S,3R)-3-(4-((R)-2- chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide (the MALT1 inhibitor) is adapted to be administrable to the subject in combination with an inhibitor of BTK , in amounts that are therapeutically effective together, and wherein the MALT1 inhibitor and the inhibitor of BTK are administered together in a single dosage form or in separate dosage forms. 87. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 84, 85, or 86 for treating or the treatment of cancer. 88. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 87, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 89. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 87, wherein the cancer is a B-cell lymphoma. 90. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 89, wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 91. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to embodiment 90, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B- cell (GCB)-DLBCL or non-GCB-DLBCL. 92. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 84–91, wherein the BTK inhibitor is Compound B. 93. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 84-92, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently. 94. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 84-92, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially. 95. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 84-92, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in a combined dosage form. 96. The use of (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide according to any one of embodiments 84-92, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms. 97. The use of the inhibitor of according to any one of embodiments 84-96, wherein the subject is a human subject. 98. An inhibitor of BTK for use in the treatment of cancer or an immunological disease , comprising administering to said subject an inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) having the structure of Formula (I) (I) , and the inhibitor 99. An inhibitor of BTK for use in the treatment of cancer or an immunological disease, wherein the BTK inhibitor is used in combination with (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide. 99b. An inhibitor of BTK for use in combination with (1S,3R)-3-(4-((R)-2-chloro-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)- 2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in the treatment of cancer or an immunological disease . 100. The inhibitor of BTK for use in the treatment of cancer or an immunological disease according to embodiment 98, 99 or 99b, wherein one or more of the limitations in any one embodiments 1-97 apply. 101. Any of the previous embodiments for use in the treatment of cancer or an immunological disease whereby levels of regulatory T cells in the subject are reduced. 102. A method of reducing levels of regulatory T cells in a subject having cancer or an immunological disease, said method comprising: administering, to said subject having the cancer or immunological disease, a combination therapy comprising: (i) an inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) having the structure of Formula (I) , and (ii) an is administered to the subject in an amount effective to reduce regulatory T cell levels in the subject relative to the levels of regulatory T cells in the subject prior to said administering. 103. The method according to embodiment 102, wherein the subject has cancer. 104. The method according to embodiment 103, wherein the cancer is selected from the group consisting of a lymphoma, a leukemia, a carcinoma, and a sarcoma. 105. The method according to embodiment 103, wherein the cancer is a B-cell lymphoma. 106. The method according to embodiment 105, wherein the B-cell lymphoma is selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma. 107. The method according to embodiment 106, wherein the B-cell lymphoma is DLBCL, in particular activated B-cell (ABC)-DLBCL, germinal center B-cell (GCB)-DLBCL or non-GCB-DLBCL. 108. The method according to any one of embodiments 102–107, wherein the BTK inhibitor is Compound B. 109. The method according to any one of embodiments 102–108, wherein (1S,3R)- 3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3- e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently. 110. The method according to any one of embodiments 102–108, wherein (1S,3R)- 3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3- e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially. 111. The method according to any one of embodiments 102–108, wherein (1S,3R)- 3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3- e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in a combined dosage form. 112. The method according to any one of embodiments 102-108, wherein (1S,3R)- 3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3- e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms. 113. The method according to any one of embodiments 102–112, wherein the subject is a human subject.

Claims

CLAIMS 1. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use in the treatment of cancer or an immunological disease, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8- dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)- 3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide is used in combination with an inhibitor of BTK.

2. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to claim 1 in the treatment of cancer.

3. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to claim 2, wherein the cancer is a B-cell lymphoma selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma.

4. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to claim 3, wherein the B-cell lymphoma is DLBCL.

5. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of claims 1- 4, wherein the BTK inhibitor isCompound B.

6. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of claims 1- 5, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered concurrently.

7. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of claims 1- 5, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and said BTK inhibitor are administered sequentially.

8. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for use according to any one of claims 1- 5, wherein (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and the BTK inhibitor are administered in separate dosage forms.

9. A method of treating cancer or an immunological disease in a subject in need thereof, said method comprising administering to said subject a combination therapy comprising: (i) (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5- a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide, and (ii) an inhibitor of BTK.

10. The method according to claim 9, wherein the method is for treating cancer.

11. The method according to claim 10, wherein the cancer is a B-cell lymphoma selected from the group consisting of a diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma (tFL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), Burkitt lymphoma, hairy cell leukemia, primary central nervous system lymphoma, and primary intraocular lymphoma.

12. The method according to claim 11, wherein the B-cell lymphoma is DLBCL.

13. The method according to any one of claims 9-12, wherein the BTK inhibitor is Compound B.

14. The method according to any one of claims 9-13, wherein (1S,3R)-3-(4-((R)- 2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and said BTK inhibitor are administered concurrently.

15. The method according to any one of claims 9-13, wherein (1S,3R)-3-(4-((R)- 2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and said BTK inhibitor are administered sequentially.

16. The method according to any one of claims 9–13, wherein (1S,3R)-3-(4-((R)- 2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide and the BTK inhibitor are administered in separate dosage forms.

17. An inhibitor of BTK for use in the treatment of cancer or an immunological disease, wherein the BTK inhibitor is used in combination with (1S,3R)-3-(4-((R)-2-chloro- 8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1- carboxamide.

18. A combination comprising (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide and an inhibitor of BTK for use in the treatment of cancer or an immunological disease.

19. (1S,3R)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro-1-methyl-N-((trans)-3- (methylsulfonyl)cyclobutyl)cyclopropane-1-carboxamide for co-administration with a BTK inhibitor for use in the treatment of cancer or an immunological disease .

20. A method of reducing levels of regulatory T cells in a subject having cancer or an immunological disease, said method comprising: administering, to said subject having the cancer or immunological disease, a combination therapy comprising: (i) an inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) having the structure of Formula (I)I), and (ii) an inhi is administered to the subject in an amount effectiv ect relative to the levels of regulatory T cells in the subject prior to said administering.

Images