Heterocyclic derivatives as MALT1 inhibitors

Abstract

The present invention relates to compounds that are MALT1 inhibitors. The compounds have the structural formula I as defined herein. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing them and their use in the treatment of diseases or disorders associated with MALT1. TIFF2025506410000187.tif4575

Description

[Technical field]

[0001] The present invention relates to compounds that are MALT1 inhibitors. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing them and their use in the treatment of diseases or disorders associated with MALT1. [Background technology]

[0002] Mucosal-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular protein that plays a key role in antigen receptor-induced NF-kB pathway activation in T and B lymphocytes through both scaffolding and protease functions. Antigen receptor triggering leads to the formation of a CBM complex containing CARMA or CARD proteins, BCL10 and MALT1, which then acts as a scaffold to recruit the ubiquitin ligase TRAF6 and the kinases TAK1 and IKK. This leads to NF-kB activation through IKK-dependent phosphorylation and proteasomal degradation of the NF-kB inhibitor IkB, which allows NF-kB to be translated into the nucleus and initiate transcription of target genes (doi.org / 10.1038 / ni1568;doi:10.1007 / s00018-015-2059-z). In addition, MALT1 proteolytically cleaves; and proteolytically self-cleaves, diverse substrates involved in NF-kB pathway regulation, including RelB, A20, CYLD, Regnase-1, HOIL, BCL10, and NIK (doi:10.1016 / j.biochi.2015.09.018). The overall effect of these cleavage events appears to be an expansion of the amplitude and duration of the NF-kB response (doi:10.1016 / j.biochi.2015.09.018).

[0003] Several genetic lines of evidence suggest a critical role for MALT1 in immune responses. Mice lacking the MALT1 protein are viable but show impaired development and peripheral T cell proliferation. regMALT1 KO mice show reduced cell activation and T cell activity. MALT1 KO mice were protected in inflammatory models of MS (EAE) and rheumatoid arthritis (doi:10.4049 / jimmunol.1201351). Mice expressing proteolytically inactive MALT1 show defects in multiple immune cell types, including mature T and B cells, as well as Treg cells, and develop progressive multiorgan inflammatory pathology (doi:10.4049 / jimmunol.1402254;doi:10.3389 / fimmu.2020.00745). A small cohort of human patients with MALT1 expression and / or functional deficiencies exhibited combined immune deficiencies (doi:10.1007 / s10875-014-0125-1;doi:10.1016 / j.jaci.2013.04.047).

[0004] The highly aggressive activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) depends on NF-kB activation through constitutive activation of the CARMA1-BCL10-MALT1 pathway for survival and proliferation (doi.org / 10.1038 / nature04687).Constitutive NF-kB activation is often caused by a variety of oncogenic mutations in pathway genes, including CARD11, MYD88, CD79A / B, and A20 (doi:10.1038 / nature07968;doi:10.1016 / j.ccr.2012.11.003). Preclinical studies have suggested that MALT1 protease inhibition may be an effective treatment strategy for ABC-DLBCL, as treatment with the MALT1 inhibitor z-VRPR-fmk reduces the expression of NF-kB target genes and thus cell proliferation and viability (doi:10.1073 / pnas.0907511106; doi:10.1084 / jem.20091167), and small molecule MALT1 inhibitors have also been shown to be active in ABC-DLBCL xenograft models (doi:10.1016 / j.ccr.2012.11.002; doi:10.1016 / j.ccr.2012.11.003). Chronic activation of the BCR-mediated CBM-NF-kB pathway has been identified in a subset of mantle cell lymphoma (MCL) lines, suggesting that a subset of MCL is also responsive to MALT1 inhibition (doi:10.1038 / nm.3435). In MALT lymphoma (a type of non-Hodgkin's lymphoma (NHL)), the fusion protein cIAP2-MALT1 leads to constitutive activation of the NF-kB pathway, and these patients may also benefit from treatment with MALT1 inhibitors (doi:10.1074 / jbc.M605116200).MALT1 inhibition may play a role in the treatment of solid tumor types, such as glioblastoma, breast cancer, melanoma, lung cancer, prostate cancer, pancreatic cancer, and osteosarcoma (doi:10.1038 / s41388-019-0958-4; doi:10.15252 / embj.2019102030; doi:10.1111 / jcmm.15383; doi:10.1038 / oncsis.2017.68; doi:10.1038 / onc.2015.146; doi:10.3390 / biomedicines9030250; doi:10.1002 / ijc.32567).

[0005] BTK inhibitors, such as ibrutinib, are important therapies for the treatment of cancers, such as MCL and chronic lymphocytic leukemia (CLL), but efficacy is limited due to innate or acquired resistance (doi:10.3390 / cancer12051328). MALT1 is downstream of BTK in the NF-kB activation pathway, and therefore may be an effective target in combination with BTK inhibitors or in BTKi-refractory tumors. MALT1 has been shown to be constitutively active in cell lines, and treatment with the MALT1 inhibitor MI-2 is effective against both naive and ibrutinib-resistant cell lines (doi:10.1158 / 0008-5472.CAN-17-2485). MALT1 inhibition was shown to be synergistic with the mTORC1 inhibitor, rapamycin, in ABC-DLBCL cell lines, PDX and in vivo models, opening further possibilities for combination treatments and mitigation strategies to MALT1i resistance (doi:10.1182 / blood.2019004713).

[0006] MALT1 inhibitors have also been proposed as an effective immunomodulatory therapy for a variety of cancers, independent of NF-kB pathway dysregulation (doi:10.1038 / s41586-019-1215-2; WO 2018 / 226150 and WO 2018 / 141749). Genetic evidence from MALT-deficient mice suggests that MALT1 promotes the development of Treg cells in vivo, which then suppress several types of immune cells and inhibit antitumor immune responses. Further studies targeting the CBM complex (MALT1 inhibition or T reg or by CARMA1 deletion in T reg This resulted in the cells acquiring effector activity and enhanced control of tumor growth. MALT1 inhibitors synergized with anti-PD1 therapy in both poorly and highly immunogenic mouse melanoma models (doi:10.1038 / s41586-019-1215-2), suggesting a possible combinatorial role for MALT1 inhibitors with immunotherapies including anti-PD1, anti-PD-L1, and anti-CTLA4.

[0007] Small molecule MALT1 inhibitors not only have use in oncology indications, but may also be effective therapies in inflammatory disorders such as multiple sclerosis, psoriasis, ulcerative colitis, and rheumatoid arthritis. MI-2 has been shown to suppress monocyte differentiation into osteoclasts in the presence or absence of TNFα and ameliorate pathological bone erosion and synovitis in a murine collagen-induced arthritis (CIA) model, suggesting a role in the treatment of rheumatoid arthritis (doi:10.1038 / s41598-017-12349-9). The skeletal protein CARD14 forms a signaling complex with BCL10 and MALT1 in keratinocytes, a process that is enhanced by pathogenic CARD14 mutations and is associated with psoriasis susceptibility (doi:10.1016 / j.jid.2016.09.031). MALT1 inhibitors have also been successfully tested in mouse models of multiple sclerosis and ulcerative colitis (doi:10.1186 / 1742-2094-11-124). Pharmacological inhibition of MALT1 protease activity has been shown to suppress endothelial activation by increasing MCPIP1 expression and inhibit TNFα-induced VCAM-1 expression in HUVECs and LPS-induced VCAM-1 expression in mice, suggesting a possible role for MALT1 inhibitors in the treatment of vascular inflammatory diseases, e.g., atherosclerosis (doi:10.1016 / j.cellig.2018.05.009).

[0008] A homozygous MALT1 W580S mutation has been identified in patients with combined immunodeficiency (CID). This was associated with low MALT1-W580S protein levels and impaired negative feedback due to reduced HOIL1 cleavage leading to reduced amplitude but prolonged duration of NF-kB, which is clinically manifested in increased skin and GI inflammation as well as increased susceptibility to infection (doi.org / 10.1016 / j.jaci.2013.10.045). Small molecule ligands known to bind to the MALT1 wild-type allosteric site have also been shown to bind to the W580S mutant, resulting in stabilization of the enzyme and restoration of protein levels even after ligand washout. Skeleton-forming and protease functions were restored: thus, allosteric MALT1 inhibitors may function as "molecular correctives" in the case of W80S MALT1 mutations (doi.org / 10.1038 / s41589-018-0222-1).

[0009] Various MALT1 inhibitors are undergoing clinical and preclinical trials. JNJ-67856633 is a small molecule MALT1 inhibitor currently undergoing PhI trials in patients with non-Hodgkin's lymphoma and CLL. A review article on MALT1 inhibitor patents was recently published (doi:10.1080 / 13543776.2021.1951703).

[0010] Thus, given the role of MALT1 in multiple indications, there is a continuing need for agents that can inhibit MALT1. Summary of the Invention

[0011] In certain aspects, the present invention provides a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention as described herein, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0013] In another aspect, the present invention relates to a compound of the invention as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in therapy.

[0014] In another aspect, the present invention relates to a compound of the invention as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a disease or disorder mediated by MALT1.

[0015] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by MALT1, said method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0016] Examples of MALT1-mediated diseases or disorders include: i) Lymphomas, leukemias, carcinomas and sarcomas, e.g. non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), primary macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic leukemia, myeloid T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer or GIST (digestive stromal tumor); and ii) Immunological diseases, including autoimmune and inflammatory disorders; for example, arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis, including atopic, dermatomyositis, psoriasis, Behcet's disease, uveitis. , myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, oedema, embolism, fibrosis, sarcoidosis, lung diseases including hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium pneumonia or polymyositis.

[0017] In another aspect, the present invention provides a compound as described herein or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

[0018] In another aspect, the present invention provides a method of treating non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), comprising administering to a subject in need of treatment a therapeutically effective amount of a compound or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition as described herein.

[0019] The present invention further provides methods of synthesizing the compounds described herein or pharma- ceutically acceptable salts thereof.

[0020] In another aspect, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, which may be obtained, is obtained, or is obtained directly by the synthetic methods described herein.

[0021] In another aspect, the present invention provides novel intermediates suitable for use in any one of the synthetic methods described herein.

[0022] Preferred, appropriate and optional features of any one of the specific aspects of the invention are also preferred, appropriate and optional features of the other aspects.

[0023] Detailed Description of the Invention definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0024] References to "treating" or "treatment" should be understood to include prevention and alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder or condition includes: (1) preventing or delaying the manifestation of clinical symptoms of the condition, disorder or condition occurring in a human who may be afflicted with or susceptible to the condition, disorder or condition, but who has not yet experienced or manifested clinical or subclinical symptoms of the disorder or condition, (2) inhibiting the condition, disorder or condition, i.e., arresting, reducing or delaying the onset of the disease or its recurrence (in the case of maintenance therapy) or at least one of its clinical or subclinical symptoms, or (3) relieving or reversing the disease, i.e., causing regression of the condition, disorder or condition or at least one of its clinical or subclinical symptoms.

[0025] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0026] As used herein, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl", are specific for the straight-chain version only, and individual branched-chain alkyl groups, such as "isopropyl", are specific for the branched-chain version only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. A similar convention applies to other radicals, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0027] As used herein, the term "alkylene" includes both straight and branched chain divalent alkyl groups. For example, "C 1-4 "Alkylene" includes methylene (-CH2-), ethylene (-CH2CH2-), propylene, and butylene.

[0028] As used herein, the term "alkoxy" includes both straight and branched chain alkyl groups singly bonded to oxygen. For example, 1-4 "Alkoxy" includes methoxy, ethoxy, iso-propoxy and t-butoxy.

[0029] The term "(m-nC)" or "(m-nC) group" used alone as a prefix refers to any group having m through n carbon atoms.

[0030] "Cycloalkyl" means a hydrocarbon monocyclic or bicyclic ring containing carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Bicyclic rings can be fused or spiro-linked; examples of bicyclic cycloalkyl groups include bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane, spiro[2.4]heptane, bicyclo[4.1.0]heptane, and bicyclo[2.2.1]heptane.

[0031] The term "halo" refers to fluoro, chloro, bromo and iodo.

[0032] The term "haloalkyl" as used herein refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen (e.g., fluorine) atom, respectively. Examples of haloalkyl groups include fluoroalkyl groups, such as -CHF2, -CH2CF3, or perfluoroalkyl / alkoxy groups, such as -CF3 or -CF2CF3.

[0033] The term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a non-aromatic saturated or partially saturated monocyclic, fused, bridged or spiro bicyclic heterocyclic ring system. Monocyclic heterocyclic rings contain about 3-12 (suitably 3-7) ring atoms and also contain 1-5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocyclic rings contain 7-17 member atoms in the ring, suitably 7-12 member atoms. Bicyclic heterocyclic rings can be fused, spiro or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl and the like. Exemplary sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiepin. Other heterocycles include dihydro-oxathiolyl, dihydroisoxazolyl (e.g., 4,5-dihydroisoxazolyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl or 1,6-dihydropyridinyl), tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, oxidized sulfur heterocycles containing SO or SO2 are also included. Examples include tetrahydrothienyl and thiomorpholinyl sulfoxides and sulfones, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide.Suitable examples of heterocyclyl groups having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing one, two or three heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocycle may be bonded to another group via any suitable atom, for example, via a carbon or nitrogen atom. Suitably, the term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a 4-, 5-, 6- or 7-membered monocyclic ring as defined above.

[0034] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or polycyclic ring containing one or more (e.g., 1 to 4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, and more usually 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings or 9- or 10-membered bicyclic rings, such as bicyclic structures formed from the fusion of a 5-membered ring with a 6-membered ring or the fusion of two 6-membered rings. Each ring can contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur and oxygen. Typically, heteroaryl rings contain up to 3 heteroatoms, more usually up to 2, e.g., a single heteroatom. In certain embodiments, heteroaryl rings contain at least one nitrogen atom. The nitrogen atoms in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, is less than 5. Suitably, the term "heteroaryl" or "heteroaromatic" refers to a 5- or 6-membered monocyclic heteroaryl ring as defined above.

[0035] Non-limiting examples of heteroaryl are furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, and isoquinolyl. , quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also includes partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other rings are non-aromatic, saturated, partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur.Examples of partially aromatic heteroaryl groups are, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 4,5,6,7-tetrahydrobenzyl, These include 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl and 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl.

[0036] Non-limiting examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0037] Non-limiting examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0038] Specific non-limiting examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0039] Specific non-limiting examples of bicyclic heteroaryl groups having two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0040] Specific non-limiting examples of bicyclic heteroaryl groups containing a 5-membered ring fused to a 5-membered ring include, but are not limited to, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl, and 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl.

[0041] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In this particular embodiment, aryl is phenyl or naphthyl, particularly phenyl.

[0042] The term "optionally substituted" refers to either groups, structures or molecules that are substituted and those groups, structures or molecules that are not substituted.

[0043] When any substituent is selected from "one or more" groups, this definition should be understood to include all substituents selected from one of the specified groups, or selected from two or more of the specified groups.

[0044] The phrase "compounds of the invention" refers to both compounds generically and specifically disclosed herein.

[0045] Compounds of the Invention In a first aspect, the present invention provides a compound of formula I: [ka] [During the ceremony, X 1 is N or CH; X 2 , O, NR 7 or CR 8 R 9 and; X 3 is N or CH; X 4 is N or CR 10 and; However, X 3 and X 4 cannot both be N; R 1 is hydrogen, C 1-4 Alkyl, Hydroxy, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, NR 11 R 12 , C 3-7 Cycloalkyl and OC 3-7 cycloalkyl; R 2 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, halo, cyano, NR 13 R 14 , C(O)OR 15 , C(O)NR 16 R 17 , OR 18, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl, wherein the 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl are selected from C 1-4 optionally substituted with one or more substituents selected from alkyl, halo, and cyano; R 3 and R 4 are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, Hydroxy, C 1-4 Alkoxy, C 1-4 Haloalkoxy, Halo, Cyano, NR 19 R 20 , 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl, wherein C 1-4 Alkyl, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl and phenyl are C 1-4 Alkyl, Hydroxy, C 1-4 optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; or R 3 and R 4 together with the carbon atom to which they are attached form an oxo group, a 4- to 7-membered heterocyclic ring, or a 3- to 6-membered cycloalkyl ring; R 5 is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl; R 6 is hydrogen, halo, C 1-4 Alkyl, C 1-4 Alkoxy, cyano and C 1-4 haloalkyl; R 7 is hydrogen, C 1-4 Alkyl, C 3-7 cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, 1-4 Alkyl, C3-7 Cycloalkyl, 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclyl are 1-4 Alkyl, C 1-4 optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; or R 7 and R 3 together with the atoms to which they are attached, C 1-4 Alkyl, C 1-4 forming a 5- or 6-membered heterocyclic ring optionally substituted with one or more substituents selected from alkoxy, halo and cyano; R 8 and R 9 are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, Hydroxy, C 1-4 Alkoxy, C 1-4 Haloalkoxy, Halo, Cyano, NR 21 R 22 , 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl, wherein C 1-4 Alkyl, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl and phenyl are C 1-4 Alkyl, C 1-4 optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; or R 8 and R 9 together with the carbon atom to which they are attached form a 4- to 7-membered heterocyclic ring, or a 3- to 6-membered cycloalkyl ring; R 10 is C(O)NR 23 R 24 , C 1-4 Haloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl, and 5- or 6-membered heteroaryl, 3-7Cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl groups are C 1-4 Alkyl, C 1-3 Alkylene-R 25 , Hydroxy, NR 26 R 27 and halo; R 11 and R 12 are independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl and C 1-4 haloalkyl; or R 11 and R 12 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring; R 13 and R 14 are independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl and C 1-4 haloalkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring; R 15 is hydrogen or C 1-4 is alkyl; R 16 and R 17 are independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl and C 1-4 haloalkyl; or R 16 and R 17 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring; R 18 is hydrogen, C 1-4 Alkyl, C 1-3 Alkylene-R 23 , C 1-4 Haloalkyl, C 3-7 selected from cycloalkyl, 4- to 7-membered heterocyclyl, and 5- or 6-membered heteroaryl; R 19 , R 20 , R21 and R 22 are independently hydrogen and C 1-4 alkyl; R 23 and R 24 are independently hydrogen, C 1-4 Alkyl and C 3-7 cycloalkyl; R 25 OH, C 1-4 Alkoxy, C 3-7 Cycloalkyl, NR 28 R 29 , C(O)OR 30 and C(O)NR 31 R 32 Selected from; R 26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 are independently hydrogen and C 1-4 alkyl; n is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0046] Certain compounds of the invention may be, for example, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 18 , R 23 , R 24and n each have any of the meanings defined above, or as defined in any of the following clauses (1) to (94), or a pharma- ceutically acceptable salt thereof. For the avoidance of doubt, the scope of the present invention includes compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein any of the substituent definitions defined herein may be combined with any other substituent definition also defined herein: (1)X 1 is N; (2)X 1 is C-H; (3) X 2 is O or NR 7 is; (4) X 2 is O; (5)X 2 is NR 7 is; (6)X 2 CR 8 R 9 is; (7)X 3 is N; (8)X 3 is C-H; (9)X 4 is N; (10)X 4 CR 10 is; (11)X 3 and X 4 One of them is N, but X 3 and X 4 cannot both be N; (12)X 3 is N and X 4 is CR 10 is; (13)R 1 is hydrogen, C 1-4 Alkyl, Hydroxy, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, NR 11 R 12 and C 3-7 selected from cycloalkyl; (14)R 1is hydrogen, C 1-4 Alkyl, Hydroxy, C 1-4 Alkoxy and NR 11 R 12 Selected from; (15)R 1 is hydrogen, C 1-4 Alkyl and NR 11 R 12 Selected from; (16)R 1 is selected from hydrogen, methyl and NH2; (17)R 1 is selected from hydrogen and methyl; (18)R 1 is hydrogen; (19)R 2 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, halo, cyano, OR 18 , 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl, wherein the 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl are selected from C 1-4 optionally substituted with one or more substituents selected from alkyl, halo, and cyano; (20)R 2 is hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, halo, cyano, OR 18 , 5- or 6-membered heteroaryl and phenyl, wherein the 5- or 6-membered heteroaryl and phenyl are selected from C 1-4 optionally substituted with one or more substituents selected from alkyl, halo, and cyano; (21)R 2 is hydrogen, C 3-7 Cycloalkyl, halo, cyano, OR 18 , 5- or 6-membered heteroaryl and phenyl; (22)R 2 is selected from hydrogen, cyclopropyl, halo, cyano, methoxy, 5-membered heteroaryl, and phenyl; (23)R2 is selected from halo, cyano, methoxy, 5-membered heteroaryl, and phenyl; (24)R 2 is selected from halo and cyano; (25)R 2 is selected from chloro and bromo; (26)R 2 is bromo; (27)R 3 and R 4 are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, Hydroxy, C 1-4 selected from alkoxy, halo, cyano, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl; (28) R 3 and R 4 are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 selected from alkoxy, halo, and cyano; (29) R 3 and R 4 are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 selected from haloalkyl and cyano; (30) R 3 and R 4 are independently hydrogen, C 1-4 selected from alkyl, ethynyl, trifluoromethyl and cyano; (31) R 3 and R 4 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and cyano; (32) R 3 is hydrogen or methyl, and R 4is selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl and cyano; (33)R 3 is hydrogen, and R 4 is selected from hydrogen, methyl and trifluoromethyl; (34)R 3 and R 4 are both hydrogen; (35)R 3 is methyl, R 4 is selected from methyl and cyano; (36)R 3 and R 4 are both methyl; (37)R 3 and R 4 together with the carbon atom to which they are attached form a 4- to 7-membered heterocyclic ring, or a 3- to 6-membered cycloalkyl ring; (38)R 3 and R 4 together with the carbon atom to which they are attached form a 5- to 6-membered heterocyclic ring or a 3- to 5-membered cycloalkyl ring; (39)R 3 and R 4 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring; (40)R 1 and R 2 cannot both be hydrogen; (41)R 2 and R 3 cannot both be hydrogen; (42)R 1 , R 2 and R 3 is not all hydrogen; (43)R 1 , R 2 , R 3 and R 4 is not all hydrogen; (44)R 5 is hydrogen and C 1-4 selected from 3-5 membered alkyl; (45)R5 is selected from hydrogen and 3-5 membered methyl; (46)R 5 is hydrogen; (47)R 6 Halo, C 1-4 Alkyl, C 1-4 Alkoxy, cyano and C 1-4 selected from 3-5 membered haloalkyl; (48)R 6 Halo, cyano and C 1-4 selected from haloalkyl; (49)R 6 Halo and C 1-4 selected from haloalkyl; (50)R 6 is selected from chloro, bromo and trifluoromethyl; (51)R 6 is selected from chloro and trifluoromethyl; (52)R 6 is chloro; (53)R 7 is hydrogen, C 1-4 alkyl or 4- to 7-membered heterocyclyl, 1-4 Alkyl and 4- to 7-membered heterocyclyl are C 1-4 Alkyl, C 1-4 optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; (54)R 7 is hydrogen, C 1-4 alkyl or 4-7 membered heterocyclyl; (55)R 7 is hydrogen or C 1-4 is alkyl; (56)R 7 is hydrogen or methyl; (57)R 7 is C 1-4 is alkyl; (58)R 7 is methyl; (59)R 7 and R 3together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring optionally substituted with one or more substituents selected from methyl, methoxy, fluoro, chloro and cyano; (60)R 7 and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring; (61)R 7 and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring; (62)R 7 and R 3 together with the atoms to which they are attached form a pyrrolidine, piperazine or piperidine ring; (63)R 7 and R 3 together with the atoms to which they are attached form a pyrrolidine or piperidine ring; (64)R 8 and R 9 are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Haloalkoxy, Halo, Cyano, NR 21 R 22 , 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl, wherein C 1-4 Alkyl, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl and phenyl are C 1-4 Alkyl, C 1-4 optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; (65)R 8 and R 9 are independently hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 selected from cycloalkyl, halo, and cyano; (66) R 8and R 9 are independently hydrogen, C 1-4 Alkyl and C 1-4 selected from haloalkyl; (67)R 8 and R 9 are independently hydrogen and C 1-4 selected from alkyl; (68)R 8 and R 9 is independently selected from hydrogen and methyl; (69)R 8 and R 9は , both are hydrogen; (70)R 8 and R 9 together with the carbon atom to which they are attached form a 4- to 6-membered heterocyclic ring or a 3- to 5-membered cycloalkyl ring; (71)R 8 and R 9 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring; (72)R 8 and R 9 together with the carbon atom to which they are attached form a cyclopropyl ring; (73)R 10 is C(O)NR 23 R 24 , C 1-4 Haloalkoxy, C 3-7 cycloalkyl and 5- or 6-membered heteroaryl, 3-7 Cycloalkyl and 5- or 6-membered heteroaryl groups are C 1-4 Alkyl, C 1-3 Alkylene-R 25 , Hydroxy, NR 26 R 27 and halo; (74)R 10 is C(O)NR 23 R 24 , C 1-4haloalkoxy, 4- to 7-membered heterocyclyl, and 5- or 6-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl groups are selected from C 1-2 Alkyl, C 1-2 Alkylene-R 25 and halo; (75)R 10 is C(O)NR 23 R 24 , C 1-2 haloalkoxy and 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl group is 1-2 Alkyl, C 1-2 Alkylene-R 25 and halo; (76)R 10 is C 1-4 Alkyl, C 1-3 Alkylene-R 25 , Hydroxy, NR 26 R 27 and halo; (77)R 10 is C 1-2 Alkyl and C 1-2 Alkylene-R 25 a 5- or 6-membered heteroaryl optionally substituted by one or more substituents selected from (78)R 10 is C 1-2 Alkyl and C 1-2 Alkylene-R 25 is triazolyl optionally substituted with one or more substituents selected from (79)R 10 is methyl and CH2-R 25 is triazolyl optionally substituted with one or more substituents selected from (80)R 10 is C 1-2 Alkyl and C 1-2 Alkylene-R 252H-1,2,3-triazol-2-yl, optionally substituted by one or more substituents selected from (81)R 10 is methyl and CH2-R 25 2H-1,2,3-triazol-2-yl, optionally substituted by one or more substituents selected from (82)R 10 is 2H-1,2,3-triazol-2-yl; (83)R 11 and R 12 is independently selected from hydrogen and methyl; (84)R 11 and R 12 are both hydrogen; (85)R 13 and R 14 is independently selected from hydrogen and methyl; (86)R 13 and R 14 are both hydrogen; (87)R 18 is hydrogen and C 1-4 selected from alkyl; (88)R 18 is C 1-4 is alkyl; (89)R 18 is methyl; (90)R 23 and R 24 are independently selected from hydrogen, methyl and cyclopropyl, e.g., hydrogen and methyl; or methyl and cyclopropyl; (91)R 23 and R 24 are both hydrogen; (92) n is 0 or 1; (93) n is 0; (94) n is 1;

[0047] Appropriately, X 1 is as defined in the above items (1) to (2). Preferably, X 1は、 As defined in paragraph (1) above.

[0048] Appropriately, X 2 is as defined in any one of the above items (3) to (6). 2 is as defined in paragraph (3) above.

[0049] Appropriately, X 3 is as defined in any one of the above items (7) to (8). 3 is as defined in paragraph (7) above.

[0050] Appropriately, X 4 is as defined in any one of the above items (9) to (10). 4 is as defined in item (10) above.

[0051] Appropriately, X 3 and X 4 is as defined in any one of the above items (11) to (12). 3 and X 4 is as defined in item (12) above.

[0052] Appropriately, R 1 is as defined in any one of the above items (13) to (18). In one embodiment, R 1 is as defined in item (18) above.

[0053] Appropriately, R 2 is as defined in any one of the above items (198) to (26). In one embodiment, R 2 is as defined in item (26) above.

[0054] Appropriately, R 3 and R 4 is as defined in any one of the above items (27) to (39). In one embodiment, R 3 and R 4is as defined in any one of the above items (33) to (36).

[0055] Appropriately, R 1 ~R 4 is as defined in any one of the above items (40) to (43).

[0056] Appropriately, R 5 is as defined in any one of the above items (44) to (46). In one embodiment, R 5 is as defined in item (46) above.

[0057] Appropriately, R 6 is as defined in any one of the above items (47) to (52). In one embodiment, R 6 is as defined in any one of the above items (51) to (52).

[0058] Appropriately, R 7 is as defined in any one of the above items (53) to (58). In one embodiment, R 7 is as defined in item (58) above.

[0059] Appropriately, R 7 and R 3 is as defined in any one of the above items (59) to (63). In one embodiment, R 7 and R 3 is as defined in paragraph (63) above.

[0060] Appropriately, R 8 and R 9 is as defined in any one of the above items (64) to (72). In one embodiment, R 8 and R 9 is as defined in any one of the above items (67) to (69).

[0061] Appropriately, R 10is as defined in any one of the above items (73) to (82). In one embodiment, R 10 is as defined in item (82) above.

[0062] Appropriately, R 11 and R 12 is as defined in any one of the above items (83) to (84). In one embodiment, R 11 and R 12 is as defined in paragraph (84) above.

[0063] Appropriately, R 13 and R 14 is as defined in any one of the above items (85) to (86).

[0064] Appropriately, R 18 is as defined in any one of the above items (87) to (89). In one embodiment, R 18 is as defined in item (89) above.

[0065] Appropriately, R 23 and R 24 is as defined in any one of the above items (90) to (91). In one embodiment, R 23 and R 24 is as defined in paragraph (91) above.

[0066] Suitably, n is as defined in any one of paragraphs (92) to (94) above. In some embodiments, n is as defined in paragraph (94) above.

[0067] Conveniently, the compound of formula (I) has one of the substructures of formulae (IA) to (IJ) described herein below.

[0068] In a further group of compounds, the compounds have the substructure formula IA shown below: [ka] [In the formula, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined above.

[0069] In a further group of compounds, the compounds have the structural formula IA shown above, where X 1 is as defined in any one of items (1) to (2); X 2 is as defined in any one of items (3) to (6); X 3 is as defined in any one of items (7) to (8); X 4 is as defined in any one of items (9) to (10); R 1 is as defined in any one of the above items (13) to (18); R 2 is as defined in any one of the above items (19) to (26); R 3 and R 4 is as defined in any one of the above items (27) to (39); R 5 is as defined in any one of the above items (44) to (46); R 6 is as defined in any one of the above items (47) to (52).

[0070] In a further group of compounds, the compounds have the substructure formula IB shown below: [ka] [In the formula, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10and n is as defined above.

[0071] In a further group of compounds, the compounds have the structural formula IB shown above, where X 1 is as defined in any one of items (1) to (2); X 2 is as defined in any one of items (3) to (6); R 1 is as defined in any one of the above items (13) to (18); R 2 is as defined in any one of the above items (19) to (26); R 3 and R 4 is as defined in any one of the above items (27) to (39); R 5 is as defined in any one of the above items (44) to (46); R 6 is as defined in any one of the above items (47) to (52); R 10 is as defined in any one of the above items (73) to (82); and n is as defined in any one of the above items (92) to (94).

[0072] In a further group of compounds, the compounds have the substructure formula IC shown below: [ka] [In the formula, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 10 is as defined above.

[0073] In a further group of compounds, the compounds have the structural formula IC shown above, where X 1 is as defined in any one of items (1) to (2); X 2 is as defined in any one of items (3) to (6); R1 is as defined in any one of the above items (13) to (18); R 2 is as defined in any one of the above items (19) to (26); R 3 and R 4 is as defined in any one of the above items (27) to (39); R 5 is as defined in any one of the above items (44) to (46); R 6 is as defined in any one of items (47) to (52); R 10 is as defined in any one of the above items (73) to (82).

[0074] In a further group of compounds, the compounds have the substructure formula ID shown below: [ka] [In the formula, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 and R 6 is as defined above.

[0075] In a further group of compounds, the compounds have the structural formula ID shown above, where X 1 is as defined in any one of items (1) to (2); X 2 is as defined in any one of items (3) to (6); R 1 is as defined in any one of the above items (13) to (18); R 2 is as defined in any one of the above items (19) to (26); R 3 and R 4 is as defined in any one of the above items (27) to (39); and R 6 is as defined in any one of the above items (47) to (52).

[0076] In a further group of compounds, the compounds have the substructure formula IE shown below: [ka] [In the formula, X 1 , X 2 , R 1 , R 3 , R 4 and R 6 is as defined above.

[0077] In a further group of compounds, the compounds have the structural formula IE shown above, where X 1 is as defined in any one of items (1) to (2); X 2 is as defined in any one of items (3) to (6); R 1 is as defined in any one of the above items (13) to (18); R 3 and R 4 is as defined in any one of the above items (27) to (39); and R 6 is as defined in any one of the above items (47) to (52).

[0078] In a further group of compounds, the compounds have the substructure formula IF shown below: [ka] [In the formula, X 1 , X 2 , R 1 , R 3 and R 4 is as defined above.

[0079] In a further group of compounds, the compounds have the structural formula IF shown above, where X 1 is as defined in any one of items (1) to (2); X 2 is as defined in any one of items (3) to (6); R 1is as defined in any one of the above items (13) to (18); R 3 and R 4 is as defined in any one of the above items (27) to (39).

[0080] In a further group of compounds, the compounds have one of the structural formulas IG, IH or IJ: [ka] [In the formula, X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 10 is as defined above.

[0081] In a further group of compounds, the compounds have one of the structural formulas IG, IH or IJ shown above, where X 2 is as defined in any one of items (3) to (6); X 3 is as defined in any one of items (7) to (8); X 4 is as defined in any one of items (9) to (10); R 1 is as defined in any one of the above items (13) to (18); R 2 is as defined in any one of the above items (19) to (26); R 3 and R 4 is as defined in any one of the above items (27) to (39); R 5 is as defined in any one of the above items (44) to (46); R 6 is as defined in any one of the above items (47) to (52); R 10 is as defined in any one of the above items (73) to (82).

[0082] In certain embodiments of the compound of formula I or formulas IA-IJ, X 2 is O or NR 7 When R 3 and R 4 are independently hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 haloalkoxy, halo, cyano, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl; 1-4 Alkyl, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl and phenyl are C 1-4 Alkyl, Hydroxy, C 1-4 or R is optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; 3 and R 4 together with the carbon atom to which they are attached form an oxo group, a 4- to 7-membered heterocyclic ring, or a 3- to 6-membered cycloalkyl ring.

[0083] Particular compounds of the invention include any one of the following: 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-bromo-3,4-dihydroquinoline-1(2H)-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methoxy-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2-cyano-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyano-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(oxazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(thiazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; Cis-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-bromo-3,4-dimethyl-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-phenyl-3,4-dihydroquinoline-1(2H)-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(1,3,4-thiadiazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,3-dimethyl-3,4-dihydroquinoline-1(2H)-carboxamide; 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethynyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyclopropyl-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2,2-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyclopropyl-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; (S)-1-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-6a,7,8,9-tetrahydropyrido[3,4-e]pyrrolo[1,2-a]pyrazine-5(6H)-carboxamide; (R)-8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1,2-dimethyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 8'-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-4,5-dihydro-2H-spiro[furan-3,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-carboxamide; 1-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3',4'-e]pyrazine-5-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-methyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1,2,2-trimethyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 8-Chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; (R)-8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethyl-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; (R)-8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-isopropyl-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 7-Amino-8-bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-isopropyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyclopropyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyano-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methoxy-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-cyano-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-cyano-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Cyano-N-(6-(cyclopropyl(methyl)carbamoyl)-5-(difluoromethyl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-cyano-7-methyl-2-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; and N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0084] The various substituents and substituents which make up the compounds of the invention are typically selected so that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound is less than 750, e.g., less than 700, or less than 650.

[0085] Any suitable or preferred feature of any compound of the invention may include any suitable feature of any other embodiment.

[0086] Suitable pharma- ceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention which are sufficiently basic, for example, with an inorganic or organic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid or maleic acid.Furthermore, suitable pharma- ceutically acceptable salts of the compounds of the invention which are sufficiently acidic are alkali metal salts, for example, sodium salts or potassium salts, alkaline earth metal salts, for example, calcium salts or magnesium salts, ammonium salts, or salts with organic bases which provide physiologically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0087] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms, or in the arrangement of their atoms in space, are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers", and non-superimposable mirror images of one another are called "enantiomers". When a compound has a misaligned center, for example, when it is bonded to four different groups, a pair of enantiomers can exist. An enantiomer can be characterized by the absolute configuration of its misaligned center and described by the R and S configuration rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0088] The compounds of the present invention typically have one or more asymmetric centers; thus, such compounds may occur as individual (R)- or (S)-stereoisomers, or as mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers, diastereoisomers and mixtures thereof, or otherwise. Methods for the determination of stereochemistry and separation of stereoisomers are known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (discussion in Chapter 4 of "Advanced Organic Chemistry", 4 th (See, e.g., J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E- and Z-isomers). It should be understood that the present invention encompasses all optical isomers, diastereoisomers and geometric isomers, and mixtures thereof, that have MALT1 inhibitory activity.

[0089] The present invention also includes compounds of the invention as defined herein that contain one or more isotopic substituents. For example, H is 1 H, 2 H(D) and 3 H can be in any isotopic form, including T; 12 C. 13 C and 14 C can be in any isotopic form; O can be in any isotopic form, including 16 O and 18 It may be in any isotopic form, including O; and so forth.

[0090] It should also be understood that the compounds of the present invention may exist in solvated and unsolvated forms, such as hydrated forms, and the present invention should be understood to encompass all such solvated forms that possess MALT1 inhibitory activity.

[0091] It is also to be understood that the compounds of the invention may exhibit polymorphism and that the invention encompasses all such forms that possess MALT1 inhibitory activity.

[0092] The compounds of the present invention may exist in a number of different tautomeric forms, and reference to the compounds of the present invention includes all such forms. For the avoidance of doubt, even if a compound may exist in one of several tautomeric forms and only one form is specifically described or shown, all other forms are encompassed by the compounds of the present invention. Examples of tautomeric forms include keto, enol and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol and nitro / acintro. [ka]

[0093] The compounds of the present invention that contain an amine function can form N-oxides. Reference herein to a compound of formula I that contains an amine function can also include N-oxides. When a compound contains multiple amine functions, one or more nitrogen atoms can be oxidized to form N-oxides. Particular examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0094] The compounds of the present invention may be administered in the form of prodrugs that are decomposed in the human or animal body and release the compounds of the present invention. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached.

[0095] The present invention therefore includes compounds of formula I as defined above when they are made available by organic synthesis and when they are made available in the human or animal body by cleavage of a prodrug. The present invention therefore includes compounds of formula I produced by organic synthesis methods, as well as such compounds produced in the human or animal body by metabolism of a precursor compound. That is, compounds of formula I can be synthetically produced compounds or metabolically produced compounds.

[0096] Suitable pharma- ceutically acceptable prodrugs of compounds of formula I are those prodrugs that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

[0097] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology , Vol. 42 , p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b)Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews , 8 , 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences , 77 , 285 (1988); f) N. Kakeya, et al. Chem. Pharm. Bull. , 32 , 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0098] The in vivo effects of the compounds of formula I may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compounds of formula I. As noted above, the in vivo effects of the compounds of formula I may also be exerted by metabolism of a precursor compound (prodrug).

[0099] In addition, it should be understood that the compounds of formula I may also be covalently attached (at any suitable position) to other groups, such as solubilizing moieties (e.g., PEG polymers), moieties capable of binding the compounds to solid supports (e.g., biotin-containing moieties), and targeting ligands (e.g., antibodies or antibody fragments).

[0100] synthesis In the description of synthetic methods which follow, and in the reference synthetic methods used to prepare starting materials, it is to be understood that all reaction conditions presented, including solvents, reaction atmospheres, reaction temperatures, test durations and work-up procedures, can be selected by one of ordinary skill in the art.

[0101] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions used.

[0102] Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in connection with the following variants of the representative procedures and the accompanying Examples. Alternatively, necessary starting materials may be obtained by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

[0103] During the synthesis of the compounds of the invention in the processes defined below, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesired reactions. Those skilled in the art will understand when such protection is necessary and how to introduce and subsequently remove such protecting groups.

[0104] For examples of protecting groups, see one of the many general references on the subject, "Protecting groups in Organic Synthesis (3rd Ed), John Wiley & Sons, NY (1999)", T. Greene & P. ​​Wuts. Protecting groups can be removed by any convenient method described in the literature or known to those skilled in the art as appropriate for the removal of the protecting group in question, such method being chosen to effect the removal of the protecting group with minimal alteration of groups elsewhere in the molecule.

[0105] Thus, if a reactant contains a group such as amino, carboxy or hydroxy, it may be desirable to protect it in some of the reactions mentioned herein.

[0106] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups, for example acetyl groups, alkoxycarbonyl groups, for example methoxycarbonyl groups, ethoxycarbonyl groups or tert-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl groups, or aroyl groups, for example benzoyl groups. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl groups or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis using a suitable base, for example an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, can be removed by hydrogenation with a catalyst, such as palladium on carbon, or by treatment with a Lewis acid, such as BF3·OEt2. Suitable protecting groups for amino or alkylamino groups are, for example, substituted benzyl groups, such as 4-methoxybenzyl or 2,4-dimethoxybenzyl. Such protecting groups can be removed by treatment with a suitable acid, such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid. Another suitable protecting group for primary amino groups is, for example, the phthaloyl group, which can be removed by treatment with an alkylamine, such as dimethylaminopropylamine, or hydrazine.

[0107] It is recognized that the compounds of the present invention can be prepared in a variety of ways, by known methods. Compounds of formula I can be prepared by the methods shown below, the methods shown in the general methods or the synthesis of the example compounds, or by methods similar thereto. The described routes are only illustrative of some of the methods that can be used to synthesize compounds of formula I, and those skilled in the art will understand that the order of reaction steps is not limited to those described. It is also understood that the assignment of nucleophiles and electrophiles is not limited to those described herein, and in some cases it is appropriate to reverse the assignment. Various approaches to synthetic chemistry strategies are described in "Organic Synthesis: The Disconnection Approach", 2nd edition, S. Warren and P. Wyatt (2008).

[0108] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 and X 4 Compounds of formula I, wherein is as defined above, may be prepared by condensation of compounds of formula II and III in step (a) using a suitable coupling agent (Scheme A). Suitable coupling agents include, for example, phosgene, diphosgene, triphosgene, phenylchloroformate, 4-nitrophenyl chlorophoformate or 1,1-carbonyldiimidazole. Scheme A [ka]

[0109] As shown in Scheme B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 and X4 Compounds of formula I, wherein is as defined above, can be prepared in step (b) by conversion of an acid of formula IV to the corresponding isocyanate, for example by use of diphenylphosphoryl azide, and coupling with an amine of formula II. Scheme B [ka]

[0110] The general preparation of some representative compounds of formula II is described below and is generally prepared from commercially available starting materials or by standard synthetic methods commonly used by those skilled in the art of organic chemistry. Compounds of formula III and IV can be prepared using reaction protocols similar to those described in WO2015181747, WO2017081641, WO2018020474 and WO202008222.

[0111] R 1 , R 2 , R 3 , R 4 and X 1 is as defined above, and X 2 Compounds of formula I where =O can be formed as shown in Scheme C. Scheme C [ka]

[0112] Step (c) of base-promoted alkylation of a suitable phenol of formula V with a suitable alkylating agent of formula VI containing a leaving group (LG) gives a compound of formula VII. Suitable bases include, for example, sodium hydride, sodium bis(trimethylsilyl)amide, lithium diisopropylamide or triethylamine, and leaving groups include, for example, chlorine, bromine or iodine. An alternative route to a compound of formula VII consists of step (f) of replacing a suitable aromatic leaving group in compound X of formula I with a suitable alcohol. Suitable leaving groups include, for example, fluorine or chlorine. Reduction of the nitro group of a compound of formula VII with a suitable reducing agent in conjunction with subsequent cyclization gives, in step (d), a compound of formula VIII, which is an amide. Suitable reducing agents include, for example, zinc-acetate solution, iron-acetate solution or palladium on carbon in the presence of hydrogen. Step (e) of reduction of a compound of formula VIII with a suitable reducing agent gives a compound of formula II. Suitable reducing agents include, for example, BH3-Me2S, lithium aluminum hydride or BH3-THF.

[0113] R 1 , R 2 , R 3 , R 4 , R 7 and X 1 is as defined above, and X 2 =N 7 Compounds of formula II, wherein: may be formed as shown in Scheme D. Step (g) of displacing a suitable leaving group of a compound of formula IX with a suitable amino ester of formula X gives compounds of formula XI. Suitable leaving groups are, for example, fluorine or chlorine. Steps (d) and (e) are as described for Scheme C. Scheme D [ka]

[0114] R 1 , R 2 , R 7 and X 1is as defined above, and X 2 =NR 7 Compounds of formula II, which are: may be formed as shown in Scheme E. Step (h) of displacement of a suitable leaving group by the primary amine of formula XIII gives compounds of formula XIV. Suitable leaving groups include, for example, fluorine or chlorine. Step (d) is as described for Scheme C. Ring closure to give compounds of formula II may be achieved using a suitable "ethylene synthon". Suitable ethylene synthons include, for example, glyoxal in the presence of a base such as triethylamine and in the presence of a reducing agent such as NaBH(OAc)3 or dibromoethane. Scheme E [ka]

[0115] R 1 , R 2 , R 3 , R 4 , X 1 and X 2 Compounds of formula II, where is as defined above, can be formed as shown in Scheme F. Scheme F [ka]

[0116] The leaving group LG in the compound of formula XVI 1 is suitably a protected diamine of formula XVII, 2 is NR 7 or ethanolamine (wherein X 2 is O) to give a compound of formula XVIII. 1 contains, for example, fluorine or chlorine. 1 Step (k) of selectively removing the appropriate PG affords a compound of formula XIX. 1contains, for example, tert-butoxycarbonyl, which can be removed with acid at room temperature. 2 With a nitrogen atom, step (l) provides a compound of formula XX. A suitable transition metal catalyzed cyclization can be carried out, for example, by the addition of Pd2(dba)3 in the presence of BINAP and a suitable leaving group LG, such as bromine or iodine. 2 This involves the use of a suitable base such as t-BuONa to react with. Step (m) of removing the final protecting group PG gives the compound of formula II. Suitable PGs include, for example, 2,4-dimethoxybenzyl, which can be removed with acid at elevated temperature.

[0117] R 1 , R 2 , R 3 , R 4 , R 8 , R 9 and X 1 is as defined above, and X 2 =CR 8 R 9 Compounds of formula II, which are may be formed as shown in Scheme G. Step (n) of conversion of a compound of formula XXI to a suitable organometallic reagent followed by addition to a compound of formula XXII provides compounds of formula XXIII. Conversion to a suitable organometallic reagent may be achieved, for example, by reaction with palladium tetrakistriphenylphosphine and a suitable base, for example sodium carbonate. Steps (d) and (e) are as described for Scheme C. Further substituents, such as R 4 In step (o), a suitable base and R 4 -LG can be introduced by treating a compound of formula XXIV with Suitable bases include, for example, sodium hydride, sodium bis(trimethylsilyl)amide and lithium diisopropylamide, and suitable LGs include, for example, bromine, iodine or triflate. Scheme G [ka]

[0118] R1 , R 2 , R 3 , R 4 , X 1 and X 2 Compounds of formula II, where R is as defined above, can be formed as shown in Scheme H. 3 L-G and R 4 R was prepared as described in Schemes C and D by using LG. 3 and R 4 is H, by step (p) of alkylating the compound of formula XXVI 3 ≠R 4 ) or potentially a single step (R 3 =R 4 ) to form a compound of formula XXVII. Suitable bases include, for example, sodium hydride, sodium bis(trimethylsilyl)amide and lithium diisopropylamide, and suitable LGs include, for example, bromine, iodine or triflate. Step (e) is as described for Scheme C. Scheme H [ka]

[0119] R 1 , R 2 , R 3 , R 4 , X 1 and X 2 Compounds of formula II, where R is as defined above, can be formed as shown in Scheme I. Bromo compounds of formula XXVIII can be formed by a variety of R 2 This conversion can be carried out, for example, by conversion of the bromo compound to the corresponding boronic acid / ester followed by addition of the appropriate R 2 -Br or with appropriate R 2 Step (e) is as described for Scheme C. Scheme I [ka]

[0120] R 1 , R 2 , R 3 , R 4 and X 1 is as defined above, and X 2 Compounds of formula II, in which R is absent, can be formed as shown in Scheme J. 3 L-G and R 4 Step (q) of alkylating the compound of formula XXX by using LG gives successive (R 3 ≠R 4 ) or potentially a single step (R 3 =R 4 ) to form a compound of formula XXXI. Suitable bases include, for example, sodium hydride, sodium bis(trimethylsilyl)amide and lithium diisopropylamide, and suitable LGs include, for example, bromine, iodine or triflate. Step (e) is as described for Scheme C. Scheme J [ka]

[0121] R 1 , R 2 , R 8 , R 9 、 R 3 , R 4 and X 1 is as defined above, and X 2 CR 8 or CR 9 Compounds of formula II, wherein: may be formed as shown in Scheme K. Step (r) of reducing the pyridyl ring of the compound of formula XXXII provides compounds of formula II. Suitable reduction conditions include, for example, hydrogen in the presence of platinum(IV) oxide or hydrogen in the presence of IrCl2(COD). Scheme K [ka]

[0122] R 1 , R 2 , R 8 , R 9 、 R 3 , R 4 and X 1 Compounds of formula II, where R is as defined above, can be formed as shown in Scheme L. Compounds of formula XXV can be formed by ring expansion step (s) of the ketone of formula XXXIII. Suitable reduction conditions include, for example, sodium azide in the presence of an acid such as sulfuric acid. Step (e) is as described for Scheme C. Scheme L [ka]

[0123] R 1 , R 2 , R 8 , R 9 、 R 3 , R 4 and X 1 is as defined above, and X 2 CR 8 R 9 Compounds of formula II, which are can be formed as shown in Scheme M. Step (t) of cyclizing a suitable acrylamide of formula XXXIV can provide amides of formula XXXV. Suitable cyclization conditions include, for example, the use of aluminum trichloride. Step (e) is as described for Scheme C. Scheme M [ka]

[0124] Pharmaceutical Compositions The compound of the present invention is usually, but not necessarily, formulated into a pharmaceutical composition before being administered to a patient.Accordingly, according to a further aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention as defined above or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0125] The pharmaceutical composition of the present invention can be prepared and packaged in bulk form, and a safe and effective amount of the compound of the present invention can be extracted and then given to the patient, for example, in a powder or syrup. Alternatively, the pharmaceutical composition of the present invention can be prepared and packaged in unit dosage form, with each physically separate unit containing a safe and effective amount of the compound of the present invention. When prepared in unit dosage form, the pharmaceutical composition of the present invention typically contains 1 mg to 1000 mg.

[0126] The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and wafers), for topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams and gels), for transdermal administration, e.g., as a transdermal patch, for administration by inhalation (e.g., as dry powders, aerosols, suspensions and solutions), for insufflation administration (e.g., as a fine powder) or for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0127] As used herein, "pharmaceutically acceptable excipient" means a pharma-ceutically acceptable material, composition or vehicle that is involved in giving form or consistency to a pharmaceutical composition. Each excipient must be compatible with the other components of the pharmaceutical composition when mixed together to avoid interactions that would substantially reduce the effectiveness of the compound of the invention when administered to a patient and interactions that would result in a pharmaceutical composition that is not pharma- ceutical acceptable. Moreover, each excipient must be of sufficiently high purity to be pharma- ceutical acceptable.

[0128] Suitable pharmaceutically acceptable excipients vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients can be selected for a particular function that they may perform in the composition. For example, certain pharmaceutically acceptable excipients can be selected for their ability to facilitate the manufacture of uniform dosage forms. Certain pharmaceutically acceptable excipients can be selected for their ability to facilitate the manufacture of stable dosage forms. Certain pharmaceutically acceptable excipients can be selected for their ability to facilitate the transport or transportation of the compounds of the present invention from one organ or part of the body to another organ or part of the body once administered to a patient. Certain pharmaceutically acceptable excipients can be selected for their ability to improve patient compliance.

[0129] Suitable pharma- ceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifying agents, sweeteners, flavoring agents, flavor masking agents, colorants, anti-caking agents, wetting agents, chelating agents, plasticizers, thickening agents, antioxidants, preservatives, stabilizers, surfactants, and buffers. One of ordinary skill in the art will appreciate that a particular pharma- ceutically acceptable excipient may serve one or more functions, and alternative functions, depending on how much of the excipient is present in the formulation and what other components are present in the formulation.

[0130] Those skilled in the art have the knowledge and skills to select suitable pharma- ceutically acceptable excipients in suitable amounts for use in the present invention. In addition, there are many documents available to those skilled in the art that describe pharma-ceutically acceptable excipients and can be useful in selecting suitable pharma-ceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0131] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0132] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active ingredient (more suitably, 0.5 to 100 mg, e.g., 1 to 30 mg), compounded with an appropriate and convenient amount of an excipient, which may vary from about 5 to about 98% by weight based on the total weight of the composition.

[0133] The magnitude of a dose of a compound of formula I for therapeutic or prophylactic purposes will of course vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with known principles of medicine.

[0134] When using the compounds of the present invention for therapeutic or prophylactic purposes, they are generally administered in a daily dose ranging, for example, from 0.1 mg / kg to 75 mg / kg body weight, divided as necessary. In general, lower doses are administered for parenteral administration. Thus, for example, for intravenous or intraperitoneal administration, doses ranging, for example, from 0.1 mg / kg to 30 mg / kg body weight are generally used. Similarly, for administration by inhalation, doses ranging, for example, from 0.05 mg / kg to 25 mg / kg body weight are used. Oral administration may also be suitable, particularly in the form of tablets. Typically, a unit dosage form contains 0.5 mg to 0.5 g of the compound of the present invention.

[0135] Route of administration

[0135] The compounds of the invention or pharmaceutical compositions containing active compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0136] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patch, bandage, etc.); transmucosal (including, e.g., by patch, bandage, etc.); intranasal (e.g., by nasal spray); ophthalmic (e.g., eye drops); pulmonary (e.g., with an aerosol, e.g., by inhalation or insufflation therapy via the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid and intrasternal; and by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly.

[0137] In a preferred embodiment, the compounds of the invention described herein or a pharma- ceutically acceptable salt thereof, or the pharmaceutical compositions described herein, are administered orally or by injection, eg, conveniently orally.

[0138] Therapeutic Uses and Applications The compounds of the present invention are MALT1 inhibitors and are therefore potentially useful for the treatment of diseases or conditions mediated by MALT1.

[0139] Thus, in one aspect, the present invention relates to a compound of the invention as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in therapy.

[0140] In another aspect, the present invention relates to a compound of the invention as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the treatment of a disease or disorder mediated by MALT1.

[0141] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by MALT1, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0142] Particular diseases or conditions which the compounds of formula (I) and their pharma- ceutically acceptable salts may be used to treat include, but are not limited to, the following: i) Lymphomas, leukemias, carcinomas and sarcomas, e.g. non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), primary macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic leukemia, myeloid T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer or GIST (digestive stromal tumor); and ii) Immunological diseases, including autoimmune and inflammatory disorders; for example, arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis, including atopic, dermatomyositis, psoriasis, Behcet's disease, uveal tract infections, inflammation, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, oedema, embolism, fibrosis, sarcoidosis, pulmonary diseases including hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium pneumonia or polymyositis.

[0143] In particular, the compounds of the present invention (including pharma- ceutically acceptable salts) may be used to treat lymphomas, such as non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

[0144] In another aspect, the present invention relates to a method for treating non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), primary macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, idiopathic ... Leukemia (CML), Hairy cell leukemia, Acute lymphoblastic T-cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Megakaryoblastic leukemia, Acute megakaryoblastic leukemia, Promyelocytic leukemia, Erythroleukemia, Brain (glioma), Glioblastoma, Breast cancer, Colorectal / colon cancer, Prostate cancer, Lung cancer including non-small cell, Gastric cancer, Endometrial cancer, Melanoma, Pancreatic cancer, Liver cancer, Kidney cancer, Squamous cell carcinoma, Ovarian cancer, Sarcoma, Osteosarcoma, Thyroid cancer, Bladder cancer, Head and neck cancer, Testicular cancer, Ewing's sarcoma, Rhabdomyosarcoma, Medulloblastoma, Neuroblastoma, Uterine Cervical cancer, kidney cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Provided is a compound as described herein or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the treatment of Hashimoto's thyroiditis, Sjogren's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, edema, embolism, fibrosis, sarcoidosis, pulmonary diseases including hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium pneumonia or polymyositis.

[0145] In another aspect, the present invention provides a compound as described herein or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL).

[0146] In another aspect, the present invention relates to a method for treating non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), primary macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), and / or other leukemias. , Hairy cell leukemia, Acute lymphoblastic T-cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Megakaryoblastic leukemia, Acute megakaryoblastic leukemia, Promyelocytic leukemia, Erythroleukemia, Brain (glioma), Glioblastoma, Breast cancer, Colorectal / colon cancer, Prostate cancer, Lung cancer including non-small cell, Gastric cancer, Endometrial cancer, Melanoma, Pancreatic cancer, Liver cancer, Kidney cancer, Squamous cell carcinoma, Ovarian cancer, Sarcoma, Osteosarcoma, Thyroid cancer, Bladder cancer, Head and neck cancer, Testicular cancer, Ewing's sarcoma, Rhabdomyosarcoma, Medulloblastoma, Neuroblastoma, Cervical cancer, Kidney cancer, Urothelial carcinoma, Vulva Cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, blister formation disorder In another aspect, the present invention provides a method for treating lung diseases including pulmonary vasculitis, antibody mediated vasculitis syndromes, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium pneumonia or polymyositis, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound as described herein or a pharmacologic acceptable salt or pharmaceutical composition thereof.

[0147] In another aspect, the present invention provides a method of treating non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL), comprising administering to a subject in need of treatment a therapeutically effective amount of a compound as described herein or a pharma- ceutical composition thereof.

[0148] In another aspect, the invention provides a method of inhibiting MALT1 in vitro, comprising administering an effective amount of a compound or a pharma- ceutically acceptable salt thereof.

[0149] In another aspect, the invention provides a method of inhibiting MALT1 in vivo, comprising administering an effective amount of a compound or a pharma- ceutically acceptable salt thereof.

[0150] In another aspect, the present invention provides a method of inhibiting MALT1 in vitro and / or in vivo, comprising contacting a cell with an effective amount of a compound defined herein, or a pharma- ceutically acceptable salt thereof.

[0151] Combination therapy The compounds of the present invention can be administered alone as monotherapy or in combination with one or more additional therapeutic agents. The choice of one or more additional therapeutic agents will, of course, depend on the disease or condition to be treated and its severity.

[0152] The use of combination therapies to treat certain medical conditions is common.

[0153] According to a particular aspect of the present invention, there is provided a combination suitable for the treatment of a disease or condition in which MALT1 is involved, comprising a compound of the invention as defined above or a pharma- ceutically acceptable salt thereof and another therapeutic agent.

[0154] According to certain aspects of the present invention, the present invention is directed to non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), primary macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), , Hairy cell leukemia, Acute lymphoblastic T-cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Megakaryoblastic leukemia, Acute megakaryoblastic leukemia, Promyelocytic leukemia, Erythroleukemia, Brain (glioma), Glioblastoma, Breast cancer, Colorectal / colon cancer, Prostate cancer, Lung cancer including non-small cell, Gastric cancer, Endometrial cancer, Melanoma, Pancreatic cancer, Liver cancer, Kidney cancer, Squamous cell carcinoma, Ovarian cancer, Sarcoma, Osteosarcoma, Thyroid cancer, Bladder cancer, Head and neck cancer, Testicular cancer, Ewing's sarcoma, Rhabdomyosarcoma, Medulloblastoma, Neuroblastoma, Cervical cancer, Kidney cancer, Urothelial carcinoma, External Vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, vesicular In accordance with the present invention, there is provided a combination suitable for the prophylaxis or treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, oedema, embolism, fibrosis, sarcoidosis, pulmonary diseases including hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium pneumonia or polymyositis, comprising a compound of the invention as defined above or a pharmacologic acceptable salt thereof and one or more further therapeutic agents.

[0155] In a further aspect of the invention there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, in combination with one or more further therapeutic agents.

[0156] In this specification, when the term "combination" is used, it should be understood that it refers to simultaneous, separate or sequential administration. In one embodiment of the present invention, "combination" refers to simultaneous administration. In another embodiment of the present invention, "combination" refers to separate administration. In a further embodiment of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such as to lose the beneficial effect of the combination, for example.

[0157] According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention, or a pharma- ceutically acceptable salt thereof, in association with a pharma- ceutically acceptable diluent or carrier, in combination with one or more further therapeutic agents.

[0158] The one or more additional therapeutic agents can include additional compounds of the invention.Thus, in certain embodiments, a pharmaceutical composition is provided that includes two compounds of the invention, or pharma-ceutically acceptable salts thereof, together with a pharma-ceutically acceptable diluent or carrier.

[0159] According to certain aspects of the invention, there are provided combinations suitable for use in the prevention or treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

[0160] Examples of other therapeutic agents that may be used as part of a combination therapy with the compounds of the invention (e.g., as one of two or more active ingredients as part of a two or three combination) include, but are not limited to, the following: (i) BTK (Bruton's tyrosine kinase) inhibitors such as ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, evobrutinib, fenebrutinib, rilzabrutinib, trebrutinib, ersbrutinib, posertinib, brambrutinib, spebrutinib, luxeptinib, DTRM-555, JnJ64264681, BGB-3959, AS-1763 and remibrutinib; (ii) SYK inhibitors such as fostamatinib, entosuretinib, HMPL-523, IC-265, SKI-O-703, celduratinib, PRT-2761, GSK-264264, SYHX-1901, MK-8457, HM-43239, R-348 and PUR-1800; (iii) PKC inhibitors such as darovasertib, MS-553, enzastaurin, safingol, ruboxistaurin, and AR-13503; (iv) Alpelisib, duvelisib, copanlisib, idelalisib, umbralisib, selavelisib, CHF-6523, BDP-681, zandelisib, ART-001, buparlisib, OP-11, HMPL-689, dezapelisib, seralithib, epibotide, IOA-244, SHC-014748M, LX-086, inavolisib, MEN-1611, eganelisib PI3K pathway inhibitors such as lenolisib, ACP-319, BGB-10188, CYH-33, HS-10352, CMX-2043, ZX-101A, KA-2237, VS-5584, ASN-003, TQ-B325, AL-58805, gedatolisib, HEC-68498, CLL-442, tenalisib, dactolisib, GSK-2126458 and bimiralisib; (v) BCL family inhibitors such as BCL-201, AZD-0466, nabitoclax, persitoclax, LP-118, FCN-338, BGB-11417, UBX-1325, LP-108, VOB-560, lisaftoclax, venetoclax, ZN-d5 and ABBV-167; (vi) Gusacitinib, delgocitinib, tofacitinib, abrocitinib, ruxolitinib, baricitinib, fedratinib, upadacitinib, filgotinib, peficitinib, TD-8236, TD-0903, CEE-321, lorpcitinib, WXSH-0150, SYHX-1901, celduratinib, isensitinib, KL-130008, WP-1066, gusacitinib, INCB-52793, AC-1101, ATI-1777, SHR-030 2, JAK inhibitors such as CPL-409116, momelotinib, brepositinib, TTL-018, TD-5202, LP-0184, INCB-054707, jactinib, TQ-05105, itacitinib, AZD-0449, GLPG-0555, LW-104, ARQ-252, WXFL-10203614, golidocitinib, durxolitinib, CJ-15314, CS-12192, lierexitinib, R-348, ATI-2138 and irdinatinib; (vii) PIM kinase inhibitors such as uzansertib, TP-3654, MEN-1703, ETH-155008, abemaciclib, and SF-1126; (viii) mTORC inhibitors such as rapamycin, sirolimus, novolimus, umirolimus, zotarolimus, temsirolimus, everolimus, melilimus, eRapa, and ridaforolimus; (ix) rituximab or B cell antigen-binding antibodies and immune cell redirecting agents (e.g., blinatumomab or CAR-T cells); (x) anti-PD1 antibodies such as nivolumab, pembrolizumab, lambrolizumab, pidiruzumab, and BGB-A317; (xi) anti-PD-L1 antibodies such as atezolizemab, avelumab, durvalumab, MEDI-4736 and MPDL3280A; (xii) an antibody that inhibits 4-1BB-ligand interaction, such as utomirumab; and (xiii) Antibodies that inhibit the interaction of CTLA-4 and its ligands, such as ipilumab, tremelimumab or those disclosed in WO 2014 / 207063.

[0161] The combinations set out above may conveniently be presented for use in the form of a pharmaceutical formulation and therefore a pharmaceutical formulation comprising a combination as defined above, together with a pharma- ceutically acceptable diluent or carrier, represents a further aspect of the invention.

[0162] Such combined / combined treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment, hi certain embodiments, the separate compounds are administered simultaneously in a combined pharmaceutical formulation.

[0163] Such combination therapy employs the compounds of the invention within the dosage ranges described herein, and other pharma- ceutical active agents within their approved dosage ranges, and / or dosages as described in the pertinent published literature. EXAMPLES

[0164] General steps: Methods for preparing the compounds of the present invention are described in the following examples. Starting materials are prepared according to methods known in the art or as shown herein, or are commercially available. Commercially available reagents are used without further purification. If no reaction temperature is included, the reaction was carried out at ambient temperature, typically 17-27°C.

[0165] It will be understood by those of skill in the art that reaction temperatures, reaction times, and amounts of reagents may vary from those described herein.

[0166] The compounds described in the present invention 1 When characterized by H NMR spectroscopy, the spectra were recorded on a 400 MHz Bruker instrument. If no temperature is included, the spectra were recorded at ambient temperature. Chemical shift values ​​are expressed in parts per million (ppm). The following abbreviations are used for the multiplicity of NMR signals: s=singlet, br=broad, t=triplet, q=quartet, m=multiplet, d=doublet.

[0167] When the compounds described in this invention are characterized by LCMS data, retention times and molecular weights are determined using the conditions listed below. Method 1: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 5-95% B in 2.2 min, hold at 95% for 1.2 min; column temperature 40 °C. Method 2: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Luna Omega C18, 100 Å, 1.6 μm, 50 × 2.1 mm. Conditions: 0.05% formic acid in water [eluent A], 0.05% formic acid in MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 5-95% B in 2.2 min, hold at 95% for 1.2 min; column temperature 40 °C. Method 3: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 0.05% formic acid in water [eluent A], 0.05% formic acid in MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 5-95% B in 6.7 min, hold at 95% for 1.2 min; column temperature 40 °C. Method 4: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 0.05% formic acid in water [eluent A], 0.05% formic acid in MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 5-95% B in 2.2 min, hold at 95% for 1.2 min; column temperature 40 °C. Method 5: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 5-95% B in 1.7 min, hold at 95% for 1.5 min; column temperature 40 °C. Method 6: Dionex Ultima 3000 (Avalon PDA 210-400 nm and Thermo Scientific LCQ Ion Trap detector). Column: Luna Omega PS C18, 100 Å, 3 μm, 50 × 2.1 mm. Conditions: 95:5 10 mM ammonium formate in water / MeCN [eluent A], 5:95 10 mM ammonium formate in water / MeCN [eluent B] (flow rate 1.0 mL / min). Gradient: 2-98% B in 3 min, hold at 98% for 0.5 min; column temperature 40 °C. Method 7: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 2-98% B in 2.9 min, hold at 98% for 1.2 min; column temperature 40 °C. Method 8: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B] (flow rate 0.5 mL / min). Gradient: 2-98% B in 2.9 min, hold at 98% for 1.2 min; column temperature 45 °C. Method 9: Dionex Ultima 3000 (Avalon PDA 210-400 nm and Thermo Scientific LCQ Ion Trap detector). Column: Luna Omega PS C18, 100 Å, 3 μm, 50 × 2.1 mm. Conditions: 95:5 10 mM ammonium formate in water / MeCN [eluent A], 5:95 10 mM ammonium formate in water / MeCN [eluent B] (flow rate 1.0 mL / min). Gradient: 2-98% B in 1.9 min, hold at 98% for 2.2 min; column temperature 40 °C. Method 10: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 2-98% B in 2.9 min, hold at 98% for 1.2 min; column temperature 45 °C. Method 11: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 10 mM NH4HCO3 in water [eluent A], MeCN [eluent B] (flow rate 0.5 mL / min). Gradient: 3-100% B in 6.7 min, hold at 100% for 1.2 min; column temperature 40 °C. Method 12: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 10 mM NH4HCO3 in water [eluent A], MeCN [eluent B] (flow rate 0.5 mL / min). Gradient: 5-95% B in 2.2 min, hold at 95% for 1.2 min; column temperature 40 °C. Method 13: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B] (flow rate 0.5 mL / min). Gradient: 5-95% B in 2.9 min, hold at 95% for 1.2 min; column temperature 40 °C. Method 14: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 5-95% B in 2.2 min, hold at 95% for 1.2 min; column temperature 40 °C. Method 15: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50 × 2.1 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 2-65% B in 7.7 min, hold at 65% for 1 min, 65-90% for 1 min, hold at 90% for 1 min; column temperature 40 °C. Method 16: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 2.5 μm, 50 × 3.5 mm. Conditions: 5 mM NH4HCO3 in water [eluent A], MeCN [eluent B] (flow rate 1.0 mL / min). Gradient: 5-95% B in 1.7 min, hold at 95% for 2 min; column temperature 40 °C. Method 17: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 3.5 μm, 50 × 4.6 mm. Conditions: 5 mM NH4HCO3 in water [eluent A], MeCN [eluent B] (flow rate 1.0 mL / min). Gradient: 5-95% B in 1.7 min, hold at 95% for 2 min; column temperature 40 °C. Method 18: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 Å, 1.7 μm, 50×2.1 mm. Conditions: 0.1% TFA in water [eluent A], MeCN [eluent B] (flow rate 0.6 mL / min). Gradient: 5-95% B in 2.2 min, hold at 95% for 1.2 min; column temperature 40° C. Method 19: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity XBridge C18, 130 Å, 3.5 μm, 50 × 4.6 mm. Conditions: 0.1% formic acid in water [eluent A], MeCN [eluent B] (flow rate 1.0 mL / min). Gradient: 5-95% B in 2.2 min, hold at 95% for 1.2 min; column temperature 40 °C.

[0168] Preparative HPLC was performed using a Shimadzu SIL 10AP. [Table 1]

[0169] Intermediate synthesis Intermediate 1: 8-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carbonitrile [ka] To a stirred solution of 2-amino-6-bromophenol (1.00 g, 5.32 mmol, CAS 28165-50-6) in DMSO was added potassium carbonate (1.47 g, 10.6 mmol). The reaction mixture was cooled to 0° C. and 2-chloroacrylonitrile (0.70 g, 7.95 mmol, CAS 920-37-6) was added dropwise. The mixture was then heated at 80° C. for 16 h. The mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 20-30% ethyl acetate in hexane) to give the title compound (0.30 g). LCMS (Method 1): 2.00 min, 239.1 [M+H] + .

[0170] Intermediate 2: tert-Butyl 5-(pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxylate [ka] To a stirring solution of tert-butyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (0.2 g, 0.64 mmol, CAS 1706449-47-9) in THF:water (3:1, 5 mL) was added pyridin-3-ylboronic acid (79 mg, 0.64 mmol, CAS 1692-25-7), Cs2CO3 (0.29 g, 0.96 mmol) and the resulting reaction was purged under N2 for 10 min. PdCl2(PPh3)2 (0.021 g, 0.035 mmol), Xantphos (17 mg, 0.035 mmol) were added and the reaction was purged with N2 for 10 min. The mixture was heated at 90 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 10-25% ethyl acetate in petroleum ether) to give the title compound (0.17 g). LCMS (Method 1): 1.73 min, 311.4 [M+H] + .

[0171] Intermediate 3: 5-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline hydrochloride [ka] A stirred solution of intermediate 2 (0.17 g, 0.54 mmol) in dioxane (2 mL) was cooled to 0° C. and 4M HCl in dioxane (10 mL) was added and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and triturated with n-pentane to give the title compound (0.11 g). LCMS (Method 1): 1.06 min, 211.2 [M+H] + .

[0172] Intermediate 4: 2-(quinolin-5-yl)oxazole [ka] To a stirring solution of quinolin-5-ylboronic acid (1.00 g, 5.78 mmol, CAS 355386-94-6) in dioxane:water (5:1 ratio, 20 mL) was added 2-bromooxazole (1.28 g, 8.67 mmol, CAS 125533-82-6) and potassium carbonate (1.60 g, 11.6 mmol) and the mixture was purged with argon for 15 min. Tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.29 mmol) was added and purged with argon for 10 min. The reaction mixture was heated at 80 °C for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 20-40% ethyl acetate in hexanes) to give the title compound (0.8 g). LCMS (Method 1): 1.20 min, 197.6 [M+H] + .

[0173] Intermediate 5: 2-(1,2,3,4-tetrahydroquinolin-5-yl)oxazole [ka] To a stirred solution of intermediate 4 (0.50 g, 2.55 mmol) in MeOH (10 mL) in a steel pressure vessel, platinum(IV) oxide (29 mg, 0.13 mmol) was added and stirred at room temperature under hydrogen pressure (50 psi) for 16 h. The reaction mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh silica gel, eluted with 15-25% ethyl acetate in petroleum ether) to give the title compound (0.15 g). LCMS (Method 1): 1.28 min, 201.2 [M+H] + .

[0174] Intermediate 6: 2-(quinolin-5-yl)thiazole [ka] The title compound (0.75 g) was prepared in a similar manner as intermediate 4 from a solution of quinolin-5-ylboronic acid (1.00 g, 5.78 mmol, CAS 355386-94-6), 2-bromothiazole (1.42 g, 8.67 mmol, CAS 3034-53-5), potassium carbonate (1.60 g, 11.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.29 mmol) in dioxane:water (4:1 ratio, 20 mL); purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 25-40% ethyl acetate in hexane). LCMS (Method 1): 1.26 min, 213.0 [M+H] + .

[0175] Intermediate 7: 2-(1,2,3,4-tetrahydroquinolin-5-yl)thiazole [ka] To a stirred solution of intermediate 6 (0.50 g, 2.35 mmol) in MeOH (10 mL) in a steel pressure vessel, IrCl2(COD) (79 mg, 0.12 mmol) was added and stirred at room temperature under hydrogen pressure (50 psi) for 48 h. The reaction mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh silica gel, eluted with 20-35% ethyl acetate in petroleum ether) to give the title compound (0.20 g). LCMS (Method 1): 1.40 min, 217.2 [M+H] + .

[0176] Intermediate 8: (E)-N-(3-bromophenyl)-2-methylbut-2-enamide [ka] To a stirring solution of 3-bromoaniline (10 g, 58.1 mmol, CAS 591-19-5) in DMF (100 mL) was added (E)-2-methylbut-2-enoic acid (5.8 g, 58.1 mmol, CAS 13201-46-2), HATU (33 g, 87.2 mmol) and DIPEA (30 mL, 174 mmol), after which the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh silica gel, eluted with 15% ethyl acetate in petroleum ether) to give the title compound (7.5 g). LCMS (Method 1): 1.90 min, 254.2 [M+H] + .

[0177] Intermediate 9: 5-Bromo-3,4-dimethyl-3,4-dihydroquinolin-2(1H)-one [ka] Intermediate 8 (7.5 g, 58.1 mmol) and aluminum trichloride (7.88 g, 59.0 mmol) were heated at 180° C. for 2 h. The mixture was cooled to 0° C., quenched with 1.5 M hydrochloric acid, diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative SFC (Chiralpak IE, 30×250 mm×5 μm, flow rate: 90 g / min, 80% CO2, 20% MeOH (with 0.2% diethylamine), back pressure 10 bar, temperature 35° C.) to give the title compound (0.60 g). LCMS (Method 1): 1.85 min, 254.1 [M+H] + .

[0178] Intermediate 10: 5-Bromo-3,4-dimethyl-1,2,3,4-tetrahydroquinoline [ka] To a solution of intermediate 9 (0.3 g, 1.2 mmol) in THF (5 mL) cooled to 0° C., borane-THF solution (1 M, 7.2 mL, 7.2 mmol) was added, then the mixture was allowed to warm to room temperature with stirring for 16 h. The mixture was quenched by the addition of MeOH at 0° C., then concentrated under reduced pressure. The residue was partitioned with water and EtOAc, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.27 g). LCMS (Method 1): 2.31 min, 240.1 [M+H] + .

[0179] Intermediate 11: tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate [ka] To a stirred solution of tert-butyl 5-bromo-1,2,3,4-tetrahydroquinoline-1-carboxylate (2.5 g, 8.02 mmol, CAS 1706449-47-9) and bis(pinacolato)diboron (2.03 g, 8.02 mmol) in 1,4-dioxane (50 mL) was added potassium acetate (1.57 g, 16.0 mmol). The reaction mixture was degassed with argon for 10 min. Pd(dppf)Cl2 (0.29 g, 0.40 mmol) was added and degassed with argon for 5 min. The mixture was then heated at 110 °C for 16 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 5-7% ethyl acetate in hexanes) to give the title compound (1.80 g). LCMS (Method 1): 2.64 min, 260.5 [M-Boc+H] + .

[0180] Intermediate 12: tert-Butyl 5-(1,3,4-thiadiazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate [ka] To a stirred solution of intermediate 11 (1.8 g, 5.01 mmol), 2-bromo-1,3,4-thiadiazole (0.99 g, 6.01 mmol, CAS 61929-24-6) in THF (40 ml) at room temperature was added K3PO4 (3.32 g, 15.0 mmol). The reaction mixture was degassed with argon for 10 min, palladium acetate (0.06 g, 0.25 mmol) and Xantphos (0.14 g, 0.25 mmol) were added and degassed for 5 min. The mixture was stirred at 110 °C for 16 h. The mixture was diluted with water, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 10-15% ethyl acetate in hexane) to give the title compound (0.35 g). LCMS (Method 1): 2.33 min, 318.3[M+H] + .

[0181] Intermediate 13: 2-(1,2,3,4-tetrahydroquinolin-5-yl)-1,3,4-thiadiazole [ka] To a stirred solution of intermediate 12 (0.35 g, 1.10 mmol) in DCM (10 mL) at 0° C. was added 4M HCl-dioxane solution (5 mL). The mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and then the residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 30-35% ethyl acetate in hexane) to give the title compound (0.15 g). LCMS (Method 1): 1.16 min, 218.4 [M+H] + .

[0182] Intermediate 14: 4-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one [ka] To a stirring solution of 4-bromo-1-indanone (5.0 g, 23.7 mmol, CAS 15115-60-3) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 1.25 g, 52.1 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was cooled to 0 °C, then methyl iodide (10.3 mL, 166 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 5-10% ethyl acetate in hexanes) to give the title compound (2.70 g). LCMS (Method 1): 2.14 min, 239.2 [M+H] + .

[0183] Intermediate 15: 5-Bromo-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one [ka] To a stirred solution of intermediate 14 (2.7 g, 11.3 mmol) in benzene (40 mL) at room temperature, 18 M sulfuric acid (0.9 mL, 16.9 mmol) was added dropwise. Sodium azide (3.67 g, 56.4 mmol) was added and the mixture was stirred at 70 °C for 30 min. The mixture was diluted with water and concentrated under reduced pressure. The residue was partitioned with water and EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 5-10% ethyl acetate in hexane) to give the title compound (0.70 g). LCMS (Method 1): 2.21 min, 254.1 [M+H] + .

[0184] Intermediate 16: 5-Bromo-3,3-dimethyl-1,2,3,4-tetrahydroquinoline [ka] To a solution of intermediate 15 (0.70 g, 2.75 mmol) in THF (20 mL) cooled to 0° C., borane-dimethylsulfide complex (2M in THF, 6.9 mL, 13.8 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was quenched by addition of MeOH and then concentrated under reduced pressure. The residue was partitioned with water and EtOAc, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 5-10% ethyl acetate in hexane) to give the title compound (0.48 g). LCMS (Method 1): 2.33 min, 240.3 [M+H] + .

[0185] Intermediate 17: 8-Bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline [ka] To a stirring solution of 6-bromo-N1-methylbenzene-1,2-diamine (0.5 g, 2.49 mmol, CAS 1150102-47-8) in DMA (15 mL) was added NaHCO3 (2.09 g, 24.9 mmol) and stirred for 30 min. Then 1,2-dibromoethane (0.56 g, 2.98 mmol) was added and the mixture was heated to reflux for 16 h. The mixture was diluted with water, brine and EtOAc. The aqueous layer was extracted with ethyl acetate, then the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 15-20% ethyl acetate in hexane) to give the title compound (0.3 g). LCMS (Method 1): 1.21 min, 227.1 [M+H] + .

[0186] Intermediate 18: tert-Butyl 8-bromo-2-cyano-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate [ka] To a stirred solution of intermediate 1 (0.89 g, 3.63 mmol) and triethylamine (0.55 g, 5.44 mmol) in THF (10 mL) was added di-tert-butyl dicarbonate (1.58 g, 7.26 mmol) and DMAP (44 mg, 0.36 mmol) and stirred at room temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned with water and EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.69 g). LCMS (Method 1): 2.19 min, 337.1 [MH] - .

[0187] Intermediate 19: tert-Butyl 8-bromo-2-cyano-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate [ka] To a stirred solution of intermediate 18 (0.69 g, 2.03 mmol) in DMF (7 mL) was added sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.15 mmol) and the mixture was stirred at room temperature for 15 min. Then, methyl iodide (2.9 g, 20.3 mmol) was added and the mixture was stirred at room temperature for 5 h. The solvent was removed under reduced pressure and the residue was partitioned with water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.62 g). LCMS (Method 1): 2.26 min, 253.1 [M-Boc+H] + .

[0188] Intermediate 20: 8-Bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carbonitrile hydrochloride [ka] Intermediate 19 (0.35 g, 1.10 mmol) was cooled to 0° C., then 4M HCl in dioxane (6 mL) was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound (0.46 g). LCMS (Method 1): 1.84 min, 253.1 [M+H] + .

[0189] Intermediate 21: 3-Amino-5-bromopyridin-4-ol [ka] To a solution of 3-bromo-5-nitropyridin-4-ol (10.0 g, 45.6 mmol, CAS 31872-65-8) in ethanol:water (4:1, 100 mL) was added iron powder (12.7 g, 228 mmol) and ammonium chloride (12.2 g, 228 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure and the crude product was then purified by flash column chromatography (neutral alumina, eluted with 20-30% MeOH in DCM) to give the title compound (8 g). LCMS (Method 1): 0.33 min, 188.9 [M+H] + .

[0190] Intermediate 22: 8-Bromo-2,2-dimethyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka] To a solution of intermediate 21 (8.0 g, 42.3 mmol) in acetonitrile (80 mL) cooled to 0 °C in a sealed tube, potassium carbonate (35.1 g, 254 mmol) and 2-bromo-2-methylpropanoyl bromide (11.7 g, 50.8 mmol) were added. The mixture was stirred at 80 °C for 16 h. The mixture was diluted with water, quenched with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 45-50% EtOAC in hexanes) to give the title compound (5.0 g). LCMS (Method 1): 1.44 min, 257.0 [M+H] + .

[0191] Intermediate 23: 8-Bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 22 (5.0 g, 19.5 mmol) in THF (50 mL) cooled to 0° C., borane-THF solution (1 M, 17.5 mL, 17.5 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched by addition of MeOH and heated at 80° C. for 6 h, then concentrated under reduced pressure. The residue was partitioned with water and EtOAc, then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 15-20% EtOAC in hexanes) to give the title compound (3.5 g). LCMS (Method 1): 1.10 min, 243.1 [M+H] + .

[0192] Intermediate 24: 4-(tert-butyl) 2-ethyl 8-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-2,4-dicarboxylate [ka] To a solution of ethyl 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (3.70 g, 12.9 mmol, CAS 1021859-84-6) and triethylamine (4.5 mL, 32.3 mmol) in THF (35 mL) was added di-tert-butyl dicarbonate (8.47 g, 38.8 mmol) and DMAP (0.16 g, 1.29 mmol). The mixture was stirred at room temperature for 14 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 2-5% ethyl acetate in petroleum ether) to give the title compound (4.4 g). LCMS (Method 1): 2.31 min, 286.2 [M-Boc+H] + .

[0193] Intermediate 25: tert-Butyl 8-bromo-2-(hydroxymethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate [ka] To a solution of intermediate 24 (4.35 g, 11.3 mmol) in ethanol (40 mL) at 0° C., sodium borohydride (1.28 g, 33.8 mmol) was added. The mixture was stirred at room temperature for 14 h. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 5-7% ethyl acetate in petroleum ether) to give the title compound (3.8 g). LCMS (Method 1): 2.00 min, 244.1 [M-Boc+H] + .

[0194] Intermediate 26: tert-Butyl 8-bromo-2-formyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate [ka] To a solution of oxalyl chloride (1.0 mL, 11.7 mmol) in DCM (10 mL) cooled to -78°C, DMSO (1.65 mL, 23.24 mmol) was added dropwise and the mixture was stirred for 1 h. Then, at -78°C, a solution of intermediate 25 (1.0 g, 2.91 mmol) in DCM (3 mL) was added dropwise and stirred for 1 h. At -78°C, triethylamine (4.05 mL, 29.1 mmol) was added and then stirred at room temperature for 1 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.07 g). LCMS (Method 1): 1.81 min, 242.1 [M-Boc+H] + .

[0195] Intermediate 27: tert-Butyl 8-bromo-2-ethynyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate [ka] To a solution of intermediate 26 (1.0 g, 2.92 mmol) in MeOH (10 mL), dimethyl (1-diazo-2-oxopropyl)phosphonate (10% in MeCN, 0.67 g, 3.50 mmol) and potassium carbonate (0.81 g, 5.84 mmol) were added. The mixture was stirred at 60° C. for 45 min under microwave irradiation. The mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 2-4% ethyl acetate in petroleum ether) to give the title compound (0.30 g). LCMS (Method 1): 2.25 min, 238.2 [M-Boc+H] + .

[0196] Intermediate 28: 8-Bromo-2-ethynyl-3,4-dihydro-2H-benzo[b][1,4]oxazine hydrochloride [ka] Intermediate 27 (0.29 g, 0.86 mmol) was cooled to 0° C., then 4M HCl in dioxane (3 mL) was added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give the title compound (0.22 g). LCMS (Method 1): 1.80 min, 238.2 [M+H] + .

[0197] Intermediate 29: 5-Cyclopropyl-1,7-naphthyridine [ka] To a solution of 5-bromo-1,7-naphthyridine (0.2 g, 0.96 mmol, CAS 17965-76-3) and cyclopropylboronic acid (82 mg, 0.95 mmol) in 1,4-dioxane:water (8:1, 4.5 mL), potassium carbonate (0.4 g, 2.87 mmol) was added and the mixture was degassed with nitrogen for 10 min. PdCl2(dppf)DCM (78 mg, 0.095 mmol) was added and the mixture was degassed with nitrogen for 15 min and then stirred at 90 °C for 16 h. The mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 50% EtOAc in petroleum ether) to give the title compound (0.15 g). LCMS (method 1): 1.04 min, 171.2[M+H] + .

[0198] Intermediate 30: 5-Cyclopropyl-1,2,3,4-tetrahydro-1,7-naphthyridine [ka] To a stirred solution of intermediate 29 (0.15 g, 0.88 mmol) in ethanol (20 mL) was added platinum(IV) oxide (20 mg, 0.09 mmol) and stirred at room temperature under hydrogen atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc, and filtered through Celite. The filtrate was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.14 g). LCMS (Method 1): 1.09 min, 175.3 [M+H] + .

[0199] Intermediate 31: 8-Cyclopropyl-2,2-dimethyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka] To a solution of intermediate 22 (1.5 g, 5.84 mmol) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.47 g, 8.75 mmol) in 1,4-dioxane:water (4:1, 15 mL), potassium carbonate (2.01 g, 14.6 mmol) was added and the mixture was degassed with nitrogen for 5 min. PdCl2(dppf)DCM (0.71 g, 0.88 mmol) was added and the mixture was stirred at 80 °C for 16 h. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 30-40% ethyl acetate in petroleum ether) to give the title compound (0.65 g). LCMS (method 2): 0.96 min, 219.2[M+H] + .

[0200] Intermediate 32: 8-Cyclopropyl-2,2-dimethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 31 (0.6 g, 2.75 mmol) in THF (10 mL) at 0° C. was added lithium aluminum hydride (2M in THF, 4.12 mL, 8.25 mmol). The mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X SELECT C18, 25×150 mm×10 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with 35%-65% MeCN for 8 min, hold at 65% for 1.7 min) to give the title compound (0.10 g). LCMS (Method 1): 1.36 min, 205.1 [M+H] + .

[0201] Intermediate 33: (3-Bromo-5-nitropyridin-4-yl)-L-proline [ka] To a solution of 3-bromo-4-chloro-5-nitropyridine (2.0 g, 8.43 mmol, CAS 31872-63-6) and L-proline (1.26 g, 10.9 mmol) in acetonitrile (20 mL) at 0° C., triethylamine (3.65 mL, 25.3 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 5-10% MeOH in DCM) to give the title compound (2.1 g). LCMS (Method 2): 1.43 min, 316.2 [M+H] + .

[0202] Intermediate 34: (S)-1-Bromo-6a,7,8,9-tetrahydropyrido[3,4-e]pyrrolo[1,2-a]pyrazin-6(5H)-one [ka] To a solution of intermediate 33 (2.0 g, 6.34 mmol) in acetic acid (8 mL) was added iron powder (1.06 g, 19.0 mmol). The mixture was stirred at 80° C. for 4 h. The mixture was concentrated under reduced pressure, then the residue was diluted with water, basified with sodium bicarbonate, and then extracted with 10% MeOH in DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.1 g). LCMS (Method 1): 0.99 min, 268.2 [M+H] + .

[0203] Intermediate 35: (S)-1-Bromo-5,6,6a,7,8,9-hexahydropyrido[3,4-e]pyrrolo[1,2-a]pyrazine [ka] To a solution of intermediate 34 (1.1 g, 4.10 mmol) in THF (10 mL) cooled to 0° C., borane-THF solution (1 M, 12.3 mL, 12.3 mmol) was added, and the mixture was then stirred at 80° C. for 3 h. MeOH was added to quench the mixture, which was then heated at 80° C. for 3 h. The mixture was diluted with water, then 1 M aqueous HCl (5 mL) was added, and heated at 80° C. for 3 h. The mixture was concentrated under reduced pressure. The residue was basified with aqueous sodium bicarbonate and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 50-100% EtOAC in hexanes) to give the title compound (0.5 g). LCMS (Method 1): 1.16 min, 254.1 [M+H] + .

[0204] Intermediate 36: N-(3-bromo-5-nitropyridin-4-yl)-N-methyl-D-alanine [ka] To a solution of 3-bromo-4-chloro-5-nitropyridine (2.0 g, 8.42 mmol, CAS 31872-63-6) and N-methyl-D-alanine (1.30 g, 12.6 mmol) in 1,4-dioxane:water (2:1, 20 mL) at 0° C., sodium carbonate (1.34 g, 12.6 mmol) was added. The mixture was stirred at room temperature for 16 h. The mixture was quenched with water and washed with EtOAc. The aqueous layer was acidified with sodium hydrogen sulfate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 50% EtOAc in hexane) to give the title compound (1.25 g). LCMS (Method 1): 1.54 min, 304.3 [M+H] + .

[0205] Intermediate 37: (R)-8-Bromo-1,2-dimethyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one [ka] To a solution of intermediate 36 (1.25 g, 4.11 mmol) in acetic acid (25 mL) was added iron powder (0.69 g, 12.3 mmol). The mixture was stirred at 80° C. for 4 h. The mixture was concentrated under reduced pressure, then the residue was diluted with water, basified with sodium bicarbonate, then extracted with 10% MeOH in DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.6 g). LCMS (Method 2): 0.80 min, 256.1 [M+H] + .

[0206] Intermediate 38: (R)-8-Bromo-1,2-dimethyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine [ka] To a solution of intermediate 37 (0.6 g, 2.34 mmol) in THF (12 mL) cooled to 0° C., borane-THF solution (1 M, 7.02 mL, 7.02 mmol) was added and the mixture was then stirred at 80° C. for 3 h. MeOH was added to quench the mixture, which was then heated at 60° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was basified with aqueous sodium bicarbonate and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.5 g). LCMS (Method 1): 1.10 min, 242.1 [M+H] + .

[0207] Intermediate 39: 8'-Bromo-4,5-dihydro-2H-spiro[furan-3,2'-pyrido[4,3-b][1,4]oxazin]-3'(4'H)-one [ka] A solution of 3-hydroxytetrahydrofuran-3-carboxylic acid (0.6 g, 4.55 mmol, CAS 183162-36-9) in thionyl chloride (6 mL) was stirred at 80° C. for 12 hours. The mixture was concentrated under reduced pressure and then flushed with nitrogen to give acid chloride A. Separately, a mixture of 3-amino-5-bromopyridin-4-ol (0.6 g, 3.17 mmol) and potassium carbonate (2.63 g, 19.0 mmol) in DMF:THF (1:1, 6 mL) was stirred at 0° C. for 30 minutes. Acid chloride A was added and the mixture was stirred at room temperature for 1 hour and then at 100° C. for 16 hours. The mixture was diluted with water and concentrated under reduced pressure. It was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 20-30% EtOAC in hexanes) to give the title compound (0.24 g). LCMS (Method 1): 1.35 min, 285.3 [M+H] + .

[0208] Intermediate 40: 8'-Bromo-3',4,4',5-tetrahydro-2H-spiro[furan-3,2'-pyrido[4,3-b][1,4]oxazine] [ka] To a solution of intermediate 39 (0.24 g, 0.84 mmol) in THF (10 mL) cooled to 0° C., borane-THF solution (1 M, 2.53 mL, 2.53 mmol) was added and the mixture was stirred at 70° C. for 3 h. MeOH was added to quench the mixture, which was then heated at 70° C. for 3 h. The mixture was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.2 g). LCMS (Method 1): 0.98 min, 271.2 [M+H] + .

[0209] Intermediate 41: 1-(3-bromo-5-nitropyridin-4-yl)piperidine-2-carboxylic acid [ka] Sodium carbonate (1.34 g, 12.6 mmol) was added to a solution of pipecolic acid (1.63 g, 12.6 mmol, CAS 535-75-1) in 1,4-dioxane:water (2:1, 40 mL) at 0° C., which was stirred for 5 min, after which 3-bromo-4-chloro-5-nitropyridine (2.0 g, 8.42 mmol, CAS 31872-63-6) was added. The mixture was stirred at room temperature for 16 h. The mixture was acidified with aqueous sodium hydrogen sulfate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 30-35% EtOAC in hexanes) to give the title compound (1.5 g). LCMS (Method 1): 1.77 min, 330.2 [M+H] + .

[0210] Intermediate 42: 1-Bromo-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3',4'-e]pyrazin-6(6aH)-one [ka] To a solution of intermediate 41 (1.25 g, 4.11 mmol) in acetic acid (14.5 mL) was added iron powder (0.74 g, 13.2 mmol). The mixture was stirred at 85° C. for 5 h. The mixture was carefully basified with aqueous sodium bicarbonate and then extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.50 g). LCMS (Method 2): 1.17 min, 282.1 [M+H] + .

[0211] Intermediate 43: 1-Bromo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3',4'-e]pyrazine [ka] To a solution of intermediate 42 (0.45 g, 1.60 mmol) in THF (5 mL) cooled to 0° C., borane-THF solution (1 M, 4.79 mL, 4.79 mmol) was added and the mixture was then stirred at 80° C. for 3 h. MeOH was added to quench the mixture, which was then heated at 80° C. for 6 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 30-35% EtOAC in hexanes) to give the title compound (0.16 g). LCMS (Method 1): 1.31 min, 268.3 [M+H] + .

[0212] Intermediate 44: N-(3-bromo-5-nitropyridin-4-yl)-N-methylglycine [ka] To a solution of methyl N-methylglycinate hydrochloride (2.20 g, 15.8 mmol, CAS 13515-93-0) in acetonitrile (25 mL) at 0° C., triethylamine (4.43 mL, 31.6 mmol) was added, which was stirred for 5 min, followed by the addition of 3-bromo-4-chloro-5-nitropyridine (2.5 g, 10.5 mmol, CAS 31872-63-6). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 35-40% ethyl acetate in petroleum ether) to give the title compound (2.0 g). LCMS (Method 1): 1.76 min, 290.9 [M+H] + .

[0213] Intermediate 45: 8-Bromo-1-methyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one [ka] To a solution of intermediate 44 (2.0 g, 6.89 mmol) in acetic acid (20 mL) was added iron powder (1.15 g, 20.7 mmol). The mixture was stirred at 80° C. for 16 h. The mixture was carefully basified with aqueous sodium bicarbonate and then filtered through Celite. The filtrate was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.50 g). LCMS (Method 3): 0.73 min, 242.2 [M+H] + .

[0214] Intermediate 46: 8-Bromo-1-methyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine [ka] To a solution of intermediate 45 (1.50 g, 6.19 mmol) in THF (15 mL) cooled to 0° C., borane-THF solution (1 M, 18.5 mL, 18.5 mmol) was added and the mixture was stirred at 80° C. for 2 h. The mixture was cooled to 0° C. and then quenched by the addition of MeOH, which was then heated at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 5-10% MeOH in DCM) to give the title compound (0.35 g). LCMS (Method 4): 0.93 min, 228.2 [M+H] + .

[0215] Intermediate 47: Methyl 2-((3-bromo-5-nitropyridin-4-yl)oxy)propanoate [ka] To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.01 g, 25.3 mmol) in THF (25 mL) at 0 °C, methyl 2-hydroxypropanoate (1.31 g, 12.6 mmol, CAS 547-64-8) was added, and the mixture was then stirred at room temperature for 30 min. Then, 3-bromo-4-chloro-5-nitropyridine (2.0 g, 8.42 mmol, CAS 31872-63-6) in THF (25 mL) was added, and the mixture was stirred at 80 °C for 2 h. The mixture was diluted with water, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 30-35% ethyl acetate in petroleum ether) to give the title compound (1.0 g). LCMS (method 4): 1.73 min, 305.2[M+H] + .

[0216] Intermediate 48: 8-Bromo-2-methyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka] To a solution of intermediate 47 (1.0 g, 3.28 mmol) in acetic acid (10 mL) was added iron powder (0.55 g, 9.84 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was concentrated under reduced pressure, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with diethyl ether, filtered and dried under reduced pressure to give the title compound (0.60 g). LCMS (Method 4): 1.30 min, 243.1 [M+H] + .

[0217] Intermediate 49: 8-Bromo-2-methyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 48 (0.60 g, 2.47 mmol) in THF (6 mL) cooled to 0° C., borane-THF solution (1 M, 7.41 mL, 7.41 mmol) was added and the mixture was then stirred at 80° C. for 2 h. The mixture was cooled to 0° C. and then quenched by the addition of MeOH, which was then heated at 80° C. for 2 h. The mixture was concentrated under reduced pressure and then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 40-45% ethyl acetate in petroleum ether) to give the title compound (0.50 g). 1 H NMR (400MHz; CDCl3) δ: 8.01 (s, 1H), 7.82 (s, 1H), 4.39-4.43 (m, 1H), 3.88 (brs, 1H), 3.41-3.46 (m, 1H), 3.11-3.16 (m, 1H), 1.45-1.47 (m, 3H).

[0218] Intermediate 50: (R)-8-Bromo-1,2-dimethyl-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one [ka] To a stirred solution of intermediate 37 (1.0 g, 3.90 mmol) in THF (20 mL) at 0° C., sodium hydride (60% dispersion in mineral oil, 0.46 g, 11.7 mmol) was added and the mixture was stirred for 15 min. To this was added (trimethylsilyl)ethoxymethyl chloride (1.3 g, 7.81 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 10% EtOAc in petroleum ether) to give the title compound (0.75 g). LCMS (Method 1): 2.18 min, 386.2 [M+H] + .

[0219] Intermediate 51: 8-Bromo-1,2,2-trimethyl-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one [ka] To a stirred solution of intermediate 50 (0.75 g, 1.94 mmol) in THF (15 mL) cooled to -40°C, LDA (1M in THF, 5.82 mL, 5.82 mmol) was added and the mixture was stirred for 15 min. To this was added iodomethane (0.83 g, 5.82 mmol) and the mixture was then stirred at -40°C for 2 h. The mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 8% EtOAc in petroleum ether) to give the title compound (0.41 g). LCMS (Method 1): 2.51 min, 400.2 [M+H] + .

[0220] Intermediate 52: 8-Bromo-1,2,2-trimethyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one [ka] Intermediate 51 (0.40 g, 0.99 mmol) was dissolved in concentrated HCl (37% aqueous solution, 8 mL) and stirred at 60° C. for 3 h. The mixture was carefully basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.23 g). LCMS (Method 1): 1.29 min, 270.0 [M+H] + .

[0221] Intermediate 53: 8-Bromo-1,2,2-trimethyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine [ka] To a solution of intermediate 52 (0.23 g, 0.85 mmol) in THF (2.3 mL) cooled to 0° C., borane-THF solution (1 M, 4.25 mL, 4.25 mmol) was added and the mixture was stirred at 80° C. for 3 h. MeOH was added to quench the mixture, which was then heated at 60° C. for 16 h. The mixture was concentrated under reduced pressure, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.23 g). LCMS (Method 1): 1.13 min, 256.1 [M+H] + .

[0222] Intermediate 54: 3-Amino-5-chloropyridin-4-ol [ka] To a solution of 3-chloro-5-nitropyridin-4-ol (2.0 g, 11.5 mmol) in ethanol:water (2:1, 20 mL) was added iron powder (3.2 g, 57.3 mmol) and ammonium chloride (3.07 g, 57.3 mmol). The mixture was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (neutral alumina, eluted with 20-30% MeOH in DCM) to give the title compound (1.0 g). LCMS (Method 1): 0.28 min, 145.2 [M+H] + .

[0223] Intermediate 55: 8-Chloro-2,2-dimethyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka] To a solution of intermediate 54 (1.0 g, 6.92 mmol) in acetonitrile (10 mL) at 0° C., potassium carbonate (5.74 g, 41.5 mmol) was added and stirred at room temperature for 30 min. The mixture was cooled to 0° C., then 2-bromo-2-methylpropanoyl bromide (1.91 g, 8.30 mmol) was added and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, then diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.6 g). LCMS (Method 1): 1.51 min, 212.9 [M+H]+ .

[0224] Intermediate 56: 8-Chloro-2,2-dimethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 55 (0.60 g, 2.82 mmol) in THF (10 mL) cooled to 0° C., borane-THF solution (1 M, 14.1 mL, 14.1 mmol) was added, and the mixture was then stirred at room temperature for 2 h. MeOH was added to quench the mixture, which was then heated at 80° C. for 8 h. The mixture was concentrated under reduced pressure, then diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.45 g). LCMS (Method 1): 1.17 min, 199.0 [M+H] + .

[0225] Intermediate 57: 3-Bromo-5-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-4-amine [ka] To a solution of 4-aminotetrahydropyran (2.55 g, 25.3 mmol, CAS 38041-19-9) in 1,4-dioxane:water (2:1, 40 mL) at 0° C., sodium carbonate (3.57 g, 33.7 mmol) was added and 3-bromo-4-chloro-5-nitropyridine (4.0 g, 16.8 mmol, CAS 31872-63-6) was added. The mixture was stirred at room temperature for 16 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.3 g). LCMS (Method 1): 1.66 min, 302.0 [M+H] + .

[0226] Intermediate 58: 5-Bromo-N4-(tetrahydro-2H-pyran-4-yl)pyridine-3,4-diamine [ka] To a solution of intermediate 57 (4.3 g, 14.2 mmol) in ethanol:water (4:1, 43 mL) was added iron powder (3.97 g, 71.2 mmol) and ammonium chloride (3.80 g, 71.2 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure, filtered through Celite and washed with 10% MeOH-DCM solution. The filtrate was concentrated and the crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 5% MeOH in DCM) to give the title compound (3.4 g). LCMS (Method 1): 0.85 min, 271.9 [M+H] + .

[0227] Intermediate 59: 8-Bromo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine [ka] To a solution of intermediate 58 (3.4 g, 12.5 mmol) in ethanol (68 mL) was added oxalaldehyde (0.87 g, 15.0 mmol) and the mixture was stirred at 100° C. for 16 h. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was suspended in THF (68 mL) followed by the addition of TFA (34 mL) and sodium borohydride (1.65 g, 43.7 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (X-Bridge C18, 25×150 mm×10 μm, flow rate: 19 mL / min, 10 mM aqueous NH4HCO3 with MeCN 20% to 50% for 7 min, hold at 50% for 2.2 min, then 98% for 3.8 min) to give the title compound (2.0 g). LCMS (Method 1): 1.09 min, 298.1 [M+H] + .

[0228] Intermediate 60: Methyl (R)-2-((3-bromo-5-nitropyridin-4-yl)(methyl)amino)butanoate [ka] To a solution of 3-bromo-4-chloro-5-nitropyridine (2.0 g, 8.42 mmol, CAS 31872-63-6) in 1,4-dioxane:water (2:1, 430 mL), sodium carbonate (3.57 g, 25.3 mmol) was added and stirred at room temperature for 10 min. Then, 4-methyl (R)-2-(methylamino)butanoate (2.55 g, 25.3 mmol, CAS 745759-46-0) was added and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 60-120 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound (0.35 g). LCMS (Method 1): 1.97 min, 332.5 [M+H] + .

[0229] Intermediate 61: (R)-8-Bromo-2-ethyl-1-methyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one [ka] To a solution of intermediate 60 (0.35 g, 1.06 mmol) in acetic acid (3.5 mL) was added iron powder (0.34 g, 6.04 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was concentrated under reduced pressure, dissolved in 10% MeOH-DCM solution, and then filtered through Celite. The filtrate was washed with aqueous sodium bicarbonate. The combined organic layers were concentrated under reduced pressure to give the title compound (0.32 g). LCMS (Method 4): 1.06 min, 270.2 [M+H] + .

[0230] Intermediate 62: (R)-8-Bromo-2-ethyl-1-methyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine [ka] To a solution of intermediate 61 (0.32 g, 1.19 mmol) in THF (3.2 mL) cooled to 0° C., borane-THF solution (1 M, 5.9 mL, 5.9 mmol) was added and the mixture was then stirred at room temperature for 2 h. MeOH was added to quench the mixture, which was then heated at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (neutral alumina, eluted with 30-40% EtOAc in hexanes) to give the title compound (0.1 g). LCMS (Method 1): 1.23 min, 256.1 [M+H] + .

[0231] Intermediate 63: Methyl N-(3-bromo-5-nitropyridin-4-yl)-N-methyl-D-vanillate [ka] A solution of methyl N-methyl-D-vanillate (2.50 g, 17.2 mmol, CAS 769890-37-1) in 1,4-dioxane:water (4:1, 25 mL) was added with sodium carbonate (3.57 g, 33.7 mmol) at 0° C. This was stirred for 10 min and 3-bromo-4-chloro-5-nitropyridine (2.86 g, 12.1 mmol, CAS 31872-63-6) was added. The mixture was stirred at 80° C. for 16 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 5-10% EtOAc in hexanes) to give the title compound (0.16 g). LCMS (method 1): 2.13 min, 346.2[M+H] + .

[0232] Intermediate 64: (R)-8-Bromo-2-isopropyl-1-methyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one [ka] To a solution of intermediate 63 (0.16 g, 0.46 mmol) in acetic acid (2.0 mL) was added iron powder (0.08 g, 1.39 mmol). The mixture was stirred at 80° C. for 4 h. The mixture was filtered through Celite, washing with EtOAc, and the filtrate was concentrated under reduced pressure to give the title compound (0.16 g). LCMS (Method 1): 1.15 min, 284.5 [M+H] + .

[0233] Intermediate 65: (R)-8-Bromo-2-isopropyl-1-methyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine [ka] To a solution of intermediate 64 (0.16 g, 0.56 mmol) in THF (3 mL) cooled to 0° C., borane-THF solution (1 M, 2.8 mL, 2.8 mmol) was added and the mixture was then stirred at room temperature for 16 h. MeOH was added to quench the mixture, which was then heated at 60° C. for 5 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 50-100% EtOAc in hexanes) to give the title compound (55 mg). LCMS (Method 1): 1.32 min, 270.1 [M+H] + .

[0234] Intermediate 66: 3-Bromo-4-chloro-5-nitropyridin-2-amine [ka] To 3-bromo-4-chloropyridin-2-amine (4 g, 19.28 mmol, CAS 221297-82-1) was added concentrated sulfuric acid (98%, 40 mL) portionwise cooled to 0° C., nitric acid (48%, 2 mL) was added, and the mixture was then stirred at room temperature for 1 h. The mixture was poured into water, the resulting solid was filtered, washed with water, and the solid was dried to give the title compound (2.6 g). LCMS (Method 1): 1.59 min, 252.1 [M+H] + .

[0235] Intermediate 67: Methyl 2-((2-amino-3-bromo-5-nitropyridin-4-yl)oxy)acetate [ka] To a stirred solution of methyl 2-hydroxyacetate (1.85 g, 20.60 mmol) in DMF (25 mL) at 0° C., sodium hydride (60% dispersion in mineral oil, 0.82 g, 20.6 mmol) was added and the mixture was stirred for 30 min. To this was added intermediate 66 (2.6 g, 10.3 mmol) in portions and the mixture was stirred at room temperature for 16 h. The mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (neutral alumina, eluted with 5-10% MeOH in DCM) to give the title compound (0.65 g). LCMS (Method 1): 1.36 min, 306.2 [M+H] + .

[0236] Intermediate 68: 7-Amino-8-bromo-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka] To a solution of intermediate 67 (0.65 g, 2.12 mmol) in acetic acid (10 mL) was added iron powder (0.34 g, 6.09 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was filtered through Celite, washing with EtOAc, and the filtrate was concentrated under reduced pressure to give the title compound (1.0 g). LCMS (Method 1): 0.55 min, 244.3 [M+H] + .

[0237] Intermediate 69: 8-Bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-7-amine [ka] To a solution of intermediate 68 (1.0 g, 4.10 mmol) in THF (10 mL) cooled to 0° C., borane-THF solution (1 M, 24.6 mL, 24.6 mmol) was added, and the mixture was then stirred at 80° C. for 2 h. The mixture was cooled to 0° C. and then quenched by the addition of MeOH, which was then heated at 80° C. for 6 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X SELECT C18, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN 10-30% for 10 min, hold at 30% for 1.25 min, then 98% for 0.01 min, and hold for 0.1 min) to give the title compound (0.1 g). 1 H NMR (400MHz; DMSO-d6) δ: 7.32 (s, 1H), 5.23 (brs, 3H), 4.25 (t, 2H), 3.18 (t, 2H).

[0238] Intermediate 70: 2-((3-bromo-5-nitropyridin-4-yl)amino)-3,3,3-trifluoropropanoic acid [ka] To a solution of 2-amino-3,3,3-trifluoropropanoic acid (0.5 g, 3.49 mmol, CAS 17463-43-3) in acetonitrile (10 mL), 3-bromo-4-chloro-5-nitropyridine (0.86 g, 3.67 mmol, CAS 31872-63-6) and DIPEA (1.92 g, 10.5 mmol) were added and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 5-10% MeOH in DCM) to give the title compound (0.70 g). LCMS (Method 1): 1.31 min, 344.0 [M+H] + .

[0239] Intermediate 71: 8-Bromo-2-(trifluoromethyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one [ka] To a solution of intermediate 70 (0.70 g, 2.04 mmol) in acetic acid (7 mL) was added iron powder (0.34 g, 6.09 mmol). The mixture was stirred at 80° C. for 4 h. The mixture was concentrated under reduced pressure, basified with aqueous sodium bicarbonate, and extracted with 10% MeOH in DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 5-10% MeOH in DCM) to give the title compound (0.45 g). LCMS (Method 1): 0.90 min, 296.0 [M+H] + .

[0240] Intermediate 72: 8-Bromo-2-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine [ka] To a solution of intermediate 71 (0.45 g, 1.52 mmol) in THF (10 mL) cooled to 0° C., borane-THF solution (1 M, 4.57 mL, 4.57 mmol) was added and the mixture was then stirred at room temperature for 3 h. MeOH was added to quench the mixture, which was then heated at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 5-10% MeOH in DCM) to give the title compound (0.12 g). LCMS (Method 1): 0.95 min, 282.0 [M+H] + .

[0241] Intermediate 73: 3-((2,4-dimethoxybenzyl)amino)-1,1,1-trifluoropropan-2-ol [ka] To a solution of 3-amino-1,1,1-trifluoropropan-2-ol (10 g, 77.5 mmol, CAS 431-38-9) in MeOH (100 mL) was added acetic acid (4.6 mL, 77.5 mmol), 2,4-dimethoxybenzaldehyde (14.2 g, 85.2 mmol) and stirred at room temperature for 30 min. The mixture was cooled to 0 °C and sodium cyanoborohydride (14.6 g, 232 mmol) was added in portions such that the temperature was maintained between 15 °C and 25 °C. The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and then quenched by the addition of water. It was extracted with EtOAc, then the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (neutral alumina, eluted with 15-20% EtOAc in petroleum ether) to give the title compound (11 g). LCMS (method 1): 1.10 min, 280.2[M+H] + .

[0242] Intermediate 74: tert-Butyl (2,4-dimethoxybenzyl) (3,3,3-trifluoro-2-hydroxypropyl)carbamate [ka] To a stirred solution of intermediate 73 (11 g, 39.4 mmol) and triethylamine (12.0 mL, 118 mmol) in DCM (10 mL) at 0° C., di-tert-butyl dicarbonate (10.3 g, 47.3 mmol) was added and stirred at room temperature for 16 h. The mixture was quenched with water and then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 20-25% EtOAc in petroleum ether) to give the title compound (8.0 g). LCMS (Method 1): 2.17 min, 324.1 [M-tBu+H] + .

[0243] Intermediate 75: tert-Butyl (2-((3,5-dibromopyridin-4-yl)oxy)-3,3,3-trifluoropropyl)(2,4-dimethoxybenzyl)carbamate [ka] To a suspension of intermediate 74 (8.0 g, 21.1 mmol), Cs2CO3 (20.6 g, 63.3 mmol) in DMF (80 mL) at 0 °C, 3,5-dibromo-4-chloropyridine (5.72 g, 21.1 mmol, CAS 13626-17-0) was added and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 10-15% EtOAc in petroleum ether) to give the title compound (11 g). LCMS (Method 1): 2.65 min, 615.2 [M+H] + .

[0244] Intermediate 76: 2-((3,5-dibromopyridin-4-yl)oxy)-N-(2,4-dimethoxybenzyl)-3,3,3-trifluoropropan-1-amine hydrochloride [ka] To a stirred solution of intermediate 75 (4.0 g, 6.5 mmol) in EtOAc (20 mL) at 0° C., 4M HCl-1,4-dioxane solution (40 mL) was added and stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give the title compound (3.5 g). LCMS (Method 1): 2.20 min, 515.3 [M+H] + .

[0245] Intermediate 77: 8-Bromo-4-(2,4-dimethoxybenzyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 76 (1.7 g, 3.08 mmol) in toluene (12.5 mL), sodium t-butoxide (2.01 g, 20.9 mmol) was added and the mixture was degassed with nitrogen for 5 min. Pd2(dba)3 (0.28 g, 0.31 mmol) and BINAP (0.39 g, 0.62 mmol) were added and the mixture was stirred in a sealed tube at 110 °C for 16 h. The mixture was diluted with water and then with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 20-25% ethyl acetate in petroleum ether) to give the title compound (0.30 g). LCMS (Method 1): 2.06 min, 433.2 [M+H] + .

[0246] Intermediate 78: 8-Bromo-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a stirred solution of intermediate 77 (0.30 g, 0.69 mmol) in EtOAc (1.5 mL) at 0° C., 4M HCl in 1,4-dioxane (3 mL) was added, which was then stirred at 60° C. for 2 h. The mixture was concentrated under reduced pressure, and then the residue was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 35-40% ethyl acetate in petroleum ether) to give the title compound (0.19 g). LCMS (Method 1): 1.39 min, 283.1 [M+H] + .

[0247] Intermediate 79: 3,5-Dibromo-2-methylpyridin-4-ol hydrobromide [ka] To a stirred solution of 2-methylpyridin-4-ol (20 g, 183 mmol, CAS 18615-86-6) in hydrobromic acid (48% aqueous, 70 mL) at 0° C., a solution of bromine (18.6 mL, 367 mmol) in acetic acid (80 mL) was added dropwise. The mixture was then stirred at room temperature for 3 h. The mixture was poured into ice water and filtered, washing the solid with water. The solid was dried under reduced pressure to give the title compound (22 g). 1 H NMR (400MHz; DMSO-d6) δ: 12.31 (brs, 1H), 8.19 (s, 1H), 3.57 (brs, 1H), 2.39 (s, 3H).

[0248] Intermediate 80: 3,5-Dibromo-4-chloro-2-methylpyridine [ka] To a stirred suspension of intermediate 79 (17 g, 48.9 mmol) in DCM (170 mL) at 0° C., thionyl chloride (13.9 mL, 191 mmol) and DMF (1.7 mL) were added. The mixture was then stirred at 60° C. for 4 h. The mixture was diluted with water and then poured into cold saturated aqueous sodium bicarbonate. It was extracted with DCM and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (18 g). LCMS (Method 1): 2.19 min, 285.9 [M+H] + .

[0249] Intermediate 81: 2-((3,5-dibromo-2-methylpyridin-4-yl)oxy)-N-(2,4-dimethoxybenzyl)ethan-1-amine [ka] To a stirred solution of 2-((2,4-dimethoxybenzyl)amino)ethan-1-ol (9.98 g, 47.3 mmol, CAS 40171-89-9) in DMF (100 mL) at 0° C., sodium hydride (60% dispersion in mineral oil, 2.52 g, 62.1 mmol) was added and the mixture was stirred for 30 min. Then, to this was added Intermediate 80 (9.0 g, 31.5 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was quenched with ice-cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (neutral alumina, eluted with 50% EtOAc in petroleum ether) to give the title compound (3.6 g). LCMS (Method 1): 1.40 min, 461.3 [M+H] + .

[0250] Intermediate 82: 8-Bromo-4-(2,4-dimethoxybenzyl)-7-methyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 81 (2.5 g, 5.43 mmol) in toluene (25 mL), sodium t-butoxide (1.56 g, 16.3 mmol) was added and the mixture was degassed with nitrogen for 5 min. Pd2(dba)3 (0.50 g, 0.54 mmol) and X-Phos (0.39 g, 0.62 mmol) were added and the mixture was stirred in a sealed tube at 100 °C for 4 h. The mixture was diluted with water and then filtered through Celite and washed with EtOAc. The filtrate was washed with water, brine and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 15% EtOAc in petroleum ether) to give the title compound (0.28 g). LCMS (Method 1): 1.50 min, 379.2 [M+H] + .

[0251] Intermediate 83: 8-Bromo-7-methyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrochloride [ka] To a stirred solution of intermediate 82 (0.28 g, 0.74 mmol) in EtOAc (3 mL) at 0° C., 4M HCl in 1,4-dioxane (3 mL) was added and stirred at 80° C. for 6 h. The mixture was concentrated under reduced pressure, the crude product was triturated with diethyl ether, and the solid was filtered to give the title compound (0.15 g). LCMS (Method 1): 0.98 min, 229.0 [M+H] + .

[0252] Intermediate 84: tert-Butyl (2-((3,5-dibromo-2-methylpyridin-4-yl)oxy)-3,3,3-trifluoropropyl)(2,4-dimethoxybenzyl)carbamate [ka] To a suspension of intermediate 74 (4.5 g, 11.9 mmol), Cs2CO3 (11.6 g, 35.7 mmol) in DMF (45 mL) at 0 °C, 3,5-dibromo-4-chloro-2-methylpyridine (3.37 g, 11.9 mmol, CAS 1188024-01-2) was added and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 30% EtOAc in petroleum ether) to give the title compound (5.1 g). LCMS (Method 1): 2.71 min, 629.2 [M+H] + .

[0253] Intermediate 85: 2-((3,5-dibromo-2-methylpyridin-4-yl)oxy)-N-(2,4-dimethoxybenzyl)-3,3,3-trifluoropropan-1-amine hydrochloride [ka] To a stirred solution of intermediate 84 (3.5 g, 5.57 mmol) in EtOAc (25 mL) at 0° C., 4M HCl-1,4-dioxane solution (50 mL) was added and stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give the title compound (2.7 g). LCMS (Method 1): 2.24 min, 529.2 [M+H] + .

[0254] Intermediate 86: 8-Bromo-4-(2,4-dimethoxybenzyl)-7-methyl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 85 (2.7 g, 4.78 mmol) in toluene (27 mL), sodium t-butoxide (1.37 g, 14.3 mmol) was added and the mixture was degassed with nitrogen for 5 min. Pd2(dba)3 (0.44 g, 0.48 mmol) and BINAP (0.59 g, 0.95 mmol) were added and the mixture was stirred in a sealed tube at 110 °C for 5 h. The mixture was diluted with water and then with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound (0.60 g). LCMS (Method 16): 3.35 min, 448.7 [M+H] + .

[0255] Intermediate 87: 8-Bromo-7-methyl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrochloride [ka] To a stirred solution of intermediate 86 (0.60 g, 1.34 mmol) in EtOAc (3 mL) at 0° C. was added 4M HCl-1,4-dioxane solution (6 mL), which was then stirred at 80° C. for 2 h. The mixture was concentrated under reduced pressure, and the solid residue was then triturated with diethyl ether and filtered to give the title compound (0.42 g). LCMS (Method 1): 1.26 min, 297.2 [M+H] + .

[0256] Intermediate 88: 8-Bromo-2-ethyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka] To a solution of 3-amino-5-bromopyridin-4-ol (3.42 g, 17.6 mmol, CAS 13073-25-1) in MeCN (35 mL) at 0° C., potassium carbonate (7.28 g, 52.7 mmol) was added and the mixture was stirred at room temperature for 30 min. 2-Bromo-butanoyl bromide (2.55 mL, 21.1 mmol) was added dropwise at 0° C., then the mixture was stirred at room temperature for 30 min and then heated at 80° C. for 16 h. The mixture was concentrated under reduced pressure, then the crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 0-100% EtOAc in petroleum ether) to give the title compound (1.32 g). 1 H NMR (400MHz; DMSO-d6) δ: 11.06 (brs, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 4.87 (dd, 1H), 1.88-1.78 (m, 2H), 1.00 (t, 3H).

[0257] Intermediate 89: 8-Bromo-2-ethyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 88 (1.31 g, 4.38 mmol) in THF (13 mL) cooled to 0° C., borane-THF solution (1 M, 21.9 mL, 21.9 mmol) was added, and the mixture was then stirred at room temperature for 2 h. The mixture was quenched by the addition of MeOH at 0° C. and heated at 60° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was partitioned with water and EtOAc, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 0-100% EtOAc in petroleum ether) to give the title compound (0.50 g). LCMS (Method 1): 1.12 min, 243.1 [M+H] + .

[0258] Intermediate 90: Methyl 2-((3-bromo-5-nitropyridin-4-yl)oxy)-3-methylbutanoate [ka] To a stirred solution of methyl 2-hydroxy-3-methylbutanoate (1.31 g, 12.6 mmol, CAS 17417-00-4) and 3-bromo-4-chloro-5-nitropyridine (2.0 g, 8.42 mmol, CAS 31872-63-6) in DMF (25 mL) was added Cs2CO3 (11.0 g, 33.7 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (40 g silica gel, eluted with 2-5% ethyl acetate in petroleum ether) to give the title compound (1.8 g). LCMS (Method 17): 3.13 min, 333.1 [M+H] + .

[0259] Intermediate 91: 8-Bromo-2-isopropyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka] To a solution of intermediate 90 (1.75 g, 5.25 mmol) in acetic acid (17.5 mL) was added iron powder (1.5 g, 26.7 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was carefully basified with aqueous sodium bicarbonate and then extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.0 g). LCMS (Method 1): 1.54 min, 271.1 [M+H] + .

[0260] Intermediate 92: 8-Bromo-2-isopropyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 91 (1.0 g, 2.58 mmol) in THF (10 mL) cooled to 0° C., borane-THF solution (1 M, 5 mL, 5.0 mmol) was added, and the mixture was then stirred at room temperature for 2 h. The mixture was quenched by the addition of MeOH (5 mL) at 0° C. and heated at 60° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was partitioned with water and EtOAc, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 2-5% MeOH in DCM) to give the title compound (0.65 g). LCMS (Method 1): 1.25 min, 257.1 [M+H] + .

[0261] Intermediate 93: Ethyl 2-((3-bromo-5-nitropyridin-4-yl)oxy)-2-cyclopropylacetate [ka] To a stirred solution of ethyl 2-cyclopropyl-2-hydroxyacetate (1.56 g, 7.58 mmol, CAS 1185387-66-9) and 3-bromo-4-chloro-5-nitropyridine (1.5 g, 6.32 mmol, CAS 31872-63-6) in DMF (20 mL) was added Cs2CO3 (1.03 g, 3.16 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (40 g silica gel, eluted with 15% EtOAc in isohexane) to give the title compound (0.4 g). LCMS (Method 1): 1.92 min, 345.2 [M+H] + .

[0262] Intermediate 94: 8-Bromo-2-cyclopropyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka] To a solution of intermediate 93 (0.4 g, 0.75 mmol) in acetic acid (4 mL) was added iron powder (0.21 g, 3.77 mmol). The mixture was stirred at 80° C. for 3 h. The mixture was concentrated under reduced pressure, dissolved in EtOAc and carefully basified with aqueous sodium bicarbonate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.2 g). LCMS (Method 1): 1.38 min, 269.1 [M+H] + .

[0263] Intermediate 95: 8-Bromo-2-cyclopropyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a solution of intermediate 94 (0.2 g, 0.56 mmol) in THF (3 mL) cooled to 0° C., borane-THF solution (1 M, 0.56 mL, 0.56 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched by the addition of MeOH at 0° C. and then heated at 60° C. for 16 h. The mixture was concentrated under reduced pressure. The crude was purified by automated flash chromatography (10 Biotage Snap neutral alumina, eluted with 50% EtOAc in isohexane) to give the title compound (60 mg). LCMS (Method 1): 1.19 min, 255.1 [M+H] + .

[0264] Intermediate 96: 8-Bromo-7-methyl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a stirred solution of intermediate 86 (0.49 g, 1.03 mmol) in EtOAc (3 mL) at 0° C., 4M HCl-1,4-dioxane solution (5 mL) was added, which was stirred at 60° C. for 3 h. The mixture was concentrated under reduced pressure, and then the residue was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 0-70% ethyl acetate in petroleum ether) to give the title compound (0.21 g). LCMS (Method 1): 1.22 min, 299.1 [M+H]+ .

[0265] Intermediate 97: 7-Methyl-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-8-carbonitrile [ka] To a solution of intermediate 96 (0.17 g, 0.44 mmol) in 1,4-dioxane (0.5 mL) was added zinc(II) cyanide (0.10 g, 0.88 mmol), and the mixture was then purged with nitrogen gas for 10 min. Cs2CO3 (0.43 g, 1.32 mmol) and Pd(dppf)Cl2 (32 mg, 0.04 mmol) were added, and the mixture was stirred in a sealed tube at 130 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 0-40% ethyl acetate in petroleum ether) to give the title compound (0.12 g). LCMS (Method 1): 1.36 min, 244.1 [M+H] + .

[0266] Intermediate 98: 4-(2,4-dimethoxybenzyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-8-carbonitrile [ka] A mixture of intermediate 77 (0.50 g, 0.84 mmol), sodium carbonate (89 mg, 0.84 mmol) and potassium hexacyanoferrate(II) (71 mg, 0.17 mmol) in DMF (5 mL) was degassed with argon for 15 min. To this was added palladium acetate (19 mg, 0.08 mmol) and the mixture was stirred in a sealed tube at 125 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 0-100% ethyl acetate in petroleum ether) to give the title compound (0.17 g). LCMS (Method 1): 1.98 min, 380.2 [M+H] + .

[0267] Intermediate 99: 2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine-8-carbonitrile [ka] To a stirred solution of intermediate 98 (0.21 g, 0.53 mmol) in EtOAc (1 mL) at 0° C. was added 4M HCl-1,4-dioxane solution (2 mL), which was stirred at 60° C. for 3 h. The mixture was concentrated under reduced pressure, and then the residue was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 30-40% ethyl acetate in petroleum ether) to give the title compound (0.21 g). LCMS (Method 1): 1.35 min, 230.1 [M+H] + .

[0268] Intermediate 100: 4-(2,4-dimethoxybenzyl)-8-methoxy-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] A solution of intermediate 77 (1.40 g, 2.20 mmol) in toluene (15 mL) was degassed with argon for 10 min. tBuBrettPhos Pd G3 (0.02 g, 0.02 mmol) was added, sodium methoxide (30% in MeOH, 0.47 g, 8.79 mmol) was added and the mixture was stirred at 80 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 0-30% ethyl acetate in petroleum ether) to give the title compound (0.38 g). LCMS (Method 1): 1.50 min, 385.3 [M+H] + .

[0269] Intermediate 101: 8-Methoxy-2-(trifluoromethyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine [ka] To a stirred solution of intermediate 100 (0.35 g, 0.88 mmol) in EtOAc (1.8 mL) at 0° C. was added 4M HCl-1,4-dioxane solution (0.88 mL), which was then stirred at 60° C. for 3 h. The mixture was concentrated under reduced pressure, and then the residue was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 0-35% ethyl acetate in petroleum ether) to give the title compound (0.20 g). LCMS (Method 1): 0.99 min, 235.1 [M+H] + .

[0270] Intermediate 102: Ethyl 3-(3-bromo-5-nitropyridin-4-yl)-2-cyanopropanoate [ka] At 0° C., to a solution of ethyl 2-cyanoacetate (3.1 mL, 29.1 mmol, CAS 105-56-6) in THF (50 mL) was added LDA (2M in THF, 19.4 mL, 38.8 mmol) and the mixture was stirred for 30 min. At 0° C., 3-bromo-4-(bromomethyl)-5-nitropyridine (7.0 g, 19.4 mmol, CAS 1807024-35-6) in THF (20 mL) was added and the mixture was then stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, eluted with 0-10% ethyl acetate in petroleum ether) to give the title compound (4.8 g). LCMS (method 1): 1.81 min, 330.2[M+H] + .

[0271] Intermediate 103: 5-Bromo-2-oxo-1,2,3,4-tetrahydro-1,7-naphthyridine-3-carbonitrile [ka] To a solution of intermediate 102 (1.8 g, 4.28 mmol) in ethanol (30 mL) and water (12 mL) was added iron powder (1.21 g, 21.7 mmol) and ammonium chloride (1.16 g, 21.7 mmol) and the mixture was stirred at 80° C. for 6 h. The mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure, dissolved in EtOAc, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.1 g). LCMS (Method 1): 1.25 min, 254.1 [M+H] + .

[0272] Intermediate 104: 5-Bromo-1,2,3,4-tetrahydro-1,7-naphthyridine-3-carbonitrile [ka] To a solution of intermediate 103 (1.6 g, 2.22 mmol) in THF (10 mL) cooled to 0° C., borane-dimethylsulfide complex (2M in THF, 2.78 mL, 5.56 mmol) was added, and the mixture was then stirred at room temperature for 2 h. The mixture was quenched by the addition of MeOH at 0° C. and heated at 60° C. for 16 h. The mixture was concentrated under reduced pressure, then dissolved in DCM, washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by preparative HPLC (X-Select C18, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN 30-38% for 7 min, 100% for 0.5 min, and hold for 3.5 min) to give the title compound (1.2 g). LCMS (Method 1): 0.95 min, 240.0 [M+H] + .

[0273] Intermediate 105: 5-Bromo-N-cyclopropyl-3-(difluoromethyl)-N-methylpicolinamide [ka] To a solution of 5-bromo-3-(difluoromethyl)pyridine-2-carboxylic acid (0.50 g, 1.98 mmol, CAS 1404337-62-7) in THF (5 mL) cooled to 0 °C, DIPEA (1.72 mL, 9.92 mmol) was added, and after 5 min, T3P (1.79 mL, 5.95 mmol) and N-methylcyclopropylamine (0.21 g, 2.98 mmol, CAS 5163-20-2) were added and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (silica gel, 0-100% EtOAC in hexanes) to give the title compound (0.35 g). LCMS (Method 4): 1.80 min, 305.3 [M+H] + .

[0274] Intermediate 106: N-cyclopropyl-3-(difluoromethyl)-5-((diphenylmethylene)amino)-N-methylpicolinamide [ka] To a solution of intermediate 105 (0.50 g, 1.49 mmol) in toluene (10 mL) was added Cs2CO3 (1.46 g, 4.47 mmol) and the mixture was degassed with argon for 20 min. Pd2(dba)3 (0.14 g, 0.15 mmol) and X-Phos (0.14 g, 0.30 mmol) were added and the mixture was stirred at 110 °C for 16 h. The mixture was diluted with water, diluted with water and extracted with EtOAc. The organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 0-100% ethyl acetate in petroleum ether) to give the title compound (0.50 g). LCMS (Method 4): 2.22 min, 406.4 [M+H] + .

[0275] Intermediate 107: 5-Amino-N-cyclopropyl-3-(difluoromethyl)-N-methylpicolinamide [ka] To a solution of intermediate 106 (0.70 g, 1.57 mmol) in DCM (10 mL) at 0° C., TFA (0.36 mL, 4.71 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with DCM. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 0-100% ethyl acetate in petroleum ether) to give the title compound (0.20 g). LCMS (Method 19): 2.34 min, 242.0 [M+H] + .

[0276] Synthesis of Example Compounds Example 1: 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of 5-bromo-1,2,3,4-tetrahydroquinoline (0.25 g, 1.17 mmol, CAS 114744-50-2) in DCM (10 mL) at 0° C., 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.25 g, 1.28 mmol, CAS 1832583-43-3) and triphosgene (0.24 g, 0.82 mmol) were added and stirred at 0° C. for 15 min. Triethylamine (0.33 mL, 2.35 mmol) was added dropwise and the mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Sunfire C18, 19×150 mm×5 μm, flow rate: 20 mL / min, 0.1% TFA in water with MeCN 10-60% for 9 min, hold at 60% for 5 min, then 100% for 0.01 min and hold for 1.9 min) to give the title compound (39 mg). 1H NMR(400MHz;DMSO-d6)δ:9.69(brs, 1H), 8.61(d, 1H), 8.36(d, 1H), 8.15(s, 2H), 7.4 4(dd, 1H), 7.38(dd, 1H), 7.13(t, 1H), 3.76(dd, 2H), 2.78(t, 2H), 1.94-2.00(m, 2H). LCMS (Method 5): 2.22 min, 431.1[MH] - .

[0277] Example 2: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-bromo-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of 5-bromo-1,2,3,4-tetrahydroquinoline (0.25 g, 1.17 mmol, CAS 114744-50-2) in DCM (10 mL) at 0° C., 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.30 g, 1.29 mmol, CAS 1832582-59-8) and triphosgene (0.24 g, 0.82 mmol) were added and stirred at 0° C. for 15 min. Triethylamine (0.33 mL, 2.35 mmol) was added dropwise and the mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X SELECT C18, 19 x 250 mm x 5 μm, flow rate: 18 mL / min, 0.1% TFA in water and MeCN 30-80% for 9 min, hold at 80% for 1 min, then 100% for 0.1 min and hold for 2.9 min) to give the title compound (57 mg). 1 H NMR(400MHz;DMSO-d6)δ:9.82(brs, 1H), 8.92(d, 1H), 8.60(d, 1H), 8.16(s, 2H), 7.4 7(dd, 1H), 7.40(dd, 1H), 7.13(t, 1H), 3.77(dd, 2H), 2.79(t, 2H), 1.95-2.01(m, 2H). LCMS (Method 5): 2.29 min, 465.1[MH] - .

[0278] Example 3: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methoxy-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.18 g, 0.92 mmol, CAS 1832583-43-3) in DCM (2 mL) at 0° C., triethylamine (0.25 mL, 1.84 mmol) and triphosgene (0.19 g, 0.64 mmol) were added and stirred at 0° C. for 30 min. 5-Methoxy-1,2,3,4-tetrahydroquinoline (0.25 g, 1.17 mmol, CAS 30389-37-8) was added and the mixture was then stirred at room temperature for 16 h. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X TERRA C18, 19×250 mm×10 μm, flow rate: 18 mL / min, 0.1% aqueous TFA with MeCN 20-70% for 9 min, hold at 70% for 5 min, then 100% for 0.1 min and hold for 1.9 min) to give the title compound (26 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.60 (brs, 1H), 8.62 (d, 1H), 8.36 (d, 1H), 8.14 (s, 2H), 7.15 (t, 1) H), 7.02(d, 1H), 6.74(d, 1H), 3.81(s, 3H), 3.72(dd, 2H), 2.66(t, 2H), 1.88-1.95(m, 2H). LCMS (Method 6): 3.45 min, 385.3[M+H] + .

[0279] Example 4: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.25 g, 1.16 mmol, CAS 625394-65-2) in DCM (2 mL) at 0° C., triphosgene (0.34 g, 1.16 mmol) and triethylamine (0.32 mL, 2.32 mmol) were added and stirred at 0° C. for 15 min. Then, 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.26 g, 1.16 mmol, CAS 1832582-59-8) was added and the mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X TERRA C18, 19×250 mm×10 μm, flow rate: 20 mL / min, 0.1% TFA in water with MeCN 20-70% for 9 min, hold at 70% for 5 min, then 100% for 0.1 min and hold for 2.9 min) to give the title compound (40 mg). 1 H NMR (400MHz; DMSO-d6) δ: 10.01 (brs, 1H), 8.94 (d, 1H), 8.61 (d, 1H), 8.17 (s, 2H), 7.61 (dd, 1H), 7.34 (dd, 1H), 6.85 (t, 1H), 4.43 (t, 2H), 3.95 (t, 2H). LCMS (method 1): 2.01 min, 467.2[MH] - .

[0280] Example 5: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of 8-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.20 g, 0.87 mmol, CAS 1267095-78-2) in THF (5 mL) at 0° C., 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.20 g, 0.87 mmol, CAS 1832582-59-8) and triphosgene (0.13 g, 0.44 mmol) were added and stirred at 0° C. for 15 min. Then, triethylamine (0.25 mL, 1.75 mmol) was added dropwise and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN 25-50% for 7 min, hold at 50% for 6.1 min, then 100% for 0.1 min and hold for 3.8 min) to give the title compound (37 mg). 1 H NMR (400MHz; DMSO-d6)δ:10.02(s, 1H), 8.94(d, 1H), 8.60(d, 1H), 8.17(s, 2H), 7.60(dd, 1H) ), 7.34(dd, 1H), 6.85(t, 1H), 4.48-4.52(m, 1H), 4.18(dd, 1H), 3.45(dd, 1H), 1.38(d, 3H). LCMS (Method 7): 2.47 min, 483.1[M+H] + .

[0281] Example 6: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2-cyano-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 1 (0.30 g, 1.25 mmol) in DCM (2 mL) at 0° C., 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.29 g, 1.25 mmol, CAS 1832582-59-8) and triphosgene (0.19 g, 0.63 mmol) were added and stirred at 0° C. for 15 min. Then, triethylamine (0.35 g, 3.50 mmol) was added dropwise and the mixture was stirred at room temperature for 4 h. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 20 mL / min, 10 mM NH4HCO3 in water and MeCN 30-50% for 4 min, hold at 50% for 16 min, then 100% for 0.1 min and hold for 2.9 min) to give the title compound (50 mg). 1 H NMR(400MHz;DMSO-d6)δ:10.29(s, 1H), 8.95(brs, 1H), 8.60(d, 1H), 8.17(s, 2H), 7 .63(brd, 1H), 7.45(dd, 1H), 7.01(t, 1H), 5.94(t, 1H), 4.66(dd, 1H), 3.93(dd, 1H). LCMS (method 1): 1.94 min, 492.1 [MH] - .

[0282] Example 7: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyano-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.20 g, 1.02 mmol, CAS 1832583-43-3) in DCM (2 mL) at 0° C., triethylamine (0.28 mL, 2.04 mmol) and triphosgene (0.37 g, 1.02 mmol) were added and stirred at 0° C. for 30 min. 1,2,3,4-tetrahydroquinoline-5-carbonitrile (0.17 g, 1.02 mmol, CAS 939758-72-2) was added and the mixture was then stirred at room temperature for 16 h. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X TERRA C18, 19×250 mm×10 μm, flow rate: 20 mL / min, 0.1% TFA in water with MeCN 20-70% for 9 min, hold at 70% for 5 min, then 100% for 0.1 min and hold for 1.9 min) to give the title compound (39 mg). 1 H NMR(400MHz;DMSO-d6)δ:9.76(s, 1H), 8.64(d, 1H), 8.37(d, 1H), 8.15(s, 2H), 7.81 (dd, 1H), 7.55(dd, 1H), 7.35(t, 1H), 3.81(t, 2H), 2.95(t, 2H), 1.98-2.06(m, 2H). LCMS (method 1): 1.75 min, 378.3 [MH] - .

[0283] Example 8: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of intermediate 3 (0.10 g, 0.47 mmol) in DCM (10 mL) at 0° C., 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.11 g, 0.47 mmol, CAS 1832582-59-8), triphosgene (75 mg, 0.23 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge Phenyl, 19 x 250 mm x 5 μm, flow rate: 18 mL / min, 0.1% TFA in water with MeCN 10-40% for 7 min, hold at 40% for 4.5 min, then 100% for 0.1 min and hold for 2.4 min) to give the title compound (22 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.76 (brs, 1H), 8.99 (d, 1H), 8.66-8.69 (m, 3H), 8.17 (s, 2H), 7.96 (d, 1H), 7.63(dd, 1H), 7.57(d, 1H), 7.33(t, 1H), 7.09(d, 1H), 3.79(t, 2H), 2.62(t, 2H), 1.87-1.91(m, 2H). LCMS (Method 8): 2.23 min, 466.4 [M+H] + .

[0284] Example 9: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(oxazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of intermediate 5 (0.13 g, 0.65 mmol) in DCM (5 mL) at 0° C., 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.15 g, 0.65 mmol, CAS 1832582-59-8) and triphosgene (135 mg, 0.45 mmol) were added and the mixture was stirred at 0° C. for 15 min. Triethylamine (0.27 mL, 1.95 mmol) was added dropwise, after which the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-SELECT C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 35% to 65% for 4 min, hold at 65% for 12 min, then 100% for 1 min and hold for 5 min) to give the title compound (46 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.76 (brs, 1H), 8.93 (d, 1H), 8.62 (d, 1H), 8.27 (d, 1H), 8.16 (s, 2H), 7. 68(dd, 1H), 7.61(d, 1H), 7.44(d, 1H), 7.35(t, 1H), 3.80(t, 2H), 3.32(t, 2H), 1.94-1.99(m, 2H). LCMS (method 1): 2.63 min, 454.0 [MH] - .

[0285] Example 10: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(thiazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of intermediate 7 (0.15 g, 0.69 mmol) in DCM (5 mL) at 0° C., 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.15 g, 0.65 mmol, CAS 1832582-59-8) and triphosgene (0.14 g, 0.48 mmol) were added and the mixture was stirred at 0° C. for 15 min. Triethylamine (0.29 mL, 2.08 mmol) was added dropwise, after which the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-SELECT C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 30% to 55 in 4 min, hold at 55% for 8.52 min then 100% for 0.1 min, and hold for 3.4 min) to give the title compound (45 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.77 (brs, 1H), 8.95 (d, 1H), 8.63 (d, 1H), 8.16 (s, 2H), 8.01 (d, 1H), 7.8 9(d, 1H), 7.59(dd, 1H), 7.44(dd, 1H), 7.33(t, 1H), 3.79(t, 2H), 3.03(t, 2H), 1.89-1.96(m, 2H). LCMS (Method 8): 2.38 min, 472.3[M+H] + .

[0286] Example 11: cis-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-bromo-3,4-dimethyl-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of intermediate 10 (0.27 g, 1.10 mmol) in DCM (10 mL) at 0° C., 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.25 g, 1.10 mmol, CAS 1832582-59-8) and triphosgene (0.24 g, 0.82 mmol) were added and the mixture was stirred at 0° C. for 15 min. Triethylamine (0.22 mL, 1.65 mmol) was added dropwise and the mixture was then stirred at room temperature for 2 h. The mixture was diluted with DCM and then washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 40% to 70 for 5 min, hold at 70% for 8 min, then 100% for 0.1 min and hold for 2.9 min) to give the title compound (60 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.67 (brs, 1H), 8.99 (d, 1H), 8.63 (d, 1H), 8.16 (s, 2H), 7.55 (d, 1H), 7.34 (dd, 1H) , 7.12(t, 1H), 3.90(dd, 1H), 3.37(d, 1H), 3.10-3.18(m, 1H), 2.01-2.12(m, 1H), 1.12(d, 3H), 0.96(d, 3H). LCMS (method 1): 2.36 min, 493.2[MH] - .

[0287] Example 12: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-phenyl-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of the compound of Example 2 (0.27 g, 1.10 mmol) in 1,4-dioxane:water (4:1 10 mL) was added Cs2CO3 (0.39 g, 1.2 mmol) and phenylboronic acid (70 mg, 0.64 mmol, CAS 98-80-6) and the mixture was degassed with nitrogen for 10 min. PdCl2(PPh3)2 (21 mg, 0.03 mmol) and X-Phos (17 mg, 0.03 mmol) were added and the mixture was degassed with nitrogen for 10 min. The mixture was stirred at 90 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-SELECT C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 40% to 60 for 4 min, hold at 60% for 16.5 min, then 100% for 0.1 min and hold for 3.4 min) to give the title compound (21 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.71 (brs, 1H), 8.98 (d, 1H), 8.65 (d, 1H), 8.16 (s, 2H), 7.48 (t, 3H), 7. 41(d, 1H), 7.37(d, 2H), 7.27(t, 1H), 7.04(dd, 1H), 3.76(t, 2H), 2.61(t, 2H), 1.83-1.90(m, 2H). LCMS (method 1): 2.29 min, 463.3 [MH] - .

[0288] Example 13: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide [ka] To a stirring solution of 5-chloro-6-(2H-1,2,3-triazol-2-yl)nicotinic acid (0.25 g, 1.03 mmol, CAS 2244109-97-3) in toluene (10 mL) was added triethylamine (0.28 mL, 2.04 mmol) and DPPA (0.3 mL, 1.24 mmol) and the mixture was stirred at 100 °C for 30 min. 8-Bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.20 g, 0.83 mmol, CAS 853683-76-8) was added and the mixture was then stirred at 100 °C for 16 h. The mixture was diluted with water, quenched with water, and then extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 x 250 mm x 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 10% to 67% in 1.14 min, then 75% in 8.44 min, then 100% in 1.5 min, then hold for 2 min) to give the title compound (45 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.95(s, 1H), 8.63(d, 1H), 8.36(d, 1H), 8.15(s, 2H), 7.52(dd, 1H), 7.35(dd, 1H), 6.85(t, 1H), 3.73(s, 2H), 1.36(s, 6H). LCMS (Method 9): 3.71 min, 463.5[M+H] + .

[0289] Example 14: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(1,3,4-thiadiazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of intermediate 13 (0.13 g, 0.58 mmol) in DCM (10 mL) at 0° C., DIPEA (0.22 g, 1.73 mmol) and 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.13 g, 0.58 mmol, CAS 1832582-59-8) were added and the mixture was stirred at 0° C. for 15 min. Phosgene (0.28 g, 0.57 mmol) was added at 0° C., after which the mixture was stirred at room temperature for 5 h. The mixture was quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-SELECT C18, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 45% to 85 in 9 min, then 90% in 5 min and 100% in 0.1 min and hold for 2.9 min) to give the title compound (16 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.81 (brs, 1H), 9.75 (s, 1H), 8.95 (d, 1H), 8.63 (d, 1H), 8.16 (s, 2) H), 7.67(dd, 1H), 7.43(dd, 1H), 7.36(t, 1H), 3.81(t, 2H), 2.94(t, 2H), 1.91-1.98(m, 2H). LCMS (Method 10): 2.12 min, 473.3[M+H] + .

[0290] Example 15: 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,3-dimethyl-3,4-dihydroquinoline-1(2H)-carboxamide [ka] To a stirred solution of intermediate 16 (0.30 g, 1.25 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.15 g, 0.75 mmol, CAS 1832583-43-3) in DCM (10 mL) at 0° C., triethylamine (0.28 mL, 2.04 mmol) was added. Triphosgene (0.28 g, 0.94 mmol) was added and the mixture was then stirred at room temperature for 3 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19×150 mm×5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 40% to 75 in 4 min, hold at 75% for 6 min) to give the title compound (56 mg). 1 H NMR (400MHz; CDCl3) δ: 8.51 (d, 1H), 8.26 (d, 1H), 7.91 (s, 2H), 7.47 (dd, 1H), 7.30 (d, 2H), 7.17 (t, 1H), 3.62 (s, 2H), 2.66 (s, 2H), 1.09 (s, 6H). LCMS (Method 14): 2.24 min, 459.1 [MH] - .

[0291] Example 16: 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxamide [ka] To a solution of intermediate 17 (0.30 g, 1.32 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.18 g, 0.92 mmol, CAS 1832583-43-3) in DCM (10 mL) was added triethylamine (0.53 g, 5.28 mmol) at 0° C. Triphosgene (0.27 g, 0.92 mmol) was added and the mixture was then stirred at room temperature for 3 h. The mixture was diluted with DCM, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-22 mesh, eluted with 15-20% EtOAc in hexanes), followed by preparative HPLC (X-Bridge C18, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 25% to 55 in 4 min, hold at 55% for 6.8 min, then 100% in 4 min) to give the title compound (30 mg). 1 H NMR (400MHz; DMSO-d6)δ:9.78(s, 1H), 8.65(d, 1H), 8.39(d, 1H), 8.15(s, 2H), 7. 57(dd, 1H), 7.30(dd, 1H), 6.87(t, 1H), 3.84(dd, 2H), 3.20(dd, 2H), 2.87(s, 3H). LCMS (method 1): 1.97 min, 446.2 [MH] - .

[0292] Example 17: 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide [ka] To a stirring solution of 5-bromo-1,2,3,4-tetrahydro-1,7-naphthyridine (95 mg, 0.44 mmol, CAS 351457-97-1) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (51 mg, 0.26 mmol, CAS 1832583-43-3) in DCM (2 mL) was added triethylamine (0.18 mL, 1.32 mmol). Triphosgene (91 mg, 0.31 mmol) was added and the mixture was then stirred at room temperature for 16 h. The mixture was quenched with water and extracted with 10% MeOH in DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 x 250 mm x 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 20% to 60 for 7 min, hold at 60% for 4.8 min, hold at 100% for 0.2 min, and hold at 100% for 5 min) to give the title compound (9 mg). 1 H NMR (400MHz; CDCl3) δ: 8.59 (s, 1H), 8.54 (s, 1H), 8.47 (d, 1H), 8.31 (d, 1H), 7.92 (s, 2H), 7.15 (s, 1H), 3.89 (t, 2H), 2.90 (t, 2H), 2.06-2.13 (m, 2H). LCMS (method 1): 1.66 min, 434.2[M+H] + .

[0293] Example 18: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 20 (0.30 g, 1.18 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.16 g, 0.83 mmol, CAS 1832583-43-3) in DCM (7 mL) at 0° C. was added triethylamine (0.36 g, 3.54 mmol). Triphosgene (0.25 g, 0.83 mmol) was added and the mixture was then stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge Phenyl, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 35% to 50 for 4 min, hold at 50% for 10 min) to give the title compound (50 mg). 1 H NMR (400MHz; DMSO-d6) δ: 10.19 (s, 1H), 8.65 (d, 1H), 8.35 (d, 1H), 8.16 (s, 2H), 7.60(d, 1H), 7.46(dd, 1H), 7.01(t, 1H), 4.89(d, 1H), 3.60(d, 1H), 1.88(s, 3H). LCMS (Method 11): 2.38 min, 474.1[M+H] + .

[0294] Example 19: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 23 (1.50 g, 6.17 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (1.20 g, 6.17 mmol, CAS 1832583-43-3) in DCM (15 mL) at 0° C., triethylamine (3.44 mL, 24.7 mmol) was added and the mixture was then stirred at room temperature for 30 min. The mixture was cooled again to 0° C. and triphosgene (1.83 g, 6.17 mmol) was added dropwise as a solution in DCM (10 mL) and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Symmetry C18, 19×250 mm×5 μm, flow rate: 17 mL / min, water and MeCN, isocratic 50:50) to give the title compound (0.51 g). 1 H NMR (400MHz; DMSO-d6) δ: 10.08 (brs, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 8.37 (d, 1H), 8.35 (s, 1H), 8.15 (s, 2H), 3.82 (s, 2H), 1.39 (s, 6H). LCMS (method 4): 1.78 min, 464.4[M+H] + .

[0295] Example 20: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethynyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 28 (0.19 g, 0.67 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (92 mg, 0.47 mmol, CAS 1832583-43-3) in DCM (7 mL) at 0° C. was added triethylamine (0.28 mL, 2.01 mmol). Triphosgene (0.14 g, 0.47 mmol) was added and the mixture was then stirred at room temperature for 1 h. The mixture was diluted with DCM, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 30 × 150 mm × 5 μm, flow rate: 18 mL / min, 10 mM NH4HCO3 aqueous solution and MeCN, 30% to 50 for 6 min, hold at 50% for 5 min, hold at 100% for 0.1 min, hold at 100% for 5.9 min) to give the title compound (10 mg). 1 H NMR (400MHz; DMSO-d6) δ:9.97(brs, 1H), 8.65(s, 1H), 8.36(d, 1H), 8.15(s, 2H), 7.55( d, 1H), 7.38(d, 1H), 6.91(t, 1H), 5.47(s, 1H), 4.24(dd, 1H), 3.83(d, 1H), 3.76(d, 1H). LCMS (Method 12): 2.05 min, 459.3 [M+H] + .

[0296] Example 21: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of 8-bromo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (0.13 g, 0.58 mmol, CAS 1379320-13-4) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (79 mg, 0.40 mmol, CAS 1832583-43-3) in DCM (5 mL) at 0° C., triethylamine (0.24 g, 1.74 mmol) was added. Triphosgene (0.12 g, 0.40 mmol) was added and the mixture was then stirred at room temperature for 16 h. The mixture was quenched with water and extracted with 10% MeOH in DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 and MeCN, 20% to 60 for 7 min, hold at 60% for 4.8 min, hold at 100% for 0.2 min, hold at 100% for 5 min) to give the title compound (30 mg). 1 H NMR (400MHz; DMSO-d6) δ: 10.01 (brs, 1H), 8.84 (s, 1H), 8.50 (s, 1H), 8.39 (d, 1H), 8.27 (s, 1H), 8.13 (s, 2H), 4.48 (t, 2H), 4.03 (t, 2H). LCMS (Method 13): 1.94 min, 436.1[M+H] + .

[0297] Example 22: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyclopropyl-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide [ka] To a stirred solution of intermediate 30 (0.17 g, 0.97 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.19 g, 0.97 mmol, CAS 1832583-43-3) in DCM (10 mL) was added triethylamine (0.30 g, 2.92 mmol). Triphosgene (0.22 g, 0.73 mmol) was added and the mixture was then stirred at room temperature for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 10% to 70 in 14 min, hold at 100% for 0.1 min, hold at 100% for 1.9 min) to give the title compound (10 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.75 (brs, 1H), 8.62 (d, 1H), 8.51 (s, 1H), 8.38 (d, 1H), 8.14 (s, 2H), 7.94 (s, 1H) ), 3.80(t, 2H), 2.91(t, 2H), 1.97-2.01(m, 2H), 1.84-1.88(m, 1H), 0.94-0.98(m, 2H), 0.70-0.73(m, 2H). LCMS (method 1): 1.30 min, 396.2[M+H] + .

[0298] Example 23: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2,2-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.19 g, 0.82 mmol, CAS 1832582-59-8) and 8-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.25 g, 1.03 mmol, CAS 853683-76-8) in DCM (15 mL) at 0° C., triethylamine (0.43 mL, 3.09 mmol) and triphosgene (0.21 g, 0.72 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 x 250 mm x 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 10% to 67% in 1.14 min, 75% in 8.44 min, 100% in 1.5 min, and hold for 2 min) to give the title compound (50 mg). 1 H NMR (400MHz; DMSO-d6) δ: 10.08 (s, 1H), 8.94 (d, 1H), 8.59 (d, 1H), 8.16 (s, 2H), 7.55 (dd, 1H), 7.36 (dd, 1H), 6.86 (t, 1H), 3.75 (s, 2H), 1.36 (s, 6H). LCMS (method 1): 2.21 min, 495.2[MH] - .

[0299] Example 24: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyclopropyl-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 32 (0.10 g, 0.49 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (67 mg, 0.34 mmol, CAS 1832583-43-3) in DCM (5 mL) at 0° C. was added pyridine (0.12 mL, 1.47 mmol). Triphosgene (0.22 g, 0.73 mmol) was added as a solution in DCM (1 mL) and the reaction was stirred at 0° C. for 15 min and then at room temperature for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 17 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 30% to 50 in 8 min, hold at 98% for 0.1 min, hold at 98% for 1.9 min) to give the title compound (39 mg). 1 H NMR(400MHz;DMSO-d6)δ:10.03(brs, 1H), 8.60(brs, 1H), 8.48(brs, 1H), 8.37(d, 1H), 8.12(s, 2H) , 7.72(s, 1H), 3.79(s, 2H), 1.93-2.00(m, 1H), 1.35(s, 6H), 0.91-0.94(m, 2H), 0.74-0.77(m, 2H). LCMS (Method 14): 1.52 min, 426.5[M+H] + .

[0300] Example 25: (S)-1-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-6a,7,8,9-tetrahydropyrido[3,4-e]pyrrolo[1,2-a]pyrazine-5(6H)-carboxamide [ka] To a stirred solution of intermediate 35 (0.30 g, 1.18 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.18 g, 0.92 mmol, CAS 1832583-43-3) in DCM (5 mL) at 0° C. was added pyridine (0.29 mL, 3.54 mmol). Triphosgene (0.35 g, 1.18 mmol) was added as a solution in DCM (1 mL) and stirred at 0° C. for 15 min and then at room temperature for 3 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Select C18, 25 × 150 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 and MeCN, 25% to 45 in 6 min, hold at 45% for 8 min, hold at 98% for 0.1 min, hold at 98% for 1.9 min) to give the title compound (50 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.75 (brs, 1H), 8.58 (s, 1H), 8.35 (d, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.14 (s, 2H), 4.43 (d, 1H), 4.17-4.23(m, 1H), 3.40-3.54(m, 2H), 2.70(dd, 1H), 2.11-2.20(m, 1H), 1.83-1.90(m, 2H), 1.69-1.69(m, 1H). LCMS (Method 14): 1.41 min, 475.5[M+H] + .

[0301] Example 26: (R)-8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1,2-dimethyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide [ka] To a stirred solution of intermediate 38 (0.25 g, 1.03 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.14 g, 0.72 mmol, CAS 1832583-43-3) in DCM (5 mL) at 0° C., triethylamine (0.43 mL, 3.09 mmol) was added. Triphosgene (0.33 g, 1.13 mmol) was added as a solution in DCM (1 mL) and stirred at 0° C. for 15 min and then at room temperature for 3 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 x 250 mm x 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 and MeCN, 20% to 45 for 7 min, hold at 45% for 7.5 min, hold at 98% for 0.1 min, hold at 98% for 2.4 min) to give the title compound (28 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.82 (brs, 1H), 8.60 (d, 1H), 8.40 (s, 1H), 8.37 (d, 1H), 8. 22(s, 1H), 8.14(s, 2H), 3.94(q, 1H), 3.52-3.57(m, 2H), 3.14(s, 3H), 1.09(d, 3H). LCMS (Method 14): 1.62 min, 463.3[M+H] + .

[0302] Example 27: 8'-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-4,5-dihydro-2H-spiro[furan-3,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-carboxamide [ka] To a stirred solution of intermediate 40 (0.14 g, 0.52 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.18 g, 0.94 mmol, CAS 1832583-43-3) in DCM (5 mL) at 0° C., triethylamine (0.22 mL, 1.55 mmol) was added. Triphosgene (0.35 g, 1.18 mmol) was added as a solution in DCM (1 mL) and stirred at 0° C. for 15 min, then at room temperature for 3 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Select C18, 25 × 150 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 25% to 45 in 6 min, hold at 45% for 8 min, hold at 98% for 0.1 min, hold at 98% for 1.9 min) to give the title compound (24 mg). 1 H NMR(400MHz;DMSO-d6)δ:10.11(brs, 1H), 8.75(s, 1H), 8.58(s, 1H), 8.35-8 .39(m, 2H), 8.14(s, 2H), 3.90-4.12(m, 4H), 3.78(s, 2H), 2.02-2.17(m, 2H). LCMS (Method 14): 1.65 min, 492.1[M+H] + .

[0303] Example 28: 1-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3',4'-e]pyrazine-5-carboxamide [ka] To a stirred solution of intermediate 43 (50 mg, 0.19 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (29 mg, 0.15 mmol, CAS 1832583-43-3) in DCM (2 mL) at 0 °C, triethylamine (0.08 mL, 0.56 mmol) was added. Triphosgene (39 mg, 0.13 mmol) was added and the mixture was then stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge Phenyl, 19 × 250 mm × 5 μm, flow rate: 17 mL / min, 10 mM aq. NH4HCO3 with MeCN, 30% to 60 for 9 min, hold at 60% for 5 min, hold at 100% for 0.1 min, hold at 100% for 2.9 min). The racemate was purified by chiral preparative SFC (Chiralcel-OJ-H, 30×250 mm×5 μm, flow rate: 100 g / min, 60% CO2 with 40% MeOH:MeCN (1:1), back pressure 10 bar, temperature 30° C.)-peak 1 was isolated to give the title compound (10 mg). 1 H NMR (400MHz; DMSO-d6)δ:9.70(s, 1H), 8.63(s, 1H), 8.37(d, 1H), 8.30(s, 1H), 8.23(s, 1H), 8.14(s, 2H), 4.55( d, 1H), 4.31(dd, 1H), 3.40-3.49(m, 1H), 3.17-3.23(m, 1H), 2.93(t, 1H), 1.52-1.90(m, 5H), 1.20-1.35(m, 1H). LCMS (Method 14): 1.50 min, 489.1[M+H] + .

[0304] Example 29: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide [ka] To a stirred solution of intermediate 46 (150 mg, 0.66 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (103 mg, 0.53 mmol, CAS 1832583-43-3) in DCM (2 mL) at 0° C., triethylamine (0.28 mL, 1.98 mmol) was added and stirred for 5 min at 0° C. Triphosgene (137 mg, 0.46 mmol) was added and the mixture was then stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 x 250 mm x 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 and MeCN, 25% to 40 in 4 min, hold at 40% for 7.6 min, hold at 98% for 0.1 min, hold at 98% for 2.3 min) to give the title compound (45 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.79 (s, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 8.37 (d, 1H), 8.22 (s, 1H), 8.14 (s, 2H), 3.89 (t, 2H), 3.37 (t, 2H), 3.18 (s, 3H). LCMS (Method 14): 1.26 min, 449.1[M+H] + .

[0305] Example 30: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-methyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 49 (0.30 g, 1.31 mmol) in DCM (6 mL) at 0° C., triethylamine (0.54 mL, 3.93 mmol) and triphosgene (312 mg, 1.05 mmol) were added and stirred at 0° C. for 15 min. 5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.21 g, 1.05 mmol, CAS 1832583-43-3) was added and the mixture was then stirred at room temperature for 2 h. The mixture was diluted with DCM, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 60-65% EtOAc in petroleum ether) followed by preparative HPLC (X-Bridge C18, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM aq. NH4HCO3 with MeCN, 10% to 75 in 14 min, hold at 75% for 1 min) to give the title compound (31 mg). 1 H NMR(400MHz;DMSO-d6)δ:10.01(s, 1H), 8.72(s, 1H), 8.62(s, 1H), 8.38(d, 1H), 8.33(s, 1H), 8.15(s, 2H), 4.61(t, 1H), 4.25(d, 1H), 3.50(dd, 1H), 1.41(t, 3H). LCMS (Method 14): 1.61 min, 450.2[M+H] + .

[0306] Example 31: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1,2,2-trimethyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide [ka] To a stirred solution of intermediate 53 (0.23 g, 0.89 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.12 g, 0.61 mmol, CAS 1832583-43-3) in DCM (7 mL) at 0° C., triethylamine (0.50 mL, 3.59 mmol) was added and stirred for 15 min at 0° C. Triphosgene (0.26 g, 0.89 mmol) was added as a solution in DCM (1 mL) and the mixture was then stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Symmetry C18, 19 x 300 mm x 5 μm, flow rate: 18 mL / min, 10 mM NH4HCO3 aqueous solution and MeCN, 40% to 50 for 5 min, hold at 50% for 7.6 min, hold at 98% for 0.1 min, hold at 98% for 5.3 min) to give the title compound (24 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.92 (brs, 1H), 8.53 (brs, 1H), 8.44 (brs, 1H), 8.36 (d, 1H), 8.17 (s, 1H), 8.13 (s, 2H), 3.70 (s, 2H), 3.05 (s, 3H), 1.23 (s, 6H). LCMS (Method 14): 1.42 min, 477.1[M+H] + .

[0307] Example 32: 8-Chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 56 (0.25 g, 1.26 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.17 g, 0.88 mmol, CAS 1832583-43-3) in DCM (5 mL) at 0° C., triethylamine (0.70 mL, 5.03 mmol) was added and stirred for 15 min at 0° C. Triphosgene (0.37 g, 1.26 mmol) was added in DCM (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Select C18, 19 × 250 mm × 5 μm, flow rate: 16 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 20% to 55% for 7 min, hold at 55% for 5.5 min, hold at 98% for 0.1 min, hold at 98% for 5.4 min) to give the title compound (53 mg). 1 H NMR (400MHz; DMSO-d6) δ: 10.09 (brs, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 8.37 (d, 1H), 8.26 (s, 1H), 8.15 (s, 2H), 3.83 (s, 2H), 1.39 (s, 6H). LCMS (Method 14): 1.76 min, 418.1[MH] - .

[0308] Example 33: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide [ka] To a stirred solution of intermediate 59 (0.10 g, 0.33 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (66 mg, 0.37 mmol, CAS 1832583-43-3) in DCM (2 mL) at 0° C., triethylamine (0.18 mL, 1.34 mmol) was added and stirred for 15 min at 0° C. Triphosgene (50 mg, 0.16 mmol) was added as a solution in DCM (0.5 mL) and the mixture was then stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 150 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 and MeCN, 25% to 50 for 8 min, hold at 50% for 3 min, hold at 100% for 0.1 min, hold at 100% for 2.9 min) to give the title compound (38 mg). 1 H NMR (400MHz; DMSO-d6)δ:9.75(s, 1H), 8.63(d, 1H), 8.45(s, 1H), 8.37(d, 1H), 8.28(s, 1H), 8.15(s, 2) H), 4.15-4.24(m, 1H), 3.95(dd, 2H), 3.79(t, 2H), 3.37-3.40(m, 4H), 1.86-1.91(m, 2H), 1.67(d, 2H). LCMS (Method 14): 1.35 min, 519.4[M+H] + .

[0309] Example 34: (R)-8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethyl-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide [ka] To a stirred solution of intermediate 62 (0.10 g, 0.27 mmol) in DCM (1 mL) at 0° C., triethylamine (0.16 mL, 1.17 mmol) was added, triphosgene (60 mg, 0.20 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (60 mg, 0.31 mmol, CAS 1832583-43-3) were added and the mixture was stirred for 1 h at 0° C. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Select C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 and MeCN, 50% to 80 for 7 min, hold at 80% for 5 min, hold at 98% for 0.1 min, hold at 98% for 4.9 min) to give the title compound (100 mg). 1 H NMR (400 MHz; DMSO-d6) δ: 9.88 (s, 1H), 8.63 (d, 1H), 8.41 (s, 1H), 8.36 (d, 1H), 8.24 (s, 1H), 8.15 (s, 2H), 3.76 (dd, 1H), 3.70 (dd, 1H), 3.11 (s, 3H), 1.38-1.47 (m, 1H), 1.29-1.38 (m, 1H), 0.89 (t, 3H)-1H Unknown signal due to water. LCMS (Method 14): 1.47 min, 477.4 [M+H] + .

[0310] Example 35: (R)-8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-isopropyl-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide [ka] To a stirred solution of intermediate 65 (55 mg, 0.20 mmol) in DCM (1 mL) at 0° C., triethylamine (0.16 mL, 1.17 mmol) was added, followed by 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (28 mg, 0.20 mmol, CAS 1832583-43-3) and the mixture was stirred for 15 min at 0° C. Triphosgene (60 mg, 0.20 mmol) was added as a solution in DCM (0.5 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure, then DCM (1 mL) was added, triethylamine (0.16 mL, 1.17 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (28 mg, 0.20 mmol, CAS 1832583-43-3) were added, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Gemini NX C18, 21×250 mm×5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 30% to 70 for 7 min, hold at 70% for 5.5 min) to give the title compound (31 mg). 1 H NMR(400MHz;DMSO-d6)δ:10.00(brs, 1H), 8.60(brs, 1H), 8.44(brs, 1H), 8.35(d, 1H), 8.16(s, 1H), 8.11(s, 2H) ), 4.22(brs, 1H), 3.39-3.43(m, 1H), 3.06(s, 3H), 2.94(brs, 1H), 1.38-1.47(m, 1H), 0.97(d, 3H), 0.84(d, 3H). LCMS (Method 14): 1.59 min, 491.4 [M+H] + .

[0311] Example 36: 7-Amino-8-bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 69 (100 mg, 0.43 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (85 mg, 0.43 mmol, CAS 1832583-43-3) in DCM (2 mL) at 0° C., triethylamine (0.15 mL, 1.09 mmol) was added and the mixture was stirred for 5 min at 0° C. Triphosgene (60 mg, 0.20 mmol) was added as a solution in DCM (0.5 mL) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 15% to 40 in 11 min, hold at 98% for 0.1 min, hold at 98% for 2.9 min) to give the title compound (5 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.69 (brs, 1H), 8.60 (brs, 1H), 8.36 (d, 1H), 8.13 (s, 3H), 5.96 (s, 2H), 4.42 (t, 2H), 3.92 (t, 2H). LCMS (Method 14): 1.31 min, 451.3[M+H] + .

[0312] Example 37: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide [ka] To a stirred solution of intermediate 72 (20 mg, 0.07 mmol) in DCM (2 mL) at 0° C., triethylamine (0.03 mL, 0.21 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (11 mg, 0.06 mmol, CAS 1832583-43-3) were added and the mixture was stirred at 0° C. for 15 min. Triphosgene (20 mg, 0.07 mmol) was added as a solution in DCM (0.5 mL) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 and MeCN, 30% to 50 in 7 min, hold at 50% for 3.3 min, hold at 98% for 0.1 min, hold at 98% for 3.6 min) to give the title compound (8 mg). 1 H NMR (400MHz; DMSO-d6)δ:9.85(brs, 1H), 8.46(brs, 2H), 8.33(d, 1H), 8.16(br s, 1H), 8.11(s, 2H), 7.25(brs, 1H), 4.98(brs, 1H), 4.49(s, 1H), 3.10(d, 1H). LCMS (Method 15): 4.47 min, 503.2 [M+H] + .

[0313] Example 38: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 78 (0.10 g, 0.35 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (69 mg, 0.35 mmol, CAS 1832583-43-3) in DCM (2 mL) at 0° C., triethylamine (0.30 mL, 2.10 mmol) was added and the mixture was stirred for 5 min at 0° C. Triphosgene (0.10 g, 0.35 mmol) was added as a solution in DCM (0.5 mL) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Gemini-NX C18, 21 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 20% to 60 for 7 min, hold at 60% for 6.5 min, then 98% for 5.5 min, hold at 98% for 2.5 min) to give the title compound (41 mg). 1 H NMR(400MHz;DMSO-d6)δ:10.10(brs, 1H), 8.76(brs, 1H), 8.60(brs, 1H), 8.4 4(s, 1H), 8.36(d, 1H), 8.15(s, 2H), 5.57(brs, 1H), 4.31(d, 1H), 4.18(d, 1H). LCMS (Method 14): 1.85 min, 504.3[M+H] + .

[0314] Example 39: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; Example 40: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide The compound of Example 38 (35 mg) was purified by chiral preparative SFC (Chiralcel-OJ-H, 46 x 250 mm x 5 μm, flow rate: 100 g / min, 70% CO2 and 30% MeOH, back pressure 10 bar, temperature 30 °C): peak 1 was the compound of Example 39 (13 mg) and peak 2 was the compound of Example 40 (13 mg). Example 39: 1 H NMR (400MHz; DMSO-d6) δ: 10.13 (brs, 1H), 8.87 (brs, 1H), 8.48 (brs, 1H), 8.36 (d, 2H), 8.12 (s, 2H), 5.50 (brs, 1H), 4.49 (brs, 1H), 4.15 (dd, 1H). LCMS (Method 14): 1.85 min, 504.3[M+H] + . Example 40: 1 H NMR (400MHz; DMSO-d6) δ: 10.17 (brs, 1H), 8.93 (brs, 1H), 8.38 (d, 2H), 8.34 (brs, 1H), 8.11 (s, 2H), 5.46 (brs, 1H), 4.44 (brs, 1H), 4.13 (dd, 1H). LCMS (Method 14): 1.85 min, 504.4[M+H] + .

[0315] Example 41: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 83 (0.20 g, 0.75 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.13 g, 0.68 mmol, CAS 1832583-43-3) in DCM (5 mL) at 0° C., triethylamine (0.42 mL, 3.10 mmol) was added and the mixture was stirred for 5 min at 0° C. Triphosgene (0.22 g, 0.75 mmol) was added as a solution in DCM (1 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 30% to 50 for 7 min, hold at 50% for 5 min, 98% for 0.1 min, hold at 98% for 1.9 min) to give the title compound (52 mg). 1 H NMR (400MHz; DMSO-d6) δ: 9.92 (brs, 1H), 8.61 (s, 2H), 8.38 (d, 1H), 8.14 (s, 2H), 4.50 (t, 2H), 3.98 (t, 2H), 2.54 (s, 3H). LCMS (method 1): 1.36 min, 450.2[M+H] + .

[0316] Example 42: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 43: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 87 (0.42 g, 1.26 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.24 g, 1.26 mmol, CAS 1832583-43-3) in DCM (5 mL) at 0° C., triethylamine (0.53 mL, 3.78 mmol) was added and the mixture was stirred for 5 min at 0° C. Triphosgene (0.37 g, 1.26 mmol) was added as a solution in DCM (1 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19×250 mm×5 μm, flow rate: 17 mL / min, 10 mM NH4HCO3 in water with MeCN, 45% to 70 in 13 min, hold at 70% for 2 min, hold at 98% for 0.1 min, hold at 98% for 1.9 min) to give the racemate (94 mg). The racemate was purified by chiral preparative SFC (Chiralpak-AD-H, 30×250 mm×5 μm, flow rate: 100 g / min, 73% CO2 with 27% MeOH, back pressure 10 bar, temperature 30° C.): peak 1 was Example 42 (36 mg) and peak 2 was Example 43 (32 mg). Example 42: 1 H NMR (400MHz; DMSO-d6) δ: 10.02 (brs, 1H), 8.62 (brs, 2H), 8.36 (d, 1H), 8.15 (s, 2H), 5.56 (brs, 1H), 4.21 (dd, 2H), 2.58 (s, 3H). LCMS (Method 18): 1.66 min, 520.1[M+H] + . Example 43: 1 H NMR (400MHz; DMSO-d6) δ: 10.02 (brs, 1H), 8.66 (brs, 1H), 8.57 (brs, 1H), 8.37 (d, 1H), 8.14 (s, 2H), 5.54 (brs, 1H), 4.23 (dd, 2H), 2.57 (s, 3H). LCMS (Method 18): 1.66 min, 520.2 [M+H] + .

[0317] Example 44: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-methyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 45: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-methyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] The compound of Example 30 (25 mg) was purified by chiral preparative SFC (Chiralpak-AS-H, 30 x 250 mm x 5 μm, flow rate: 100 g / min, 60% CO2 and 40% MeOH, back pressure 10 bar, temperature 30 °C): peak 1 was Example 44 (12 mg) and peak 2 was Example 45 (12 mg). Example 44: 1 H NMR(400MHz;DMSO-d6)δ:10.01(brs, 1H), 8.71(brs, 1H), 8.62(brs, 1H), 8.37(d, 1H), 8.33(s, 1H), 8.15(brs, 2H), 4.62(t, 1H), 4.24(d, 1H) 3.50(dd, 1H), 1.40(d, 3H). LCMS (Method 14): 1.55 min, 452.1[M+H] + . Example 45: 1 H NMR(400MHz;DMSO-d6)δ:10.01(brs, 1H), 8.73(brs, 1H), 8.60(brs, 1H), 8.37(brd, 1H), 8.32(brs, 1H), 8.15(brs, 2H), 4.61(t, 1H), 4.24(d, 1H) 3.50(dd, 1H), 1.39(d, 3H). LCMS (Method 14): 1.55 min, 452.1[M+H] + .

[0318] Example 46: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 47: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 89 (0.27 g, 1.10 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.34 g, 1.65 mmol, CAS 1832583-43-3) in DCM (3 mL) was added 4-nitrophenyl chloroformate (0.33 g, 1.65 mmol) and stirred at room temperature for 15 min. The mixture was cooled to 0° C., then triethylamine (0.46 mL, 3.30 mmol) was added dropwise and the mixture was stirred at room temperature for 5 h. The mixture was diluted with water and extracted with EtOAc. The organics were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge Phenyl, 19×250 mm×5 μm, flow rate: 17 mL / min, 10 mM NH4HCO3 aqueous solution with MeCN, 30% to 60 for 10 min, 65% for 3.5 min, hold at 100% for 0.1 min, hold at 100% for 2.4 min) to give the racemate (310 mg). The racemate was purified by chiral preparative SFC (Chiralpak-AS-H, 30×250 mm×5 μm, flow rate: 100 g / min, 70% CO2 and 30% MeOH, back pressure 10 bar, temperature 30° C.): peak 1 was the compound of Example 46 (127 mg) and peak 2 was the compound of Example 47 (150 mg). Example 46: 1 H NMR(400MHz;DMSO-d6)δ:10.00(brs, 1H), 8.69(brs, 1H), 8.64(d, 1H), 8.37(d, 1H), 8.35(s, 1H), 8.16(s, 2H), 4.41-4.47(m, 1H), 4.18-4.24(m, 1H), 3.59(dd, 1H), 1.75-1.66(m, 2H), 1.05(t, 3H). LCMS (Method 14): 1.72 min, 466.2 [M+H] + . Example 47: 1H NMR (400MHz; DMSO-d6) δ: 10.00 (brs, 1H), 8.69 (brs, 1H), 8.63 (d, 1H), 8.37 (d, 1H), 8.35 (s, 1H), 8.16(s, 2H), 4.41-4.47(m, 1H), 4.18-4.24(m, 1H), 3.59(dd, 1H), 1.75-1.66(m, 2H), 1.05(t, 3H). LCMS (Method 14): 1.72 min, 466.2 [M+H] + .

[0319] Example 48: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-isopropyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 49: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-isopropyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 92 (0.30 g, 0.99 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.21 g, 0.99 mmol, CAS 1832583-43-3) in DCM (10 mL) at 0° C., triethylamine (0.55 mL, 3.97 mmol) was added and the mixture was stirred for 5 min at 0° C. Triphosgene (0.21 g, 0.69 mmol) was added as a solution in DCM (1 mL) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM NH4HCO3 in water with MeCN, 35% to 60 for 9 min, hold at 60% for 2 min, hold at 100% for 0.1 min, hold at 100% for 3.9 min) to give the racemate (120 mg). The racemate was purified by chiral preparative SFC (Chiralpak-AD-H, 30×250 mm×5 μm, flow rate: 100 g / min, 60% CO2 with 40% MeOH, back pressure 10 bar, temperature 30° C.): peak 1 was the compound of Example 48 (32 mg) and peak 2 was the compound of Example 49 (40 mg). Example 48: 1H NMR (400 MHz; DMSO-d6) δ: 9.98 (brs, 1H), 8.70 (brs, 1H), 8.62 (brs, 1H), 8.39 (d, 1H), 8.35 (s, 1H), 8.15 (s, 2H), 4.18-4.28 (m, 2H), 3.59 (dd, 1H), 1.90-1.98 (m, 1H), 1.08 (d, 3H), 1.02 (d, 3H). LCMS (Method 18): 1.65 min, 480.2 [M+H] + . Example 49: 1 H NMR (400 MHz; DMSO-d6) δ: 9.99 (brs, 1H), 8.70 (brs, 1H), 8.62 (brs, 1H), 8.39 (d, 1H), 8.34 (s, 1H), 8.15 (s, 2H), 4.18-4.28 (m, 2H), 3.59 (dd, 1H), 1.90-1.98 (m, 1H), 1.07 (d, 3H), 1.03 (d, 3H). LCMS (Method 18): 1.65 min, 480.2 [M+H] + .

[0320] Example 50: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyclopropyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 51: 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyclopropyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide

change

[0321] Example 52: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 53: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 97 (0.10 g, 0.37 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (0.12 g, 0.56 mmol, CAS 1832583-43-3) in DCM (1 mL) was added 4-nitrophenyl chloroformate (0.11 g, 0.56 mmol) and stirred at room temperature for 30 min. The mixture was cooled to 0° C., then triethylamine (0.15 mL, 1.11 mmol) was added dropwise and the mixture was stirred at room temperature for 5 h. The mixture was diluted with water and extracted with EtOAc. The organics were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge C18, 19×250 mm×5 μm, flow rate: 17 mL / min, 10 mM NH4HCO3 aqueous solution with MeCN, 40% to 45 for 8 min, hold at 45% for 3 min, hold at 98% for 0.1 min, hold at 98% for 1.9 min) to give the racemate (54 mg). The racemate was purified by chiral preparative SFC (Chiralcel-OJ-H, 30×250 mm×5 μm, flow rate: 100 g / min, 65% CO2 and 35% MeOH, back pressure 10 bar, temperature 30° C.): peak 1 was the compound of Example 52 (15 mg) and peak 2 was the compound of Example 53 (15 mg). Example 52: 1H NMR (400 MHz; DMSO-d6) δ: 10.09 (brs, 1H), 8.89 (brs, 1H), 8.63 (brs, 1H), 8.36 (d, 1H), 8.16 (s, 2H), 5.71-5.63 (m, 1H), 4.35-4.20 (m, 2H), 2.64 (s, 3H). LCMS (Method 14): 1.77 points, 465.2 [M+H] + . Example 53: 1 H NMR (400 MHz; DMSO-d6) δ: 10.10 (brs, 1H), 8.90 (brs, 1H), 8.62 (brs, 1H), 8.36 (d, 1H), 8.16 (s, 2H), 5.71-5.63 (m, 1H), 4.35-4.20 (m, 2H), 2.64 (s, 3H). LCMS (Method 14): 1.77 points, 465.2 [M+H] + .

[0322] Example 54: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyano-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 55: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyano-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide

change

[0323] Example 56: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methoxy-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 57: N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methoxy-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 101 (0.18 g, 0.46 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (96 mg, 0.46 mmol, CAS 1832583-43-3) in DCM (2 mL) was added 4-nitrophenyl chloroformate (93 mg, 0.46 mmol) and stirred at room temperature for 15 min. The mixture was cooled to 0° C., then triethylamine (0.19 mL, 1.38 mmol) was added dropwise and the mixture was stirred at room temperature for 5 h. The mixture was diluted with water and extracted with EtOAc. The organics were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Bridge Phenyl, 19×250 mm×5 μm, flow rate: 17 mL / min, 10 mM NH4HCO3 in water with MeCN, 20% to 50 for 9 min, hold at 50% for 4 min, hold at 100% for 0.1 min, hold at 100% for 2.9 min) to give the racemate (240 mg). The racemate was purified by chiral preparative SFC (Chiralpak-IC, 30×250 mm×5 μm, flow rate: 100 g / min, 60% CO2 with 40% MeOH, back pressure 10 bar, temperature 30° C.): peak 1 was the compound of Example 56 (46 mg) and peak 2 was the compound of Example 57 (53 mg). Example 56: 1 H NMR (400MHz; DMSO-d6) δ: 10.04 (brs, 1H), 8.65 (brd, 1H), 8.42 (brs, 1H), 8.36 (d, 1H), 8.16(s, 2H), 8.12(s, 1H), 5.49-5.42(m, 1H), 4.23-4.10(m, 2H), 3.93(s, 3H). LCMS (Method 14): 1.41 min, 456.2[M+H] + . Example 57: 1H NMR (400MHz; DMSO-d6) δ: 10.04 (brs, 1H), 8.65 (brd, 1H), 8.42 (brs, 1H), 8.36 (d, 1H), 8.16(s, 2H), 8.12(s, 1H), 5.49-5.42(m, 1H), 4.23-4.10(m, 2H), 3.93(s, 3H). LCMS (Method 14): 1.41 min, 456.2[M+H] + .

[0324] Example 58: 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-cyano-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide [ka] To a stirred solution of intermediate 104 (55 mg, 0.22 mmol) and 5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (44 mg, 0.22 mmol, CAS 1832583-43-3) in DCM (2.8 mL) at 0° C., triethylamine (0.09 mL, 0.64 mmol) was added and the mixture was stirred for 5 min at 0° C. Triphosgene (70 mg, 0.24 mmol) was added as a solution in DCM (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (X-Select C18, 19 × 250 mm × 5 μm, flow rate: 18 mL / min, 10 mM aqueous NH4HCO3 with MeCN, 30% to 45 in 8 min, hold at 45% for 2.2 min, 100% in 0.2 min) to give the title compound (13 mg). 1 H NMR(400MHz;DMSO-d6)δ:10.16(brs, 1H), 8.72(brs, 1H), 8.58(brs, 1H), 8.47(brs, 1H), 8.34( d, 1H), 8.15(s, 2H), 4.30(dd, 1H), 3.94(d, 1H), 3.72-3.66(m, 1H), 3.21(dd, 1H), 3.07(dd, 1H). LCMS (Method 14): 1.55 min, 461.1[M+H] + .

[0325] Example 59: 8-Cyano-7-methyl-2-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 97 (0.10 g, 0.36 mmol) and 2-(trifluoromethyl)pyridin-4-amine (70 mg, 0.43 mmol, CAS 147149-98-2) in DCM (2.8 mL) at 0 °C, triethylamine (0.24 mL, 1.73 mmol) was added and the mixture was stirred at 0 °C for 15 min. Triphosgene (137 mg, 0.43 mmol) was added as a solution in DCM (1 mL) and the mixture was stirred at room temperature for 5 h. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 0-30% ethyl acetate in hexanes) to give the racemic compound (78 mg). The racemate was separated by chiral preparative SFC (Lux cellulose, 30×250 mm×5 μm, flow rate: 100 g / min, 80% CO2 and 20% MeOH, back pressure 10 bar, temperature 30° C.): Peak 2 was the compound of Example 59 (29 mg). 1 H NMR (400MHz; DMSO-d6) δ: 10.14 (brs, 1H), 8.83 (s, 1H), 8.58 (d, 1H), 7.98 (d, 1H), 7.72 (d, 1H), 5.69-5.61 (m, 1H), 4.28-4.20 (m, 2H), 2.63 (s, 3H). LCMS (Method 14): 1.80 min, 432.3[M+H] + .

[0326] Example 60: N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 61: N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 97 (0.12 g, 0.38 mmol) and 5-chloro-6-(difluoromethoxy)pyridin-3-amine (92 mg, 0.45 mmol, CAS 1832583-48-8) in DCM (1.2 mL) at 0 °C, triethylamine (0.16 mL, 1.13 mmol) was added and the mixture was stirred at 0 °C for 5 min. Triphosgene (0.11 g, 0.38 mmol) was added as a solution in DCM (1 mL) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 0-100% ethyl acetate in petroleum ether) to give the racemic compound (45 mg). The racemate was purified by chiral preparative SFC (Lux Cellulose, 30×250 mm×5 μm, flow rate: 100 g / min, 75% CO2 and 25% MeOH, back pressure 10 bar, temperature 30° C.): peak 1 was the compound of Example 60 (11 mg) and peak 2 was the compound of Example 61 (11 mg). Example 60: 1 H NMR (400MHz; DMSO-d6) δ: 9.74 (brs, 1H), 8.85 (brs, 1H), 8.24 (brs, 1H), 8.19 (brd, 1H), 7.67 (t, 1H), 5.68-5.59 (m, 1H), 4.28-4.18 (m, 2H), 2.62 (s, 3H). LCMS (Method 14): 1.98 min, 464.2 [M+H] + . Example 61: 1 H NMR (400MHz; DMSO-d6) δ: 9.76 (brs, 1H), 8.86 (brs, 1H), 8.24 (brs, 1H), 8.19 (d, 1H), 7.67 (t, 1H), 5.68-5.58 (m, 1H), 4.29-4.18 (m, 2H), 2.62 (s, 3H). LCMS (Method 14): 1.98 min, 464.2 [M+H] + .

[0327] Example 62: 8-Cyano-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 63: 8-cyano-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 97 (0.11 g, 0.37 mmol) and 5-amino-2-(triazol-2-yl)pyridine-3-carbonitrile (0.10 g, 0.46 mmol, CAS 2097854-16-3) in DCM (1.7 mL) at 0 °C, triethylamine (0.19 mL, 1.37 mmol) was added and the mixture was stirred at 0 °C for 5 min. Triphosgene (0.11 g, 0.38 mmol) was added as DCM (1.7 mL) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with DCM. The combined organics were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 0-100% ethyl acetate in petroleum ether) to give the racemic compound (48 mg). The racemate was purified by chiral preparative SFC (Chiralpak IJ, 30×250 mm×5 μm, flow rate: 100 g / min, 60% CO2 and 40% MeOH, back pressure 10 bar, temperature 30° C.): peak 1 was the compound of Example 62 (12 mg) and peak 2 was the compound of Example 63 (15 mg). Example 62: 1 H NMR(400MHz;DMSO-d6)δ:10.19(brs, 1H), 8.95(brs, 1H), 8.82(brs, 1H), 8.57(d , 1H), 8.27(s, 2H), 5.63(brs, 1H), 4.35-4.30(m, 1H), 4.23(dd, 1H), 2.63(s, 3H). LCMS (Method 14): 1.63 min, 456.3 [M+H] + . Example 63: 1 H NMR (400MHz; DMSO-d6) δ: 10.16 (brs, 1H), 8.90-8.87 (m, 2H), 8.57 (d, 1H), 8.29 (s, 2H), 5.69-5.65 (m, 1H), 4.33-4.21 (m, 2H), 2.64 (s, 3H). LCMS (Method 14): 1.63 min, 456.3 [M+H] + .

[0328] Example 64: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 65: N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 97 (0.15 g, 0.57 mmol) and 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine (0.14 g, 0.63 mmol, CAS 1832582-59-8) in DCM (10 mL) at 0° C., triethylamine (0.24 mL, 1.72 mmol) was added and the mixture was stirred at 0° C. for 5 min. Triphosgene (0.17 g, 0.57 mmol) was added as a solution in DCM (3 mL) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with DCM. The combined organics were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 0-50% ethyl acetate in petroleum ether to give the racemate (90 mg). The racemate was purified by chiral preparative SFC (Chiralpak-IJ, 30 x 250 mm x 5 μm, flow rate: 100 g / min, 80% CO2 and 20% MeOH, back pressure 10 bar, temperature 30 °C): peak 1 was the compound of Example 64 (28 mg) and peak 2 was the compound of Example 65 (28 mg). Example 64: 1 H NMR (400MHz; DMSO-d6) δ: 10.23 (brs, 1H), 8.93 (brs, 2H), 8.58 (d, 1H), 8.17 (s, 2H), 5.66 (brs, 1H), 4.38-4.20 (m, 2H), 2.64 (s, 3H). LCMS (Method 14): 1.83 min, 499.3[M+H] + . Example 65: 1 H NMR (400MHz; DMSO-d6) δ: 10.23 (brs, 1H), 8.93 (brs, 2H), 8.58 (d, 1H), 8.17 (s, 2H), 5.65 (brs, 1H), 4.38-4.21 (m, 2H), 2.64 (s, 3H). LCMS (Method 14): 1.83 min, 499.3[M+H] + .

[0329] Example 66: 8-Cyano-N-(6-(cyclopropyl(methyl)carbamoyl)-5-(difluoromethyl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide Example 67: 8-Cyano-N-(6-(cyclopropyl(methyl)carbamoyl)-5-(difluoromethyl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide [ka] To a stirred solution of intermediate 97 (70 mg, 0.28 mmol) and intermediate 107 (70 mg, 0.29 mmol) in THF (5 mL) at 0 °C, DIPEA (0.12 mL, 0.70 mmol) was added and the mixture was stirred at 0 °C for 5 min. Triphosgene (69 mg, 0.23 mmol) was added as DCM (1 mL) and the mixture was stirred at 60 °C for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 230-400 mesh, eluted with 0-100% ethyl acetate in petroleum ether) to give the racemic compound (80 mg). The racemate was purified by chiral preparative SFC (Chiralpak-IK, 30×250 mm×5 μm, flow rate: 100 g / min, 75% CO2 and 25% MeOH, back pressure 10 bar, temperature 30° C.): peak 1 was the compound of Example 66 (18 mg) and peak 2 was the compound of Example 67 (20 mg). Example 66: 1 H NMR (400MHz; DMSO-d6)δ:9.92(brs, 1H), 8.89(brs, 1H), 8.79(brs, 1H), 8.25(s, 1H), 7.11(t, 1H) ), 5.63(brs, 1H), 4.38-4.15(m, 2H), 3.01(s, 3H), 2.83(d, 1H), 2.62(s, 3H), 0.46-0.37(m, 4H). LCMS (Method 14): 1.73 min, 511.4[M+H] + . Example 67: 1H NMR (400MHz; DMSO-d6) δ: 9.92 (brs, 1H), 8.91 (brs, 1H), 8.77 (brs, 1H), 8.25 (s, 1H), 7.10 (t, 1H) ), 5.62(brs, 1H), 4.38-4.15(m, 2H), 3.01(s, 3H), 2.83(d, 1H), 2.62(s, 3H), 0.46-0.37(m, 4H). LCMS (Method 14): 1.73 min, 511.4[M+H] + .

[0330] Biological assays MALT1 Protease Assay 1 (Assay 1) MALT1 protease activity was assessed in vitro by measuring the cleavage of a fluorescent tetrapeptide substrate.

[0331] According to standard protocols, a protein containing 6-His-hMALT-1 (residues 339–715) condensed with ubiquitin by an 8×GGS linker (MALT1-GS-Ub) was expressed in Escherichia coli, purified using chitin resin to remove impurities, purified by affinity chromatography, and subjected to size-exclusion chromatography.

[0332] Briefly, MALT1-GS-Ub (300-600 nM) was incubated with substrate (Ac-LVSR-AMC, 100 μM) in a reaction buffer containing 50 mM HEPES (pH 7.0), 25 mM KCl, 0.1% (v / v) CHAPS and 1 mM TCEP.

[0333] Test compounds dissolved in DMSO were dispensed into assay plates (384-well, black, shallow-bottom ProxiPlates). 7 μl of enzyme solution was added and incubated at room temperature for 30 min to allow compound binding to occur. 2 μl of substrate solution was then added and fluorescence (excitation 360 nm, emission 460 nm) was read every 15 min using an appropriate plate reader. Final assay DMSO concentration was 1%. Linearity was confirmed over 60 min and assay signal was calculated by subtracting the counts at 0 h from the counts at 60 min. % inhibition was calculated for each well using no enzyme for 100% inhibition control and no compound for 0% inhibition control. A four-parameter nonlinear regression curve fit was used to calculate IC using GraphPad Prism. 50 was calculated.

[0334] MALT1 protease assay 2 (Assay 2) MALT1 protease activity was assessed in vitro by measuring the cleavage of a fluorescent tetrapeptide substrate.

[0335] For a more sensitive assay, commercially available FL hMALT1 enzyme (Abcam, 1–10 nM) was incubated with the substrate (Ac-LVSR-AMC, 100 μM) in a reaction buffer containing 50 mM HEPES (pH 7.0), 25 mM KCl, 0.1% (v / v) CHAPS, 1 mM TCEP, and 0.7 M sodium citrate.

[0336] Test compounds dissolved in DMSO were dispensed into assay plates (384-well, black, shallow-bottom ProxiPlates). 7 μl of enzyme solution was added and incubated at room temperature for 30 min to allow compound binding to occur. 2 μl of substrate solution was then added and fluorescence (excitation 360 nm, emission 460 nm) was read every 15 min using an appropriate plate reader. Final assay DMSO concentration was 1%. Linearity was confirmed over 60 min and assay signal was calculated by subtracting the counts at 0 h from the counts at 60 min. % inhibition was calculated for each well using no enzyme for 100% inhibition control and no compound for 0% inhibition control. A four-parameter nonlinear regression curve fit was used to calculate IC using GraphPad Prism. 50 was calculated.

[0337] Human IL-2 release phenotype assay (Assay 3) This assay measured the inhibition of IL-2 release by MALT1 inhibitors from stimulated Jurkat cells, a human immortalized T lymphocyte cell line, whose production is regulated by activation of NFκB signaling, which is regulated by MALT1 protease activity.

[0338] Jurkat cells (clone E6-1, ATCC) were cultured in RPMI1640 supplemented with 10% (v / v) FBS and 1% (v / v) penicillin / streptomycin (100x stock solution). Cells were seeded at 50000 cells / well in 96-well white tissue culture treated plates (Perkin Elmer) and incubated overnight at 37°C, 5% CO2. Half-log dilutions of test compounds in DMSO were added to the cells and incubated for 30 min. The final DMSO concentration was 0.5%. Cells were stimulated with 200ng / mL PMA+300ng / mL ionomycin and incubated for 48 h. IL-2 present in the supernatant was then measured by ELISA according to the kit's instructions (ELISA MAX Deluxe Set human IL-2, BioLegend). Percent inhibition was calculated for each well using 30 μM of a commercially available MALT1 inhibitor, MLT-748, for a 100% inhibition control, and no compound for a 0% inhibition control. A four-parameter nonlinear regression curve fit was used to calculate IC using GraphPad Prism. 50 was calculated.

[0339] The results of testing example compounds in one or more of the three above-mentioned in vitro assays are shown in Table 1. [Table 2]

[0340] IL-2 release PK / PD model Approximately 6-week-old female C57BL / 6 mice are grouped based on body weight and orally dosed with compounds at T-1 hour in a vehicle containing 20% ​​HPBCD (w / v), 0.5% Tween 80 (v / v) and 10% (v / v) N,N-di-methylacetamide saline solution in a volume of 10 mL / kg. One hour later, at T0, mice are dosed with anti-CD3 antibody (Ultra-LEAF) appropriately diluted in sterile PBS to be administered at 10 μg / mouse in a volume of 100 μL. TMMice were challenged with an intravenous injection of aCD3 antibody (Biolegend, #100340). Four hours after aCD3 challenge, mice were anesthetized and a terminal blood sample was taken from the carotid artery. 20 μL of blood samples were diluted 1:1 with water and frozen at -20°C until bioanalysis by LC-MS / MS. The remaining blood samples were allowed to clot for 30 min, centrifuged to separate serum, snap frozen, and stored at -80°C until IL-2 analysis by ELISA (Mouse IL-2 DuoSet ELISA, R&D Systems). IL-2 concentrations in serum were calculated by interpolation from a standard curve. Statistical analysis (conventional one-way ANOVA and Dunnett's multiple comparisons) was performed using GraphPad Prism.

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, X １ is N or CH; X ２ , O, NR ７ or CR ８ R ９ and X ３ is N or CH; X ４ is N or CR １０ and However, X ３ and X ４ cannot both be N; R １ is hydrogen, C １－４ Alkyl, Hydroxy, C １－４ Alkoxy, C １－４ Haloalkyl, Halo, NR １１ R １２ , C ３－７ Cycloalkyl and O-C ３－７ cycloalkyl; R ２ is hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, C ３－７ Cycloalkyl, halo, cyano, NR １３ R １４ , C(O)OR １５ , C(O)NR １６ R １７ , OR １８ , 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl, wherein said 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl are selected from C １－４ optionally substituted with one or more substituents selected from alkyl, halo, and cyano; R ３ and R ４ are independently hydrogen, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Haloalkyl, C ３－７ Cycloalkyl, hydroxy, C １－４ Alkoxy, C １－４ Haloalkoxy, halo, cyano, NR １９ R ２０ , 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl and phenyl, wherein said C １－４ Alkyl, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl and phenyl are C １－４ Alkyl, Hydroxy, C １－４ optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; or R ３ and R ４ together with the carbon atom to which they are attached form an oxo group, a 4- to 7-membered heterocyclic ring, or a 3- to 6-membered cycloalkyl ring; R ５ is hydrogen, C １－４ Alkyl, C １－４ Alkoxy and C １－４ haloalkyl; R ６ is hydrogen, halo, C １－４ Alkyl, C １－４ Alkoxy, cyano and C １－４ haloalkyl; R ７ is hydrogen, C １－４ Alkyl, C ３－７ cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl, １－４ Alkyl, C ３－７ Cycloalkyl, 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclyl are C １－４ Alkyl, C １－４ optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; or R ７ and R ３ together with the atoms to which they are attached, １－４ Alkyl, C １－４ forming a 5- or 6-membered heterocyclic ring optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; R ８ and R ９ are independently hydrogen, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Haloalkyl, C ３－７ Cycloalkyl, hydroxy, C １－４ Alkoxy, C １－４ Haloalkoxy, halo, cyano, NR ２１ R ２２ , 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl, wherein said C １－４ Alkyl, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl and phenyl are C １－４ Alkyl, C １－４ optionally substituted with one or more substituents selected from alkoxy, halo, and cyano; or R ８ and R ９ together with the carbon atoms to which they are attached form a 4- to 7-membered heterocyclic ring, or a 3- to 6-membered cycloalkyl ring; R １０ is C(O)NR ２３ R ２４ , C １－４ Haloalkoxy, C １－４ Haloalkyl, C １－４ Alkoxy, C ３－７ cycloalkyl, 4- to 7-membered heterocyclyl, and 5- or 6-membered heteroaryl, wherein said C ３－７ Cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl groups are １－４ Alkyl, C １－３ Alkylene-R ２５ , Hydroxy, NR ２６ R ２７ and halo; R １１ and R １２ are independently hydrogen, C １－４ Alkyl, C ３－７ Cycloalkyl and C １－４ haloalkyl; or R １１ and R １２ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring; R １３ and R １４ are independently hydrogen, C １－４ Alkyl, C ３－７ Cycloalkyl and C １－４ haloalkyl; or R １３ and R １４ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring; R １５ is hydrogen or C １－４ is alkyl; R １６ and R １７ are independently hydrogen, C １－４ Alkyl, C ３－７ Cycloalkyl and C １－４ haloalkyl; or R １６ and R １７ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring; R １８ is hydrogen, C １－４ Alkyl, C １－３ Alkylene-R ２３ , C １－４ Haloalkyl, C ３－７ selected from cycloalkyl, 4- to 7-membered heterocyclyl, and 5- or 6-membered heteroaryl; R １９ , R ２０ , R ２１ and R ２２ are independently hydrogen and C １－４ alkyl; R ２３ and R ２４ are independently hydrogen, C １－４ Alkyl and C ３－７ cycloalkyl; R ２５ OH, C １－４ Alkoxy, C ３－７ Cycloalkyl, NR ２８ R ２９ , C(O)OR ３０ and C(O)NR ３１ R ３２ Selected from: R ２６ , R ２７ , R ２８ , R ２９ , R ３０ , R ３１ and R ３２ are independently hydrogen and C １－４ alkyl; n is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

2. X １ The compound of claim 1 , wherein is N.

3. X ２ is O or NR ７ 3. The compound according to claim 1 or 2,

4. X ３ is N and X ４ is CR １０ The compound according to any one of claims 1 to 3,

5. R １ But below: a. Hydrogen, C １－４ Alkyl, Hydroxy, C １－４ Alkoxy and NR １１ R １２ ; b. Hydrogen, C １－４ Alkyl and NR １１ R １２ ; c. Hydrogen, methyl and NH ２ ;or d. Hydrogen and methyl The compound according to any one of claims 1 to 4, which is selected from:

6. R ２ but, a. Hydrogen, C １－４ Alkyl, C ３－７ Cycloalkyl, halo, cyano, OR １８ , 5- or 6-membered heteroaryl and phenyl, wherein the 5- or 6-membered heteroaryl and phenyl are １－４ optionally substituted with one or more substituents selected from alkyl, halo, and cyano; b. Hydrogen, C ３－７ Cycloalkyl, halo, cyano, OR １８ , 5- or 6-membered heteroaryl and phenyl; c. hydrogen, cyclopropyl, halo, cyano, methoxy, 5-membered heteroaryl and phenyl; d. halo, cyano, methoxy, 5-membered heteroaryl and phenyl; e. halo and cyano; or f. Chloro and bromo The compound according to any one of claims 1 to 5, which is selected from:

7. R ３ and R ４ became independent, a. Hydrogen, C １－４ Alkyl, C ２－４ Alkynyl, C １－４ Haloalkyl, C ３－７ Cycloalkyl, hydroxy, C １－４ alkoxy, halo, cyano, 4- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, and phenyl; b. Hydrogen, C １－４ Alkyl, C ２－４ Alkynyl, C １－４ haloalkyl and cyano; c. Hydrogen, C １－４ Alkyl, ethynyl, trifluoromethyl and cyano; or d. Hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl and cyano The compound according to any one of claims 1 to 6, which is selected from:

8. R ３ and R ４ The compound according to any one of claims 1 to 6, wherein: together with the carbon atom to which they are attached, form a 5- to 6-membered heterocyclic ring or a 3- to 5-membered cycloalkyl ring.

9. R ５ A compound according to any one of claims 1 to 8, wherein is hydrogen or methyl, for example hydrogen.

10. R ６ But halo and C １－４ The compound of any one of claims 1 to 9, which is selected from haloalkyl.

11. R ６ The compound of claim 10, wherein is chloro.

12. R ７ but, a. Hydrogen, C １－４ alkyl and 4- to 7-membered heterocyclyl; b. Hydrogen and C １－４ Alkyl; or c. Hydrogen and methyl The compound according to any one of claims 1 to 11, which is selected from:

13. R ７ and R ３ A compound according to any one of claims 1 to 11, wherein together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring, for example a pyrrolidine or piperidine ring.

14. R ８ and R ９ are independently hydrogen and C １－４ A compound according to any one of claims 1 to 13, wherein alkyl is selected from, for example, hydrogen and methyl.

15. R ８ and R ９ The compound according to any one of claims 1 to 13, wherein both are hydrogen.

16. R １ But C(O)NR ２３ R ２４ , C １－４ haloalkoxy, 4- to 7-membered heterocyclyl, and 5- or 6-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl groups are C １－２ Alkyl, C １－２ Alkylene-R ２５ The compound according to any one of claims 1 to 15, which is optionally substituted with one or more substituents selected from:

17. R １０ But, C １－２ Alkyl and C １－２ Alkylene-R ２５ 17. The compound of claim 16, which is a 5- or 6-membered heteroaryl (e.g., triazolyl) optionally substituted with one or more substituents selected from:

18. A compound according to any one of claims 1 to 17, wherein n is 0 or 1, for example 1.

19. 2. The compound of claim 1, wherein the compound is selected from one of the following compounds or a pharma- ceutically acceptable salt thereof: 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-bromo-3,4-dihydroquinoline-1(2H)-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-methoxy-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2-cyano-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyano-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(pyridin-3-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(oxazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(thiazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; Cis-N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-bromo-3,4-dimethyl-3,4-dihydroquinoline-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-phenyl-3,4-dihydroquinoline-1(2H)-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(1,3,4-thiadiazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxamide; 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,3-dimethyl-3,4-dihydroquinoline-1(2H)-carboxamide; 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyano-2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethynyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-5-cyclopropyl-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-bromo-2,2-dimethyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyclopropyl-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; (S)-1-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-6a,7,8,9-tetrahydropyrido[3,4-e]pyrrolo[1,2-a]pyrazine-5(6H)-carboxamide; (R)-8-bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1,2-dimethyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 8'-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-4,5-dihydro-2H-spiro[furan-3,2'-pyrido[4,3-b][1,4]oxazine]-4'(3'H)-carboxamide; 1-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3',4'-e]pyrazine-5-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-methyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1,2,2-trimethyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 8-chloro-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,2-dimethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; (R)-8-bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethyl-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; (R)-8-bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-isopropyl-1-methyl-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 7-amino-8-bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydropyrido[3,4-b]pyrazine-4(1H)-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-ethyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-isopropyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-2-cyclopropyl-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-cyano-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-8-methoxy-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 5-Bromo-N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-cyano-3,4-dihydro-1,7-naphthyridine-1(2H)-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-cyano-N-(5-cyano-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-cyano-N-(6-(cyclopropyl(methyl)carbamoyl)-5-(difluoromethyl)pyridin-3-yl)-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; 8-cyano-7-methyl-2-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide; and N-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-8-cyano-7-methyl-2-(trifluoromethyl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxamide.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

21. 20. A compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in therapy.

22. A compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for use in the treatment of a disease or disorder mediated by MALT1.

23. Non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), primary macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia Disease, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial carcinoma, vulvar cancer , esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome 21. A compound according to any one of claims 1 to 19 or a pharmacologic acceptable salt thereof, or a pharmaceutical composition according to claim 20, for use in the treatment of pulmonary diseases including pulmonary edema, blistering disorders, antibody mediated vasculitis syndromes, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, beryllium pneumonia or polymyositis.

24. A method for treating a disease or disorder mediated by MALT1, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20.

25. Non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), primary macroglobulinemia, lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), hairy cell leukemia, acute lymphoblastic leukemia, Blastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, Oral cancer, GIST (gastrointestinal stromal tumor), arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or graft rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, blistering disorders, antibody-mediated vasculitis syndrome, immune complex vasculitis, 20. A method of treating allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, edema, embolism, fibrosis, sarcoidosis, pulmonary diseases including hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, pulmonary beryllium or polymyositis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20.

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