MALT1 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S.S.N.63/006,946 filed April 8, 2020, the contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to compounds which are inhibitors of the protease MALT1 and pharmaceutical compositions and combinations thereof, processes for preparing the compounds and their use in cancer therapy in mammals, including humans. BACKGROUND TO THE INVENTION MALT1 (mucosa associated lymphoid tissue lymphoma translocation protein 1) is an intracellular signalling protein, known from innate (natural killer cells NK, dendritic cells DC, and mast cells) and adaptive immune cells (T cells and B cells). The function of MALT1 is best known in the context of T cell receptor (TCR signalling), where it mediates nuclear factor κB (NFκB) signalling leading to T cell activation and proliferation. Accordingly MALT1 was of interest in the mechanism of autoimmune and inflammatory pathologies. Additionally, it was noted that constitutive (dysregulated) MALT1 activity is associated with MALT lymphoma and activated B cell-like diffuse large B Cell lymphoma (ABC-DLBCL). MALT1 is a paracaspase with both scaffold functions (contributing to the assembly of other signalling complexes) and protease functions cleaving a limited repertoire of proteins. The MALT1 proteolytic activity appears essential for T cell activation and also the B cell lymphomas identified above. Several groups have identified inhibitors of MALT1 activity as potential therapeutics. Rebaud et al. Nat. Immunol., 20089(3), 272-81 describes a warhead-equipped substrate analogue zVRPRfmk, while Lim et al., J. Med. Chem., 201558(21), 8591-8502 describes the small molecule MALT1 inhibitor MI2. Nagel et al., Cancer Cell 201222(6), 825-37 describes another small molecule inhibitor mepazine. Novartis has published, in international patent applications WO2015/181747 and WO2017/081641, small molecule MALT1 inhibitors believed to interact with an allosteric site on the enzyme. Characteristic for these prior art inhibitors of MALT1 is that the compounds are proposed for autoimmune or inflammatory pathways, or cancers dependent on dysregulated NFκB pathway activity. 1 ACTIVE/109135237.1 SUMMARY OF THE INVENTION MALT1 inhibitors have previously been proposed for treatment of cancers in which the NFκB pathway is overactive (e.g. ABC-DLBCL). Blockade/inhibition of MALT1 directly down- regulates the NFκB pathway in such cancers, resulting in treatment. In addition to this, the present invention also comprises the appreciation of an activity of MALT1 inhibitors which is independent of the direct inhibition of dysregulated NFκB pathway activity in tumor cells. It is rather a function of the effect on various components of the immune system of inhibiting MALT1. In other words, in addition to MALT1 inhibitors acting directly on the tumor tissue, the present invention envisages that the site of MALT1 action is within specified T cell populations of a subject. This appreciation dramatically expands the range of cancers for which administration of a MALT1 inhibitor is desirable, because a MALT1 inhibitor can now additionally be used as an immunomodulatory agent to activate or augment the T cell anti-cancer response in a subject, irrespective of whether the cancer has dysregulated NFκB pathway activity. The invention thus provides a MALT1 inhibitor of formula I or any subgroup thereof. The invention further provides a compound of formula I or any subgroup thereof for use in the treatment of a disease, a disorder, or a condition characterized by dysregulated NF-kB activation, for example, autoimmune or immunological and inflammatory disorders, allergic disorders, respiratory disorders and oncological disorders. The invention further provides a compound of formula I or any subgroup thereof for use as an immunomodulatory agent in the prevention or treatment of cancer, independently of dysregulated NFκB pathway activation within the cancer cells. The present invention further provides a method for the prevention or treatment of cancer in a subject, the method comprising administering to said subject a compound of formula I or any subgroup thereof as an immunomodulatory agent. The method may additionally comprise administering to the subject a further therapeutic agent. The further therapeutic agent may be: (i) an additional immunomodulatory agent which blocks or inhibits an immune system checkpoint, which checkpoint may or may not be a component of the NFκB pathway; and/or (ii) an agent which directly stimulates an immune effector response, such as a cytokine, or a tumor specific adoptively transferred T cell population, or an antibody specific for a protein expressed by a tumor cell; and/or (iii) a composition comprising a tumor antigen or immunogenic fragment thereof. 2 ACTIVE/109135237.1

BRIEF DESCRIPTION OF THE FIGURES Figure 1 depicts the ratio of FOXP3+CD25+ as a percentage of control for three concentrations of a MALT1 inhibitor, in three donors, as described more fully in Biological Example 1. DESCRIPTION OF THE INVENTION In accordance with the invention, in one aspect described herein are compounds of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from H, halo, cyano, C ₁ -C ₄ alkyl, haloC ₁ -C ₄ alkyl, C1-C4alkoxy, haloC1-C4alkoxy, amino, hydroxymethyl, -CONRaRb, and S(=O) ₂ NH ₂ ; R ² is H; or R ² is selected from C1-C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heterocyclyl-C1-C3alkyl-, 5- to 6-membered heterocyclyl-O-, phenyl, and 5- or 6-membered heteroaryl; any of which are optionally substituted with one to three substituents independent selected from C ₁ -C ₄ alkyl, C1-C4haloalkyl, C1- C4alkoxy, C1-C4haloalkoxy, hydroxy, C1-C4 alkenyl, cyano, azido, NRaRb, C3- C ₆ cycloalkyl, C ₁ -C ₄ alkoxyC ₁ -C ₄ alkoxy, 5- to 6-membered heterocyclyl-O-, 5- to 6- membered heterocyclyl, and phenyl; wherein C3-C6cycloalkyl, 5- to 6-membered heterocyclyl-O-, 5- to 6-membered heterocyclyl, and phenyl are optionally substituted with one two or three substituents each independently selected from halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy, C ₁ - C4alkoxy, C1-C4alkoxyC ₁ -C ₄ alkyl, NRaRb and aminoC1-C3alkyl; R ³ is selected from phenyl, 4- to 11-membered heterocyclyl, and 5- to 11-membered heteroaryl, any of which is optionally substituted with one, two or three R ¹³ ; each R ¹³ is independently selected from halo, hydroxy, cyano, NRaRb, C1-C4alkoxy, and C1- C4haloalkoxy; or R ¹³ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, phenyl, phenylC ₁ -C ₃ alkyl-, 4- to 11-membered heterocyclyl, 4- to 11-membered heterocyclyl-C ₁ -C ₃ alkyl-, 4- to 11-membered heterocyclyl-O-, and 5- to 11- membered heteroaryl, any of which is optionally substituted with one, two or three substituents 3 ACTIVE/109135237.1 each independently selected from halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ - C4haloalkoxy, hydroxy, oxo, cyano, azido, NRaRb, C3-C6cycloalkyl, C1-C4alkoxyC1-C4alkoxy, 5- to 6-membered heterocyclyl-O-, 5- to 6-membered heterocyclyl, and phenyl; and wherein, if the 4- to 11-membered heterocyclyl, 4- to 11-membered heterocyclyl-C ₁ -C ₃ alkyl-, 4- to 11- membered heterocyclyl-O-, or 5- to 11-membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by C1-6alkyl; R ⁴ and R ⁵ are each independently selected from H, halo, cyano, amino, hydroxy, methoxy, methyl, halomethyl and halomethoxy; and Ra and Rb are each independently selected from H, C1-C6alkyl, haloC1-C6alkyl and C3- C ₄ cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-, 5- or 6- membered heterocyclyl or 4-, 5- or 6-membered heteroaryl, wherein the 4-, 5- or 6-membered heterocyclyl or 4-, 5- or 6-membered heteroaryl may contain a further nitrogen atom or an oxygen atom and are optionally substituted with one or two fluoro. The compounds of Formula (I) or any subgroup thereof may optionally be provided in the form of a pharmaceutically acceptable salt and/or solvate. In one embodiment a compound of the invention is provided in the form of a pharmaceutically acceptable salt. In another embodiment a compound of the invention is provided in the form of a pharmaceutically acceptable solvate. In another embodiment a compound of the invention is provided in its free form. In one embodiment of the invention, R ¹ is selected from H, halo, C ₁ -C ₃ alkyl, haloC ₁ -C ₃ alkyl, and haloC ₁ -C ₃ alkoxy. In certain embodiments, R ¹ is selected from H, chloro, fluoro, methyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy. In certain embodiments, R ¹ is selected from H, chloro, fluoro, methyl, and trifluoromethyl. In one embodiment of the invention, R ² is selected from H, C1-C6alkyl, C3-C7cycloalkyl, 5- to 6- membered heterocyclyl, and 5- or 6-membered heteroaryl, wherein C1-C6alkyl is optionally substituted with 1-3 substituents each independently selected from C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, hydroxy, and C ₁ -C ₄ alkoxyC ₁ -C ₄ alkoxy. 4 ACTIVE/109135237.1

In certain embodiments, R ² is selected from H, , , , , , In certain embodiments, R ² is selected from H, , , , , , In one embodiment of the invention, R ³ is pyridinyl or pyridazinyl either of which is optionally substituted with one, two or three R ¹³ . In a typical embodiment of the invention, R ³ is pyridinyl or pyridazinyl either of which is optionally substituted in the meta-position relative the bond to the urea-NH with halo, C1- C ₄ alkyl, C ₁ -C ₄ haloalkyl or cyano, and either of which is optionally substituted with triazole, tetrazole, haloC ₁ -C ₄ alkoxy, methoxyethoxy-, dimethylaminoethoxy-, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or pyrazole substituted with methyl, oxo, amino, or aminomethyl. In one embodiment of the invention, R ³ is optionally substituted pyridin-3-yl, thus providing compounds of the general formula (II): wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ¹³ are as defined for compounds of formula (I). In certain embodiments, the pyridin-3-yl is optionally substituted with one or two substituents. In some embodiments, the substituents are each independently selected from halo, C1-C3alkyl, C1- C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, and a 5-membered heteroaryl. In some 5 ACTIVE/109135237.1

embodiments, substituents are each independently selected from methyl, chloro, difluoromethoxy, trifluoromethyl, and a 5-membered heteroaryl. In certain embodiments, R ³ is 3-pyridinyl optionally substituted with one or two substituents each independently selected from halo, haloC ₁ -C ₄ alkoxy, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, triazole, and tetrazole. In an alternative embodiment of the invention, R ³ is pyridazin-4-yl which is optionally substituted with one, two or three R ¹³ , thus providing compounds of the general formula (III): wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ¹³ are as defined for compounds of formula (I). In certain embodiments, the pyridazin-4-yl is substituted with one or two substituents. In some embodiments, substituents are each independently selected from halo, C ₁ -C ₃ alkyl, C ₁ - C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoy, and a 5-membered heteroaryl. In some embodiments, substituents are selected from methyl, chloro, difluoromethoxy, trifluoromethyl, and a 5- membered heteroaryl. In certain embodiments, R ³ is 4-pyridinyl optionally substituted with C ₁ -C ₄ haloalkyl. In certain embodiments, R ³ is selected from , , 6 ACTIVE/109135237.1

. In certain embodiments, R ³ is selected from: . In certain embodiments, R ³ is selected from , , 7 ACTIVE/109135237.1

In certain embodiments, R ³ is . In one embodiment of the invention, R ⁴ and R ⁵ are both H. In certain embodiments, R ⁴ is halo and R ⁵ is H. In certain embodiments, R ⁴ is chloro or fluoro. In certain embodiments, R ⁴ is H and R ⁵ is fluoro. In one embodiment of the invention, one or two of R ¹ , R ⁴ and R ⁵ is/are halo, typically fluoro or chloro. In certain embodiments, R ¹ and R ⁴ are both halo such as fluoro or chloro, preferably fluoro; or R ¹ and R ⁵ are both halo such as fluoro or chloro, preferably fluoro; or R ⁴ and R ⁵ are both halo such as fluoro or chloro, preferably fluoro. In certain embodiments, R ¹ is selected from H, chloro, fluoro, methyl, and trifluoromethyl; R ² is selected from R ⁴ is selected from H, chloro, and fluoro; and R ⁵ is H or fluoro. In an additional aspect, described herein are compounds of formula (Ia) 8 ACTIVE/109135237.1 or a pharmaceutically acceptable salt thereof, wherein X1 is CH or N; X2 is CRc or N; R ¹ is selected from H, halo, C ₁ -C ₄ alkyl, and haloC ₁ -C ₄ alkyl; R ² is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, 5- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; wherein C1-C6alkyl is optionally substituted with C1-C4alkoxy, C ₁ -C ₄ haloalkyl or hydroxy; R ⁴ and R ⁵ are each independently H or halo; R ¹³ is halo or C ₁ -C ₄ alkyl; wherein C ₁ -C ₄ alkyl is optionally substituted with one, two or three halo substituents; and Rc is selected from C ₁ -C ₄ haloalkoxy, 5- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; wherein, if the 5- or 6-membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by C1-6alkyl; and wherein the 5- to 6- membered heterocyclyl or 5- to 6- membered heteroaryl may optionally be substituted with oxo. In certain embodiments, R ¹ is selected from H, chloro, fluoro, methyl, and trifluoromethyl. In certain embodiments, R ² is selected from H, , , , , , In certain embodiments, R ⁴ is selected from H, chloro, and fluoro. In certain embodiments, R ⁵ is H or chloro. In certain embodiments, X1 is N and X2 is CRc. 9 ACTIVE/109135237.1

In certain embodiments, Rc is selected from In certain embodiments, R ¹³ is chloro. In certain embodiments, X ₁ is CH and X ₂ is N. In certain embodiments, R ¹³ is methyl or trifluoromethyl. In an additional aspect, described herein are compounds of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein X1 is CH; X ₂ is N; R ¹ is H; R ² is C3-C7cycloalkyl; R ⁴ and R ⁵ are each independently H or halo; and R ¹³ is C ₁ -C ₄ alkyl; wherein C ₁ -C ₄ alkyl is optionally substituted with one, two or three halo substituents. In certain embodiments, R ² is cyclopropyl. In certain embodiments, R ⁴ and R ⁵ are each independently selected from H and chloro. For example, R ⁴ may be chloro and R ⁵ is H. 10 ACTIVE/109135237.1

In certain embodiments, R ¹³ is trifluoromethyl. Specific embodiments of the invention include: 11 ACTIVE/109135237.1

12 ACTIVE/109135237.1

or pharmaceutically acceptable salt thereof. In an aspect, the invention provides a compound of formula (I), (Ia), (II) or (III), or any subgroup or series thereof for use as a medicament. A second aspect of the invention provides a compound of formula (I), (Ia), (II) or (III), or any subgroup or series thereof for use in the treatment of cancer, wherein the tumoral tissue is characterized by infiltration of a) Fox P3 positive T-regulatory (Treg) lymphocytes, and b) CD4+ and CD8+ T-effector (T _eff ) lymphocytes. A third aspect of the invention provides the use of a compound of formula (I), (Ia), (II) or (III), or any subgroup or series thereof in the treatment of cancer, in combination with a treatment regime comprising at least one further immuno-oncology agent. In this embodiment, the tumoral tissue is preferably characterized by infiltration of a) Fox P3 positive Treg lymphocytes, and b) CD4+ and CD8+ T _eff lymphocytes. Accordingly, the invention provides a compound of formula (I), (Ia), (II) or (III), or any subgroup thereof for use in the treatment of cancer. 13 ACTIVE/109135237.1

In an additional aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (Ia), (II) or (III), or any subgroup or series thereof in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Further according to this aspect, the invention provides a pharmaceutical composition for use in the treatment of cancer. Especially according to this aspect, the invention provides a pharmaceutical composition for use in the treatment of bladder cancer, colon cancer, hepatocellular cancer or Small Cell or Non- Small Cell lung cancer. The invention additionally provides a pharmaceutical composition for use in the treatment of glioblastoma, cutaneous T-cell lymphoma or head and neck cancers. In an additional aspect, the invention provides a pharmaceutical combination comprising a therapeutically effective amount of compound of formula (I), (Ia), (II) or (III), or any subgroup thereof, further comprising one or more additional therapeutic agent(s) selected from the group consisting of chemotherapeutical agent, multi-drug resistance reversing agent and immuno- oncology agent. In one embodiment of this aspect, the further therapeutic agent is a chemotherapeutic agent. In one embodiment of this aspect, the immuno-oncology agent is selected from antibodies, cytokine therapy, adoptive T-cell therapy and immunostimulatory polysaccharides. Typically, the antibody according to this embodiment is a check point inhibitor. In an additional aspect, the invention provides the use of a compound of formula (I), (Ia), (II) or (III), or any subgroup thereof in the manufacture of a medicament for the treatment of cancer. In an additional aspect, the invention provides a method for the treatment of cancer comprising the administration of a compound of formula (I), (Ia), (II) or (III), or any subgroup thereof. In an additional aspect, the invention provides a compound of formula (I), (Ia), (II) or (III), or any subgroup or series thereof, for use in the treatment of an autoimmune or inflammatory disorder or disease in a patient in need thereof. 14 ACTIVE/109135237.1

In an additional aspect, the invention provides a pharmaceutical combination comprising a therapeutically effective amount of compound of formula (I), (Ia), (II) or (III), or any subgroup thereof or series thereof, for use in the treatment of an autoimmune or inflammatory disorder or disease in a patient in need thereof. In certain embodiments, the autoimmune or inflammatory disorder or disease is selected from the group consisting of acute graft-versus-host disease, chronic graft-versus-host disease, lupus, scleroderma, rheumatoid arthritis, psoriatic arthritis, primary sclerosing cholangitis, multiple sclerosis, and an inflammatory bowel disease. IMMUNE SYSTEM INVOLVEMENT IN CANCER Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T- cells and a high ratio of CD8+ Teff cells compared to FoxP3+ Treg cells correlates with improved prognosis and long-term survival in solid cancers, e.g. colorectal- and ovarian cancer, hepatocellular carcinoma, bladder cancer, malignant melanoma and renal cell carcinoma. Similarly, high levels of infiltrating Treg have been found to be associated with poor prognosis in a number of cancers, e.g. ovarian carcinoma, breast cancer, cervical and renal carcinoma, and malignant melanoma. Therapies resulting in reduction of T _reg and thereby changing the T _eff /T _reg ratio would therefore be expected to have a positive influence on cancer outcome. FoxP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses and appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. While the precise control mechanism has not yet been established, Fox proteins belong to the forkhead/winged-helix family of transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription. In regulatory T cell model systems, the FoxP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function. FoxP3 is a specific marker for natural T regulatory cells (nTreg, a lineage of T cells) and adaptive/induced T regulatory cells (a/iT _reg ), also identified by other less specific markers such as CD25 or CD45RB. In animal studies, T _reg that express FoxP3 are critical in the transfer of immune tolerance, especially self-tolerance. The induction or administration of FoxP3 positive T cells has, in animal studies, led to marked reductions in autoimmune disease severity in models 15 ACTIVE/109135237.1

of diabetes, MS, asthma, inflammatory bowel disease and renal disease. Human trials using regulatory T cells to treat graft versus host disease have shown efficacy. Several FoxP3 recognizing antibodies are commercially available, and immunohistochemistry (IHC) or flow cytometry methods are widely available for recognising FoxP3 positive T _reg lymphocytes, and the tumors which they infiltrate. CD8+ T effector lymphocytes, also known as cytotoxic T lymphocyte or CTL bearing the CD8 glycoprotein, which binds to the constant portion of the class 1 MHC molecule during antigen recognition and apoptosis. CD8+ T effector lymphocytes are readily identified by IHCor by flow cytometry. CD4+ T effector lymphocytes, also known as T helper cells, express the surface protein CD4, a co-receptor of the TCR complex which binds to a different location on the class II MHC molecule. In embodiments of the third aspect of the invention, the further immuno-oncology treatment regime is selected from antibodies, cytokine therapy, adoptive T-cell therapy and immune- stimulatory polysaccharides. In a favored embodiment, the antibody is a checkpoint inhibitor, such as a PD1 inhibitor, for example BGB-A317, or more preferably nivolumab or pembrolizumab. In another embodiment, the checkpoint antibody is a PD-L1 antibody, preferably atezolizemab, avelumab or durvalumab. In another embodiment, the antibody is an immune-stimulatory antibody, such as a 4-1BB (CD137) antibody, such as Utomilumab, a GITR antibody, an OX40 (CD134) antibody, or a CD40 antibody In another embodiment, the antibody is: an anti-CD52 antibody such as alemtuzumab; a CTLA4 antibody such as ipilimumab; a CD20 antibody such as ofatumumab or rituximab. In a further embodiment of the third aspect of the invention, the cytokine therapy comprises an interferon selected from IFNα, IFNβ, IFNγ and IFNλ, or an interleukin, preferably IL-2. 16 ACTIVE/109135237.1

It will thus be appreciated that the method of the invention employing a compound of formula I, as defined above, but excluding the proviso directed to compounds published in CN 103833827, may additionally comprise administering to the cancer patient a further therapeutic agent. The further therapeutic agent may be: (i) an additional immunomodulatory agent which blocks or inhibits an immune system checkpoint, which checkpoint may or may not be a component of the NFκB pathway; and/or (ii) an agent which directly stimulates an immune effector response, such as a cytokine or chemokine (or an agent which stimulates production of either), a tumor specific adoptively transferred T cell population, or an antibody specific for a protein expressed by a tumor cell; and/or (iii) a composition comprising a tumor antigen or immunogenic fragment thereof; and/or (iv) a chemotherapeutic agent. It will be appreciated that many conventional immuno-oncology agents for use in the third aspect of the invention, such as those illustrated above, are biologicals requiring intravenous, intraperitoneal or depot administration. In a favored embodiment of the invention, the MALT1 inhibitor is an orally administered small molecule inhibitor and the further immune-oncology treatment regime is administered parenterally, for example intravenously, intraperitoneally or as a depot. Where the subject receives other medicaments, whether as part of a method of the invention or otherwise, it may be convenient to administer the MALT1 inhibitor by the same route as the other medicaments. Such routes may include parenterally in the case of many immunomodulatory agents, or as TACE for hepatocellular cancer or intrathecally / intracerebrally for glioblastoma, astrocytoma or other nerve tissue cancers. The MALT1 inhibitor may change the ratio of T _reg /T _eff cells infiltrating a tumor in favor of the Teff cells. This may typically be achieved by reducing the number of infiltrating Treg cells whilst maintaining or increasing the level of infiltrating Teff cells. The ratio of Treg/Teff cells in a tumor may be determined by any suitable method, but typically involves the quantification of each cell type in a tumor sample or a sample from a tumor draining lymph node. Suitable methods include, but are not limited to, flow cytometry. In one embodiment of the invention, the compound of the invention is orally administered. In certain forms of cancer it may be preferable to administer the compound of the invention locally, e.g. topically, or intravesically in the case of bladder cancer. Alternatively, as the patient may 17 ACTIVE/109135237.1

also be receiving further parenteral medicaments, for example the further immune-oncology agent of the third aspect of the invention, it may be convenient to deliver the compound of the invention by the same route. In other embodiments, the patient may be receiving other medicaments by still further routes, such as TACE for hepatocellular cancer or intrathecally/intracerebrally for glioblastoma, astrocytoma or other nerve tissue cancers. It may be convenient to co-administer the MALT1 inhibitor by the same route. In various embodiments of the invention the cancer is selected from bladder cancer, colon cancer, hepatocellular cancer, or Small Cell or Non-Small Cell lung cancer. In a further embodiment of the invention, the cancer is selected from B-cell malignancies such as B-cell lymphoma, e.g. Diffuse large cell B-cell lymphoma (DLBCL) and Mantle cell lymphoma (MCL), and Leukemias, e.g. chronicle lymphatic leukemia (CLL). METHODS FOR THE PREVENTION OR TREATMENT OF CANCER All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. The invention concerns preventing or treating cancer. The cancer is preferably of a type which is not characterised by abnormally high activity in the NF-κB pathway. The cancer may be characterised by the presence of both infiltrating regulatory T cells (Treg cells) and infiltrating effector T cells (T _eff cells) in the tumor. T _reg cells are typically characterised as FOXP3+. Teff cells are typically characterised as CD4+ or CD8+. The number of Treg and Teff cells in a tumor may be determined by any suitable method, but typically this involves the quantification of each cell type in a tumor sample or a sample from a tumor draining lymph node. Suitable methods for the quantification of cells include flow cytometry, which may be performed in accordance with the protocols set out in the Examples. 18 ACTIVE/109135237.1

The cancer may be prostate cancer, brain cancer, breast cancer, colorectal cancer, pancreatic cancer, ovarian cancer, lung cancer, cervical cancer, liver cancer, head/neck/throat cancer, skin cancer, bladder cancer or a hematologic cancer. The cancer may take the form of a tumor or a blood born cancer. The tumor may be solid. The tumor is typically malignant and may be metastatic. The tumor may be an adenoma, an adenocarcinoma, a blastoma, a carcinoma, a desmoid tumor, a desmoplastic small round cell tumor, an endocrine tumor, a germ cell tumor, a lymphoma, a leukaemia, a sarcoma, a Wilms tumor, a lung tumor, a colon tumor, a lymph tumor, a breast tumor or a melanoma. Types of blastoma include, but are not limited to, hepatoblastoma, glioblastoma, neuroblastoma or retinoblastoma. Types of carcinoma include, but are not limited to, colorectal carcinoma or hepatocellular carcinoma, pancreatic, prostate, gastric, esophageal, cervical, and head and neck carcinomas, and adenocarcinoma. Types of sarcoma include, but are not limited to, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or any other soft tissue sarcoma. Types of melanoma include, but are not limited to, Lentigo maligna, Lentigo maligna melanoma, Superficial spreading melanoma, Acral lentiginous melanoma, Mucosal melanoma, Nodular melanoma, Polypoid melanoma, Desmoplastic melanoma, Amelanotic melanoma, Soft-tissue melanoma, Melanoma with small nevus-like cells, Melanoma with features of a Spitz nevus and Uveal melanoma. Types of lymphoma and leukaemia include, but are not limited to, Precursor T-cell leukemia/lymphoma, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphocytic leukaemia, Follicular lymphoma, Diffuse large B cell lymphoma, Mantle cell lymphoma, chronic lymphocytic leukemia/lymphoma, MALT lymphoma, Burkitt's lymphoma, Mycosis fungoides, Peripheral T-cell lymphoma, Nodular sclerosis form of Hodgkin lymphoma, Mixed- cellularity subtype of Hodgkin lymphoma. Types of lung tumor include, but are not limited to, tumors of non-small-cell lung cancer (adenocarcinoma, squamous-cell carcinoma and large-cell carcinoma) and small-cell lung carcinoma. 19 ACTIVE/109135237.1

The cancer may preferably be selected from bladder cancer, colon cancer, hepatocellular cancer, or Small Cell or Non-Small Cell lung cancer. In a further embodiment of the invention, the compounds of formula (I), (Ia), (II) or (III), or any subgroup thereof are proposed for autoimmune or inflammatory pathways, or cancers dependent on dysregulated NFκB pathway activity. In certain embodiments, the cancer is selected from the group consisting of carcinoma, sarcoma, lymphoma, leukemia and germ cell tumors, adenocarcinoma, bladder cancer, clear cell carcinoma, skin cancer, brain cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, brain tumors, breast cancer, gastric cancer, germ cell tumors, glioblastoma, hepatic adenomas, Hodgkin's lymphoma, liver cancer, kidney cancer, lung cancer, pancreatic cancer, head/neck/throat cancer, ovarian cancer, dermal tumors, prostate cancer, renal cell carcinoma, stomach cancer, hematologic cancer, medulloblastoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B cell-like diffuse large B Cell lymphoma (ABC-DLBCL), mantle cell lymphoma, marginal zone lymphoma, T cell lymphomas, in particular Sezary syndrome, Mycosis fungoides, cutaneous T-cell lymphoma, T-cell acute lymphoblastic leukemia, melanoma, mucosa-associated lymphoid tissue (MALT) lymphoma, multiple myeloma, plasma cell neoplasm, lentigo maligna melanomas, acral lentiginous melanoma, squamous cell carcinoma, chronic myelogenous leukemia, myeloid leukemia, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft-tissue melanoma, melanoma with small nevus-like cells, melanoma with features of a Spitz nevus, uveal melanoma, precursor T-cell, leukemia/lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, follicular lymphoma, chronic lymphocytic leukemia/lymphoma, Burkitt's lymphoma, mycosis fungoides, peripheral T-cell lymphoma, nodular sclerosis form of Hodgkin lymphoma, mixed-cellularity subtype of Hodgkin lymphoma, non-small-cell lung cancer, large-cell carcinoma, and small-cell lung carcinoma. In certain embodiments, the cancer is a cancer in the form of a tumor or a blood born cancer. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is malignant and/or metastatic. In some embodiments, the tumor is selected from an adenoma, an 20 ACTIVE/109135237.1

adenocarcinoma, a blastoma (e.g., hepatoblastoma, glioblastoma, neuroblastoma and retinoblastoma), a carcinoma (e.g., colorectal carcinoma or hepatocellular carcinoma, pancreatic, prostate, gastric, esophageal, cervical, and head and neck carcinomas, and adenocarcinoma), a desmoid tumor, a desmoplastic small round cell tumor, an endocrine tumor, a germ cell tumor, a lymphoma, a leukemia, a sarcoma (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or any other soft tissue sarcoma), a Wilms tumor, a lung tumor, a colon tumor, a lymph tumor, a breast tumor or a melanoma. COMBINATIONS The invention may additionally comprise administering to the subject a further therapeutic agent. The further therapeutic agent may preferably be: (i) an additional immunomodulatory agent which blocks or inhibits an immune system checkpoint, which checkpoint may or may not be a component of the NFκB pathway; and/or (ii) an agent which directly stimulates an immune effector response, such as a cytokine, or a tumor specific adoptively transferred T cell population, or an antibody specific for a protein expressed by a tumor cell; and/or (iii) a composition comprising a tumor antigen or immunogenic fragment thereof; and/or (iv) a chemotherapeutic agent. The compound of the invention may be administered either simultaneously with, or before or after, the further therapeutic agent. The MALT1 inhibitor may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the further therapeutic agent. The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of formula (I), (Ia), (II) or (III), and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non- fixed combination" means that the active ingredients, e.g. a compound of formula (I), (Ia), (II) or 21 ACTIVE/109135237.1

(III), and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients. In one embodiment, the Invention provides a product comprising a compound of the invention, such as a compound of formula (I), (Ia), (II) or (III), or any subgroup thereof and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. Products provided as a combined preparation include a composition comprising the compound of the invention such as a compound of formula (I), (Ia), (II) or (III), or any subgroup thereof and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I), (Ia), (II) or (III), or any subgroup thereof and the other therapeutic agent(s) in separate form, e.g. in the form of a kit. In one embodiment, the invention provides a pharmaceutical composition for use in therapy comprising a compound of formula (I), (Ia), (II) or (III), or any subgroup thereof and an additional immunomodulatory agent or a composition comprising a tumor antigen or immunogenic fragment thereof. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient. It will be appreciated that many of the further therapeutic agents used in the methods of the invention may be biologicals requiring intravenous, intraperitoneal or depot administration. In a favored embodiment the compound of the invention is orally administered and the further therapeutic agent is administered parenterally, for example intravenously, intraperitoneally or as a depot. IMMUNE SYSTEM CHECKPOINT Effector T cell activation is normally triggered by the T cell receptor recognising antigenic peptide presented by the MHC complex. The type and level of activation achieved is then determined by the balance between signals which stimulate and signals which inhibit the effector T cell response. The term “immune system checkpoint” is used herein to refer to any molecular interaction which alters the balance in favor of inhibition of the effector T cell response. That is, a molecular interaction which, when it occurs, negatively regulates the activation of an effector T cell. Such an interaction might be direct, such as the interaction between a ligand and a cell surface receptor which transmits an inhibitory signal into an effector T cell. Or it might be indirect, such as the blocking or inhibition of an interaction between a ligand and a cell surface receptor which would otherwise transmit an activatory signal into the effector T cell, or an 22 ACTIVE/109135237.1

interaction which promotes the upregulation of an inhibitory molecule or cell, or the depletion by an enzyme of a metabolite required by the effector T cell, or any combination thereof. Examples of immune system checkpoints include, but are not limited to: a) The interaction between indoleamine 2,3-dioxygenase (IDO1) and its substrate; b) The interaction between PD1 and PDL1 and/or PD1 and PDL2; c) The interaction between CTLA4 and CD86 and/or CTLA4 and CD80; d) The interaction between B7-H3 and/or B7-H4 and their respective ligands; e) The interaction between HVEM and BTLA; f) The interaction between GAL9 and TIM3; g) The interaction between MHC class I or II and LAG3; h) The interaction between MHC class I or II and KIR; i) The interaction between OX40(CD134) and OX40L (CD252); k) The interaction between CD40 and CD40L (CD154); l) The interaction between 4-1BB (CD137) and ligands including 4-1BBL; and m) The interaction between GITR and ligands including GITRL. A preferred checkpoint for the purposes of the present invention is checkpoint (b), namely the interaction between PD1 and either of its ligands PD-L1 and PD-L2. PD1 is expressed on effector T cells. Engagement with either ligand results in a signal which downregulates activation. The ligands are expressed by some tumors. PD-L1 in particular is expressed by many solid tumors, including melanoma. These tumors may therefore down regulate immune mediated anti-tumor effects through activation of the inhibitory PD-1 receptors on T cells. By blocking the interaction between PD1 and one or both of its ligands, a checkpoint of the immune response may be removed, leading to augmented anti-tumor T cell responses. Therefore PD1 and its ligands are examples of components of an immune system checkpoint which may preferably be targeted in the method of the invention Another preferred checkpoint for the purposes of the present invention is checkpoint (c), namely the interaction between the T cell receptor CTLA-4 and its ligands, the B7 proteins (B7-1 and B7-2). CTLA-4 is ordinarily upregulated on the T cell surface following initial activation, and ligand binding results in a signal which inhibits further/continued activation. CTLA-4 competes for binding to the B7 proteins with the receptor CD28, which is also expressed on the T cell surface but which upregulates activation. Thus, by blocking the CTLA-4 interaction with the B7 proteins, but not the CD28 interaction with the B7 proteins, one of the normal check points of 23 ACTIVE/109135237.1

the immune response may be removed, leading to augmented anti-tumor T cell responses. Therefore CTLA4 and its ligands are examples of components of an immune system checkpoint which may preferably be targeted in the method of the invention. IMMUNOMODULATORY AGENT An “immunomodulatory agent” is used herein to mean any agent which, when administered to a subject, blocks or inhibits the action of an immune system checkpoint, resulting in the upregulation of an immune effector response in the subject, typically a T cell effector response, which preferably comprises an anti-tumor T cell effector response. The immunomodulatory agent used in the method of the present invention may block or inhibit any of the immune system checkpoints described above. The agent may be an antibody or any other suitable agent which results in said blocking or inhibition. The agent may thus be referred to generally as an inhibitor of a said checkpoint. An “antibody” as used herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chains thereof. An antibody may be a polyclonal antibody or a monoclonal antibody and may be produced by any suitable method. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include, but are not limited to, a Fab fragment, a F(ab')2 fragment, a Fab’ fragment, a Fd fragment, a Fv fragment, a dAb fragment and an isolated complementarity determining region (CDR). Single chain antibodies such as scFv and heavy chain antibodies such as VHH and camel antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. Preferred antibodies which block or inhibit the CTLA-4 interaction with B7 proteins include , but are not limited to, ipilumumab, tremelimumab, or any of the antibodies disclosed in WO2014/207063. Other molecules include polypeptides, or soluble mutant CD86 polypeptides. Ipilumumab is most preferred. Preferred antibodies which block or inhibit the PD1 interaction with PD-L1 include, but are not limited to, Nivolumab, Pembrolizumab, Lambrolizumab, Pidilzumab, BGB-A317 and AMP- 224. Nivolumab or pembrolizumab is most preferred. Anti-PD-L1 antibodies include, but are not limited to, atezolizemab, avelumab or durvalumab, MEDI-4736 and MPDL3280A. Preferred antibodies which block or inhibit the interaction between 4-1BB and its ligand include utomilumab. 24 ACTIVE/109135237.1

Other suitable inhibitors include small molecule inhibitors (SMI), which are typically small organic molecules. Preferred inhibitors of IDO1 include, but are not limited to, Epacadostat (INCB24360), Indoximod, GDC-0919 (NLG919) and F001287. Other inhibitors of IDO1 include 1-methyltryptophan (1MT). DIRECT STIMULATION OF IMMUNE EFFECTOR RESPONSES As used herein, “an agent which directly stimulates an immune effector response” means any suitable agent, but typically refers to a cytokine or chemokine (or an agent which stimulates production of either), a tumor specific adoptively transferred T cell population, or an antibody specific for a protein expressed by a tumor cell. The cytokine may be an interferon selected from IFNα, IFNβ, IFNγ and IFNλ, or an interleukin, preferably IL-2. The chemokine may be an inflammatory mediator, for example selected from CXCL9, 10, and 11, which attract T cells expressing CXCR3. The agent which stimulates production of a cytokine or chemokine may be an adjuvant suitable for administration to humans. A preferred example is Bacille Calmette-Guerin (BCG), which is typically administered intravesically (i.e. urethral catheter) for treatment of bladder cancer. A typical dosage regime of BCG for bladder cancer is once per week for six weeks, but given its long safety history it is also administered indefinitely as maintenance. BCG has been shown to stimulate immune responses to bladder cancer. BCG has also been used as an adjuvant in combination with compositions which comprise tumor antigens (i.e. with cancer vaccines), particularly for colon cancer when it is administered typically intradermally. Such uses of BCG are also envisaged in the present invention. The tumor specific adoptively transferred T cell population directly increases the size of the tumor specific T cell population in an individual, and may be generated by any suitable means. However, typically the process involves isolating tumor specific T cells from a tumor sample taken from a patient, and selectively culturing those cells before returning the expanded population of tumor-specific T cells to the patient. Alternatively a tumor specific T cell population may be produced by genetic engineering of the T cell receptor locus, followed by expansion of the altered cell. Antibodies specific for proteins expressed by a tumor cell typically stimulate immune activity by binding to the tumor cell and promoting destruction of the cell via antibody-dependent cell- mediated cytotoxicity (ADCC). Preferred examples of antibodies of this type include, but are not 25 ACTIVE/109135237.1

limited to, anti-CD20 antibodies such as ofatumumab or rituximab, and anti-CD52 antibodies such as alemtuzumab. COMPOSITIONS COMPRISING TUMOR ANTIGENS A composition of the invention may comprise any tumor antigen or any antigenic fragment thereof. Such a composition may alternatively be described as a vaccine against the said tumor antigen, which stimulates an adaptive immune response to the antigen when administered to a subject. The tumor antigen or fragment may be present in the composition in polypeptide (or peptide) form, or may be encoded by a nucleic acid, for example an RNA or DNA molecule, or may be present as whole cells (e.g., an autologous tumor cell vaccine). Tumor antigens are typically molecules which are located on the surface of the tumor cell. Tumor antigens may be selected from proteins which are overexpressed in tumor cells compared to a normal, non-cancerous cell. Tumor antigens include antigens expressed in cells which are not cancerous but are associated with a tumor. Antigens which are connected with tumor- supplying vessels or formation thereof, in particular those antigens which are associated with neo-vascularization, e.g. VEGF, bFGF, are also included herein. Antigens associated with a tumor furthermore include antigens from cells or tissues, typically embedding the tumor. Tumor antigens can be divided further into tumor-specific antigens (TSAs) and tumor- associated-antigens (TAAs). TSAs can only be expressed by tumor cells and not by normal “healthy” cells. They typically result from a tumor specific mutation. TAAs, which are more common, may be expressed by both tumor and healthy cells. These antigens are recognized and the antigen-expressing cell can be destroyed by cytotoxic T cells. Additionally, tumor antigens can also occur on the surface of the tumor in the form of, e.g., a mutated receptor. In this case, they can be recognized by antibodies. Further, tumor associated antigens may be classified as tissue-specific antigens, examples of which include, but are not limited to, melanocyte-specific antigens, cancer-testis antigens and tumor-specific antigens. Cancer-testis antigens are typically understood to be peptides or proteins of germ-line associated genes which may be activated in a wide variety of tumors. Human cancer-testis antigens may be further subdivided into antigens which are encoded on the X chromosome, so-called CT-X antigens, and those antigens which are not encoded on the X chromosome, the so-called non-X CT antigens. Cancer-testis antigens which are encoded on the X-chromosome comprise, for example, the family of melanoma antigen genes, the so-called MAGE-family. The genes of the MAGE-family may be characterised by a shared MAGE homology domain (MHD). Each of these antigens, i.e. 26 ACTIVE/109135237.1

melanocyte-specific antigens, cancer-testis antigens and tumor-specific antigens, may elicit autologous cellular and humoral immune responses. Preferred tumor antigens of the invention include, but are not limited to, a melanocyte-specific antigen, a cancer-testis antigen or a tumor- specific antigen, preferably a CT-X antigen, a non-X CT-antigen, a binding partner for a CT-X antigen or a binding partner for a non-X CT-antigen or a tumor-specific antigen, more preferably a CT-X antigen, a binding partner for a non-X CT-antigen or a tumor-specific antigen. Particularly preferred tumor antigens are selected from 5T4, 707-AP, 9D7, AFP, AlbZlP HPG1, alpha-5-beta-1-integrin, alpha-5-beta-6-integrin, alpha-actinin-4/m, alpha-methylacyl-coenzyme A racemase, ART-4, ARTC1/m, B7H4, BAGE-1, BCL-2, bcr/abl, beta-catenin/m, BING-4, BRCA1/m, BRCA2/m, CA 15-3/CA 27-29, CA 19-9, CA72-4, CA125, calreticulin, CAMEL, CASP-8/m, cathepsin B, cathepsin L, CD19, CD20, CD22, CD25, CDE30, CD33, CD4, CD52, CD55, CD56, CD80, CDC27/m, CDK4/m, CDKN2A/m, CEA, CLCA2, CML28, CML66, COA-1/m, coactosin-like protein, collage XXIII, COX-2, CT-9/BRD6, Cten, cyclin B1, cyclin D1, cyp-B, CYPB1, DAM-10, DAM-6, DEK-CAN, EFTUD2/m, EGFR, ELF2/m, EMMPRIN, EpCam, EphA2, EphA3, ErbB3, ETV6-AML1, EZH2, FGF-5, FN, Frau-1, G250, GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE7b, GAGE-8, GDEP, GnT-V, gp100, GPC3, GPNMB/m, HAGE, HAST-2, hepsin, Her2/neu, HERV-K-MEL, HLA-A*0201-R17I, HLA-A11/m, HLA-A2/m, HNE, homeobox NKX3.1, HOM-TES-14/SCP-1, HOM-TES-85, HPV-E6, HPV-E7, HSP70-2M, HST-2, hTERT, iCE, IGF-1R, IL-13Ra2, IL-2R, IL-5, immature laminin receptor, kallikrein-2, kallikrein-4, Ki67, KIAA0205, KIAA0205/m, KK-LC-1, K- Ras/m, LAGE-A1, LDLR-FUT, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-A10, MAGE-A12, MAGE-B1, MAGE-B2, MAGE-B3, MAGE-B4, MAGE-B5, MAGE-B6, MAGE-B10, MAGE-B16, MAGE-B17, MAGE-C1, MAGE-C2, MAGE-C3, MAGE-D1, MAGE-D2, MAGE-D4, MAGE-E1, MAGE-E2, MAGE-F1, MAGE- H1, MAGEL2, mammaglobin A, MART-1/melan-A, MART-2, MART-2/m, matrix protein 22, MC1R, M-CSF, ME1/m, mesothelin, MG50/PXDN, MMP11, MN/CA IX-antigen, MRP-3, MUC-1, MUC-2, MUM-1/m, MUM-2/m, MUM-3/m, myosin class l/m, NA88-A, N- acetylglucosaminyltransferase-V, Neo-PAP, Neo-PAP/m, NFYC/m, NGEP, NMP22, NPM/ALK, N-Ras/m, NSE, NY-ESO-B, NY-ESO-1, OA1, OFA-iLRP, OGT, OGT/m, OS-9, OS-9/m, osteocalcin, osteopontin, p15, p190 minor bcr-abl, p53, p53/m, PAGE-4, PAI-1, PAI-2, PAP, PART-1, PATE, PDEF, Pim-1-Kinase, Pin-1, Pml/PARalpha, POTE, PRAME, PRDX5/m, prostein, proteinase-3, PSA, PSCA, PSGR, PSM, PSMA, PTPRK/m, RAGE-1, RBAF600/m, RHAMM/CD168, RU1, RU2, S-100, SAGE, SART-1, SART-2, SART-3, SCC, SIRT2/m, Sp17, 27 ACTIVE/109135237.1

SSX-1, SSX-2/HOM-MEL-40, SSX-4, STAMP-1, STEAP-1, survivin, survivin-2B, SYT-SSX- 1, SYT-SSX-2, TA-90, TAG-72, TARP, TEL-AML1, TGFbeta, TGFbetaRII, TGM-4, TPI/m, TRAG-3, TRG, TRP-1, TRP-2/6b, TRP/INT2, TRP-p8, tyrosinase, UPA, VEGFR1, VEGFR- 2/FLK-1, and WT1. Most preferred tumor antigens are selected from p53, CAl25, EGFR, Her2/neu, hTERT, PAP, MAGE-A1, MAGE-A3, Mesothelin, MUC-1, GP100, MART-1, Tyrosinase, PSA, PSCA, PSMA, STEAP-1, VEGF, VEGFR1, VEGFR2, Ras, CEA or WT1. Tumor antigens also may encompass idiotypic antigens associated with a cancer or tumor disease, particularly lymphoma or a lymphoma associated disease, wherein said idiotypic antigen is an immunoglobulin idiotype of a lymphoid blood cell or a T cell receptor idiotype of a lymphoid blood cell. In a particular embodiment, provided herein is a method for the treatment of bladder cancer comprising the administration of a MALT1 inhibitor and at least one of BCG and a chemotherapeutic agent selected from mitomycin, valrubicin, docetaxel, thiotepa and gemcitabine, wherein at least the BCG and the chemotherapeutic agent are preferably administered intravesically, i.e. via urethral catheter. In another embodiment, provided herein is a method for the treatment of colon cancer comprising the administration of a MALT1 inhibitor and at least one of BCG and a composition comprising a tumor antigen, preferably an autologous tumor cell vaccine. At least the BCG and the composition comprising a tumor antigen are preferably administered parenterally, optionally as a single combined preparation. METHODS FOR THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISORDERS In one aspect, provided herein are methods of treating an autoimmune or inflammatory disorder or disease in a patient in need thereof, the method generally comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula (I), (Ia), (II) or (III), or a pharmaceutical composition described herein. In certain embodiments, the autoimmune or inflammatory disorder or disease is selected from the group consisting of acute graft-versus-host disease, chronic graft-versus-host disease, lupus, scleroderma, rheumatoid arthritis, psoriatic arthritis, primary sclerosing cholangitis, multiple sclerosis, and an inflammatory bowel disease. 28 ACTIVE/109135237.1

METHODS FOR THE TREATMENT OF AN ALLERGIC DISORDER In one aspect, provided herein are methods of treating an allergic disorder or disease in a patient in need thereof, the method generally comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula (I), (Ia), (II) or (III)) or a pharmaceutical composition described herein. In certain embodiments, the allergic disorder is selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, and berylliosis. METHODS FOR THE TREATMENT OF A RESPIRATORY DISORDER In one aspect, provided herein are methods of treating a respiratory disorder or disease in a patient in need thereof, the method generally comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula (I), (Ia), (II) or (III)) or a pharmaceutical composition described herein. In certain embodiments, the respiratory disorder is selected from asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension and emphysema. DEFINITIONS As used in the foregoing and hereinafter, the scientific and technological terms and nomenclature have the same meaning as commonly understood by a person of ordinary skill in the art, in addition, the following definitions apply unless otherwise noted. The term ‘C _m -C _n alkyl’ as a group or part of a group such as C _m -C _n haloalkyl, C _m - Cnalkylcarbonyl, Cm-Cnalkylamine, etc. wherein m and n are integers ≥ 0, and m < n, denotes a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms indicated, e.g. C ₁ -C ₄ alkyl means an alkyl radical having from 1 to 4 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl and isobutyl, similarly, C1-C6alkyl means a straight or branched alkyl radical having from 1 to 6 carbon atoms, including also all straight and branched chain isomers of pentyl and hexyl. The term ‘C ₂ -C _n alkenyl’ as a group or part of a group denotes a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon double bond, and having the number of carbon atoms indicated wherein n is an integer < 1, e.g. 29 ACTIVE/109135237.1

C ₂ -C ₆ alkenyl means an alkenyl group having from 2 to 6 carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), isopropenyl, butenyl, and the like. The term ‘C ₂ -C _n alkynyl’ as a group or part of a group denoted s a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon triple bond, and having the number of carbon atoms indicated wherein n is an integer > 1, e.g. C2- C ₆ alkynyl means an alkynyl group having from 2 to 6 carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, propynyl, butynyl, and the like. The term ‘C3-Cncycloalkyl’ as a group or part of a group denotes a saturated cyclic hydrocarbon radical having the number of carbon atoms indicated wherein n is an integer ≥ 3, e.g. C ₃ - C ₆ cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6, carbon atoms. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, especially cyclopropyl. The term ‘C ₃ -C _n’ cycloalkylC _m -C _n alkyl’ denotes a C _m -C _n alkyl radical which is substituted with a C3-Cn’cycloalkyl moiety, wherein C3-Cn’cycloalkyl and Cm-Cnalkyl are as defined above for C3- Cncycloalkyl and Cm-Cnalkyl respectively. Exemplary C3-Cn’cycloalkylCm-Cnalkyl groups include, but are not limited to, C ₃ -C ₇ cycloalkylC ₁ -C ₃ alkyl, i.e. the cycloalkyl moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group. The term ‘C3-Cncycloalkenyl’ as a group or part of a group defines a cyclic hydrocarbon radical having the number of carbon atoms designated and one double bond, e.g. C ₃ -C ₆ cycloalkenyl means a cycloalkenyl group having 3, 4, 5 or 6, carbon atoms. Exemplary cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. The term ‘C1-Cnalkoxy’ defines a radical O-C1-Cnalkyl wherein C1-Cnalkyl is as defined for Cm- C _n alkyl above. Preferred alkoxy groups for use in the invention are C ₁ -C ₆ alkoxy, i.e. alkoxy groups having from 1 to 6 carbon atoms. Exemplary alkoxy groups include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy, and the like. The term "Me" means methyl and "MeO" means methoxy. The term ‘halo’ or ‘halogen’ is generic to fluoro, chloro, bromo and iodo. 30 ACTIVE/109135237.1

The terms ‘haloC _m -C _n alkyl’ or ‘C _m -C _n haloalkyl’ as a group or part of a group, represent a C _m - Cnalkyl wherein at least one C-atom is substituted with one or more halogen atom(s), in particular C ₁ -C ₄ alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. In case more than one halogen atom is attached to an alkyl group within the definition of haloCm-Cnalkyl or Cm-Cnhaloalkyl, the halogen atoms may be the same or different. The terms ‘haloC _n -C _m alkoxy’ or ‘C _n -C _m haloalkoxy’ represents a C _n -C _m alkoxy having the number of carbon atoms indicated, wherein at least one C-atom is substituted with one or more halogen atom(s), typically chloro or fluoro. Of particular interest is C1-C6haloalkoxy. In many cases trifluoromethyl is preferred. The term ‘oxo’ or ‘(=O)’ represents double bonded oxygen atom, i.e. forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulphur atom and a sulphonyl moiety when two of said terms are attached to the same sulphur atom. It should be noted that an atom can only be substituted with an oxo group when the valence of that atom so permits. The term ‘amino’ means NH2. The term ‘cyano’ means CN. The term ‘azido’ means N ₃ . The terms ‘aminoCm-Cnalkyl’ and ‘amino(Cm-Cnalkyl)2’ denotes an amino group wherein one or two of the hydrogen atoms respectively is replaced by C _m -C _n alkyl wherein C _m -C _n alkyl is as defined above and wherein the m and n in the (C _m -C _n alkyl) ₂ are selected independently of each other. Included are also radicals wherein the two Cm-Cnalkyl groups of the -N(Cm-Cnalkyl)2 together with the nitrogen atom to which they are attached form a saturated 3 to 6 membered cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl. The term 'aryl' as a group or part of a group as applied herein represents an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a C4-C6cycloalkyl (for example indanyl), or a C4- C ₆ cycloalkenyl. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. 31 ACTIVE/109135237.1

The term ‘arylC _m -C _n alkyl’ represents a C _m -C _n alkyl which is substituted with aryl, wherein aryl and Cm-Cnalkyl are as defined above. Preferred arylCm-Cnalkyl groups for use in the invention are arylC1-C3alkyl, i.e. the aryl moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group. The term 'heterocyclyl', ‘heterocyclic’ or ‘heterocycle’ as applied herein denotes a 4- to 11- membered saturated or partially unsaturated mono-, bi-, or spirocyclic ring system containing 1, 2, 3 or 4 are heteroatoms each independently selected from N, O and S. Examples of suitable heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrazolinyl, pyrazolidinyl, thiazolidinyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, azetidinyl etc. Unless otherwise indicated the heterocyclyl group is optionally substituted with one, two or three substituents. The term ‘heterocylylCm-Cnalkyl’ represents a Cm-Cnalkyl which is substituted with heterocyclyl, wherein heterocyclyl and C _m -C _n alkyl are as defined above. Preferred heterocyclylCm-Cnalkyl groups for use in the invention are heterocyclylC1-C3alkyl, i.e. the heterocyclyl moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group. The term ‘heteroaryl’ as applied herein denotes a 5- to 11- membered mono- or bicyclic aromatic ring system containing 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S. Examples of suitable heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl, benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzo- 1,2,3-triazolyl, benzo-1,2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazolyl, indolyl, isoindolyl indolinyl, isoindolinyl, indanyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrazolopyridinyl, etc. Unless otherwise indicated the heteroaryl group is optionally substituted with one, two or three substituents. The term ‘heteroarylC _m -C _n alkyl’ represents a C _m -C _n alkyl which is substituted with heteroaryl, wherein heteroaryl and Cm-Cnalkyl are as defined above. Preferred heteroarylCm-Cnalkyl groups for use in the invention are heteroarylC ₁ -C ₃ alkyl, i.e. the heteroaryl moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group. 32 ACTIVE/109135237.1

Typically, an aryl, heterocyclyl and heteroaryl moiety within the scope of the above definitions is thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring. It should be noted that the radical position(s) on any moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable. Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl. The term “optionally substituted” as used herein, means that substitution is optional, i.e. the group may or may not be substituted. For instance, the expression “alkyl group optionally substituted with one or more substituents” means that the alkyl group is substituted by 0, 1 or more substituents. The term “substituted” refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. The term “substitutable” refers to an atom to which hydrogen may be covalently attached, and to which another substituent may be present instead of the hydrogen. A non-limiting example of substitutable atoms includes the carbon atoms of pyridine. The nitrogen atom of pyridine is not substitutable according to this definition. Further, according to the same definition, the imine nitrogen at position 3 in imidazole is not substitutable, while the amine nitrogen at position 1 is. When a variable occurs more than one time in any constituent, each definition is independent. As used herein, the terms "salt" or "salts" refers to an acid addition or base addition salt of a compound. "Salts" include in particular "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable, in many cases, the compounds are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, 33 ACTIVE/109135237.1

isothionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, poiygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. The pharmaceutically acceptable salts can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non- aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002). 34 ACTIVE/109135237.1

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavouring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. The term "a therapeutically effective amount" refers to an amount of a substance that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of a compound of the invention that, when administered to a subject, is sufficient to achieve an immunomodulatory effect which at least partially alleviates, inhibits, prevents and/or ameliorates a cancerous condition, independently of dysregulated NFkB pathway activation within the cancer cells. As used herein, “chemotherapeutic agent” means any agent which has been approved for use as a chemotherapy for cancer. Examples include but are not limited to: all-trans retinoic acid, actimide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, irinotecan, lenalidomide, leucovorin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, revlimid, temozolomide, teniposide, thioguanine, thiotepa, valrubicin, vinblastine, vincristine, vindesine and vinorelbine. a chemotherapeutic agent for use in the combinations described herein may, itself, be a combination of different chemotherapeutic agents. suitable combinations include a combination of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (may be referred to as FOLFOX), or a combination of irinotecan, 5-FU, and leucovorin (may be referred to as IFL).As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like, in certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. 35 ACTIVE/109135237.1

As used herein, the term "inhibit," "inhibition," or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof), in another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder. As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. ISOTOPES The present invention includes unlabelled compounds as well compounds wherein one or more of the atom(s) is/are replaced by an isotope of that atom(s), i.e. an atom having the same atomic number but an atomic mass different from the one(s) typically found in nature. Examples of isotopes that may be incorporated into the compounds of the invention, include but are not limited to isotopes of hydrogen, such as ² H and ³ H (also denoted D for deuterium and T for tritium, respectively), carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus, such as ³¹ P and ³² P, fluorine, such as ¹⁸ F, chlorine, such as ³⁶ Cl and bromine such as ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. Isotopically labelled compounds include for example those wherein radioactive isotopes, such as ³ H and ¹⁴ C are present, or those wherein non-radioactive isotopes, such as ² H and ¹³ C are present. The choice of isotope included in an isotope-containing compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays or in metabolic studies compounds wherein a radioactive isotope such as ³ H or ¹⁴ C is incorporated, 36 ACTIVE/109135237.1

will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as ¹¹ C, ¹⁸ F, ¹³ N or ¹⁵ O will be useful. The incorporation of a heavier isotope, such as deuterium, i.e. ² H, may provide certain therapeutic advantages resulting from greater metabolic stability to a compound of the invention, which may result in, for example, an increased in vivo half-life of the compound, reduced dosage requirements or an improvement in therapeutic index. Isotopically-labelled compounds of formula (I), (Ia), (II) or (III), or any subgroup thereof can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Schemes and/or Examples herein by using the appropriate isotopically-labelled reagents or starting material instead of the corresponding non- isotopically-labelled reagent or starting material. Pharmaceutically acceptable solvates include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. Compounds of formula (I), (Ia), (II) or (III), or any subgroup thereof that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I), (Ia), (II) or (III), or any subgroup thereof by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I), (Ia), (II) or (III), or any subgroup thereof with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163, Any asymmetric atom (e.g., carbon or the like) of a compound of the invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)-or trans-(E)- form. Accordingly, as used herein a compound of the invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as 37 ACTIVE/109135237.1

substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization. Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di- O,O’-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral stationary phase. Furthermore, compound of the invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. A compound of the invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that a compound of the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water. A compound of the invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs. In another aspect, a compound of the invention is presented as a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical 38 ACTIVE/109135237.1

compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. Typically, for oral administration the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in the art. Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin, or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. 39 ACTIVE/109135237.1

Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient. Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Suitable compositions for intravesical administration include nanocarriers such as solid lipid nanoparticles, protein nanoparticles with targeted ligands grafted on the surface, branched polymeric dendrimers, mucoadhesive biopolymers (such as chitosan), mucoadhesive nanogels or synthetic polymers, magnetic particles, gold nanoshells, and in situ gelling systems. A review is found at Zacche et al, Research and Reports in Urology 2015:7169-178. A suitable approach is the use of hydrogels as depot formulations on the bladder walls. An example is thermosensitive hydrogels such as aqueous solutions of poly (ethylene glycol-b-[di- lactic acid-co-glycolic acid]-β-ethyleneglycol) triblock copolymers that form a free-flowing solution at room temperature and become a viscous gel at body temperature of 37 °C. Additionally, liposomal vesicles shown to enhance the therapeutic index of chemotherapeutic agents may be used. A reservoir-based intravesical device that can be inserted and remain in the bladder may also be used. The drug is then released from the device in a controlled and extended manner. The device can be either biodegradable or nondegradable. Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including 40 ACTIVE/109135237.1

cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant. Another embodiment presents anhydrous pharmaceutical compositions and dosage forms comprising a compound of the invention as active ingredients, since water may facilitate the degradation of certain compounds. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs. The pharmaceutical compositions and dosage forms may comprise one or more agents that reduce the rate by which a compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. GENERAL SYNTHESIS OF COMPOUNDS OF THE INVENTION Compounds of the present invention and intermediates useful for the synthesis of these compounds may be prepared by a variety of methods and techniques known to those skilled in the art. The general synthetic schemes and preparative examples shown and described below illustrate typical synthetic routes to the compounds of the invention and intermediates to these compounds, but as will be readily apparent to the ordinary skilled organic chemist, alternative routes may also be used for the preparation of the entire compounds or to various portions of the 41 ACTIVE/109135237.1

compounds. Starting materials and reagents used are available from commercial suppliers or can be prepared according to literature procedures using methods well known to those skilled in the art. Compounds of the invention are prepared from commercially available starting material using techniques and methods known in the art of synthetic organic chemistry. Intermediates and final compounds are prepared according to literature procedures and/or as illustrated in the general synthetic schemes and as detailed in the experimental part herein below. In the case any functional groups are present on any of the building blocks that may interfere in reactions, these are suitably protected during the reaction in order to avoid undesired side reactions, and deprotected at the end of the synthesis. Appropriate protecting groups that can be used are extensively described in the literature, e.g. in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981). In addition to the definitions above, the following abbreviations are used in the general synthetic schemes and examples. If an abbreviation used herein is not defined it has its generally accepted meaning. Bn Benzyl Boc tert-butyloxycarbonyl BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride CDI Carbonyl diimidazole DCM Dichloromethane DDQ 2,3.Dichloro-5,6-dicyano-1,4-benzoquinone DIEA Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide EtOAc Ethyl acetate Et3N Triethylamine EtOH Ethanol Et ₂ O Diethyl ether LC Liquid chromatography Lg Leaving group HOAc Acetic acid 42 ACTIVE/109135237.1 HPLC High performance liquid chromatography MeCN Acetonitrile MeOH Methanol on Over night p.ether Petroleum ether Pg Protecting group Ph Phenyl rt Room temperature THF Tetrahydrofuran TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride TIPS Triisopropylsilyl If there is any inconsistency between the chemical name of an exemplified chemical compound and corresponding structure of said example, then the chemical structure should be used for determining the chemical compound of said example. Compounds of the invention are typically obtained by first preparing a pyrrolopyridazine carboxylic acid carrying the desired groups R ¹ , R ² , R ⁴ and R ⁵ , and an amine R ³ -NH ₂ . The two building blocks are then coupled together as generally illustrated in Scheme 1. The compound of formula (I) is typically prepared in a one pot Curtius rearrangement reaction of acid 1A and the desired amine H ₂ N-R ³ . The reaction is suitably performed using standard conditions such as by treatment with diphenyl phosphorus azide (DPPA) in the presence of a base like triethylamine or similar, thus providing the intermediate isocyanate (1B) which is directly reacted with the amine to form the desired urea derivative of formula (I). Alternatively, the isocyanate (1B) may be hydrolysed to the corresponding amine (1C). The amine is then 43 ACTIVE/109135237.1

transformed to an electrophilic carbamic derivative effected by reaction with a reagent like phosgene, triphosgene or carbonyl diimidazole (CDI) or the like, and subsequently reacted with the desired H2N-R ³ to provide the urea derivative of formula (I). Methods for synthesizing pyrrolopyridazines are extensively described in the literature, a review is published in Archive for Organic Chemistry. Arkivoc 2008 (i) 232-270. An example of a route to pyrrolopyridazine carboxylic acids for use in the preparation of compounds of formula (I) or any subgroup thereof is outlined in Scheme 2. The N-amino pyrrole carboxylic acid ester carrying the desired substituent R ¹ (2B) is typically prepared by N-amination of the corresponding pyrrole carboxylic acid ester (2A) using literature methods. The amination can for example be performed by subjecting the pyrrole derivative to a base like sodium hydride in DMF or similar followed by monochloramine typically as a solution in diethyl ether or ethanol thus providing aminopyrrole derivative (2B). Alternatively, the N- amination can be performed by reaction of the pyrrole carboxylic acid ester with (aminooxy)sulfonic acid in the presence of a base like tBuOK or similar, typically in a solvent like N-methylpyrrolidinone (NMP) or similar, or by reaction with (aminooxy)diphenylphosphine oxide in the presence of a base like NaH using DMF or similar as solvent. Condensation of the aminopyrrole derivative (2B) with an α,β-unsaturated ester (2C) under acidic conditions such as in the presence of p-toluene sulfonic acid (pTSA) or equivalent in a solvent like EtOH followed by cyclisation provides the bicyclic derivative (2D). In order to enable introduction of various groups R ² to the bicycle, the hydroxy group is converted to a leaving group (Lg) typically a halide like chloride, bromide or iodide, or a pseudo halide like a tosylate or a triflate. For instance, treatment of the hydroxy compound with phosphorus trichloride or phosphorus tribromide in the presence of a base like triethylamine or similar provides the chloride or bromide respectively, whereas treatment of the alcohol with a sulfonylating agent, typically the 44 ACTIVE/109135237.1

chloride or anhydride of the desired group, e.g. tosylchloride or trifluoromethanesulfonic anhydride provides the tosylate or the triflate respectively. The substituent R ² is typically introduced to the pyrrolopyridazine moiety by way of a palladium catalysed reaction such as a Suzuki, Stille or Negishi reaction or the like, or by a nucleophilic aromatic substitution with the appropriate R ² -derivative. In the preparation of compounds of formula (I) or any subgroup thereof wherein R ² is H, the suitable pyrrolopyridazine derivative is typically obtained by reductive removal of the group Lg effected for instance by catalytic hydrogenation. The obtained R ² substituted compound (2F) is then subjected to hydrolysis of the ester using the appropriate conditions according to the ester used provides acid (2G). In the case of a methyl or ethyl ester, treatment with LiOH or equivalent in a solvent like THF and/or MeOH or the like is suitable. The pyrrolopyridazine moiety may alternatively be prepared by reacting a β-ketoester carrying the desired group R ² with N-aminopyrrole. This route is illustrated in Scheme 3. N-amination of substituted pyrrole (3A) by reaction with (aminooxy)diphenylphosphine oxide in the presence of a base like NaH using DMF or similar as solvent provides aminopyrrole derivative (3B). Alternatively, the N-amination can be performed using conditions like (aminooxy)sulfonic acid in the presence of a base like tBuOK or similar in a solvent like N- methylpyrrolidinone (NMP) or similar, or conditions like treatment with monochloramine typically as a solution in diethyl ether or ethanol, in the presence of a base like sodium hydride using a solvent like DMF or similar. The group R ¹ /R ⁴ is a group within the definition of R ¹ and R ⁴ which are compatible with the reaction conditions. Included in this group are e.g. H, F, Cl, Br, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy. Condensation of the aminopyrrole derivative (3B) with an α-alkoxymethylene β-ketoester carrying the desired group R ² (3C) under acidic conditions such as in the presence of HCl, typically at elevated temperature in a solvent like ethanol or similar and subsequent cyclisation provides the bicycle (3D). The bicycle (3D) is then subjected to ester hydrolysis using conditions like LiOH in methanol optionally in the presence 45 ACTIVE/109135237.1 of water and a co-solvent like THF or similar, thus providing the acids (3E). A Curtius rearrangement of the formed acid and reaction with the amine H ₂ N-R ³ then provides the compound of formula (I). Alkoxymethylene substituted β-keto esters (3C), e.g. α- ethoxymethylene β-ketoester are conveniently prepared by reacting the corresponding R ² - substituted β-keto ester with trialkylorthoformate e.g. triethylorthoformate in the presence of acetic anhydride. R ³ -amines to be used in the preparation of compounds of formula (I) wherein can be prepared using the route illustrated in Scheme 4. Reaction of an optionally substituted halo e.g. chloro derivative (4A) with a nucleophile (R ¹³ -H) in the presence of a base such as NaH, K2CO3 or the like in an inert solvent like DMF, provides the substitution product (4B). The nucleophile R ¹³ -H can be an alcohol, amine, lactam or heterocycle. For example, R ¹³ -H can be 1,2,3-triazole. Reduction of the nitro substituent using any suitable reduction conditions such as tin or iron in acidic media provides the desired R ¹³ - substituted amine (4C). Alternatively, R ³ -amines can be prepared via Curtius rearrangement of the corresponding acid as shown in Scheme 5: Treatment of acid 5A with DPPA and a base like triethylamine or similar in t-butanol provides the Boc-protected amino compound 5B. Removal of the Boc group under acidic conditions using e.g. HCl or TFA provides the desired aniline or aminopyridine 5C. Certain substituted anilines and aminoheteroaryls can be prepared by a palladium-catalyzed coupling with a boronic acid derivative of the desired substituent R ¹³ . The method is illustrated with aniline or aminopyridine in Scheme 6. 46 ACTIVE/109135237.1

Coupling of halo substituted aniline or aminopyridine (6A) with a boronic acid or ester of the desired group R ¹³ in the presence of a Pd-catalyst such as PdCl2(PPh3)2 or similar and a base like K ₂ CO ₃ or the like, typically at elevated temperature provides the diaryl compound (6B). R ³ -amines to be used in the preparation of compounds of the invention wherein R ¹³ is alkoxy or haloalkoxy are generally prepared by alkylation of the corresponding hydroxy, nitro compound followed by reduction of the nitro group to the amine. This strategy is generally depicted in Scheme 7. The alkoxy or haloalkoxy substituent R ¹³ is typically introduced on the ring R ³ by reaction of the corresponding hydroxy compound (7A) with the halide of the desired substituent R ¹³ effected by treatment with a base such as NaH or potassium carbonate or similar, thus providing alkoxy or haloalkoxy derivative (7B). Alternatively, compound (7B) may be obtained by using Mitsunobu conditions, i.e. reaction of the hydroxy compound (7A) with the alcohol of the desired substituent R ¹³ using an azodicarboxylate like DEAD or similar in the presence of triphenylphosphine. The nitro group is then reduced using any suitable reduction method, for instance an iron or tin mediated reduction method to provide the amino derivative (7C). Some carboxylic acid intermediates utilized in the preparation of compounds of the invention are prepared through pyridazine formation, followed by chlorination, selective hydrogenation, and saponification to the carboxylic acid. This strategy is generally depicted in Scheme 8 47 ACTIVE/109135237.1

Hydrazine starting material 8A is condensed with R- and R ² -bearing β-ketoester 3C by treatment with p-toluenesulfonic acid in toluene at elevated temperatures to afford pyridazine intermediate 8B. The intermediate is then dichlorinated by treatment with N-chlorosuccinimide in THF at 60 °C to afford dichloro product 8C, which is then selectively hydrogenated by treatment with hydrogen gas and palladium on carbon catalyst in ethanol to afford product 8D. Product 8D is finally saponified by treatment with sodium hydroxide in aqueous ethanol to afford the carboxylic acid intermediate 8E. Tetrazole-containing amine intermediates utilized in the preparation of some compounds of the invention are prepared through azide cycloaddition and tetrazole methylation. This strategy is generally depicted in Scheme 9. 48 ACTIVE/109135237.1

A pyridine starting material bearing R ¹³ , nitrile, and amine groups (9A) is Boc protected by treatment with Boc anhydride, 4-dimethylaminopyridine, and triethylamine in DCM at low temperatures to afford protected intermediate 9C. Alternatively, a pyridine starting material bearing R ¹³ , nitrile, and bromide groups (9B) is converted to 9C through treatment with tert-butyl carbamate, Pd ₂ (dba) ₃ , Xantphos, and cesium carbonate in dioxane at 100 °C. Compound 9C undergoes cycloaddition and methylation by treatment with sodium azide and methyl trifluoromethanesulfonate in the presence of ammonium chloride and potassium carbonate in DMF at 0-100 °C to afford methylated tetrazole-containing isomers 9D and 9E. The Boc protecting group is removed from these products by treatment with hydrochloric acid in dioxane to afford amine intermediates 9F and 9G. Other compounds of the invention utilize in their preparation amine fragments containing a 1,3,4- oxadiazol-2(3H)-one moiety. Such intermediates are prepared through conversion of an 49 ACTIVE/109135237.1

appropriate ester to a hydrazide followed by cyclization. This strategy is generally depicted in Scheme 10. A pyridine starting material bearing R ¹³ , bromide, and ester substituents is converted to Boc- protected amine material 10B by treatment with tert-butyl carbamate, Pd ₂ (dba) ₃ , Xantphos, and cesium carbonate in dioxane at 100 °C. The material is then converted to its corresponding hydrazide (10C) by treatment with hydrazine hydrate in ethanol at 85 °C. The hydrazide moiety of 10C is then converted to the 1,3,4-oxadiazol-2(3H)-one by treatment with carbonyldiimidazole and triethylamine in DMF to afford cyclized product 10D. Final Boc deprotection by treatment with HCl in dioxane at 40 °C provides the amine intermediate 10E. Lactam-containing amine intermediates utilized in the synthesis of some compounds of the invention are prepared by cross coupling, followed by chlorination, a second cross coupling, and acidic deprotection. This strategy is generally depicted in Scheme 11. A dibromopyridine starting material is cross coupled with a β-lactam by treatment with Pd ₂ (dba) ₃ , Xantphos, and cesium carbonate in toluene at 90 °C to afford cross-coupled product 50 ACTIVE/109135237.1

11A.11A is then selectively chlorinated by treatment with N-chlorosuccinimide and p- toluenesulfonic acid monohydrate in dimethylformamide to afford bromochloropyridine product 11B. The bromide of 11B is replaced with a tert-butyl carbamate moiety by treatment with tert- butyl carbamate, Pd ₂ (dba) ₃ , Xantphos, and cesium carbonate in dioxane at 90 °C to afford Boc- protected product 11C. Finally, the Boc group of 11C is removed by treatment with silica gel in toluene at 110 °C to afford lactam-containing amine intermediate 11D. DETAILED DESCRIPTION OF THE EMBODIMENTS Various embodiments of the compounds invention and intermediates therefore will now be illustrated by the following examples. The Examples are just intended to further illustrate the invention and are by no means limiting the scope of the invention. The compound names were generated by ChemDraw Ultra software, Cambridgesoft, versions 12.0.2 and 18.2. As is well known to a person skilled in the art, reactions are performed in an inert atmosphere (including but not limited to nitrogen or argon) where necessary to protect reaction components from air or moisture. Temperatures are given in degrees Celsius (°C). Solution percentages and ratios express a volume to volume relationship, unless stated otherwise. The reactants used in the examples below may be obtained from commercial sources or they may be prepared from commercially available starting materials as described herein or by methods known in the art. The compounds of the invention including intermediates are prepared as described in the Examples and in the general schemes herein. It will be apparent to a skilled person that analogous synthetic routes may be used, with appropriate modifications, to prepare the compounds of the invention as described herein. The progress of the reactions described herein were followed as appropriate by e.g. LC, GC or TLC, and as the skilled person will readily realise, reaction times and temperatures may be adjusted accordingly. Intermediate 1 Step a) 3-chloro-1-(triisopropylsilyl)-1H-pyrrole (I-1a) t-BuLi (1.7M) (60 mL, 102.0 mmol) was added dropwise at -78 °C under argon to a solution of 3-bromo-1-(triisopropylsilyl)-1H-pyrrole (15 g, 49.6 mmol) in dry THF (225 mL). The solution 51 ACTIVE/109135237.1

was stirred for 30 min at -78 °C, then a solution of hexachloroethane (23.5 g, 99.3 mmol) in THF (150 mL) was added at -78 °C and stirred at that temperature for 30 min followed by 30 min at rt. The reaction mixture was poured into saturated ammonium chloride solution and the mixture was extracted with DCM (3 x 200 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel which was treated with Et3N and eluted with p. ether, which gave the title compound (12 g, 77%) as a liquid. MS (ES+) 258.28 [M+H] ⁺ . Step b) 3-chloro-1H-pyrrole (I-1b) A solution of 1M TBAF in THF (104 mL, 104 mmol) was added at rt under nitrogen to a stirred solution of I-1a (12 g, 46.5 mmol) in THF (200 mL) at 0 °C. The reaction mixture was stirred at rt for 15 min. The reaction mixture was diluted with water (100 mL) and extracted with methyl tert-butyl ether (3 x 80 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum, which gave the crude title compound (4.5 g). Step c) 3-chloro-1H-pyrrol-1-amine (I-1c) NaH (60%, 2.5 g, 62.5 mmol) was added at 0 °C to a solution of I-1b (4.5 g, 44.3 mmol) in DMF (300 mL). The mixture was stirred for 30 min at 0 °C, then O- (diphenylphosphinyl)hydroxylamine (12.7 g, 53.4 mmol) was added at 0 °C and the mixture was stirred at rt for 1 h. The reaction mixture was poured into ice cold water and was extracted with DCM (5 x 70 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 15%-25% EtOAc / p. ether, which gave the title compound (2.5 g, 44%) as a liquid. MS (ES+) 116.98 [M+H] ⁺ . Intermediate 2 52 ACTIVE/109135237.1

Step a) ethyl (S)-4-methoxy-3-oxopentanoate (I-2a) Solution 1: N,N'-carbonyldiimidazole (40.5 g, 250 mmol) was added at 0 °C to a solution of (S)- 2-methoxypropanoic acid (20 g, 192 mmol) in acetonitrile (500 mL). The resulting mixture was stirred at rt for 3 h. Solution 2: Et3N (80 mL, 574 mmol) and anhydrous magnesium chloride (11 g, 115.54 mmol) were added at 0 °C to a suspension of potassium 3-ethoxy-3-oxopropanoate (39.3 g, 230.6 mmol) in acetonitrile (500 mL). The resulting mixture was stirred at rt for 3 h, then solution 1 was added dropwise at 0 °C and the resulting mixture was stirred at rt for 16 h. The reaction mixture was quenched by adding aqueous 3N HCl solution and was extracted with EtOAc (5 x 250 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 10% EtOAc / p. ether, which gave the title compound (20 g, 59%) as a liquid. MS (ES+) 175.13 [M+H] ⁺ . A mixture of I-2a (20 g, 114.8 mmol), triethyl orthoformate (21 mL, 139 mmol) and acetic anhydride (22 mL, 232.7 mmol) was heated to 120 °C for 12 h, then concentrated under reduced pressure, which gave the crude title compound (24 g, 82%) as a liquid. MS (ES+) 231.18 [M+H] ⁺ . A mixture of I-1b (2.5 g, 19.5 mmol), I-2b (5.5 g, 21.8 mmol) was stirred at rt for 10 min, then 10 M HCl (10.5 mL, 105 mmol) and ethanol (100 mL) were added at 0 °C and the mixture was heated to 80 °C for 2 h, then concentrated under reduced pressure. The reaction mixture was poured into saturated sodium bicarbonate solution (150 mL) and was extracted with DCM (4 x 80 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 0-3% EtOAc / p. ether, which gave the title compound (400 mg, 7%) as a liquid. MS (ES+) 283.24 [M+H] ⁺ . Lithium hydroxide (85 mg, 3.6 mmol) was added at 0 °C to a stirred solution of I-2c (400 mg, 1.42 mmol) in THF (20.0 mL) and water (4.0 mL). The resulting reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The afforded crude was acidified with 10% NaHSO4 (aq) solution at 0 °C and was extracted with EtOAc (5 x 80 mL). The combined 53 ACTIVE/109135237.1

organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum, which gave the title _{compound (330 mg, 89%) as a sticky semi-solid. LCMS (ES+) M/z = 255.21 [M+H]} ⁺ _. Intermediate 3 Step a) ethyl 4-ethoxy-3-oxopentanoate (I-3a) Solution 1: N,N'-carbonyldiimidazole (4.5 g, 27.8 mmol) was added at 0 °C to a solution of (2- ethoxypropanoic acid (3 g, 25.4 mmol) in THF (20 mL). The resulting mixture was stirred at rt for 3 h. Solution 2: Isopropyl magnesium chloride (2M in THF) (39 mL, 78 mmol) was added at 0 °C to a solution of 3-ethoxy-3-oxopropanoic acid (3.3 g, 25 mmol) in THF (20 mL). The resulting mixture was stirred at rt for 3 h. Solution 2 was added dropwise at 0 °C to solution 1 and the resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched by adding aqueous 10% citric acid solution (50 mL), diluted with water (100 mL) and was extracted with EtOAc (2 x 200 mL) and washed with saturated sodium bicarbonate solution (100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 0-30% EtOAc / p. ether, which gave the title compound (3 g) as a liquid. The compound was used in the next step without further purification. Step b) ethyl (Z)-4-ethoxy-2-(ethoxymethylene)-3-oxopentanoate (I-3b) A mixture of I-3a (3 g, 16 mmol), triethyl orthoformate (4 mL, 26.5 mmol) and acetic anhydride (4 mL, 42.3 mmol) was heated to 120 °C for 16 h, then concentrated under reduced pressure, which gave the crude title compound (3.6 g) as a liquid. MS (ES+) 245.25 [M+H] ⁺ . The compound was used in the next step without further purification. 54 ACTIVE/109135237.1

Step c) ethyl 4-(1-ethoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (I-3c) A mixture of 1H-pyrrol-1-amine (800 mg, 9.7 mmol), I-3b (3.5 g, 8.6 mmol) was stirred at rt for 10 min, then ethanol (50 mL) and 10 M HCl (4 mL, 40 mmol) were added at 0 °C and heated to 80 °C for 3 h. The reaction mixture was diluted with water (50 mL) and was extracted with EtOAc (2 x 200 mL) and washed with saturated sodium bicarbonate solution (50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 10-20% EtOAc / p. ether, which gave the title compound (2 g) as a liquid. MS (ES+) 263.3 [M+H] ⁺ . The compound was used in the next step without further purification. A solution of lithium hydroxide (130 mg, 3.01 mmol) in water (5.0 mL) was added at rt to a stirred solution of I-3c (2 g, 2.44 mmol) in THF (20.0 mL) and methanol (1 mL). The resulting reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The afforded crude was diluted with water (50 mL) and extracted with diethyl ether (2 x 150 mL). The aqueous layer was acidified to pH 6 with 1N HCl (aq) solution and extracted with EtOAc (2 x 150 mL) and washed with water (50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (200 mg, 34%) as a solid. MS (ES+) m/z 235.26 [M+H]+. Intermediate 4 Step a) 3-bromo-1H-pyrrole (I-4a) A solution of 1M TBAF in THF (53 mL, 53 mmol) was added at 0 °C under nitrogen to a stirred solution of 3-bromo-1-(triisopropylsilyl)-1H-pyrrole (15 g, 49.6 mmol) in THF (200 mL) at 0 °C. The reaction mixture was stirred at rt for 15 min. The reaction mixture was diluted with water (60 mL) and extracted with methyl tert-butyl ether (3 x 150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 5-10% EtOAc / p. ether, which gave the title compound (6 g). MS (ES-) m/z 144.11 [M-H]+. The compound was used in the next step without further purification. 55 ACTIVE/109135237.1

Step b) 3-bromo-1H-pyrrol-1-amine (I-4b) NaH (60%, 2.3 g, 56.8 mmol) was added at 0 °C to a solution of I-4a (6 g, 41.1 mmol) in DMF (100 mL). The mixture was stirred for 30 min at 0 °C, then O- (diphenylphosphinyl)hydroxylamine (10.8 g, 45.2 mmol) was added at 0 °C and stirred at rt for 1 h. The reaction mixture was poured into ice cold water and was extracted with methyl tert-butyl ether (5 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 10-20% EtOAc / p. ether, which gave the title compound (3.2 g) as a liquid. MS (ES+) 163.25 [M+2] ⁺ . Intermediate 5 Step a) ethyl bromo-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxyla te (I-5a) A mixture of I-4b (2.4 g, 15 mmol), I-2b (4.5 g, 19.4 mmol) was stirred at rt for 10 min, then ethanol (40 mL) and 10M HCl (8 mL, 79.11 mmol) were added at 0 °C and heated to 80 °C for 5 h. The reaction mixture was concentrated under reduced pressure and poured into saturated sodium bicarbonate solution (10 mL) and was extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 3-7% EtOAc / p. ether, which gave the title compound (400 mg) as a solid. MS (ES+) 327.29 [M+H] ⁺ . The compound was used in the next step without further purification. Step b) ethyl (S)-4-(1-methoxyethyl)-6-methylpyrrolo[1,2-b]pyridazine-3-ca rboxylate & ethyl (S)-4-(1-hydroxyethyl) ,2-b]pyridazine-3-carboxylate (I-5b) A stirred solution of the compound of I-5a (400 mg, 1.22 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed by bubbling with argon for 15 minutes, then [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (90 mg, 0.12 mmol) was added followed 56 ACTIVE/109135237.1

by addition of sodium carbonate (260 mg, 2.5 mmol) and trimethyl boroxine (390 mg, 3.1 mmol). The resulting reaction mixture was stirred at 110 °C for 4 h in a sealed tube. The reaction mixture was filtered through the celite bed. The layers separated and the organic layers was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure, which gave the crude title compound (390 mg) as a solid. MS (ES+) 263.46 [M+H] ⁺ and 249.44 [M+H] ⁺ respectively. The compound was used in the next step without further purification. Step c) (S)-4-(1-methoxyethyl)-6-methylpyrrolo[1,2-b]pyridazine-3-ca rboxylic acid & (S)-4-(1- methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid (I-5c) A solution of lithium hydroxide (40 mg, 1.6 mmol) in water (2.0 mL) was added at rt to a stirred solution of I-5b (400 mg, 0.8 mmol) in THF (10.0 mL). The resulting reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The afforded crude was diluted with water and acidified to pH 4 with 2N HCl (aq) solution at 0 °C and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum, which gave the title compound (356 mg) as a solid. MS (ES-) m/z 233.26 [M-H]- and 219.25 [M-H]- respectively. The compound was used in the next step without further purification. Intermediate 6 Step a) 3-fluoro-1H-pyrrole (I-6a) A solution of TBAF (12.35 g, 39.14 mmol) in DCM (70 mL) was added at 0 °C under nitrogen to a stirred solution of 3-fluoro-1-(triisopropylsilyl)-1H-pyrrole (9 g, 37.3 mmol) in DCM (70 mL) at 0 °C. The reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted with water (60 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum at 20 °C under 400 millibar, which gave 57 ACTIVE/109135237.1

the title compound (3.1 g).The compound was used in the next step without further purification. Step b) 3-fluoro-1H-pyrrol-1-amine (I-6b) NaH (60%, 2.0 g, 50 mmol) was added at 0 °C to a solution of I-6a (3.1 g, 36.4 mmol) in DMF (200 mL). The mixture was stirred for 30 min at 0 °C, then O- (diphenylphosphinyl)hydroxylamine (10.4 g, 43.7 mmol) was added at 0 °C and stirred at rt for 1 h. The reaction mixture was poured into ice cold water and was extracted with DCM (5 x 80 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 15-20% EtOAc / p. ether, which gave the title compound (900 mg, 24%) as a liquid. Step c) ethyl fluoro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxyl ate & ethyl (S)-6-fluoro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-ca rboxylate (I-6c) A mixture of I-6b (900 mg, 8.7 mmol), I-2b (2.9 g, 9.6 mmol) was stirred at rt for 10 min, then ethanol (50 mL) and 10M HCl (4.5 mL, 45.2 mmol) were added at 0 °C and heated to 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and poured into saturated sodium bicarbonate solution (10 mL) and was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 2-5% EtOAc / p. ether, which gave the mixture of title compounds (1 g) as a solid. MS (ES+) 267.28 [M+H] ⁺ . The compound was used in the next step without further purification. Step d) (S)-5-fluoro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-ca rboxylic acid & fluoro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxyl ic acid (I-6d) Lithium hydroxide (90 mg, 3.8 mmol) was added at 0 °C to a stirred solution of I-6c (1 g, 1.9 mmol) in THF (30.0 mL) and water (3.0 mL). The resulting reaction mixture was stirred at 50 °C for 26 h, then concentrated under reduced pressure. The afforded crude was acidified with 10% NaHSO4 (aq) solution at 0 °C and was extracted with EtOAc (5 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum, which gave the mixture of _{title compounds (800 mg, 87%) as a sticky semi-solid. LCMS (ES+) M/z = 239.29 [M+H]} ⁺ _{. The} compound was used in the next step without further purification. 58 ACTIVE/109135237.1

Intermediate 7 Step a) ethyl (S)-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (I-7a) A mixture of 1H-pyrrol-1-amine (700 mg, 8.6 mmol), I-2b (3 g, 9.1 mmol) was stirred at rt for 15 min, then ethanol (15 mL) and 10M HCl (4.0 mL, 40 mmol) were added at 0 °C and heated to 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and poured into saturated sodium bicarbonate solution (30 mL) and was extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum, which gave the mixture of title compounds (800 mg) as a liquid. MS (ES+) 249.21 [M+H] ⁺ . The compound was used in the next step without further purification. Step b) (S)-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid (I-7b) A solution of lithium hydroxide (200 mg, 8.4 mmol) in water (2.0 mL) was added at rt to a stirred solution of I-7a (800 mg, 3.22 mmol) in EtOH (10.0 mL). The resulting reaction mixture was stirred at 60 °C for 6 h, then concentrated under reduced pressure. The afforded crude was dissolved in water and acidified to pH 4 with 2N HCl (aq) solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum, which gave the title compound (550 mg) as a solid. MS (ES-) m/z 219.26 [M-H]-. The compound was used in next step without further purification. 59 ACTIVE/109135237.1

Step a) ethyl 4-hydroxy-6-methylpyrrolo[1,2-b]pyridazine-3-carboxylate (I-8a) A mixture of ethyl 1-amino-4-methyl-1H-pyrrole-2-carboxylate(1.5 g, 7.13 mmol), methyl (E)- 3-methoxyacrylate (1.24 g, 10.7 mmol) and PTSA (370 mg, 2.2 mmol) in ethanol (25 mL) was stirred at 85 °C for 2 h and at 100 °C for 2 h, then concentrated under reduced pressure. The residue was co-distilled with ethanol. The obtained residue was dissolved in ethanol (25 mL) and tBuONa (1.4 g, 14.3 mmol) was added to afford clear orange solution, which was heated to 85 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL), neutralised with 1N HCl and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. The obtained crude was combined with other batches and purified by column chromatography on silica gel and eluted with 0-10% EtOAc / p. ether, which gave the title compound (350 mg) as a solid. MS (ES-) m/z 219.42 [M-H]-. Et ₃ N (0.5 mL, 3.6 mmol) was added dropwise at rt to a mixture of compound 1-8b (350 mg, 1.6 mmol) and phosphorus oxychloride (5.0 mL). The mixture was heated for 3 h at 110 °C, then cooled to rt and concentrated under reduced pressure. The residue was basified by addition of saturated NaHCO ₃ solution and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure, which gave the title compound (270 mg, 59%). LCMS (ES+) 239.32 [M+H] ⁺ . A mixture of compound I-8b (270 mg, 1.13 mmol) ,4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2- dioxaborolane (285 mg, 1.7 mmol) and sodium carbonate (300 mg, 2.8 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was degassed for 5 minutes with argon, then Pd(dppf)Cl2•CH2Cl2 (93 mg, 0.11 mmol) was added. The mixture was stirred at 120 °C for 1 h in a microwave, then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (25 mL) and washed with water (20 mL). The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure, which gave the title compound (230 mg, 66%) as a liquid. LCMS (ES+) 245.23 [M+H] ⁺ . Pd/C (300 mg, 2.53 mmol) was added to a stirred solution of compound I-8c (230 mg, 0.94 mmol) in EtOH (5.0 mL). The mixture was put under light pressure of H ₂ (balloon) and stirred for 31 h, then filtered through Celite and the filtrate was concentrated, which gave the title 60 ACTIVE/109135237.1

compound (200 mg, 83%) as a liquid. LCMS (ES+) 247.29 [M+H] ⁺ . Step e) 4-isopropyl-6-methylpyrrolo[1,2-b]pyridazine-3-carboxylic acid (I-8e) A mixture of I-8d (200 mg, 0.81 mmol) and lithium hydroxide (40 mg, 1.70 mmol) in THF (2.0 mL), methanol (2 mL) and water (2.0 mL) was stirred at rt for 3 h, then concentrated under reduced pressure. The afforded crude was diluted with water (5 mL), acidified to pH 4 with 1N HCl (aq) solution. The precipitated solid was filtered and dried, which gave the title compound (150 mg, 74%) as a solid. MS (ES+) m/z 219.39 [M+H] ⁺ . Intermediate 9 Step a) ethyl chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxyl ate & ethyl (S)-6-chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-ca rboxylate (I-9a) A mixture of I-1c (1.0 g, 6.0 mmol), I-2b (2.5 g, 7.13 mmol) was stirred at rt for 10 min, then ethanol (30 mL) and 10M HCl (3.2 mL, 32 mmol) were added at 0 °C and heated to 80 °C for 2 h, then concentrated under reduced pressure The reaction mixture was poured into saturated sodium bicarbonate solution (80 mL) and was extracted with DCM (4 x 40 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 3-5% EtOAc / p. ether, which gave the mixture of title compounds (600 mg) as a liquid. MS (ES+) 283.32 [M+H] ⁺ . Step chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxyl ic acid & (S)-6- chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxyl ic acid (I-9b) Lithium hydroxide (70 mg, 2.9 mmol) was added at 0 °C to a stirred solution of I-9a (600 mg, 1.1 mmol) in THF (15.0 mL) and water (3.0 mL). The resulting reaction mixture was stirred at rt for 27 h, then concentrated under reduced pressure. The afforded crude was acidified with 10% 61 ACTIVE/109135237.1

NaHSO ₄ (aq) solution at 0 °C and was extracted with EtOAc (4 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum, which gave the mixture of _{title compounds (400 mg) as a sticky semi-solid. LCMS (ES-) M/z 253.4 [M-H]} - _. Intermediate 10 Step a) ethyl (E)-2-(cyclopropanecarbonyl)-3-ethoxyacrylate (I-10a) A mixture of ethyl 3-cyclopropyl-3-oxopropanoate (4.6 g, 29.5 mmol), triethyl orthoformate (7 mL, 46.34 mmol) and acetic anhydride (7 mL, 74.1 mmol) was heated to 120 °C for 16 h, then concentrated under reduced pressure, which gave the crude title compound (5.0 g) as a liquid. MS (ES+) 213.17 [M+H] ⁺ . The compound was used in the next step without further purification. Step b) ethyl 4-cyclopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (I-10b) A mixture of I-10a (1.9 g, 5.82 mmol), 1H-pyrrol-1-amine (500 mg, 5.8 mmol) was stirred at rt for 10 min, then 10M HCl (6 mL, 60 mmol) and ethanol (10 mL) were added at 0 °C and heated to 80 °C for 3 h. The reaction mixture was diluted with water (50 mL) and was extracted with EtOAc (2 x 150 mL). The organic layer was washed with saturated sodium bicarbonate solution (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 0-30% EtOAc / p. ether, which gave the mixture of title compounds (1.5 g) as a liquid. MS (ES+) 231.18 [M+H] ⁺ . The compound was used in the next step without further purification. Step c) 4-cyclopropylpyrrolo[1,2-b]pyridazine-3-carboxylic acid (I-10c) A solution of lithium hydroxide (325 mg, 7.7 mmol) in water (10.0 mL) was added at rt to a stirred solution of I-10b (1.5 g, 6.5 mmol) in THF (20.0 mL) and methanol (0.5 mL). The resulting reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The afforded crude was diluted with water (50 mL) and extracted with diethyl ether (2 x 100 mL). The aqueous layer was acidified to pH 6 with 1N HCl (aq) solution and extracted with EtOAc (2 x 50 mL) and washed with water (20 mL). The combined organic layers were dried 62 ACTIVE/109135237.1

(Na ₂ SO ₄ ), filtered and concentrated under reduced pressure, which gave the title compound (600 mg, 39%) as a solid. MS (ES+) m/z 203.15 [M+H]+. Intermediate 11 Step a) ethyl (S)-6-bromo-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-car boxylate & ethyl (S)-6-bromo-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-car boxylate (I-11a) A mixture of I-4b (5.5 g, 33.6 mmol), I-2b (11 g, 36.5 mmol) was stirred at rt for 10 min, then ethanol (150 mL) and 10M HCl (17.2 mL, 172 mmol) were added at 0 °C and heated to 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and poured into saturated sodium bicarbonate solution (80 mL) and was extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 2-4% EtOAc / p. ether, which gave the mixture of title compounds (400 mg) as a solid. MS (ES+) 329.2 [M+H] ⁺ . The compound was used in the next step without further purification. Step b) ethyl (S)-4-(1-methoxyethyl)-5-methylpyrrolo[1,2-b]pyridazine-3-ca rboxylate & ethyl (S)-4-(1-methoxyethyl)-6-methylpyrrolo[1,2-b]pyridazine-3-ca rboxylate (I-11b) A stirred solution of the compound of I-11a (400 mg, 0.61 mmol) in 1,4-dioxane (25 mL) and water (3 mL) in a sealed tube was degassed by bubbling with argon for 30 minutes, then sodium carbonate (130 mg, 1.23 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.1 mmol) was added followed by addition of and trimethyl boroxine (200 mg, 1.6 mmol). The resulting reaction mixture was stirred at 110 °C for 20 h in a sealed tube. The reaction mixture was filtered through the celite bed, filtrate was poured into water and extracted with EtOAc. The layers separated and the 63 ACTIVE/109135237.1

organic layers was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel and eluted with 2-5% EtOAc / p. ether, which gave the crude title compound (250 mg) as a solid. MS (ES+) 263.21 [M+H] ⁺ . The compound was used in the next step without further purification. Step c) (S)-4-(1-methoxyethyl)-6-methylpyrrolo[1,2-b]pyridazine-3-ca rboxylic acid (I-11c) A solution of 5M sodium hydroxide in water (0.5 mL, 2.5 mmol) was added at 0 °C to a stirred solution of I-11b (250 mg, 1.0 mmol) in THF (20.0 mL). The resulting reaction mixture was stirred at 50 °C for 20 h, then concentrated under reduced pressure. The afforded crude was acidified with 10% NaHSO4 (aq) solution at 0 °C and was extracted with EtOAc (5 x 80 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum, which gave the title compound (200 mg, 76%) as a sticky semi-solid. LCMS (ES+) M/z = 235.26 [M+H]+. Intermediate 12 Step a) 2-benzyl 1-(tert-butyl) (2S)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxyl ate (I-12a) Trimethyl(trifluoromethyl)silane (6.9 mL, 46.5 mmol) and 1M TBAF in THF (1.5 mL, 1.5 mmol) were added under nitrogen at 0 °C to a stirred solution of 2-benzyl 1-(tert-butyl) (S)-4- oxopyrrolidine-1,2-dicarboxylate (14 g, 43.8 mmol) in THF (200 mL). The mixture was stirred at rt for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution and stirred at rt for 15 min, then TBAF solution (75 mL) was added and extracted with EtOAc (2 x 200 mL). The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel and eluted with 10% EtOAc / p. ether, which gave the crude title 64 ACTIVE/109135237.1

compound (13.5 g) as a solid. MS (ES+) 390.42 [M+H]+. The compound was used in the next step without further purification. Thionyl chloride (25.2 mL, 346.7 mmol) was added under nitrogen at 0 °C to a stirred solution of compound I-12a (13.5 g, 34.7 mmol) in pyridine (250 mL). The mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2 x 500 mL). The organic layer was washed with 1N HCl, saturated sodium bicarbonate solution, water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel and eluted with 5% EtOAc / p. ether, which gave the crude title compound (5.5 g, 41%) as a solid. MS (ES+) 372.36 [M+H]+. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (10.1 g, 44.4 mmol) was added under nitrogen at rt to a stirred solution of compound I-12b (5.5 g, 14.8 mmol) in 1,4-dioxane (50 mL). The mixture was stirred at 85 °C for 12 h. The reaction mixture was filtered through and the filtrate was diluted with water and extracted with DCM (2 x 100 mL). The combined organic layer was washed with saturated sodium bicarbonate solution, water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel and eluted with 5% EtOAc / p. ether, which gave the crude title compound (2.2 g, 52%) as a solid. MS (ES-) 268.33 [M-H]-. Step d) benzyl 1-amino-4-(trifluoromethyl)-1H-pyrrole-2-carboxylate (I-12d) Solution 1: 28% NH4OH (45.14 mL, 324.6 mmol) was added at -20 °C to a mixture of NH4Cl (2.84 g, 53.12 mmol) in methyl tert-butyl ether (100 mL) and then 9% sodium hypochlorite solution in water (90.3 mL, 131 mmol) was added. The resulting mixture was stirred at -20 °C for 15 min. The organic layer was separated, washed with brine and dried (Na2SO4) to afford the chloramine solution. Solution 2: NaH (60%, 400 mg, 9.8 mmol)) was added at 0 °C to a solution of compound I-12c (2.2 g, 8.2 mmol) in DMF (20 mL). The resulting mixture was stirred at 0 °C for 30 min, the solution 1 was added dropwise at -20 °C and the resulting mixture was stirred at rt for 90 min. The reaction mixture was diluted with saturated sodium thiosulfate solution and was extracted with methyl tert-butyl ether (2 x 100 mL). The combined organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under vacuum, which gave the title compound 65 ACTIVE/109135237.1

(2.4 g) as a solid. The compound was used in the next step without further purification. A mixture of compound I-12d (2.4 g, 8.44 mmol), ethyl (E)-3-ethoxyacrylate (1.84 mL, 12.7 mmol) and PTSA (436 mg, 2.53 mmol) in ethanol (30 mL) was stirred at 85 °C for 2 h and at 100 °C for 2 h, then concentrated under reduced pressure. The residue was co-distilled with ethanol. The obtained residue was dissolved in ethanol (30 mL) and tBuONa (1.6 g, 16.9 mmol) was added to afford clear orange solution, which was heated to 85 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL), acidified with 1N HCl and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The obtained crude was purified by column chromatography on silica gel and eluted with 5% EtOAc / p. ether, which gave the title compound (800 mg) as a semi-solid. MS (ES-) m/z 273.38 [M-H]- . The compound was used in the next step without further purification. DIPEA (1.44 mL, 8.3 mmol) was added dropwise at 0 °C to a solution of compound I-12f (750 mg, 2.7 mmol) in phosphorus oxychloride (25.0 mL). The mixture was heated for 4 h at 110 °C, then cooled to rt and concentrated under reduced pressure. The residue was basified by addition of saturated NaHCO ₃ solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained crude was purified by column chromatography on silica gel and eluted with 4% EtOAc / p. ether, which gave the title compound (150 mg, 18%) as a semi-solid. MS (ES+) m/z 293.21 [M+H]+. 12g) A stirred solution of the compound of I-12f (170 mg, 0.6 mmol) in toluene (5 mL) was degassed by bubbling with argon for 15 minutes, then tributyl(1-ethoxyvinyl)stannane (0.28 mL, 0.81 mmol) was added followed by addition of Pd(PPh₃)₄ (34 mg, 0.03 mmol). The resulting reaction mixture was stirred at 120 °C for 12 h in a sealed tube. The reaction mixture was filtered through the celite bed, filtrate was diluted with KF solution and extracted with EtOAc (2 x 10 mL). The o ^{rganic layers were washed with water, brine, dried (Na} ₂ ^SO ₄ ^{), filtered and concentrated under} reduced pressure. The crude compound was purified by column chromatography on silica gel and eluted with 3% EtOAc / p. ether, which gave the title compound (140 mg, 72%) as a solid. 66 ACTIVE/109135237.1

MS (ES+) 329.35 [M+H] ⁺ . Step h) ethyl 4-(1-ethoxyethyl)-6-(trifluoromethyl)pyrrolo[1,2-b]pyridazin e-3-carboxylate (I- 12h) Pd(OH) ₂ /C (120 mg, 0.9 mmol) was added to a stirred solution of compound I-12g (140 mg, 0.43 mmol) in MeOH (10.0 mL). The mixture was put under light pressure of H2 (balloon) and stirred for 6 h, then filtered through Celite and the filtrate was concentrated, which gave the title compound (110 mg, 71%) as a semi-solid. LCMS (ES+) 331.33 [M+H] ⁺ . Step i) 4-(1-ethoxyethyl)-6-(trifluoromethyl)pyrrolo[1,2-b]pyridazin e-3-carboxylic acid (I-12i) Lithium hydroxide (20 mg, 0.7 mmol) was added at 0 °C to a stirred solution of I-12h (110 mg, 0.33 mmol) in THF (5.0 mL) and water (5.0 mL). The resulting reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure. The afforded crude was acidified with 1N HCl (aq) solution and the precipitated solid was filtered and dried, which gave the title compound (75 _{mg, 69%) as a sticky semi-solid. LCMS (ES-) M/z = 301.33 [M-H]} - _. Intermediate 13 Step a) diethyl 2-(((3-bromo-1H-pyrrol-1-yl)amino)methylene)malonate (I-13a) A mixture of compound I-4b (6 g, 37.3 mmol) and diethyl 2-(ethoxymethylene)malonate (9 g, 41.6 mmol) in ethanol (80 mL) was heated to 85 °C for 5 h, then concentrated under reduced pressure. The precipitated solid was triturated with hexane, filtered, washed with hexane and dried under vacuum, which gave the title compound (8 g, 63%) as a solid. LCMS (ES+) M/z = _{333.20 [M+H]} ⁺ _. Step b) ethyl 6-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate & ethyl 6-chloro-4- hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (I-13b) Phosphorus oxychloride (20 mL, 214 mmol) was added dropwise at rt to a suspension of 67 ACTIVE/109135237.1

compound I-13a (8 g, 24.2 mmol) in toluene (100 mL). The mixture was heated for 16 h at 100 °C, then cooled to rt and concentrated under reduced pressure. The residue was basified by addition of saturated NaHCO3 solution at 0 °C and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained crude was purified by column chromatography on silica gel and eluted with 2-10% EtOAc / p. ether, which gave the mixture of title compounds (3.2 g) as a semi-solid. MS (ES+) m/z 285.07 [M+H]+ & MS (ES+) m/z 241.13 [M+H]+ respectively. The compound was used in the next step without further purification. Step c) ethyl 4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (I-13c) Pd/C (300 mg, 2.53 mmol) was added to a stirred solution of compound I-13b (3.2 g, 13.3 mmol) in EtOH (40.0 mL). The mixture was stirred under pressure of H ₂ (balloon) and stirred for 16 h, then filtered through Celite and the filtrate was concentrated, which gave the title compound (2.1 g, 70%) as a solid. LCMS (ES+) 207.17 [M+H] ⁺ . DIPEA (3.5 mL, 19.7 mmol) was added dropwise at 0 °C to a solution of compound I-13c (2.1 g, 10.2 mmol) in phosphorus oxychloride (25.0 mL). The mixture was heated for 6 h at 100 °C, then cooled to rt and concentrated under reduced pressure. The residue was basified by addition of saturated NaHCO ₃ solution and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure, which gave the title compound (1.5 g, 52%) as a liquid. MS (ES+) m/z 225.12 [M+H]+. Morpholine (2.0 g, 23 mmol) was added under nitrogen at rt to a stirred solution of compound I- 13e (1.5 g, 6.7 mmol) in acetonitrile (20 mL). The mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 80 mL), the combined organic layers were washed with brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained crude was purified by column chromatography on silica gel and eluted with 5-25% EtOAc / p. ether, which gave the title compound (1.2 g, 58%) as a solid. MS (ES+) m/z 276.20 [M+H]+. A solution of lithium hydroxide (260 mg, 10.9 mmol) in water (5.0 mL) was added at rt to a stirred solution of I-13e (1.2 g, 4.4 mmol) in methanol (20 mL). The resulting reaction mixture was stirred at 80 °C for 1 h, then concentrated under reduced pressure. The afforded crude was 68 ACTIVE/109135237.1

dissolved in water and acidified to pH 4 with 2N HCl (aq) solution and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum, which gave the title compound (800 mg, 64%) as a solid. MS (ES+) m/z 248.19 [M+H]+. Intermediate 14 Step a) ethyl 6-methylpyrrolo[1,2-b]pyridazine-3-carboxylate (I-14a) Pd/C (200 mg, 1.7 mmol) was added to a stirred solution of compound I-8b (200 mg, 0.84 mmol) in EtOH (5.0 mL). The mixture was stirred under pressure of H2 (balloon) and stirred for 5 h, then filtered through Celite and the filtrate was concentrated, which gave the title compound (140 mg, 71%) as a liquid. LCMS (ES+) 205.29 [M+H] ⁺ . Step b) 6-methylpyrrolo[1,2-b]pyridazine-3-carboxylic acid (I-14b) A mixture of I-14a (140 mg, 0.7 mmol) and lithium hydroxide (33 mg, 1.4 mmol) in THF (2.0 mL), methanol (2 mL) water (2.0 mL) was stirred at rt for 3 h, then concentrated under reduced pressure. The afforded solid was diluted with water and adjusted to pH 4 with 1N HCl (aq) solution and the precipitated solid was filtered and dried, which gave the title compound (85 mg) as a solid. MS (ES+) m/z 177.22 [M+H] ⁺ . Intermediate 15 Step a) ethyl 6-methyl-4-(oxazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxyla te (I-15a) A stirred solution of the compound of I-8b (150 mg, 0.6 mmol) in toluene (6 mL) was degassed by bubbling with argon for 15 minutes, then [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol) was added followed by addition of triphenylphosphine (15 mg, 0.06 mmol) and 2-(Tri-n-butylstannyl) oxazole (0.15 mL, 0.73 mmol). The resulting reaction mixture was stirred at 120 °C for 4 h in a microwave. The reaction mixture was combined with another batch, filtered through the celite bed. The 69 ACTIVE/109135237.1

filtrate was concentrated under reduced pressure. The obtained crude was purified by column chromatography on silica gel and eluted with 2-10% EtOAc / p. ether, which gave the title compound (120 mg) as a semi-solid. MS (ES+) m/z 272.17 [M+H]+. A solution of lithium hydroxide (20 mg, 0.8 mmol) in water (1.0 mL) was added at rt to a stirred solution of I-15a (120 mg, 0.4 mmol) in EtOH (4.0 mL). The resulting reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The afforded crude was dissolved in water and acidified to pH 4 with 2N HCl (aq) solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum, which gave the title compound (90 mg, 90%) as a solid. MS (ES+) m/z 244.17 [M+H]+. Intermediate 16 Step a) 3-Chloro-5-nitro-2-(2H-1 triazol-2-yl)pyridine (I-16a) Potassium carbonate (14.0 g, 101.35 mmol) was added to solution of 2,3-dichloro-5- nitropyridine (10.0 g, 51.82 mmol) in THF (60 mL) followed by addition of 2H-1,2,3-triazole (3.4 mL, 58.7 mmol). The resulting mixture was stirred at rt until reaction was deemed completed as judged by TLC (~16 h), then diluted with water (300 mL). The aqueous layer was extracted with EtOAc (2 x 300 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 20% EtOAc in p.ether which gave the title compound (7.0 g, 60%) as a solid with 99.42% LCMS purity. MS (ES+) 226.03 [M+H] ⁺ . Step b) 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (I-16b) Tin(II) chloride (30.0 g, 158 mmol) was added portion wise at rt to a solution of compound I-16a (7.0 g, 31 mmol) in 1M HCl in MeOH (158 mL). The resulting mixture was stirred at rt for 3 h, then concentrated under reduced pressure. The residue was diluted with DCM (100 mL) and the mixture was basified with 1N aqueous NaOH solution (50 mL). The phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated, which gave the title compound (5.0 g, 77%) as a solid MS (ES+) 196.02 [M+H] ⁺ . 70 ACTIVE/109135237.1

Intermediate 17 Step a) 3-Chloro-2-(difluoromethoxy)-5-nitropyridine (I-17a) Sodium hydride (60%, 4.3 g, 0.11 mol) was added portion wise at rt under nitrogen to a stirred solution of 3-chloro-5-nitropyridin-2-ol (7.0 g, 40.1 mmol) in acetonitrile (700 mL). After 10 min 2,2-difluoro-2-(fluorosulfonyl)acetic acid (12.5 g, 70.2 mmol) was added and the reaction was stirred for 20 min at rt. The reaction mixture was cooled to 0 °C, ice water (300 mL) was added dropwise and the mixture was extracted with EtOAc (2 x 300 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The afforded crude material was purified by column chromatography on silica gel eluted with 10% EtOAc in p. ether. Appropriate fractions were combined and concentrated which gave the title compound (1.9 g, 21%). Step b) 5-Chloro-6-(difluoromethoxy)pyridin-3-amine (I-17b) Fe (4.8 g, 85.95 mmol) was added at rt to a stirred solution of I-17a (1.9 g, 8.46 mmol) in HOAc (27.1 mL, 474 mmol). The resulting reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure, diluted with DCM (50 mL) and filtered through Celite. The filtrate was washed with saturated sodium bicarbonate solution (2 x 50 mL), dried (Na2SO4), filtered and concentrated which gave the title compound (1.4 g, 83%) as a solid. LCMS (ES+) m/z 195.08 [M+H] ⁺ . 71 ACTIVE/109135237.1

Intermediate 18 Step a) ethyl 5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazine-3-carboxylate & ethyl 6-chloro-4- cyclopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (I-18a) A mixture of I-1c (500 mg, 4.3 mmol) and I-10a (1.0 g, 4.7 mmol) was stirred at rt for 30 min, then ethanol (30 mL) and 10M HCl (2.6 mL, 26 mmol) were added at 0 °C and heated to 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and poured into saturated sodium bicarbonate solution (20 mL) and was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 0-2% EtOAc / pet ether, which gave the mixture of title compounds (500 mg) as a liquid. MS (ES+) 265.19 [M+H] ⁺ . The compound was used in the next step without further purification. Step b) 5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazine-3-carboxylic acid & 6-chloro-4- cyclopropylpyrrolo[1,2-b]pyridazine-3-carboxylic acid (I-18b) A solution of 5M sodium hydroxide in water (1 mL, 5 mmol) was added at 0 °C to a stirred solution of I-18a (490 mg, 1.9 mmol) in EtOH (15 mL). The resulting reaction mixture was stirred at 80 °C for 3 h, then concentrated under reduced pressure and acidified with 10% aqueous solution of NaHSO4 at 0 °C. The precipitated solid was filtered, washed with water and dried, which gave the mixture of title compounds (350 mg) as a solid. LCMS (ES+) M/z = 235.26 [M+H]+. The compound was used in the next step without further purification. 72 ACTIVE/109135237.1

Intermediate 19 Step a) 4-(3-chloro-5-nitropyridin-2-yl)morpholine (I-19a) K2CO3 (689 mg, 5.0 mmol) and morpholine (196 mg, 2.2 mmol) were added under nitrogen at rt to a stirred solution of 2,3-dichloro-5-nitropyridine (500 mg, 2.5 mmol) in THF (10 mL). The mixture was stirred at rt for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained crude was triturated with diethyl ether, which gave the title compound (630 mg) as a solid. MS (ES=) m/z 244.24 [M+H]+. Step b) 5-chloro-6-morpholinopyridin-3-amine (I-19b) Tin (II) chloride (2.4 g, 12.4 mmol) was added at 0 °C to a solution of compound I-19a (630 mg, 2.5 mmol) in 1M HCl in MeOH (10 mL). The resulting mixture was stirred at rt for 2 h, then reaction mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained crude was triturated with diethyl ether, which gave the title compound (430 mg, 77%) as a solid. MS (ES=) m/z 214.27 [M+H]+. Intermediate 20 Step a) benzyl (E)-2-(ethoxymethylene)-5,5,5-trifluoro-3-oxopentanoate (I-20a) A mixture of benzyl 5,5,5-trifluoro-3-oxopentanoate (2 g, 7.7 mmol), triethyl orthoformate (2 mL, 13.2 mmol) and acetic anhydride (2 mL, 21.2 mmol) was heated to 120 °C for 16 h, then concentrated under reduced pressure, which gave the crude title compound (2.2 g, 49%) as a 73 ACTIVE/109135237.1

liquid. MS (ES+) 317.26 [M+H] ⁺ . A mixture of I-1c (300 mg, 2.5 mmol) and I-20a (1.5 g, 2.5 mmol) was stirred at rt for 10 min, then ethanol (20 mL) and 10M HCl (3 mL, 30 mmol) were added at 0 °C and heated to 80 °C for 3 h. The reaction mixture was diluted with water (100 mL) and was extracted with EtOAc (2 x 100 mL). The organic layer was washed with saturated sodium bicarbonate solution (50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was combined with another batch and purified by column chromatography on silica gel and eluted with 30-100% EtOAc / pet ether, which gave the mixture of title compounds (1.2 g) as a liquid. MS (ES+) 369.15 [M+H] ⁺ . The compound was used in next step without further purification. Step c) 5-chloro-4- trifluoroethyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid & 6-chloro- 4-(2,2,2-trifluoroethyl)pyrrolo[1,2-b]pyridazine-3-carboxyli c acid (I-20c) Pd/C (100 mg, 0.9 mmol) was added to a stirred solution of compound I-20b (1 g, 2.7 mmol) in EtOH (10.0 mL). The mixture was put under light pressure of H2 (balloon) and stirred at rt for 4 h, then filtered through Celite bed, washed with methanol and the filtrate was concentrated under reduced pressure, which gave the mixture of title compounds (800 mg) as a solid. LCMS (ES-) 227.22 [M-H] -. Intermediate 21 Step a) 4-(5-nitropyridin-2-yl)morpholine (I-21a) K ₂ CO ₃ (689 mg, 5 mmol) and morpholine (196 mg, 2.2 mmol) were added under nitrogen at rt to a stirred solution of 2-chloro-5-nitropyridine (500 mg, 2.5 mmol) in THF (10 mL). The mixture was stirred at rt for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The obtained crude was triturated with diethyl ether, which gave the title compound (630 mg) as a solid. MS (ES=) m/z 244.24 [M+H]+. 74 ACTIVE/109135237.1

Step b) 6-morpholinopyridin-3-amine (I-21b) Tin (II) chloride (2.4 g, 12.3 mmol) was added at 0 °C to a solution of compound I-21a (630 mg, 2.5 mmol) in 1M HCl in MeOH (11 mL, 32.4 mmol). The resulting mixture was stirred at rt for 2 h, then reaction mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained crude was triturated with diethyl ether, which gave the title compound (430 mg, 77%) as a solid. MS (ES=) m/z 214.27 [M+H]+. Intermediate 22 Step a) 3,4-difluoro-1-(triisopropylsilyl)-1H-pyrrole (I-22a) n-BuLi (1.6M in hexane) (5 mL, 8.0 mmol) was added dropwise at -78 °C under argon to a solution of 3,4-dibromo-1-(triisopropylsilyl)-1H-pyrrole (3 g, 7.9 mmol) in dry THF (75 mL). The solution was stirred for 15 min at -78 °C, then a solution of N-fluorobenzenesulfonimide (2.5 g, 7.9 mmol) in THF (15 mL) was added at -78 °C, warmed to rt and stirred at rt for 1 h. Again n-BuLi (1.6M in hexane) (5 mL, 8.0 mmol) was added dropwise at -78 °C under argon and stirred for 30 min at -78 °C, then a solution of N-fluorobenzenesulfonimide (2.5 g, 7.9 mmol) in THF (15 mL) was added at -78 °C, slowly warmed to rt and stirred at rt for 1 h. The reaction mixture was poured into saturated ammonium chloride solution and the mixture was extracted with DCM (3 x 80 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with pet ether, which gave the title compound (1 g) as a liquid. The compound was used in the next step without further purification. 75 ACTIVE/109135237.1

Step b) 3,4-difluoro-1H-pyrrole (I-22b) A solution of 1M TBAF in THF (33 mL, 33 mmol) was added at rt under nitrogen to a stirred solution of I-22a (7 g, 27 mmol) in THF (150 mL) at 0 °C. The reaction mixture was stirred at rt for 15 min. The reaction mixture was diluted with water (50 mL) and extracted with DCM (5 x 70 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum, which gave the crude title compound (3 g). The crude compound was used in the next step without further purification. Step c) 3,4-difluoro-1H-pyrrol-1-amine (I-22c) NaH (60%, 1.4 g, 35 mmol) was added at 0 °C to a solution of I-22b (3 g, 29.1 mmol) in DMF (300 mL). The mixture was stirred for 30 min at 0 °C, then O- (diphenylphosphinyl)hydroxylamine (7.7 g, 32.4 mmol) was added at 0 °C and stirred at rt for 1 h. The reaction mixture was poured into ice cold water and was extracted with DCM (5 x 80 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 10-15% EtOAc / pet ether, which gave the title compound (700 mg) as a liquid. MS (ES+) 163.25 [M+2] ⁺ . The crude compound was used in the next step without further purification. Step d) ethyl (S)-5,6-difluoro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine- 3-carboxylate (I-22d) A mixture of I-22c (700 mg, 5.9 mmol), I-2b (1.5 g, 6.5 mmol) was stirred at rt for 30 min, then ethanol (50 mL) and 10M HCl (3.5 mL, 35 mmol) were added at 0 °C and heated to 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and poured into saturated sodium bicarbonate solution (20 mL) and was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel and eluted with 2-5% EtOAc / pet ether, which gave the mixture of title compounds (900 mg) as a liquid. MS (ES+) 285.30 [M+H] ⁺ . The compound was used in the next step without further purification. Step e) (S)-5,6-difluoro-4-(1-methoxyethyl) ,2-b]pyridazine-3-carboxylic acid (I-22e) Lithium hydroxide (50 mg, 2.1 mmol) was added at 0 °C to a stirred solution of I-22d (290 mg, 1.0 mmol) in THF (10.0 mL) and water (2.0 mL). The resulting reaction mixture was stirred at rt for 5 h, then concentrated under reduced pressure. The afforded crude was acidified with 10% NaHSO ₄ (aq) solution at 0 °C and was extracted with EtOAc (4 x 40 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum, which gave the title compound (220 mg, 77%) as a sticky solid. MS (ES+) M/z = 257.19 [M+H] ⁺ . 76 ACTIVE/109135237.1

Intermediate 23 Step a) ethyl (S)-7-fluoro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-ca rboxylate (I-23a) Selectfluor (1.0 g, 2.8 mmol) was added under nitrogen at rt to a stirred solution of compound I- 7a (700 mg, 2.8 mmol) in acetonitrile (20 mL). The mixture was stirred at rt for 16 h. The reaction mixture was quenched with ice water (20 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure, which gave the title compound (650 g) as a semi-solid. MS (ES+) m/z 267.29 [M+H] ⁺ .The compound was used in the next step without further purification. Step fluoro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxyl ic acid (I-23b) A solution of lithium hydroxide (80 mg, 3.3 mmol) in water (5.0 mL) was added at rt to a stirred solution of I-23a (650 mg, 1.2 mmol) in methanol (10 mL). The resulting reaction mixture was stirred at 80 °C for 1 h, then concentrated under reduced pressure. The afforded crude was dissolved in water (50 mL) and acidified to pH 4 with 2N HCl (aq) solution and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum, which gave the title compound (500 mg) as a solid. MS (ES+) m/z 239.22 [M+H] ⁺ . The compound was used in the next step without further purification. Intermediate 24 77 ACTIVE/109135237.1

Step a) ethyl 5,7-dichloro-4-cyclopropylpyrrolo[1,2-b]pyridazine-3-carboxy late (I-24a) To a solution of I-10b in THF (217 mL) was added N-chlorosuccinimide (8.97 g, 67.2 mmol) at r.t.. This mixture was stirred at 60 ^o C for 1 h. Saturated aqueous NaHCO3 was added to the reaction mixture. The resulting mixture was extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 (3x), water (3x) and brine. The organic layer was concentrated under reduced pressure to afford the crude product. The crude product was divided into three portions and purified by flash chromatography on C18 column (CH ₃ CN/water = 1/9 to 9/1) to give the title compound (4.51 g, 15.1 mmol, 69.4% yield) as a yellow solid. MS (ES+) m/z 299.0 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 6.82 (s, 1H), 4.41 - 4.36 (m, 2H), 2.39 - 2.32 (m, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.25 - 1.20 (m, 2H), 0.71 - 0.67 (m, 2H). To a solution I-24a (4040 mg, 13.5 mmol) in EtOH (269 mL) was added 10% palladium on carbon (2.87 g, 2.70 mmol). The resulting mixture was stirred at r.t. under a hydrogen balloon. The mixture was stirred at r.t. overnight, after which it was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude product, which was divided into two batches and purified by flash chromatography on C18 column (CH ₃ CN/water = 1/9 to 4/1) to give the title compound (2.39 g, 9.04 mmol, 66.9% yield) as a yellow oil. MS (ES+) m/z 265.05 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 7.66 (t, J = 2.3 Hz, 1H), 6.81 - 6.80 (m, 1H), 4.40 - 4.35 (m, 2H), 2.37-2.32 (m, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.24 - 1.19 (m, 2H), 0.71 - 0.67 (m, 2H). Sodium hydroxide (1.76 g, 44.1 mmol) and water (35.3 mL) were added to a mixture of I-24b (2340 mg, 8.83 mmol) in ethanol (107 mL). The mixture was heated at 50 ºC overnight. The mixture was cooled to room temperature and concentrated. Water was added to the residue, and the pH of the resulting mixture was adjusted to 4-5. The mixture was filtered and washed with water. The solid was dried under high vacuum to give the title compound (2.10 g, 8.89 mmol, 100% yield) as a yellow solid. MS (ES+) m/z 237.0 [M+H] ⁺ . 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.71 (m, 1H), 6.86 (m, 1H), 2.41-2.34 (m, 1H), 1.34 - 1.29 (m, 2H), 0.80-0.76 (m, 2H). 78 ACTIVE/109135237.1

Intermediate 25 Step a) tert-butyl N-(5-chloro-6-cyanopyridin-3-yl)carbamate (I-25a) A solution of 5-bromo-3-chloropyridine-2-carbonitrile (5 g, 22.9 mmol), tert-butyl carbamate (2.41 g, 20.6 mmol), Xantphos (2.65 g, 4.58 mmol), cesium carbonate (22.3 g, 68.7 mmol), and tris(dibenzylideneacetone) dipalladium (2.09 g, 2.29 mmol) in dioxane (20 mL) was stirred at 100 ^o C for 1 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 0/1 to 3/7) to give the title compound (5.20 g, 20.4 mmol, 89% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 1.49 (s, 9H). Step b) tert-butyl N-[5-chloro-6-(1- methyl-1H-1 tetrazol-5-yl)pyridin-3-yl]carbamate and tert-butyl N-[5-chloro-6-(2-methyl-2H-1 tetrazol-5-yl)pyridin-3-yl]carbamate (I-25b & I- 25c) To a solution of I-25a (3.1 g, 12.2 mmol) and NH4Cl (652 mg, 12.2 mmol) in DMF (30 mL) was added azidosodium (2.05 g, 31.5 mmol) and the reaction mixture was stirred at 100 ^o C for 16 h under nitrogen. LCMS showed the reactant was consumed completely. The reaction mixture was cooled to 20 ^o C and K2CO3 (3.37 g, 24.4 mmol) was added. The resulting mixture was stirred at 20 ^o C for 30 min. Finally, methyl trifluoromethanesulfonate (10.0 g, 61.0 mmol) was added to 79 ACTIVE/109135237.1

the mixture at 0 ^o C and the reaction mixture was stirred at 20 ^o C for another 2 h. The reaction mixture was combined with quenched material from a separate run of this reaction (1.97 mmol scale), diluted with water (50 mL) and extracted with EtOAC (50 mL x 3). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/hexane =0/1 to 2/3) to provide tert-butyl N-[5-chloro-6-(1- methyl-1H-1,2,3,4-tetrazol-5-yl)pyridin-3-yl]carbamate (1.20 g, 3.86 mmol, 27% yield) as a yellow solid and tert-butyl N-[5-chloro-6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)pyridin-3- yl]carbamate (1 g, 3.21 mmol, 23% yield) as a yellow oil. Tert-butyl N-[5-chloro-6-(1- methyl-1H-1,2,3,4-tetrazol-5-yl)pyridin-3-yl]carbamate MS (ES+) m/z 310.8 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 4.13 (s, 3H), 1.52 (s, 9H). Tert-butyl N-[5-chloro-6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)pyridin-3-y l]carbamate MS (ES+) m/z 310.8 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 4.46 (s, 3H), 1.50 (s, 9H). Step c) 5-chloro-6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)pyridin-3-amin e (I-25d) A solution of I-25c (1 g, 3.21 mmol) in 4 N HCl in dioxane (10 mL) was stirred at 20 ^o C for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude title compound (900 mg, 4.27 mmol) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 4.42 (s, 3H). A solution of I-25b (200 mg, 643 μmol) in 4 M HCl/dioxane (10 mL) was stirred at 40 ^o C for 12 h. The reaction mixture was concentrated under reduced pressure to afford crude title compound (135 mg, 640 μmol, 100% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 5.73 - 5.65 (m, 2H), 4.08 (s, 3H). 80 ACTIVE/109135237.1

Intermediate 26 Step a) tert-butyl N-[(tert-butoxy)carbonyl]-N-[6-cyano-5-(trifluoromethyl)pyri din-3- yl]carbamate (I-26a) To a stirred solution of 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (3 g, 16.0 mmol), DMAP (390 mg, 3.20 mmol), and Et3N (15.5 mL, 112 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (18.3 mL, 80.0 mmol) at 0 ^o C. The resulting mixture was stirred at 15 ^o C for 12 h. The reaction mixture was poured into water (60 mL) and extracted with CH2Cl2 (30 mL x 3). The combined organic layers were washed with water (120 mL x 2) and brine (120 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 0/1 to 3/7) to provide the title compound (4.40 g, 11.3 mmol, 71% yield) as a pale yellow oil. ¹ H NMR (400 MHz, CD3OD) δ 8.89 (d, J = 2 Hz, 1H), 8.45 (d, J = 2 Hz, 1H), 1.47 (s, 18H). Step b) tert-butyl (6-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)pyridin-3- yl)carbamate and tert-butyl (6-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)pyridin-3- yl)carbamate(I-26b and I- 26c) To a solution of I-26a (2.5 g, 6.45 mmol) and NH4Cl (345 mg, 6.45 mmol) in DMF (5 mL) was added azidosodium (1.08 g, 16.6 mmol) and the reaction mixture was stirred at 100 ^o C for 16 h 81 ACTIVE/109135237.1

under nitrogen. The reaction mixture was cooled to 20 ^o C. K ₂ CO ₃ (1.78 g, 12.9 mmol) was added and the mixture was stirred at 20 ^o C for 30 min, after which methyl trifluoromethanesulfonate (5.28 g, 32.2 mmol) was added and the resulting mixture was stirred at 20 ^o C for 2 h. The reaction mixture was diluted with water (50 mL) and was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the crude material. The crude material was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 0/1 to 3/7) to give tert-butyl (6-(1-methyl-1H-tetrazol-5-yl)-5- methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)pyridin-3-yl)car bamate (479 mg, 1.39 mmol, 22% yield) as yellow oils. Tert-butyl (6-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)pyridin-3- yl)carbamate MS (ES+) m/z 344.8 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 4.09 (s, 3H), 1.53 (s, 9H). Tert-butyl (6-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)pyridin-3- yl)carbamate MS (ES+) m/z 344.8 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 1.2 Hz, 1H), 4.48 (s, 3H), 1.52 (s, 9H). Step c) 6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-5-(trifluoromethyl)pyr idin-3-amine (I-26d) A solution of I-26c (479 mg, 1.39 mmol) in 4 M HCl/dioxane (10 mL) was stirred at 40 ^o C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (382 mg, 1.56 mmol) as a brown solid. MS (ES+) m/z 245.1 [M+H] ⁺ . A solution of I-26b (522 mg, 1.51 mmol) in 4 M HCl/dioxane (10 mL) was stirred at 40 ^o C for 2 h. The reaction was concentrated under reduced pressure to give the title compound (472 mg, 1.93 mmol) as a brown solid. MS (ES+) m/z 245.1 [M+H] ⁺ . 82 ACTIVE/109135237.1

Intermediate 27 Step a) methyl 5-{[(tert-butoxy)carbonyl]amino}-3-methylpyridine-2-carboxyl ate (I-27a) A mixture of methyl 5-bromo-3-methylpyridine-2-carboxylate (5 g, 21.7 mmol), tert-butyl carbamate (2.78 g, 23.8 mmol), Pd2(dba)3 (988 mg, 1.08 mmol), Xantphos (1.25 g, 2.17 mmol) and Cs ₂ CO ₃ (14.1 g, 43.4 mmol) in dioxane (50 mL) was stirred at 100 ^o C for 16 hr. The mixture was filtered through Celite and washed with EtOAc (50 mL x 2). The filtrate was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 1/10 to 1/4) to afford the title compound (4.50 g, 16.8 mmol, 78% yield) as a yellow solid. MS (ES+) m/z 267.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.0 Hz, 1H), 8.04 (br s, 1H), 6.80 (br s, 1H), 3.95 (s, 3H), 2.63 (s, 3H), 1.53 (s, 9H). Step b) tert-butyl N-[6-(hydrazinecarbonyl)-5-methylpyridin-3-yl]carbamate (I-27b) To a mixture of I-27a (4.5 g, 16.8 mmol) in EtOH (40 mL) was added hydrazine hydrate (3.36 g, 67.2 mmol) and the mixture was stirred at 85 ^o C for 12 hr. The mixture was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 1/4 to 1/0) to give the title compound (4.40 g, 16.5 mmol, 98% yield) as a colorless oil. MS (ES+) m/z 267.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (br s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.85 (br s, 1H), 6.91 (s, 1H), 4.01 (br d, J = 2.8 Hz, 2H), 2.71 (s, 3H), 1.53 (s, 9H). Step c) tert-butyl N-[5-methyl-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)pyridin-3- yl]carbamate (I-27c) To a mixture of I-27b (2 g, 7.51 mmol) in DMF (20 mL) was added Et3N (1.89 g, 18.7 mmol) and CDI (1.89 g, 15.0 mmol) and the mixture was stirred at 25 ^o C for 3 hr. The mixture was 83 ACTIVE/109135237.1

concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 1/10 to 1/1) to give the title compound (1.46 g, 4.99 mmol, 67% yield) as a white solid. MS (ES+) m/z 292.8 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (br s, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 6.95 (br s, 1H), 2.62 (s, 3H), 1.55 (s, 9H). Step d) 5-(5-amino-3-methylpyridin-2-yl)-2,3-dihydro- oxadiazol-2-one hydrochloride (I- 27d) A mixture of I-27c (1.46 g, 4.99 mmol) in 4M HCl/dioxane (15 mL) was stirred at 20 ^o C for 12 hr. The mixture was concentrated under reduced pressure to afford the crude title compound (1.14 g, 4.98 mmol, 100% yield) as a brown solid, which was used directly in the next step without further purification. MS (ES+) m/z 192.8 [M+H] ⁺ . Intermediate 28 Step a) 1-(5-bromopyridin-2- yl)azetidin-2-one (I-28a) A mixture of 2,5-dibromopyridine (14.6 g, 61.9 mmol), azetidin-2-one (4.2 g, 59.0 mmol), cesium carbonate (38.4 g, 118 mmol), tris(dibenzylideneacetone) dipalladium (1.08 g, 1.18 mmol) and Xantphos (1.36 g, 2.36 mmol) in toluene (200 mL) was stirred at 90 ^o C under N2 atmosphere for 12 h. The reaction mixture was diluted with water (100 mL) and was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was triturated with petroleum ether/EtOAc (v/v = 10/1, 200 mL) to give the title compound (11.0 g, 48.4 mmol, 83% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 2.4, 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 3.68 (t, J = 4.8 Hz, 2H), 3.11 (t, J = 4.8 Hz, 2H). 84 ACTIVE/109135237.1

Step b) 1-(5-bromo-3-chloropyridin-2-yl)azetidin-2-one (I-28b) To a mixture of I-28a (5 g, 22.0 mmol) in dimethylformamide (100 mL) was added 1- chloropyrrolidine-2,5-dione (8.81 g, 66.0 mmol) and para-toluene sulfonate hydrate (418 mg, 2.20 mmol). The mixture was stirred at 20 ^o C for 60 h. LCMS showed that 18% desired mass was detected.1-chloropyrrolidine-2,5-dione (25 g, 187.2 mmol) was added. The mixture was stirred at 20 °C for an additional 6 days. LCMS showed that 41% desired mass was detected. The reaction was quenched by adding water (100 mL) and was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 1:0 to 0:1) and further purified by prep-HPLC (column:Xtimate C18150*40mm*5mm, table: 24-54% B (A = water (0.05% NH3H2O), B = acetonitrile), flow rate: 55 mL/min, UV Detector 220 nm) to afford the title compound (1 g, 3.82 mmol, 17% yield) as a white solid. MS (ES+) m/z 261.0 [M+H] ⁺ . Step c) tert-butyl N-[5-chloro-6-(2-oxoazetidin-1-yl)pyridin-3-yl]carbamate (I-28c) A mixture of I-28b (0.8 g, 3.05 mmol), tert-butyl carbamate (427 mg, 3.65 mmol), cesium carbonate (1.98 g, 6.10 mmol), Xantphos (176 mg, 305 mmol) and tris(dibenzylideneacetone) dipalladium (139 mg, 152 mmol) in 1,4-dioxane (20 mL) was stirred at 90 ^o C for 12 h under N ₂ atmosphere. The reaction mixture was combined with another reaction (764 mmol scale). The mixture was quenched by adding water (30 mL) and was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 0/1 to 3/1) to give the title compound (800 mg, 2.68 mmol, 70% yield) as a yellow solid. MS (ES+) m/z 298.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 8.20 (br s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 6.63 (s, 1H), 3.93 (t, J = 4.8 Hz, 2H), 3.14 (t, J = 4.8 Hz, 2H), 1.53 (s, 9H). Step d) 1-(5-amino-3-chloropyridin-2-yl)azetidin-2-one (I-28d) To a mixture of I-28c (400 mg, 1.34 mmol) in toluene (20 mL) was added silica gel (1 g). The mixture was stirred at 110 ^o C for 16 h. LCMS showed that part of starting material I-28c remained.1 g of silica gel was added. The mixture was stirred at 110 ^o C for 48 h. The reaction mixture was filtered through a thin celite pad and the filter cake was washed with DCM (20 mL x 3). The filtrate was concentrated under reduced pressure to give the crude title compound (140 mg, 708 mmol, 53% yield) as a yellow solid. MS (ES+) m/z 198.1 [M+H] ⁺ . 85 ACTIVE/109135237.1

¹ H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 5.69 (s, 2H), 3.65 (t, J = 4.4 Hz, 2H), 3.02 (t, J = 4.4 Hz, 2H). Example 1 Step a) (S)-1-(6-chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(5-chloro-6-(2H- DPPA (0.34 mL, 1.6 mmol) and Et3N (0.9 mL, 6.5 mmol) were added under nitrogen at rt to a stirred solution of I-2d (330 mg, 1.3 mmol) in toluene (25 mL). The mixture was stirred at rt for 15 min, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (I-16b) (280 mg, 1.43 mmol) was added and the reaction mixture was stirred at 110 °C for 3 h. The mixture was poured water (10 mL) and extracted with EtOAc (3 x 40 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by trituration with diethyl ether, the precipitated solid was filtered and dried, which gave the title compound (300 mg, 44%) as a solid. MS (ES+) m/z 447.36 [M+H] ⁺ . Step b) (S)-1-(6-chloro-4-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(5-chloro-6-(2H- 1,2,3-triazol-2-yl)pyridin-3-yl)urea (1b) BBr3 (0.1 mL, 1.04 mmol) was added under nitrogen to a stirred solution of 1a (200 mg, 0.45 mmol) in DCM (20 mL) at -78 °C. The reaction mixture was stirred at rt for 14 h, then poured into ice cold sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (3 x 50 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (40 mg, 20%) as a solid. MS (ES+) m/z 433.39 [M+H]+. 1H NMR (500 MHz, DMSO): δ 10.30 (s, 1H), 8.96 (s, 1H), 8.62 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.15 (s, 2H), 7.95 (d, J = 1.9 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 86 ACTIVE/109135237.1

6.27 (d, J = 3.0 Hz, 1H), 5.21 (q, J = 3.2 Hz, 1H), 1.46 (d, J = 6.7 Hz, 3H). Example 2 Step a) 1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(4-(1-e thoxyethyl)pyrrolo[1,2- b]pyridazin-3-yl)urea (2-1, 2-2) DPPA (2.4 mL, 11.2 mmol) and Et ₃ N (2.4 mL, 17.2 mmol) were added under nitrogen at rt to a stirred suspension of I-3d (200 mg, 0.83 mmol) in toluene (20 mL). The mixture was stirred at rt for 30 min, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (165 mg, 0.84 mmol) was added and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 200 mL), the combined organic layers were washed with aqueous saturated sodium bicarbonate (50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase. The isomers were separated using normal phase chiral prep HPLC. Both isomers were again purified separately by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O : MeCN as mobile phase, which gave the title compounds 2-1 (12 mg, 3%) and 2-2 (10 mg, 3%) as a solid. MS (ES+) m/z 427.45 [M+H] ⁺ . 10.02 (s, 1H), 8.56 (d, J = 2.4 Hz, 2H), 8.48 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H), 8.15 (s, 2H), 7.79 (q, J = 1.4 Hz, 1H), 6.83 (q, J = 2.3 Hz, 1H), 6.72 (q, J = 1.9 Hz, 1H), 4.97 (q, J = 6.6 Hz, 1H), 3.42 (m, J = 3.3 Hz, 1H), 3.35 (q, J = 4.7 Hz, 1H), 1.51 (d, J = 6.7 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H). (2-2) ¹ H NMR (500 MHz, DMSO): δ 9.98 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.37 (s, 1H), 8.15 (s, 2H), 7.79 (q, J = 1.4 Hz, 1H), 6.84 (q, J = 2.3 Hz, 1H), 6.73 (q, J = 1.9 Hz, 1H), 4.97 (q, J = 6.6 Hz, 1H), 3.42 (m, J = 3.9 Hz, 1H), 3.35 (m, J = 4.1 Hz, 1H), 1.51 (d, J = 6.6 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H). 87 ACTIVE/109135237.1

Preparative normal phase HPLC Conditions Column/dimensions : Chiralpak- IG (250X30)mm, 5μ Mobile Phase : n-Hexane: Ethanol (60:40) Flow : 38.0ml /min Temperature : Ambient Wave length : 280 nm Stack time : 8 min Load ability/Inj : 5 mg/Inj Total No of injections : 12 Example 3 & 4 Step a) (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(4- (1-methoxyethyl)-6- methylpyrrolo[1,2-b]pyridazin-3-yl)urea with 1-(5-chloro-6-(2H-1 triazol-2-yl)pyridin-3-yl)- 3-(4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazin-3-yl)urea Et ₃ N (0.8 mL, 5.7 mmol) and DPPA (0.3 mL, 1.4 mmol) were added under nitrogen at rt to a stirred solution of I-5c (230 mg, 0.51 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at rt for 1 h, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (200 mg, 1.02 mmol) was added and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase to afford two fractions. The first fraction was combined with another batch and purified by prep HPLC on an X-Select C18 column using a gradient of 10 mM NH ₄ OAc in H ₂ O: MeCN as mobile phase. The afforded residue was further purified by chiral SFC. The afforded residue was further purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase to afford the title compound (6 mg, 3%) as a solid. MS (ES+) m/z 427.38 [M+H] ⁺ . 1H NMR (500 MHz, DMSO): δ 10.03 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.48 (t, J = 4.2 Hz, 2H), 88 ACTIVE/109135237.1

8.33 (s, 1H), 8.15 (s, 2H), 7.62 (q, J = 0.8 Hz, 1H), 6.52 (d, J = 1.1 Hz, 1H), 4.82 (q, J = 6.6 Hz, 1H), 3.23 (s, 3H), 2.28 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H). Conditions for chiral SFC Column/dimensions : Chiralpak IG (30 X 250) mm, 5μ % CO2 : 65.0% % Co solvent : 35.0% (EtOH) Total Flow : 70.0 g/min Back Pressure : 90.0 bar UV : 254 nm Stack time : 11 min Load/Inj : 7.2 mg Example 4: The second fraction was combined with another batch and purified by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (6 mg, 3%) as a solid. MS (ES+) m/z 413.40 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.03 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.15 (s, 2H), 7.80 (q, J = 1.4 Hz, 1H), 6.84 (q, J = 2.3 Hz, 1H), 6.69 (q, J = 2.0 Hz, 1H), 4.88 (d, J = 6.7 Hz, 1H), 3.24 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H). Example 5 Step a) (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(5- fluoro-4-(1- methoxyethyl)pyrrolo[1,2-b]pyridazin-3-yl)urea (5) DPPA (0.45 mL, 2.1 mmol) and Et3N (1.3 mL, 9.3 mmol) were added under nitrogen at rt to a stirred suspension of I-6d (400 mg, 0.84 mmol) in toluene (20 mL). The mixture was stirred at rt for 15 min, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (330 mg, 1.7 mmol) was added and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with EtOAc (4 x 40 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude compound was purified 89 ACTIVE/109135237.1

by column chromatography on silica gel and eluted with 30-50% EtOAc / pet ether. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The residue obtained from second fraction was further purified by chiral SFC, which gave the title compound (130 mg, 35%) as a solid. MS (ES+) m/z 431.41 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.19 (s, 1H), 8.53 (d, J = 2.4 Hz, 2H), 8.48 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.15 (s, 2H), 7.65 (q, J = 2.5 Hz, 1H), 6.77 (d, J = 3.3 Hz, 1H), 4.92 (m, J = 3.9 Hz, 1H), 3.29 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H). Conditions for chiral SFC Column/dimensions : Chiralpak- AD-H (250X30)mm,5μ % CO ₂ : 60.0% % Co solvent : 40.0% (EtOH) Total Flow : 100.0 g/min Back Pressure : 100.0 bar UV : 280 nm Stack time : 8.4 min Load/Inj : 18.5 mg Example 6 Step a) (S)-1-(6-chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(5-chloro-6-(2H- 1,2,3-triazol-2-yl)pyridin-3-yl)urea (6) DPPA (0.34 mL, 1.6 mmol) and Et ₃ N (0.9 mL, 6.5 mmol) were added under nitrogen at rt to a stirred suspension of I-2d (330 mg, 1.3 mmol) in toluene (25 mL). The mixture was stirred at rt for 15 min, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (280 mg, 1.43 mmol) was added and the reaction mixture was stirred at 110 °C for 3 h. The mixture was poured water (10 mL) and extracted with EtOAc (3 x 40 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by trituration with diethyl ether, the precipitated solid was filtered and dried to afford 300 mg of the crude compound. 100 mg of the crude compound was further purified by prep HPLC on a Kromasil® C18 column 90 ACTIVE/109135237.1

using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase. The afforded residue was further purified by chiral SFC, which gave the title compound (60 mg) as a solid. MS (ES+) m/z 447.36 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.11 (s, 1H), 8.65 (s, 1H), 8.54 (d, J = 2.8 Hz, 2H), 8.48 (d, J = 2.3 Hz, 1H), 8.15 (s, 2H), 8.00 (d, J = 1.8 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 4.86 (q, J = 6.6 Hz, 1H), 3.24 (s, 3H), 1.49 (d, J = 6.7 Hz, 3H). Conditions for chiral SFC Column/dimensions : Chiralpak IC (30 X 250) mm, 5μ % CO ₂ : 60.0% % Co solvent : 40.0% (MeOH) Total Flow : 70.0 g/min Back Pressure : 90.0 bar UV : 214 nm Stack time : 5.5 min Load/Inj : 5.0 mg Example 7 Step a) (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(4- (1-hydroxyethyl)-6- methylpyrrolo[1,2-b]pyridazin-3-yl)urea (7) BBr ₃ (0.02 mL, 0.21 mmol) was added under nitrogen to a stirred solution of compound 3 (60 mg, 0.14 mmol) in DCM (10 mL) at -78 °C. The reaction mixture was stirred at 0 °C for 4 h, then poured into ice cold sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (3 x 20 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The afforded residue was purified twice by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (8 mg, 13%) as a solid. MS (ES+) m/z 413.43[M+H]+. ¹ H NMR (500 MHz, DMSO): δ 10.26 (s, 1H), 8.86 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.44 (s, 1H), 8.15 (s, 2H), 7.58 (q, J = 0.8 Hz, 1H), 6.46 (d, J = 1.2 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 5.19 (m, J = 3.3 Hz, 1H), 2.27 (s, 3H),1.45 (d, J=6.5 Hz, 3H). 91 ACTIVE/109135237.1

Example 8 Step a) (5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(4-(1-met hoxyethyl)pyrrolo[1,2- b]pyridazin-3-yl)urea (8a) Et3N (2.3 mL, 16.1 mmol) and DPPA (0.8 mL, 3.7 mmol) were added under nitrogen at rt to a stirred solution of I-7b (450 mg, 1.7 mmol) in toluene (15 mL). The mixture was stirred at rt, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (300 mg, 1.4 mmol) was added and the reaction mixture was stirred at 100 °C for 20 min in a microwave. The reaction mixture was combined with reaction mixture from another batch and quenched with ice water (60 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The obtained residue was further purified by chiral SFC. The impure product was further purified by prep HPLC on a Kromosil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (29 mg) as a solid. MS (ES+) m/z 413.40 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.02 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.51 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.42 (s, 1H), 8.15 (s, 2H), 7.80 (q, J = 1.4 Hz, 1H), 6.84 (q, J = 2.3 Hz, 1H), 6.69 (q, J = 1.9 Hz, 1H), 4.88 (q, J = 6.6 Hz, 1H), 3.24 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H). Conditions for chiral SFC Column/dimensions : Chiralpak- AD-H (250X30) mm, 5μ % CO2 : 55.0% % Co solvent : 45.0% (MeOH) Total Flow : 70.0 g/min Back Pressure : 100.0 bar UV : 214 nm 92 ACTIVE/109135237.1

Stack time : 15 min Load/Inj : 7.8 mg Step b) (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(4- (1-hydroxyethyl)pyrrolo[1,2- b]pyridazin-3-yl)urea (8) BBr3 (0.15 mL, 1.6 mmol) was added under nitrogen to a stirred solution of compound 8a (100 mg, 0.24 mmol) in DCM (5 mL) at -78 °C. The reaction mixture was stirred at rt for 16 h, concentrated under reduced pressure. The residue was then basified using sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (3 x 80 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The afforded residue was purified by column chromatography on silica gel and eluted with 20-60% EtOAc / pet ether. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH ₄ HCO ₃ in H2O: MeCN as mobile phase. The obtained product was washed with water, filtered and lyophilised, which gave the title compound (10 mg, 10%) as a solid. MS (ES+) m/z 399.38 [M+H]+. ¹ H NMR (500 MHz, DMSO): δ 10.30 (s, 1H), 8.90 (s, 1H), 8.53 (t, J = 5.3 Hz, 2H), 8.48 (d, J = 2.3 Hz, 1H), 8.15 (s, 2H), 7.76 (q, J = 1.4 Hz, 1H), 6.81 (q, J = 2.3 Hz, 1H), 6.64 (q, J = 1.9 Hz, 1H), 6.23 (s, 1H), 5.25 (q, J = 6.6 Hz, 1H), 1.48 (d, J = 6.7 Hz, 3H). Example 9 Step a) (S)-1-(5-fluoro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(2-(trifluoromethyl)pyridin- 4-yl)urea (9) DPPA (0.5 mL, 2.3 mmol) and Et3N (1.4 mL, 9.7 mmol) were added under nitrogen at rt to a stirred suspension of I-6d (400 mg, 0.84 mmol) in toluene (20 mL). The mixture was stirred at rt for 15 min, then 2-(trifluoromethyl)pyridin-4-amine (270 mg, 1.7 mmol) was added and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with EtOAc (4 x 40 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude compound was purified by column chromatography on silica gel and eluted with 30-50% EtOAc / pet ether. The afforded residue was 93 ACTIVE/109135237.1

purified by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase. The residue obtained from the second fraction was further purified by chiral SFC, which gave the title compound (45 mg, 13%) as a solid. MS (ES+) m/z 398.38 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.27 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.66 (q, J = 2.5 Hz, 1H), 7.60 (q, J = 2.5 Hz, 1H), 6.77 (d, J = 3.3 Hz, 1H), 4.90 (m, J = 3.9 Hz, 1H), 3.27 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H). Conditions for chiral SFC Column/dimensions : (R,R) WHELK-01 (250X30) mm, 5μ % CO2 : 90.0% % Co solvent : 10.0% (EtOH) Total Flow : 60.0 g/min Back Pressure : 90.0 bar UV : 268 nm Stack time : 7.5 min Load/Inj : 4.05 mg Example 10 Step a) 1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(4-isop ropyl-6-methylpyrrolo[1,2- b]pyridazin-3-yl)urea (10) Et3N (0.2 mL, 1.44 mmol) and DPPA (0.1 mL, 0.5 mmol) were added under nitrogen at rt to a stirred solution of I-8e (60 mg, 0.3 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (43 mg, 0.22 mmol) in toluene (3 mL) and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 15 mL). The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The afforded residue was combined with another batch and purified by prep HPLC on a Sunfire C18 (30X150) mm 5u using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The obtained residue was further purified by achiral SFC. The afforded product was further purified by prep HPLC on an X-Select C18 using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (6 mg, 5%) as a solid. MS (ES+) m/z 411.42 [M+H] ⁺ . 94 ACTIVE/109135237.1

¹ H NMR (500 MHz, DMSO): δ 9.76 (s, 1H), 8.56 (d, J = 2.3 Hz, 2H), 8.45 (d, J = 2.3 Hz, 1H), 8.14 (s, 2H), 8.01 (s, 1H), 7.59 (d, J = 0.5 Hz, 1H), 6.52 (d, J = 1.0 Hz, 1H), 3.40 (t, J = 7.1 Hz, 1H), 2.29 (s, 3H), 1.38 (d, J = 7.1 Hz, 6H). Example 11 & 12 Step a) (R)-1-(6-chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(5-chloro-6-(2H- 1,2,3-triazol-2-yl)pyridin-3-yl)urea compound with 1-(5-chloro-4-(1-methoxyethyl)pyrrolo[1,2- b]pyridazin-3-yl)-3-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyrid in-3-yl)urea (11 & 12) DPPA (0.2 mL, 0.93 mmol) and Et ₃ N (0.6 mL, 4.3 mmol) were added under nitrogen at rt to a stirred suspension of I-9b (200 mg, 0.4 mmol) in toluene (10 mL). The mixture was stirred at rt for 15 min, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (170 mg, 0.9 mmol) was added and the reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was poured into saturated water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude compound was purified by column chromatography on silica gel and eluted with 30-40% EtOAc / pet ether. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which afforded three compounds. Example 11 The residue obtained from the first fraction was further purified by chiral SFC, which gave the title compound (5 mg) as a solid. MS (ES+) m/z 447.32 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.09 (s, 1H), 8.60 (s, 1H), 8.54 (t, J = 2.9 Hz, 2H), 8.47 (d, J = 2.4 Hz, 1H), 8.15 (s, 2H), 8.00 (d, J = 1.9 Hz, 1H), 6.75 (d, J = 1.9 Hz, 1H), 4.85 (q, J = 6.6 Hz, 1H), 3.24 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H). Conditions for chiral SFC for Example 11 Column/dimensions : Chiralpak IC (30 X 250) mm, 5μ % CO ₂ : 60.0% % Co solvent : 40.0% (MeOH) Total Flow : 70.0 g/min Back Pressure : 90.0 bar UV : 214 nm 95 ACTIVE/109135237.1

Stack time : 5.0 min Example 12 The impure compound obtained from the second fraction was further purified by prep HPLC on an X-Select C18 using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (3 mg) as a solid. MS (ES+) m/z 447.36 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO):δ 10.48 (s, 1H), 8.67 (d, J = 12.6 Hz, 2H), 8.51 (q, J = 6.7 Hz, 2H), 8.16 (s, 2H), 7.83 (d, J = 3.1 Hz, 1H), 6.89 (d, J = 3.1 Hz, 1H), 5.62 (q, J = 6.7 Hz, 1H), 3.36 (s, 3H), 1.56 (d, J = 6.7 Hz, 3H). Conditions for chiral SFC for Example 11 Column/dimensions : Chiralpak IC (30 X 250) mm, 5μ % CO ₂ : 60.0% % Co solvent : 40.0% (MeOH) Total Flow : 70.0 g/min Back Pressure : 90.0 bar UV : 214 nm Stack time : 5.0 min Load/Inj : 2.17 mg Example 13 Step a) 1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(4-cycl opropylpyrrolo[1,2- b]pyridazin-3-yl)urea (13) DPPA (2.4 mL, 11.2 mmol) and Et3N (2.4 mL, 17.2 mmol) were added under nitrogen at rt to a stirred suspension of I-10c (200 mg, 1.0 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at rt for 30 min, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (190 mg, 1.0 mmol) was added and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 200 mL), the combined organic layers were washed with aqueous saturated sodium bicarbonate (50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The afforded residue was purified by prep HPLC on a 96 ACTIVE/109135237.1

Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compounds (50 mg, 13%) as a solid. MS (ES+) m/z 395.38 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.78 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.51 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 2H), 7.75 (q, J = 1.4 Hz, 1H), 6.80 (q, J = 2.3 Hz, 1H), 6.55 (q, J = 2.0 Hz, 1H), 2.05 (m, J = 3.2 Hz, 1H), 1.11 (m, J = 2.8 Hz, 2H), 1.01 (m, J = 3.2 Hz, 2H). Example 14 Step a) (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(5- fluoro-4-(1- hydroxyethyl)pyrrolo[1,2-b]pyridazin-3-yl)urea (14) BBr ₃ (0.01 mL, 0.104 mmol) was added under nitrogen to a stirred solution of 5 (20 mg, 0.046 mmol) in DCM (5 mL) at -78 °C. The reaction mixture was stirred at rt for 14 h, then poured into ice cold saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (3 x 20 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The afforded impure compound was further purified by prep HPLC on a Kromosil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (7 mg, 35%) as a solid. MS (ES+) m/z 417.39 [M+H]+. ¹ H NMR (500 MHz, DMSO): δ 10.44 (s, 1H), 9.00 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.15 (s, 2H), 7.61 (q, J = 2.5 Hz, 1H), 6.74 (d, J = 3.3 Hz, 1H), 6.44 (s, 1H), 5.35 (q, J= 6.7 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H). Example 15 97 ACTIVE/109135237.1

Step a) (S)-1-(4-(1-methoxyethyl)-6-methylpyrrolo[1,2-b]pyridazin-3- yl)-3-(2- (trifluoromethyl)pyridin-4-yl)urea (15) DPPA (0.26 mL, 1.21 mmol) and Et3N (0.6 mL, 4.3 mmol) were added under nitrogen at rt to a stirred suspension of I-11c (200 mg, 0.9 mmol) in toluene (10 mL). The mixture was stirred at rt for 15 min, then 2-(trifluoromethyl)pyridin-4-amine (140 mg, 0.9 mmol) was added and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with 10% NaHSO4 (aq) solution, water, brine dried (Na ₂ SO ₄ ), filtered and concentrated. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H ₂ O: MeCN as mobile phase. The impure compound was further purified by chiral SFC. The afforded residue was further purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (14 mg, 4%) as a solid. MS (ES+) m/z 394.45 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.12 (s, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.61 (m, J = 1.9 Hz, 2H), 6.51 (d, J = 1.1 Hz, 1H), 4.80 (q, J = 6.6 Hz, 1H), 3.21 (s, 3H), 2.28 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H). Conditions for chiral SFC Column/dimensions : (R,R) WHELK-01 (250X4.6) mm, 5μ % CO2 : 65% % Co solvent : 35.0% (Isopropanol) Total Flow : 3.0 g/min Back Pressure : 100.0 bar UV : 254 nm Example 16 Step a) (S)-1-(6-chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(2- (trifluoromethyl)pyridin-4-yl)urea (16) DPPA (0.2 mL, 0.93 mmol) and Et3N (0.6 mL, 4.3 mmol) were added under nitrogen at rt to a stirred suspension of I-9b (200 mg, 0.4 mmol) in toluene (10 mL). The mixture was stirred at rt 98 ACTIVE/109135237.1

for 15 min, then 2-(trifluoromethyl)pyridin-4-amine (130 mg, 0.8 mmol) was added and the reaction mixture was stirred at 110 °C for 2 h. The mixture was poured water (10 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel and eluted with 30-40% EtOAc / pet ether. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The residue obtained was further purified by chiral SFC, which gave the title compound (17 mg, 10%) as a solid. MS (ES+) m/z 414.33 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.17 (s, 1H), 8.55 (t, J = 2.7 Hz, 2H), 8.50 (s, 1H), 8.06 (d, J = 1.9 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.61 (q, J = 2.5 Hz, 1H), 6.75 (d, J = 1.9 Hz, 1H), 4.83 (q, J = 6.7 Hz, 1H), 3.23 (s, 3H), 1.48 (d, J = 6.7 Hz, 3H). Conditions for chiral SFC Column/dimensions : Chiralpak IC (30 X 250) mm, 5μ % CO ₂ : 90.0% % Co solvent : 10.0% (Isopropanol) Total Flow : 70.0 g/min Back Pressure : 100.0 bar UV : 254 nm Stack time : 8.2 min Load/Inj : 3.0 mg Example 17 & 18 Step a) 1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(4-(1-e thoxyethyl)-6- (trifluoromethyl)pyrrolo[1,2-b]pyridazin-3-yl)urea (17 & 18) DPPA (0.11 mL, 0.53 mmol) and Et3N (0.23 mL, 1.6 mmol) were added under nitrogen at rt to a stirred suspension of I-12i (75 mg, 0.25 mmol) in toluene (5 mL). The mixture was stirred at rt for 30 min, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (58.5 mg, 0.3 mmol) was 99 ACTIVE/109135237.1

added and the reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL), the combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The isomers were separated by chiral SFC. Example 17 The compound obtained from the first fraction was further purified by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ OAc in H ₂ O: MeCN as mobile phase, which gave the title compound (13 mg, 10%) as a solid. MS (ES+) m/z 495.46 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.11 (s, 1H), 8.68 (s, 1H), 8.64 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 2H), 7.02 (d, J = 1.1 Hz, 1H), 5.02 (q, J = 6.6 Hz, 1H), 3.45 (m, J = 3.9 Hz, 1H), 3.36 (m, J = 4.1 Hz, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H). Example 18 The compound obtained from the second fraction was further purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (12 mg, 10%) as a solid. MS (ES+) m/z 495.42 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.10 (s, 1H), 8.66 (s, 1H), 8.64 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 2H), 7.02 (d, J = 1.1 Hz, 1H), 5.02 (q, J = 6.6 Hz, 1H), 3.45 (m, J = 3.9 Hz, 1H), 3.35 (m, J = 3.3 Hz, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H). Conditions for chiral SFC Column/dimensions : Chiralcel OD-H (250X30) mm, 5μ % CO ₂ : 70.0% % Co solvent : 30.0% (Methanol) Total Flow : 70.0 g/min Back Pressure : 90.0 bar UV : 214 nm Stack time : 9.6 min Load/Inj : 5.0 mg 100 ACTIVE/109135237.1

Example 19 Step a) 1-(5-chloro-6-(2H-1 triazol-2-yl)pyridin-3-yl)-3-(4-morpholinopyrrolo[1,2- b]pyridazin-3-yl)urea (19) Et3N (1.1 mL, 8 mmol) and DPPA (0.4 mL, 1.9 mmol) were added under nitrogen at rt to a stirred solution of I-13f (250 mg, 1.0 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at rt for 2 h, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (100 mg, 1.02 mmol) was added and the reaction mixture was stirred at 100 °C for 3 h. The mixture was quenched with ice water (20 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (30 mg, 7%) as a solid. MS (ES+) m/z 440.41 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.74 (s, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 2H), 8.06 (s, 1H), 7.70 (q, J = 1.4 Hz, 1H), 6.75 (q, J = 2.3 Hz, 1H), 6.58 (q, J = 2.0 Hz, 1H), 3.76 (t, J = 4.5 Hz, 4H), 3.40 (t, J = 4.5 Hz, 4H). Example 20 Step a) 1-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-3-(4-isopropyl- 6-methylpyrrolo[1,2- b]pyridazin-3-yl)urea (20) Et3N (0.35 mL, 2.5 mmol) and DPPA (0.18 mL, 0.84 mmol) were added under nitrogen at rt to a stirred solution of I-8e (140 mg, 0.5 mmol) in 1,4-dioxane (5 mL). The mixture was stirred at rt for 30 min, then 5-chloro-6-(difluoromethoxy)pyridin-3-amine ¹ (I-17b) (122 mg, 0.5 mmol) was added and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 10 mL), the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude 101 ACTIVE/109135237.1

compound was purified by column chromatography on silica gel and eluted with 0-5% MeOH / DCM. The afforded residue was purified by prep HPLC on an X-Select C18 using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (6 mg, 3%) as a solid. MS (ES+) m/z 410.37 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.19 (s, 1H), 8.28 (d, J = 2.5 Hz, 2H), 8.22 (d, J = 2.4 Hz, 1H), 7.98 (s, 1H), 7.65 (q, J = 48.3 Hz, 2H), 6.50 (s, 1H), 3.37 (t, J = 7.1 Hz, 1H), 2.28 (s, 3H), 1.36 (d, J = 7.1 Hz, 6H). Example 21 Step a) 1-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-3-(6-methylpyrr olo[1,2-b]pyridazin-3- yl)urea (21) Et ₃ N (0.35 mL, 2.5 mmol) and DPPA (0.18 mL, 0.81 mmol) were added under nitrogen at rt to a stirred solution of I-14b (85 mg, 0.5 mmol) in 1,4-dioxane (3 mL). The mixture was stirred at rt for 30 min, then 5-chloro-6-(difluoromethoxy)pyridin-3-amine ¹ (I-17b) (94 mg, 0.5 mmol) was added and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2 x 15 mL), the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by Sunfire C18 column using a gradient of 0.1% formic acid in H ₂ O: MeCN as mobile phase, which gave the title compound (15 mg, 8%) as a solid. LCMS (ES+) 368.25 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.19 (s, 1H), 9.00 (s, 1H), 8.26 (d, J = 12.4 Hz, 2H), 8.09 (s, 1H), 7.90 (s, 1H), 7.67 (t, J = 69.6 Hz, 2H), 6.21 (s, 1H), 2.26 (s, 3H). Example 22 102 ACTIVE/109135237.1

Step a) 1-(4-cyclopropylpyrrolo[1,2-b]pyridazin-3-yl)-3-(2-(trifluor omethyl)pyridin-4-yl)urea (22) DPPA (2.4 mL, 11.2 mmol) and Et3N (2.4 mL, 17.22 mmol) were added under nitrogen at rt to a stirred suspension of I-10c (200 mg, 1.0 mmol) in toluene (10 mL). The mixture was stirred at rt for 30 min, then 2-(trifluoromethyl)pyridin-4-amine (160 mg, 1.0 mmol) was added and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL), the combined organic layers were washed with aqueous saturated sodium bicarbonate (50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The afforded residue was purified twice by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compounds (50 mg, 13%) as a solid. MS (ES+) m/z 362.35 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.88 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.75 (q, J = 1.4 Hz, 1H), 7.62 (q, J = 2.5 Hz, 1H), 6.80 (q, J = 2.3 Hz, 1H), 6.55 (q, J = 2.0 Hz, 1H), 2.03 (m, J = 3.5 Hz, 1H), 1.09 (m, J = 2.8 Hz, 2H), 0.99 (m, J = 3.2 Hz, 2H). Example 23 1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(6-meth yl-4-(oxazol-2-yl)pyrrolo[1,2- b]pyridazin-3-yl)urea (23) Et ₃ N (0.32 mL, 2.3 mmol) and DPPA (0.13 mL, 0.6 mmol) were added under nitrogen at rt to a stirred suspension of I-15b (80 mg, 0.33 mmol) in 1,4-dioxane (3 mL). The mixture was stirred at rt for 1 h, then 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I-16b) (96 mg, 0.5 mmol) was added and the reaction mixture was stirred at 100 °C for 3 h. The mixture was quenched with ice water (10 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (4 mg, 3%). MS (ES+) m/z 436.22 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.77 (s, 1H), 10.59 (s, 1H), 9.02 (s, 1H), 8.61 (d, J = 2.3 Hz, 103 ACTIVE/109135237.1

1H), 8.56 (d, J = 0.6 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.16 (s, 2H), 7.75 (d, J = 0.6 Hz, 1H), 7.70 (d, J = 0.6 Hz, 1H), 6.89 (d, J = 1.3 Hz, 1H), 2.34 (s, 3H). Example 24 1-(4-morpholinopyrrolo[1,2-b]pyridazin-3-yl)-3-(2-(trifluoro methyl)pyridin-4-yl)urea (24) Et ₃ N (1.5 mL, 10. 8 mmol) and DPPA (0.5 mL, 2.4 mmol) were added under nitrogen at rt to a stirred suspension of I-13f (300 mg, 1.2 mmol) in toluene (15 mL), then 2- (trifluoromethyl)pyridin-4-amine (200 mg, 1.2 mmol) was added and the reaction mixture was stirred at 100 °C for 20 min in a microwave. The mixture was quenched with ice water (20 mL) and extracted with EtOAc (3 x 50 mL). The crude compound was purified by column chromatography on silica gel and eluted with 20-60% EtOAc / pet ether. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase. The obtained crude was further purified by achiral SFC. The afforded impure compound was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H ₂ O: MeCN as mobile phase, which gave the title compound (12 mg, 2.4%) as a solid. MS (ES+) m/z 407.42 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.82 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.24 (s, 1H), 8.05 (t, J = 8.3 Hz, 2H), 7.68 (m, J = 5.1 Hz, 2H), 6.75 (q, J = 2.3 Hz, 1H), 6.57 (q, J = 2.0 Hz, 1H), 3.74 (t, J = 4.5 Hz, 4H), 3.37 (t, J = 4.5 Hz, 4H). Conditions for achiral SFC Column/dimensions : Chiralpak IG (30 X 250) mm, 5μ % CO ₂ : 50.0% % Co solvent : 50.0% (MeOH) Total Flow : 70.0 g/min Back Pressure : 90.0 bar UV : 254 nm Stack time : 8.6 min 104 ACTIVE/109135237.1 Load/Inj : 5.6 mg

Example 25 & 26

Step a) l-(5-chloro-6-(2H-L2.3-triazol-2-vDpvridin-3-vD-3-(4-(T-etho xvethvD-6- (trifluoromethvnpvrrolorL2-blpvridazin-3-vnurea (25a)

DPPA (0.2 mL, 0.93 mmol) and Et3N (0.3 mL, 2.2 mmol) were added under nitrogen at rt to a stirred suspension of I-12i (110 mg, 0.4 mmol) in toluene (5 mL). The mixture was stirred at rt for 30 min, then 5 -chloro-6-(2E[-l,2,3-triazol-2-yl)pyri din-3 -amine ¹ (I- 16b) (85 mg, 0.44 mmol) was added and the reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 25 mL), the combined organic layers were washed with water, brine, dried (NaiSOr), filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel and eluted with 45-50% EtOAc / pet ether. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (53 mg, 29%) as a solid. MS (ES+) m/z 495.46 [M+H] ⁺ .

Step b) l-(5-chloro-6-(2H-L2.3-triazol-2-vOpvridin-3-vO-3-(4-(T-hvdr oxyethvO-6-

(trifluoromethyl ) .2-b1pyridazin-3-yl )urea (25 & 26)

BBr3 (0.10 mL, 1.1 mmol) was added under nitrogen to a stirred solution of compound 25a (53 mg, 0.24 mmol) in DCM (3 mL) at -78 °C. The reaction mixture was stirred at rt for 12 h. The reaction mixture was basified using sodium bicarbonate solution (10 mL). The aqueous layer was extracted with DCM (2 x 10 mL), the organic layer was washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The afforded residue was purified by column chromatography. The afforded residue was purified by prep HPLC on a Kromosil® Cl 8 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The enantiomers were separated by chiral SFC.

105

Example 25 The compound obtained from the first fraction was further purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (9 mg, 17%) as a solid. MS (ES+) m/z 467.43 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.33 (s, 1H), 9.01 (s, 1H), 8.73 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.32 (q, J = 1.0 Hz, 1H), 8.15 (s, 2H), 7.01 (d, J = 1.2 Hz, 1H), 6.29 (s, 1H), 5.28 (d, J = 6.8 Hz, 1H), 1.48 (d, J = 6.7 Hz, 3H). Example 26 The compound obtained from the second fraction was further purified by prep HPLC on a Kromasil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (10 mg, 20%) as a solid. MS (ES+) m/z 467.43 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.32 (s, 1H), 9.02 (s, 1H), 8.73 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.32 (q, J = 1.0 Hz, 1H), 8.15 (s, 2H), 7.01 (d, J = 1.2 Hz, 1H), 6.30 (s, 1H), 5.27 (t, J = 6.6 Hz, 1H), 1.48 (d, J = 6.6 Hz, 3H). Conditions for chiral SFC Column/dimensions : Chiralcel OD-H (250X30) mm, 5μ % CO ₂ : 60.0% % Co solvent : 40.0% (Methanol) Total Flow : 70.0 g/min Back Pressure : 100.0 bar UV : 214 nm Stack time : 6.5 min Load/Inj : 3.0 mg Examples 2-40 can be depicted as shown in the table below: 106 ACTIVE/109135237.1 107 ACTIVE/109135237.1

108 ACTIVE/109135237.1

109 ACTIVE/109135237.1

110 ACTIVE/109135237.1

111 ACTIVE/109135237.1

1 The methyl ether was cleaved as described in Example 1, step b prior to prep. HPLC purification. 2 Unequal ratio of enantiomers. 3 Isolated as minor enantiomer. 112 ACTIVE/109135237.1

Example 27 methoxyethyl)pyrrolo[1,2-b]pyridazin-3-yl)urea (27a) DPPA (0.2 mL, 0.93 mmol) and Et ₃ N (0.6 mL, 4.3 mmol) were added under nitrogen at rt to a stirred mixture of I-22e (210 mg, 0.82 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3- amine ¹ (I-16b) (180 mg, 0.92 mmol) in toluene (15 mL). The mixture was stirred at rt for 30 min, then stirred at 110 °C for 2 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 x 40 mL), the combined organic layers was dried (Na2SO4), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase. The enantiomers were separated by chiral SFC (peak-1), which gave the title compound (90 mg, 24%) as a solid. MS (ES+) m/z 449.34 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.24 (s, 1H), 8.72 (s, 1H), 8.53 (t, J = 8.5 Hz, 2H), 8.47 (d, J = 2.3 Hz, 1H), 8.15 (s, 2H), 7.97 (q, J = 1.8 Hz, 1H), 4.88 (m, J = 3.8 Hz, 1H), 3.27 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H). Conditions for chiral SFC Column/dimensions : Chiralpak IG (30 X 250) mm, 5μ % CO2 : 75.0% % Co solvent : 25.0% (MeOH) Total Flow : 90.0 g/min Back Pressure : 100.0 bar UV : 214 nm Stack time : 16 min 113 ACTIVE/109135237.1

Load/Inj : 40 mg Step b) (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(5, 6-difluoro-4-(1- hydroxyethyl)pyrrolo[1,2-b]pyridazin-3-yl)urea (27) Aluminium chloride (1.5 g, 11.3 mmol) was added at 0 °C to a suspension of compound 27a (150 mg, 0.33 mmol) in DCM (20 mL). The resulting mixture was stirred at rt for 44 h, then the mixture was poured into saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The crude compound was purified by prep HPLC on an X-Select C18 using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (30 mg, 20%) as a liquid. MS (ES+) 435.40 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 10.42 (s, 1H), 9.05 (s, 1H), 8.62 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.15 (s, 2H), 7.92 (q, J = 1.8 Hz, 1H), 6.45 (s, 1H), 5.29 (t, J = 6.5 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H). Example 28 Step a) (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(7- fluoro-4-(1- methoxyethyl)pyrrolo[1,2-b]pyridazin-3-yl)urea (28) Et ₃ N (1.2 mL, 8.6 mmol) and DPPA (0.5 mL, 2.2 mmol) were added under nitrogen at rt to a stirred solution of I-17b (450 mg, 1.0 mmol) in toluene (15 mL), then 5-chloro-6-(2H-1,2,3- triazol-2-yl)pyridin-3-amine ¹ (I-16b) (190 mg, 0.94 mmol) was added and the reaction mixture was stirred at 100 °C for 20 min in a sealed tube. The mixture was quenched with ice water (20 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layers was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The afforded residue was purified twice by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The obtained crude was subjected to normal phase achiral purification. The afforded residue was further purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (7 mg, 2%) as a solid. MS (ES+) m/z 431.37 [M+H] ⁺ . 114 ACTIVE/109135237.1

¹ H NMR (500 MHz, DMSO): δ 10.00 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.45 (s, 1H), 8.15 (s, 2H), 6.63 (t, J = 5.0 Hz, 1H), 6.55 (q, J = 2.6 Hz, 1H), 4.86 (q, J = 6.6 Hz, 1H), 3.24 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H). Preparative normal phase HPLC Conditions Column/dimensions : Chiralpak- AD-H (250X30)mm,5μ Mobile Phase : n-Hexane: Ethanol (70:30) Flow : 42.0ml /min Temperature : Ambient Wave length : 275 nm Stack time : 15 min Load ability/Inj : 5 mg/Inj Total No of injections : 4 Example 29 & 30 Step a) 1-(6-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazin-3-yl)-3-(5- chloro-6-(2H-1 triazol- 2-yl)pyridin-3-yl)urea (29) & 1-(5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazin-3-yl)-3-(5- chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)urea (30) DPPA (0.4 mL, 1.9 mmol) and Et3N (1 mL, 7.2 mmol) were added under nitrogen at rt to a stirred solution of I-18b (340 mg, 1.4 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine ¹ (I- 16b) (310 mg, 1.6 mmol) in toluene (5 mL). The mixture was stirred at rt for 30 min, then stirred at 110 °C for 2 h. The mixture was poured into saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase. The residue was further purified by achiral SFC. 115 ACTIVE/109135237.1

Example 29 The compound obtained from the first fraction was further purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4OAc in H2O: MeCN as mobile phase, which gave the title compound (20 mg, 3%) as a solid. MS (ES+) m/z 429.35 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.84 (s, 1H), 8.57 (q, J = 3.6 Hz, 2H), 8.48 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H), 8.15 (s, 2H), 7.95 (d, J = 1.9 Hz, 1H), 6.61 (d, J = 1.9 Hz, 1H), 2.00 (m, J = 3.6 Hz, 1H), 1.12 (m, J = 2.8 Hz, 2H), 0.94 (m, J = 3.2 Hz, 2H). Example 30 The compound obtained from the second fraction was concentrated under reduced pressure, which gave the title compound (100 mg, 15%) as a solid. MS (ES+) m/z 429.39 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.87 (s, 1H), 8.58 (t, J = 6.7 Hz, 2H), 8.48 (d, J = 2.3 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 2H), 7.76 (d, J = 3.1 Hz, 1H), 6.85 (d, J = 3.1 Hz, 1H), 2.01 (m, J = 2.8 Hz, 1H), 1.17 (m, J = 3.3 Hz, 2H), 0.75 (m, J = 3.3 Hz, 2H). Conditions for SFC Column/dimensions : Chiralpak- AD-H (250X30) mm, 5μ % CO2 : 50.0% % Co solvent : 50.0% (EtOH) Total Flow : 90.0 g/min Back Pressure : 100.0 bar UV : 280 nm Stack time : 13 min Load/Inj : 9.2 mg 116 ACTIVE/109135237.1

Example 31 Step a) (S)-1-(6-chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(5-chloro-6- morpholinopyridin-3-yl)urea (31a) DPPA (0.25 mL, 1.2 mmol) and Et3N (0.7 mL, 5.0 mmol) were added under nitrogen at rt to a stirred solution of compound I-2d (250 mg, 1.0 mmol) and compound I-19b (230 mg, 1.1 mmol) in toluene (10 mL). The mixture was stirred at rt for 30 min, then stirred at 110 °C for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (100 mg, 21%) as a solid. MS (ES+) m/z 465.45 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.50 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 6.71 (d, J = 1.9 Hz, 1H), 4.82 (q, J = 6.6 Hz, 1H), 3.73 (t, J = 4.6 Hz, 4H), 3.22 (s, 3H), 3.15 (t, J = 4.6 Hz, 4H), 1.47 (d, J = 6.6 Hz, 3H). Step b) (S)-1-(6-chloro-4-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(5-chloro-6- morpholinopyridin-3-yl)urea (31) BBr3 (0.06 mL, 0.6 mmol) was added under nitrogen to a stirred solution of compound 31a (75 mg, 0.2 mmol) in DCM (10 mL) at -78 °C. The reaction mixture was stirred at 0 °C for 4 h, then the reaction mixture was poured into saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc, the organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (25 mg, 33%) as a solid. MS (ES+) m/z 451.40 [M+H]+. 117 ACTIVE/109135237.1

¹ H NMR (500 MHz, DMSO): δ 9.70 (s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 1.3 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 6.21 (d, J = 3.2 Hz, 1H), 5.17 (m, J = 4.5 Hz, 1H), 3.73 (t, J = 4.5 Hz, 4H), 3.14 (t, J = 4.5 Hz, 4H), 1.44 (d, J = 6.6 Hz, 3H). Example 32 Step a) 1-(5-chloro-4-(2,2,2-trifluoroethyl)pyrrolo[1,2-b]pyridazin- 3-yl)-3-(5-chloro-6-(2H- 1,2,3-triazol-2-yl)pyridin-3-yl)urea (32) Et3N (1.6 mL, 11.5 mmol) and DPPA (1.6 mL, 7.4 mmol) were added under nitrogen at rt to a stirred solution of I-20c (800 mg, 2.9 mmol) in toluene (2 mL), then 5-chloro-6-(2H-1,2,3-triazol- 2-yl)pyridin-3-amine ¹ (674 mg, 3.5 mmol) was added and the reaction mixture was stirred at 100 °C for 30 min in a microwave. The mixture was basified with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was washed with ice water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The impure product was further purified by prep HPLC on an X-Select C18 using 10 mM NH ₄ HCO ₃ in H ₂ O: MeCN as mobile phase, which gave the title compound (170 mg, 12%) as a solid. MS (ES+) m/z 471.35 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.82 (s, 1H), 8.64 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.15 (s, 2H), 7.90 (d, J = 3.1 Hz, 1H), 6.96 (t, J = 1.5 Hz, 1H), 4.22 (q, J = 10.6 Hz, 2H). 118 ACTIVE/109135237.1

Example 33 Step a) (S)-1-(6-chloro-4-(1-methoxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(6- morpholinopyridin-3-yl)urea (33a) DPPA (0.25 mL, 1.2 mmol) and Et ₃ N (0.7 mL, 5.0 mmol) were added under nitrogen at rt to a stirred solution of compound I-2d (250 mg, 1.0 mmol) and compound I-21b (200 mg, 1.1 mmol) in toluene (10 mL). The mixture was stirred at rt for 30 min, then stirred at 110 °C for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase, which gave the title compound (180 mg, 41%) as a solid. MS (ES+) m/z 431.48 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO): δ 9.12 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.74 (q, J = 3.9 Hz, 1H), 6.83 (d, J = 9.1 Hz, 1H), 6.68 (d, J = 1.9 Hz, 1H), 4.82 (q, J = 6.6 Hz, 1H), 3.70 (t, J = 4.9 Hz, 4H), 3.35 (t, J = 4.9 Hz, 4H), 3.22 (s, 3H), 1.47 (d, J = 6.7 Hz, 3H). Step b) (S)-1-(6-chloro-4-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-3- yl)-3-(6- morpholinopyridin-3-yl)urea (33) BBr ₃ (0.1 mL, 1.04 mmol) was added under nitrogen to a stirred solution of compound 33a (100 mg, 0.23 mmol) in DCM (10 mL) at -78 °C. The reaction mixture was stirred at 0 °C for 4 h, then the reaction mixture was poured into saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc, the organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The afforded residue was purified by prep HPLC on a Kromosil® C18 column using 10 mM NH4HCO3 in H2O: MeCN as mobile phase. The obtained product was washed with water, filtered and lyophilised, which gave the title compound (20 mg, 20%) as a solid. MS (ES+) 119 ACTIVE/109135237.1

m/z 417.47 [M+H]+. ¹ H NMR (500 MHz, DMSO): δ 9.29 (s, 1H), 8.61 (d, J = 7.2 Hz, 2H), 8.19 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.75 (q, J = 3.9 Hz, 1H), 6.82 (d, J = 9.1 Hz, 1H), 6.68 (d, J = 1.9 Hz, 1H), 6.15 (d, J = 2.5 Hz, 1H), 5.17 (m, J = 3.3 Hz, 1H), 3.70 (t, J = 4.9 Hz, 4H), 3.34 (d, J = 4.9 Hz, 4H), 1.44 (d, J = 6.6 Hz, 3H). Example 34 Step a) 1-(5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazin-3-yl)-3-(2- (trifluoromethyl)pyridin-4- yl)urea (34) 2-(trifluoromethyl)pyridin-4-amine (616 mg, 3.80 mmol) and powder 4Å molecular sieves (50 mg) were loaded into a flame dried microwave vial and the vial was sealed. I-24c (900 mg, 3.80 mmol) and triethylamine (1.05 mL, 7.60 mmol) in anhydrous toluene (20.0 mL) were added via syringe and the mixture was stirred at room temperature for 0.5 hr. Then, diphenylphosphoryl azide (814 mL, 3.80 mmol) was added and the mixture was stirred for another 0.5 hr. The mixture was heated to 120 °C for 2 hours, then cooled to room temperature. The mixture was then filtered and the solid was washed with toluene and acetone. The mixture was concentrated under reduced pressure to give the crude product, which was purified twice by flash chromatography on silica gel (acetone/hexane = 0/1 to 1/0) to give a mixture of product and other byproducts. This mixture was purified by flash chromatography on C18 column (CH ₃ CN/water = 1/9 to 9/1) to give the title compound (1.00 g, 2.53 mmol, 67% yield) as a yellow solid after freeze drying from water/CH3CN. MS (ES+) m/z 396.08 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.54 (m, 2H), 8.25 (s, 1H), 8.07 (s, 1H), 7.75 (d, J = 3.1 Hz, 1H), 7.62 (d, J = 5.6 Hz, 1H), 6.85 (d, J = 3.0 Hz, 1H), 2.02 - 1.95 (m, 1H), 1.16 - 1.11 (m, 2H), 0.75 - 0.71 (m, 2H). Example 35 120 ACTIVE/109135237.1

Step a) 1-(5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazin-3-yl)-3-(5- chloro-6-(2-methyl-2H- tetrazol-5-yl)pyridin-3-yl)urea (35) Et3N (238 mg, 2.36 mmol) and DPPA (156 mg, 568 μmol) were added to a stirred solution of I- 24c (112 mg, 474 μmol) in 1,4-dioxane (2 mL) and the reaction was stirred for 30 minutes at 20 ^o C under N2. I-25d (100 mg, 474 μmol) was added and the mixture was heated to 100 ^o C for 1 hour, quenched with sat. aqueous NaHCO3 solution and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried over MgSO ₄ , concentrated and purified by prep-HPLC (column:YMC Triart C18250*50 mm*7 mm, table:30-70% B (A = water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford the title compound (38.8 mg, 87.3 μmol, 18% yield) as a yellow dry powder. MS (ES+) m/z 444.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 7.76 (d, J = 3.2 Hz, 1H), 6.85 (d, J = 3.2 Hz, 1H), 4.48 (s, 3H), 2.06 - 1.93 (m, 1H), 1.25 - 1.12 (m, 2H), 0.79 - 0.71 (m, 2H). Example 36 Step a) 3-{5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazin-3-yl 1-methyl-1H- 1,2,3,4-tetrazol-5-yl)pyridin-3-yl]urea (36) Et3N (238 mg, 2.36 mmol) and DPPA (156 mg, 568 μmol) were added to a stirred solution of I- 24c (112 mg, 474 μmol) in 1,4-dioxane (2 mL) and the reaction was stirred for 30 minutes at 20 ^o C under N2. I-25e (100 mg, 474 μmol) was added and the mixture was heated to 100 ^o C for 1 hour, quenched with sat. aqueous NaHCO3 solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO ₄ , concentrated and purified by prep-HPLC (column:YMC Triart C18250*50 mm*7 mm, table:30- 70% B (A = water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford crude product. The crude was purified by Prep-HPLC (column:Fuji Silica 25*150 mm*15 mm, table:5-95% B (A = Heptane, B = EtOH,), flow rate: 35 mL/min,UV Detector 220 nm) to afford the title compound (5.80 mg, 13.0 μmol, 3% yield) as a yellow dry powder. MS (ES+) m/z 444.2 [M+H] ⁺ . 121 ACTIVE/109135237.1

¹ H NMR (400 MHz, DMSO-d6) δ 10.04 (br s, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.75 (br s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.33 (s, 1H), 7.82 (d, J = 3.2 Hz, 1H), 6.91 (d, J = 2.8 Hz, 1H), 4.21 (s, 3H), 2.13 - 2.01 (m, 1H), 1.26 - 1.18 (m, 2H), 0.85 - 0.77 (m, 2H). Example 37 Step a) 3-{5-chloro-4-cyclopropylpyrrolo[1,2- b]pyridazin-3-yl}-1-[6-(2-methyl-2H-1,2,3,4- tetrazol-5-yl)-5-(trifluoromethyl)pyridin-3-yl]urea (37) Et3N (213 mg, 2.11 mmol) and DPPA (139 mg, 506 μmol) were added to a stirred solution of I- 24c (100 mg, 422 μmol) in 1,4-dioxane (2 mL) and the reaction was stirred for 30 minutes at 20 ^o C under N ₂ . I-26d (103 mg, 422 μmol) was added and the mixture heated to 100 ^o C for 1 hour, quenched with sat. aqueous NaHCO3 solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4, concentrated and purified by prep-HPLC (column:Welch Xtimate C18100*25 mm*3 mm, table:43-83% B (A = water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 25 mL/min,UV Detector 220 nm) to afford the title compound (15.1 mg, 31.6 μmol, 8% yield) as a yellow dry powder. MS (ES+) m/z 478.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 1H), 8.97 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.62 (br s, 1H), 8.30 (s, 1H), 7.77 (d, J = 3.2 Hz, 1H), 6.86 (d, J = 3.2 Hz, 1H), 4.49 (s, 3H), 2.02 (tt, J = 5.6, 8.4 Hz, 1H), 1.22 - 1.09 (m, 2H), 0.82 - 0.70 (m, 2H). Example 38 Step a) 3-{5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazin-3-yl}-1-[6- (1-methyl-1H-1,2,3,4- tetrazol-5-yl)-5-(trifluoromethyl)pyridin-3-yl]urea (38) Et3N (213 mg, 2.11 mmol) and DPPA (139 mg, 506 μmol) were added to a stirred solution of I- 24c (100 mg, 422 μmol) in 1,4-dioxane (2 mL) and the reaction was stirred for 30 minutes at 20 122 ACTIVE/109135237.1

^o C under N ₂ . I-26e (103 mg, 422 μmol) was added and the mixture was heated to 100 ^o C for 12 hours, quenched with sat. aqueous NaHCO3 solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated and purified by prep-HPLC (column:YMC Triart C18250*50 mm*7 mm, table:33- 73% B (A = water (0.05% ammonia hydroxide v/v), B = ACN,), flow rate: 60 mL/min,UV Detector 220 nm) to afford the title compound (7.40 mg, 15.4 μmol, 4% yield) as a yellow dry powder. MS (ES+) m/z 478.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.07 (br s, 1H), 9.04 (s, 1H), 8.71 (s, 2H), 8.27 (s, 1H), 7.77 (d, J = 3.2 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 4.11 (s, 3H), 2.06 - 1.93 (m, 1H), 1.26 - 1.10 (m, 2H), 0.76 (br d, J = 4.8 Hz, 2H). Example 39 Step a) 1-(5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazin-3-yl)-3-(5- methyl-6-(5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)pyridin-3-yl)urea (39) To a mixture of I-24c (500 mg, 2.11 mmol) and I-27d (482 mg, 2.11 mmol) in dioxane (6 mL) was added DPPA (869 mg, 3.16 mmol) and Et ₃ N (533 mg, 5.27 mmol) and the mixture was stirred at 100 ^o C for 3 hr. The mixture was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (methanol/dichloromethane = 0/1 to 1/10) to afford the crude product (about 1 g as a green solid). CH ₂ Cl ₂ (20 mL) was added and the mixture was stirred at 20 ^o C for 4 hr. The precipitate (about 400 mg as a green solid) was collected by filtration and washed with CH2Cl2 (10 mL x 2). MeOH (20 mL) was added to the solid and the mixture was stirred at 70 ^o C for 4 hr. The precipitate was collected by filtration and washed with MeOH (10 mL x 2). The solid was dried by lyophilization to afford the title compound (142 mg, 334 μmol, 16% yield) as a yellow dry powder. MS (ES+) m/z 426.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 12.61 (br s, 1H), 9.61 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 3.2 Hz, 1H), 6.83 (d, J = 3.2 Hz, 1H), 2.53 - 2.52 (m, 1H), 2.52 (s, 2H), 2.04 - 1.94 (m, 1H), 1.20 - 1.13 (m, 2H), 0.77 - 0.69 (m, 2H). 123 ACTIVE/109135237.1

Example 40 Step a) 3-{5-chloro-4-cyclopropylpyrrolo[1,2-b]pyridazin-3- 1-[5-chloro-6-(2-oxoazetidin-1- yl)pyridin-3-yl]urea (40) To a mixture of I-24c (175 mg, 743 μmol) in dioxane (10 mL) was added Et3N (214 mg, 2.12 mmol) and DPPA (291 mg, 1.06 mmol). The mixture was stirred at 50 ^o C for 10 min. Then I-28d (140 mg, 708 μmol) was added. The mixture was stirred at 100 ^o C for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude residue, which was purified by flash column chromatography on silica gel (DCM/MeOH = 1:0 to 10:1) to afford the title compound (74.0 mg, 171 μmol, 24% yield) as a yellow solid. MS (ES+) m/z 431.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.52 (br s, 1H), 8.41 (br s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 6.83 (d, J = 2.8 Hz, 1H), 3.78 (t, J = 4.4 Hz, 2H), 3.09 (t, J = 4.4 Hz, 2H), 2.03 - 1.94 (m, 1H), 1.19 - 1.11 (m, 2H), 0.76 - 0.67 (m, 2H). GENERAL BIOLOGY METHODS MALT1 BIOCHEMICAL ASSAY Full-length MALT1 enzyme at 2 nM was assayed in 50 mM HEPES, 100 mM NaCl, 0.9 M NaCitrate, 1 mM EDTA, pH 7.5, with 50 μM Ac-Leu-Arg-Ser-Arg-AMC as substrate. Compound was added in an 11-point concentration series from 100 μM to 1 nM in half-log dilution. Compounds were distributed in 384 well plates by Echo550, and the assay was run with fluorescence readings at 460 nm, every 2 minutes for 60 minutes. BIOLOGY EXAMPLE 1 Compounds of the invention were evaluated for inhibition of MALT1 using the above described MALT1 biochemical assay. The resulting Ki values are listed in TABLE 1. TABLE 1 124 ACTIVE/109135237.1

MALT1 CELL-BASED ACTIVITY ASSAY Jurkat clone E6-1 cells (ATCC) were grown in standard cell culture conditions (RPMI 1640 with 10% fetal bovine serum, Penicillin 100 U/mL, Streptomycin 0.1 mg/mL). In-cell MALT1 protease activity was measured as inhibition of PMA/Ionomycin-induced cleavage of HOIL1. Day 10.75x10 ⁶ cells/well were seeded in a 48 well plate. Day 2 cells were stimulated by PMA/Ionomycin (1:500 dilution) with addition of vehicle or compound in a 5-point concentration series, 1:3 dilution. After 60 minutes cells were washed in PBS and then lysed on ice in CelLytic MT cell lysis reagent (Sigma) with protease and phosphatase inhibitors (2% Protease Inhibitor Cocktail, 10 μM MG-132, 1% Phosphatase Inhibitor Cocktail 1, 1% Phosphatase Inhibitor Cocktail 2, 1% Phosphatase Inhibitor Cocktail 3 (all from Sigma). After a quick centrifugation, supernatant was recovered. Samples were analysed by Protein Simple using the Peggy Sue Master kit for size separation with anti-HOIL1 antibody at 1:200 dilution (Santa Cruz). The approx.50 kDa cleavage fragment of HOIL1 was used for quantification of protease activity. Down-stream MALT1 activity was measured by PMA/Ionomycin-induced expression of IL-2 in Jurkat (E6-1) cells. Compounds were distributed in a 96 well plate, 8-point concentration series, 1:3 dilution. Jurkat clone E6-1, 4x10 ⁴ cells/well, were added, and stimulated by PMA/Ionomycin 125 ACTIVE/109135237.1

(1:500 dilution) for 24 hours at 37 °C. Measurement was performed using a MesoScale Sector S600 with the Human IL-2 Tissue Culture kit according to the manufacturers recommendation. QUANTIFICATION OF T CELL POPULATIONS Evaluation of T _reg and T _eff cell numbers was performed by flow cytometry. From a tumor sample (resected piece or biopsy), tumor cells and TILs are dispersed into single cell suspension. Cells are then washed with PBS and stained by antibodies. Samples were stained with antibodies to identify T-cell subpopulations; CD3-BV421 (Biolegend 100228), CD8-FITC (Biolegend 100706), CD4-PE (Biolegend 116005), CD25-PerCP Cy5.5 (Biolegend 101912, clone 3C7), for 15 minutes at room temperature, followed by addition of erythrocyte lysis buffer (cat no. 349202, BD BioSciences, Franklin Lakes, NJ, USA) for 8 minutes. Cells were permeabilized with FoxP3 fix/Perm (cat no.421401, Biolegend San Diego, CA, USA), washed with FoxP3 Perm buffer (Cat no.421402, Biolegend) and stained with an Alexa Fluor® 647 labelled FoxP3 antibody (Cat no.320013, Biolegend) according to the manufacturer’s instructions. The cells were washed twice in PBS with 1% BSA and analyzed on a FACSCanto II (BD Biosciences). Data analysis was performed using FlowJo software (TreeStar, Ashland, OR, USA). For intracellular staining of cytokines, inclusion of transport inhibitors e.g. Monensin or Brefeldin A. Alternatively, immunohistochemical (IHC) evaluation of CD3, CD8, CD4, CD25 and FoxP3 expressing cells is done in Formalin-fixed, paraffin-embedded (FFPE) blocks of biopsies or tumor samples from cancer patients. IHC staining of CD3, CD8, CD4 and FoxP3 is performed with a horseradish-peroxidase technique using a DAKO Autostainer. Antigen retrieval is carried out by the pretreatment of microscope slides with an Epitope Retrieval Solution (Trilog, Cell Marque, Rocklin, CA, USA) for 30 min. Following that, staining is conducted with standardized Dako EnVision FLEX Peroxidase Blocking reagent (K800, DAKO) and polyclonal antibodies for CD3, CD8, CD4 (dilution 1 : 50; Dako) and FoxP3 (dilution 1 : 100: Sigma) following incubation for 120 min at room temperature. Dextran polymer-conjugated horseradish- peroxidase and 3,3′-diaminobenzidine (DAB) chromogen is used for visualisation followed by counterstaining with hematoxylin solution (Gill 3, Sigma). Negative control slides in the absence of primary antibodies are included for each staining. TIL scoring of tumors by IHC is performed semi-quantitatively by measuring the densities of CD3+, CD8+, CD4+ and FoxP3+ cells, with scores from (1) no, or sporadic cells; (2) moderate numbers of cells; (3) abundant occurrence of cells; to (4) highly abundant occurrence of cells. TILs are evaluated in the following three different areas of the tumor: the intra-epithelial 126 ACTIVE/109135237.1

compartment (cells within tumor cell nests); the stroma (cells within the intratumoral stroma) and the tumor periphery (cells localized in tumor periphery). Three random fields are examined, whereas necrotic areas are excluded from the measurements. The total score for CD3, CD8, CD4 and FoxP3 is calculated as the sum of the individual scores from the three tumor areas (intra- epithelial compartment, stroma and tumor periphery), respectively. The total score ranges from 3 to 12, and the median value was used as a cut-off point. The ratios of CD3 and CD8 to both CD4 and FoxP3 (CD3 : CD4; CD8 : CD4; CD3 : FoxP3; and CD8 : FoxP3 ratio, respectively) are calculated for each individual tumor based on the cut-off value of each TIL marker. DEVELOPMENT AND FUNCTION OF HUMAN T-REGULATORY CELLS Naïve CD4 T cell sorting and stimulation for regulatory T cell development A flat-bottom 48 well plate was coated with 250 μl of purified functional grade anti-human CD3 at 2 μg/ml in PBS. The plate was sealed and incubated at 37 °C for one hour. Peripheral blood mononuclear cells (PBMC) were isolated from human leucocyte reduction system cones by differential density centrifugation using Ficoll-PLUS (GE Healthcare). Cells were washed three times in RPMI + 1% HI-FCS + 1% penicillin/streptomycin (P/S) (1% RPMI), then resuspended at a concentration of 200x10 ⁶ /ml of 1% RPMI. An aliquot of cells was set aside for single colour controls, and the sample was stained at a dilution of 1:20 with anti-human CD4, anti-human CD45RA, anti-human CD25, and anti-human CD127 (antibodies from BioLegend and eBioscience) for 20 minutes on ice. Following the incubation, the stained PBMC were washed and resuspended at 50x10 ⁶ /ml in PBS + 1% HI-FCS. Cells were sorted on a BD FACSARIA high speed cell sorter for the phenotype CD4+CD45RA+CD127+CD25-. Following the sort, cells were resuspended at 4x106/ml in pre-warmed cRPMI containing 4x 400 U/ml human IL-2 (final concentration 100 U/ml). In each well of the washed anti-CD3-coated 48 well plate, 250 μl of 4x 8.0 μg/ml anti-CD28 (eBioscience) and 250 μl of appropriate 4x concentration of compound were added. Either 250 μl of cRPMI or 250 μl of 4x 4.0 ng/ml TGFβ were added per well, as appropriate. Finally, 250 μl of cells were added per well. The plate was incubated for 5 days at 37 °C with 5% CO ₂ . After five days, cells were transferred to polypropylene 5 ml tubes and washed twice with cRPMI. Cells were then resuspended in IL-2 ± TGFβ with the appropriate vehicle control or compound. The plate was incubated for an additional 5 days at 37 °C with 5% CO ₂ . STAINING REGULATORY T CELL CULTURES Induced regulatory T cell cultures were washed and counted. Aliquots were stained with Fixable Viability Dye eFluor® 780 (eBioscience) for 30 minutes at 4 °C. Then cells were washed with 127 ACTIVE/109135237.1

PBS and stained for surface expression of CD25 for 15 minutes at 4 °C. After the staining, cells were fixed, permeabilised and stained for intracellular expression of Foxp3 per manufacturer’s instructions (Human Foxp3 Buffer set and anti-human Foxp3 antibody from BD Pharmingen). Following staining, cells were washed and resuspended in PBS + 1% HI-FCS (FACS buffer). Samples were run within four hours on a CyAn™ ADP Analyzer. CD4+ naïve T cells cultured for 10 days were analysed for their expression of FoxP3 and CD25. In the IL-2 + TGFβ condition, promoting in vitro differentiation of T _reg cells, there was a clear induction of a population of viable FoxP3+CD25+ T cells in all three donors (Figure 1; vehicle). T _REG SUPPRESSIVE ACTIVITY PBMC were isolated from fresh blood by differential density centrifugation using Ficoll-PLUS (GE Healthcare). Cells were washed three times in RPMI + 1% heat-inactivated foetal calf serum (HI-FCS) + 1% penicillin/streptomycin (P/S) (1% RPMI), then resuspended in PBS + 2% heat inactivated foetal calf serum (HI-FCS) + 2.0 mM EDTA (isolation buffer). CD4+CD25- and CD4+CD25+ T cells were isolated, per the manufacturer’s instructions (Miltenyi CD4+CD25+ Regulatory T cell Isolation Kit, human). Isolated CD4+CD25- T cells were then labelled with Cell Proliferation Dye eFluor® 450 per manufacturer’s instructions (eBioscience). An aliquot of cells was stained with anti-CD3 and anti-CD4 (BioLegend and eBioscience) to assess cell purity and dye labelling by flow cytometry. Cultures were plated in cRPMI, with 2.5x104 CD4+CD25- cells per well. Cells from the regulatory T cell cultures were added to achieve ratios of 1 effector: 4 regulatory cells (donors 2-3), 1:2, 1:1, 2:1, 4:1 and 8:1. Anti-CD3/CD28 beads (Dynabeads® T Activator CD3/CD28 beads) were added at a 1:1 ratio with the total number of cells per well. Unstimulated CD4+CD25- T cells and stimulated without regulatory T cells were plated as controls. Cells were incubated for four days at 37 °C with 5% CO2. After four days, cells were stained with Fixable Viability Dye eFluor® 780 (eBioscience) for 30 minutes at 4 °C. Following staining, cells were washed and resuspended in PBS + 1% HI-FCS (FACS buffer). Samples were run within four hours on a CyAn™ ADP Analyzer. Immediately prior to acquisition, cells were transferred to FACS tubes with an exact volume of CountBright™ Absolute Counting Beads (ThermoFisher Scientific). IMPACT ON T-EFFECTOR CELLS IN HUMAN WHOLE BLOOD Freshly drawn whole blood from healthy volunteers (2 mL) in a tube was incubated under rotation at 37 °C for 6 hours. Directly after blood sampling, vehicle, 4 μM Example 2, 1μg/ml of CMV-lysate or combinations thereof were added. After 2 hours Brefeldin-A was added to allow 128 ACTIVE/109135237.1

intra-cellular analysis of cytokines (IFNγ and TNFα). Antigen-specific CD8+ T-cells were identified by fluorescence-conjugated tetrameric complexes of HLA-A2 molecules loaded with the NLV peptide epitope (NLVPMVATV) of CMV pp65. IN VIVO EFFECTS ON MB49 MOUSE BLADDER CANCER The murine bladder urothelial carcinoma cell line Mouse Bladder (MB) -49 is a C57BL/6- derived cell line cultured at 37 °C and 5% CO2 in DMEM + GlutaMax supplemented with 10% FBS, 0.1 mM sodium pyruvate, 100 U/ml Penicillin–Streptomycin. For determining the effects of MALT1 inhibitor on the presence of T-effector and T-regulatory cells in vivo, 3x10 ⁵ MB49 cells were injected s.c. on the right flank of female C57BL/6 mice. MALT1 inhibitor therapy was administered p.o. once daily on day 8, 9, 10, 11, example 2 at two doses 3 μmol/kg (1.34 mg/kg) or 30 μmol/kg (13.4 mg/kg). As reference 200 μg of anti-CD25 antibody (clone PC61) in 100 μL PBS was administered i.v. on day 8 and 11. The levels of Treg and Teff cells were analyzed by flow cytometry in the tumor (T) and in tumor-draining lymph nodes (TDLN) on day 12. IMPACT ON T-EFFECTOR CELLS IN HUMAN WHOLE BLOOD STIMULATED WITH CMV-VACCINE Freshly drawn whole blood from healthy volunteers (2 mL) in a tube was incubated under rotation at 37 °C for 6 hours. Directly after blood sampling, vehicle, 30 μM A-8c dia-B of Example A-8, 120 nM of a peptide conjugate, minimal tetanus toxin epitope (MTTE) ₃ -CMV or combinations thereof were added. After 2 hours Brefeldin-A was added to allow intra-cellular analysis of cytokines (IFNγ and TNFα) by flow-cytometry. Antigen-specific CD8+ T-cells were identified by fluorescence-conjugated tetrameric complexes of HLA-A2 molecules loaded with the NLV peptide epitope (NLVPMVATV) of CMV pp65. BIOLOGY EXAMPLE 2 Inhibitor potency was evaluated by measuring enzymatic activity of full length MALT1 at varying concentrations of compound. The enzymatic assay consists of a single substrate reaction that monitors the release of a fluorescent dye upon cleavage of the peptide substrate. The peptide substrate has the following sequence: Ac-Leu-Arg-Ser-Arg-Rh110-dPro (custom synthesis from WuXi AppTec, Shanghai, China). The assay buffer consists of 50 mM Hepes, pH 7.5, 0.8 M sodium citrate, 1 mM DTT, 0.004% tween-20, and 0.005% bovine serum albumin (BSA). Steady-state kinetic analysis of peptide substrate binding resulted in a Michaelis-Menten constant (KM) of 150 μM. The assay was performed in a 384-well F-bottom polypropylene, black microplate (Greiner Bio One, Catalog no.781209) at 15 nM enzyme and 30 μM peptide 129 ACTIVE/109135237.1

substrate. The reaction was quenched after 60 minutes with the addition of iodoacetate at a final concentration of 10 mM. Total fluorescence was measured using an Envision (PerkinElmer) with fluorescence excitation at 485 nm and emission at 520 nm. For potency determination, 1 μL of serially diluted compound (in 100% DMSO) was pre-incubated with 40 μL of enzyme for 30 minutes. The reaction was initiated with the addition of 10 μL of peptide substrate. The relative fluorescence units were transformed to percent inhibition by using 0% and 100% inhibition controls as reference. The 100% inhibition control consisted of 1 μM final concentration of (S)- 1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5- a]pyrimidin-6-yl)urea (IC50 = 15 nM), while the 0% inhibition control consisted of 2% DMSO. IC ₅₀ values were calculated by fitting the concentration-response curves to a four-parameter logistic equation in GraphPad Prism. Results from this assay are summarized in the Table 2 below (IC50 values represent an average when more than one value was generated for any compound). TABLE 2 130 ACTIVE/109135237.1

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