Indane derivatives as MALT1 inhibitors

Abstract

The present invention relates to compounds as MALT1 inhibitors. The compounds have the structural formula I as defined herein. The invention also relates to processes for the preparation of these compounds, pharmaceutical compositions comprising said compounds and their use in the treatment of diseases or conditions associated with MALT1.

Description

Technical Field

[0001] The present invention relates to compounds that are MALT1 inhibitors. The present invention also relates to processes for preparing these compounds, pharmaceutical compositions containing the compounds, and their use in treating diseases or conditions associated with MALT1. Background Art

[0002] Mucosa-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 scaffold and protease functions. Antigen receptor triggering leads to the formation of the CBM complex, which contains the CARMA or CARD protein 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, allowing NF-kB to be translated in 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 multiple substrates involved in NF-κB pathway regulation, including RelB, A20, CYLD, regnase-1, HOIL, BCL10, and NIK; as well as autoproteolytic cleavage (doi:10.1016 / j.biochi.2015.09.018). The overall effect of these cleavage events is thought to amplify the magnitude and duration of NF-κB responses (doi:10.1016 / j.biochi.2015.09.018).

[0003] Several lines of genetic evidence suggest that MALT1 plays a key role in immune responses. Mice lacking the MALT1 protein are viable but do not respond to T reg The generation and activation of cells were impaired, and there were fewer activated T cells in the periphery. MALT1 KO mice were protected in inflammatory models of MS (EAE) and rheumatoid arthritis (doi:10.4049 / jimmunol.1201351). Mice expressing proteolytically inactive MALT1 showed defects in multiple immune cell types, including mature T cells and B cells and T regcells and develop progressive multi-organ inflammatory disease (doi:10.4049 / jimmunol.1402254; doi:10.3389 / fimmu.2020.00745). A small group of human patients with defective MALT1 expression and / or function have developed combined immunodeficiency (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) relies on NF-κB activation via constitutive activation of the CARMA1-BCL10-MALT1 pathway for survival and proliferation (doi.org / 10.1038 / nature04687). This constitutive NF-κB activation frequently occurs due to multiple 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 therapeutic principle for ABC-DLBCL, as treatment with the MALT1 inhibitor z-VRPR-fmk reduces the expression of NF-kB target genes, accompanied by decreased cell growth and survival (doi:10.1073 / pnas.0907511106; doi:10.1084 / jem.20091167), and small molecule MALT1 inhibitors have also been shown to be active in xenograft models of ABC-DLBCL (doi:10.1016 / j.ccr.2012.11.002; doi:10.1016 / j.ccr.2012.11.003). Long-term activation of the BCR-mediated CBM-NF-κB pathway has been identified in a subset of mantle cell lymphoma (MCL) lines, suggesting that this subset of MCL may also respond to MALT1 inhibition (doi:10.1038 / nm.3435). In MALT lymphoma, a type of non-Hodgkin lymphoma (NHL), the fusion protein cIAP2-MALT1 leads to constitutive activation of the NF-κB 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 several 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 (e.g., ibrutinib) are important therapies for cancers such as MCL and chronic lymphocytic leukemia (CLL), but their effectiveness is limited due to primary or acquired resistance (doi:10.3390 / cancers12051328). MALT1 is downstream of BTK in the NF-kB activation pathway and therefore may be a valid target in combination with BTK inhibitors or in BTKi-refractory tumors. MALT1 has been shown to be constitutively active in CLL cell lines, and treatment with the MALT-1 inhibitor MI-2 is effective against both naive and ibrutinib-resistant cell lines (doi:10.1158 / 0008-5472.CAN-17-2485). In ABC-DLBCL cell lines, PDX, and in vivo models, MALT1 inhibition has also been shown to synergize with the mTORC1 inhibitor rapamycin, providing further possibilities for combination therapy and mitigation strategies against MALT1i resistance (doi:10.1182 / blood.2019004713). Combinations of MALT1 inhibitors together with Bcl-2 family protein inhibitors have also been shown to show synergistic benefits in animal models of B-cell lymphoma (WO2023 / 016995).

[0006] As immunomodulatory therapies, MALT1 inhibitors have also been proposed as effective treatments for a range of cancers not associated with NF-κB pathway dysregulation (doi:10.1038 / s41586-019-1215-2; WO2018 / 226150 and WO2018 / 141749). Genetic evidence from MALT1-deficient mice suggests that MALT1 promotes T cell proliferation in vivo. reg This in turn inhibits the development of several types of immune cells, thereby suppressing the anti-tumor immune response. reg MALT1 inhibition or CARMA1 loss in T cells reg The cells' effector activity increased and control of tumor growth was enhanced. MALT1 inhibitors synergized with anti-PD1 therapy in both poorly immunogenic and immunogenic murine melanoma models (doi:10.1038 / s41586-019-1215-2), suggesting a potential combination effect of MALT1 inhibitors and immunotherapies, including anti-PD1, anti-PD-L1, and anti-CTLA4.

[0007] In addition to their use in oncology indications, small molecule MALT1 inhibitors may also be effective therapies for inflammatory conditions such as multiple sclerosis, psoriasis, ulcerative colitis, and rheumatoid arthritis. MI-2 has been shown to inhibit monocyte differentiation into osteoclasts in the presence or absence of TNFα and to ameliorate pathological bone erosion and synovitis in a mouse collagen-induced arthritis (CIA) model, suggesting a role for MALT1 inhibitors in the treatment of rheumatoid arthritis (doi:10.1038 / s41598-017-12349-9). In keratinocytes, the scaffold protein CARD14 forms a signaling complex with BCL10 and MALT1, and this process is enhanced in the presence of pathogenic CARD14 mutations, which in turn are associated with susceptibility to psoriasis (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 inhibit endothelial activation by increasing MCPIP1 expression, inhibiting TNFα-induced VCAM-1 expression in HUVECs, and inhibiting LPS-induced VCAM-1 expression in mice, suggesting that MALT1 inhibitors may have a role in the treatment of vascular inflammatory diseases such as atherosclerosis (doi:10.1016 / j.cellsig.2018.05.009).

[0008] Homozygous MALT1 W580S mutations have been detected in patients with combined immunodeficiency (CID). This is associated with low MALT1-W580S protein levels, resulting in reduced but prolonged NF-kB activation due to impaired negative feedback via reduced HOIL1 cleavage, clinically manifesting as increased skin and GI inflammation and increased susceptibility to infection (doi.org / 10.1016 / j.jaci.2013.10.045). Small molecule ligands known to bind to the wild-type allosteric site of MALT1 have been shown to also bind to the W580S mutant, leading to enzyme stabilization and protein remodeling even after ligand clearance. Both scaffold and protease function are restored; therefore, in the case of the W80S MALT1 mutation, allosteric MALT1 inhibitors may be useful as "molecular correctors" (doi.org / 10.1038 / s41589-018-0222-1).

[0009] Several MALT1 inhibitors are under clinical and preclinical investigation. JNJ-67856633 is a small molecule MALT1 inhibitor currently under investigation in patients with NHL and CLL. A review of MALT1 inhibitor patents has been recently published (doi:10.1080 / 13543776.2021.1951703).

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

[0011] In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0013] In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

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

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

[0016] Examples of diseases or conditions mediated by MALT1 include:

[0017] 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), Waldenstrom's macroglobulinemia (WM), macroglobulinemia), lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroid leukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), stomach 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 sarcoma), rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, kidney cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek cancer, oral cancer, or GIST (gastrointestinal stromal tumor); and

[0018] ii) immune 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 transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis (including atopic dermatitis), dermatomyositis, psoriasis, Behcet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjoergen's syndrome, blistering disorder), antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung disease (including edema, embolism, fibrosis, sarcoidosis, hypertension, and emphysema), silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0019] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 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).

[0020] In another aspect, the present invention provides 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, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0021] The present invention further provides a process for the synthesis of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, the present invention provides a compound obtainable by, or obtained by, or directly obtained by a synthetic process as defined herein, or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, the invention provides novel intermediates as defined herein, which are suitable for use in any of the synthetic methods set out herein.

[0024] Preferred, suitable and optional features of any particular aspect of the invention are also preferred, suitable and optional features of any other aspect. DETAILED DESCRIPTION

[0025] definition

[0026] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0027] It will be understood that references to "treating" or "treatment" include prevention as well as alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition in a human who may be susceptible to or susceptible to the condition, disorder, or condition but who does not yet experience or exhibit clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0028] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to achieve such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0029] In this specification, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to single alkyl groups (e.g., "propyl") are specific only for the straight-chain form, and references to single branched-chain alkyl groups (e.g., "isopropyl") are specific only for the branched form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl. Similar conventions apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0030] In this specification, the term "alkylene" includes both straight-chain and branched divalent alkyl groups. For example, "C 1-4 "Alkylene" includes methylene (-CH2-), ethylene (-CH2CH2-), propylene and butylene.

[0031] In this specification, the term "alkoxy" includes both straight and branched chain alkyl groups bonded solely to oxygen. For example, "C 1-4 "Alkoxy" includes methoxy, ethoxy, isopropoxy and tert-butoxy.

[0032] The term "Cm-n" used alone or as a prefix refers to any group having from m to n carbon atoms.

[0033] "Cycloalkyl" means a hydrocarbon monocyclic or bicyclic ring containing carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Bicyclic rings may be fused or spiro-connected; examples of bicyclic cycloalkyls 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.

[0034] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0035] The term "haloalkyl" is used herein to refer to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl groups include fluoroalkyl groups, such as -CHF2, -CH2CF3, or perfluoroalkyl / alkoxy groups, such as -CF3 or -CF2CF3.

[0036] The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged or spiro bicyclic heterocyclic ring system. The monocyclic heterocycle contains about 3 to 12 (suitably 3 to 7) ring atoms and has 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. The bicyclic heterocycle contains 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. The bicyclic heterocycle can be a fused, spiro or bridged ring system. Examples of heterocyclic groups include cyclic ethers such as oxirane, oxetane, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl and the like. Typical sulfur-containing heterocycles include tetrahydrothiophenyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. 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. Sulfur-containing heterocycles also include oxidized sulfur heterocycles containing SO or SO2 groups. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene and thiomorpholinyl, for example tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclic radicals with 1 or 2 oxo (=O) or thioketo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioketopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioketoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclic groups are saturated monocyclic 3- to 7-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. Examples of bridged bicyclic heterocyclic ring systems include quinuclidine and 3-thiabicyclo[3.1.0]hexane. Examples of spirobicyclic heterocyclic ring systems include 1-azaspiro[3.3]heptane, 6-oxa-8-azaspiro[3.5]nonane, 5-azaspiro[3.4]octane and 7-oxa-5-azaspiro[3.4]octane. As will be appreciated by those skilled in the art, any heterocycle can be connected to another group via any suitable atom (e.g., via a carbon or nitrogen atom).Suitably, the term "heterocyclyl", "heterocyclic" or "heterocycle" shall mean a 4-, 5-, 6- or 7-membered monocyclic ring as defined above.

[0037] The term "heteroaryl" or "heteroaromatic" means an aromatic monocyclic, bicyclic or polycyclic ring incorporating one or more (e.g., 1-4, specifically 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 typically 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, such as a bicyclic structure formed by fused 5- and 6-membered rings or two fused 6-membered rings. Each ring can contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic (as in the case of imidazole or pyridine) or substantially non-basic (as in the case of indole or pyrrole nitrogen). In general, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituent of the ring) will be less than 5. Suitably, the term "heteroaryl" or "heteroaromatic" will refer to a 5- or 6-membered monocyclic heteroaryl ring as defined above.

[0038] Non-limiting examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazene, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl , cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, 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, imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl” also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other ring(s) is non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothiophenyl, 4,5,6,7-tetrahydrobenzofuranyl, indolyl, 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-tetrahydrobenzo[d] Isoxazolyl, 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.

[0039] 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.

[0040] Non-limiting examples of 6-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0041] 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, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridinyl, and pyrazolopyridinyl.

[0042] Specific non-limiting examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0043] 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.

[0044] The term "aryl" means 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.

[0045] The term "optionally substituted" refers to both substituted groups, structures or molecules and those that are unsubstituted.

[0046] When optional substituents are selected from "one or more" groups, it is understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0047] The phrase "compounds of the present invention" refers to those compounds disclosed both generically and specifically herein.

[0048] Compounds of the present invention

[0049] In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0050]

[0051] in:

[0052] X 1 and X 2 Independently selected from CR 9 or N;

[0053] X 3 、X 4 、X 5 and X 6 Independently selected from CR 10 or N, provided that X is the prerequisite 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0054] Y is

[0055] Z 1 Does not exist,

[0056] Z 2 Does not exist or is C 1-4 an alkylene linker group, which is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, cyano, hydroxyl and C 3-7 and optionally spiro-linked to a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl ring, wherein the cycloalkyl and heterocyclyl rings are optionally substituted by one or more independently selected C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 3-6 Substitution of cycloalkyl, halogen and cyano substituents;

[0057] R 1 and R 2 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, halogen, cyano, hydroxyl, C 3-7 Cycloalkyl and S(O)2C 1-4 alkyl;

[0058] R 3a 、R 3b 、R 4a and R 4b are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, halogen, cyano, NR 13 R 14 、C(O)OR 15 、C(O)NR 16 R 17 and OR 18 ;

[0059] R 5 is hydrogen or C 1-3 alkyl;

[0060] R 6 C 1-3 Alkyl, C 1-3 Haloalkyl or C 3-5 Cycloalkyl;

[0061] R 7 For hydrogen, C 1-3 Alkyl or CD3;

[0062] R 8 Selected from OR 19 NR 20 R 21 、C(O)R 22 、S(O)2NR 23 R 24 , cyano, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and phenyl, wherein the C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl and phenyl are optionally substituted with one or more radicals of formula C 0-3 Alkylene-R 25 substituted with a substituent, wherein each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-membered to 6-membered heterocyclic group, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 and NR 32 S(O)2R 33 ;and

[0063] wherein the C 3-8 Cycloalkyl and 4- to 10-membered heterocyclic groups R 8 Groups may:

[0064] i) is a monocyclic or polycyclic ring system, wherein the rings in the polycyclic ring system are fused, bridged or spiro-connected; and

[0065] ii) Except for any C 0-3 Alkylene-R 25 In addition to the substituents, it may also be optionally substituted with one or more oxo groups;

[0066] R 9 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, halogen, cyano, hydroxyl, C 3-7 Cycloalkyl and S(O)2C 1-4 alkyl;

[0067] R 10 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, halogen, cyano, and hydroxy;

[0068] R 11 and R 12 are independently selected from hydrogen, C 1-4 Alkyl and halogen;

[0069] R 13 、R 14 、R 15 、R 16 and R 17 independently selected from hydrogen and C 1-4 alkyl;

[0070] R 18 and R 19 are independently selected from hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, wherein the C 1-4 Alkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl are optionally substituted by one or more selected from C 1-4 Alkyl, halogen, OH, C 1-4 Alkoxy, C 3-7 Cycloalkyl, NR 34 R 35 、C(O)OR 36 and C(O)NR37 R 38 Substituents substituted;

[0071] R 20 and R 21 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, C(O)C 1-4 Alkyl, C(O)NR 39 R 40 and S(O)2R 41 ;

[0072] R 22 Selected from hydroxyl, C 1-4 Alkoxy and NR 42 R 43 ;

[0073] R 23 and R 24 independently selected from hydrogen and C 1-4 alkyl;

[0074] R 26 and R 27 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-7 Cycloalkyl;

[0075] R 28 is hydrogen or C 1-4 alkyl;

[0076] R 29 C 1-4 Alkyl, C 1-4 Halogenated alkyl or NR 44 R 45 ;

[0077] R 30 Selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, NR 46 R 47 and a 4- to 6-membered heterocyclic group;

[0078] R 31 C 1-4 Alkyl or NR 48 R 49 ;and

[0079] R 32 、R 33 、R 34 、R 35 、R 36 、R 37、R 38 、R 39 、R 40 、R 41 、R 42 、R 43 、R 44 、R 45 、R 46 、R 47 、R 48 and R 49 independently selected from hydrogen and C 1-4 alkyl; or

[0080] R 34 and R 35 ; R 37 and R 38 ; R 39 and R 40 ; R 42 and R 43 ; R 44 and R 45 ; R 46 and R 47 ; or R 48 and R 49 Together with the corresponding nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocyclic ring.

[0081] Specific compounds of the present invention include, for example, compounds of Formula I or pharmaceutically acceptable salts thereof, wherein unless otherwise specified, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , Y, Z 1 , Z 2 、R 1 、R 2 、R 3a 、R 3b 、R 4a 、R 4b 、R 5 、R 6 、R 7 、R 8 、R 9 、R 18 、R 19 、R 20 and R 21 Each of has any meaning defined in any of paragraphs (1) to (67) above or below. For the avoidance of doubt, the scope of the present invention encompasses compounds of Formula I or pharmaceutically acceptable salts thereof, wherein any of the definitions of substituents defined herein may be combined with any of the definitions of other substituents also defined herein:

[0082] (1)X 1 is CH or N;

[0083] (2)X 1 CR 9 , such as CH;

[0084] (3)X 2 is CH or N;

[0085] (4)X 2 CR 9 , such as CH;

[0086] (5)X 3 、X 4 、X 5 and X 6 are independently selected from CH or N, provided that X 3 、X 4 、X 5 and X 6 No more than two of them are N;

[0087] (6)X 3 、X 4 、X 5 and X 6 One of them is N, and the other three are CH;

[0088] (7)X 3 is N, and X 4 、X 5 and X 6 for CH;

[0089] (8)X 5 is N, and X 3 、X 4 and X 6 for CH;

[0090] (9)X 3 and X 6 is N, and X 4 and X 5 for CH;

[0091] (10)X 3 and X 4 is N, and X 5 and X 6 for CH;

[0092] (11)X 3 and X 4 is CH, and X 5 and X 6 is N;

[0093] (12)X3 and X 5 is N, and X 4 and X 6 for CH;

[0094] (13)X 3 、X 4 、X 5 and X 6 All are CH;

[0095] (14) Y is

[0096] (15)Z 1 Does not exist,

[0097] (16)Z 1 Does not exist or is

[0098] (17)Z 1 does not exist;

[0099] (18)Z 1 for

[0100] (19)Z 1 for And Z 2 does not exist;

[0101] (20)Z 1 Does not exist and Z 2 does not exist;

[0102] (21)Z 2 Does not exist or is C 1-4 an alkylene linker group, which is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, cyano, hydroxyl and C 3-7 Substitution of cycloalkyl groups;

[0103] (22)Z 2 does not exist;

[0104] (23)Z 2 C 1-3 an alkylene linker group, which is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, cyano, hydroxyl and C 3-7 Substitution of cycloalkyl groups;

[0105] (24)Z2 C 1-3 an alkylene linker group, which is optionally substituted by one or more independently selected from C 1-4 substitution with alkyl, halogen, cyano, hydroxyl and cyclopropyl substituents;

[0106] (25)Z 2 is -CH2-, -CH2CH2- or -CH2CH2CH2-;

[0107] (26)R 1 and R 2 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, hydroxy, cyano and C 3-7 Cycloalkyl;

[0108] (27)R 1 and R 2 independently selected from hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluorine, chlorine, bromine, cyano and cyclopropyl;

[0109] (28)R 1 and R 2 independently selected from hydrogen, methoxy, fluoro, chloro and cyano;

[0110] (29)R 1 is selected from methyl, ethyl, methoxy, trifluoromethyl, fluorine, chlorine and cyano, and R 2 is hydrogen;

[0111] (30)R 1 is hydrogen, and R 2 is selected from the group consisting of methyl, ethyl, methoxy, trifluoromethyl, fluorine, chlorine and cyano;

[0112] (31)R 1 and R 2 Both are hydrogen;

[0113] (32)R 3a 、R 3b 、R 4a and R 4b are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, halogen and OR 18 ;

[0114] (33)R 3a 、R 3b 、R 4a and R 4b are independently selected from hydrogen, C 1-4 Alkyl, hydroxyl and C1-4 alkoxy;

[0115] (34)R 3a 、R 3b 、R 4a and R 4b are independently selected from hydrogen, C 1-4 Alkyl and C 1-4 alkoxy;

[0116] (35)R 3a 、R 3b 、R 4a and R 4b independently selected from hydrogen, methyl, ethyl and methoxy;

[0117] (36)R 3a 、R 3b 、R 4a and R 4b All are hydrogen;

[0118] (37)R 3a C 1-4 Alkyl, such as methyl, and R 3b 、R 4a and R 4b is hydrogen;

[0119] (38)R 3a C 1-4 Alkoxy, such as methoxy, and R 3b 、R 4a and R 4b is hydrogen;

[0120] (39)R 3a and R 3b Both are C 1-4 Alkyl groups, for example, are all methyl groups;

[0121] (40)R 3a and R 3b Both are C 1-4 Alkyl groups, for example, are all methyl groups, and R 4a and R 4b Both are hydrogen;

[0122] (41)R 3a and R 4a Both are C 1-4 Alkyl groups, for example, are all methyl groups;

[0123] (42)R 3a and R 4a Both are C 1-4 Alkyl groups, for example, are all methyl groups, and R 3b and R 4b Both are hydrogen;

[0124] (43)R 5 is hydrogen or methyl;

[0125] (44)R 5 is hydrogen;

[0126] (45)R 6 C 1-2 Alkyl, C 1-2 Haloalkyl or C 3-4 Cycloalkyl;

[0127] (46)R 6 Methyl, C 1-2 Fluoroalkyl or cyclopropyl;

[0128] (47)R 6 C 1-3 Alkyl or C 1-3 alkyl halide;

[0129] (48)R 6 is methyl;

[0130] (49)R 6 C 1-3 alkyl halide;

[0131] (50)R 6 C 1-3 Fluoroalkyl;

[0132] (51)R 6 is trifluoromethyl;

[0133] (52)R 7 is hydrogen, methyl or CD3;

[0134] (53)R 7 C 1-3 alkyl;

[0135] (54)R 7 is methyl;

[0136] (55)R 8 Selected from OR 19 NR 20 R 21 、C(O)R 22 、S(O)2NR 23 R 24 , cyano, C 3-8 Cycloalkyl, 4-membered to 10-membered heterocyclyl and 5-membered to 10-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are optionally substituted with one or more of the formula C 0-3 Alkylene-R25 substituted with a substituent, wherein each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-membered to 6-membered heterocyclic group, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 and NR 32 S(O)2R 33 ;and

[0137] wherein the C 3-8 Cycloalkyl and 4- to 10-membered heterocyclic groups R 8 Groups may:

[0138] is a monocyclic or polycyclic ring system, wherein the rings in the polycyclic ring system are fused, bridged or spiro-connected; and except for optional C 0-3 Alkylene-R 25 In addition to the substituent, it may also be optionally substituted by one or more oxo groups; (56) R 8 Selected from OR 19 NR 20 R 21 、C(O)R 22 、S(O)2NR 23 R 24 , cyano, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally substituted with one or more of the formula C 0-3 Alkylene-R 25 substituted with a substituent, wherein each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-membered to 6-membered heterocyclic group, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 and NR 32 S(O)2R 33 ;and

[0139] wherein the C3-8 Cycloalkyl and 4- to 10-membered heterocyclic groups R 8 Groups may:

[0140] is a monocyclic or polycyclic ring system, wherein the rings in the polycyclic ring system are fused, bridged or spiro-connected; and except for optional C 0-3 Alkylene-R 25 In addition to the substituent, it may also be optionally substituted by one or more oxo groups; (57) R 8 Selected from OR 19 NR 20 R 21 、C(O)R 22 、S(O)2NR 23 R 24 , cyano, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally substituted with one or more of the formula C 0-3 Alkylene-R 25 substituted with a substituent, wherein each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 and NR 32 S(O)2R 33 ;and

[0141] wherein the C 3-8 Cycloalkyl and 4- to 10-membered heterocyclic groups R 8 Groups may:

[0142] is a monocyclic or polycyclic ring system, wherein the rings in the polycyclic ring system are fused, bridged or spiro-connected; and except for optional C 0-3 Alkylene-R 25 In addition to the substituent, it may also be optionally substituted by one or more oxo groups; (58) R 8 Selected from C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally substituted with one or more of the formula C 0-3 Alkylene-R 25 substituted with a substituent, wherein each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C1-4 Alkoxy, halogen, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 and NR 32 S(O)2R 33 ;and

[0143] wherein the C 3-8 Cycloalkyl and 4- to 10-membered heterocyclic groups R 8 Groups may:

[0144] is a monocyclic or polycyclic ring system, wherein the rings in the polycyclic ring system are fused, bridged or spiro-connected; and except for optional C 0-3 Alkylene-R 25 In addition to the substituent, it may also be optionally substituted by one or more oxo groups; (59) R 8 selected from azetidine, pyrrolidine, piperidine, piperazine, pyrazolidine, 1,2-dihydropyridine, imidazolidine, oxazolidine, morpholine, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, thiomorpholine, quinuclidine, tetrahydrothiazine, thietane, tetrahydrothiophene, 1-azaspiro[3.3]heptane, 6-oxa-8-azaspiro[3.5]nonane, 7-oxa-5-azaspiro[3.4]octane, thiabicyclo[3.1.0]hexane, 5-azaspiro[3.4]octane and isothiazolidine, which is optionally substituted with one or more oxo groups and optionally substituted with one or more compounds of formula C 0-3 Alkylene-R 25 substituted with a substituent, wherein each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 NR 32 S(O)2R 33 、C 3-6 Cycloalkyl and 4- to 6-membered heterocyclic groups;

[0145] (60)R 8 Selected from OR 19 NR 20 R 21 、C(O)R 22 、S(O)2NR 23 R 24 , cyano or one of the following groups:

[0146]

[0147] It is optionally replaced by one or more compounds of formula C 0-3 Alkylene-R 25 substituted with a substituent, wherein each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 NR 32 S(O)2R 33 、C 3-6 Cycloalkyl and 4- to 6-membered heterocyclic groups;

[0148] (61)R 8 for:

[0149]

[0150] It is optionally replaced by one or more compounds of formula C 0-3 Alkylene-R 25 substituted with a substituent, wherein each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 and NR 32 S(O)2R 33 ;

[0151] (62)R 9 Selected from hydrogen, C 1-4 Alkyl, C 1-4 haloalkoxy and halogen;

[0152] (63)R 9 is selected from hydrogen, methyl, difluoromethoxy, fluorine, chlorine and bromine;

[0153] (64)R 18 and R 19 independently selected from hydrogen and C 1-4 alkyl;

[0154] (65)R 18 and R 19independently selected from hydrogen, methyl and ethyl;

[0155] (66)R 20 and R 21 are independently selected from hydrogen, C 1-4 Alkyl and C(O)C 1-4 alkyl;

[0156] (67)R 20 and R 21 Independently selected from hydrogen, methyl and C(O)Me.

[0157] Appropriately, X 1 As defined in any of paragraphs (1) to (2) above.

[0158] Appropriately, X 2 As defined in any of paragraphs (3) to (4) above.

[0159] Appropriately, X 3 To X 6 As defined in any of paragraphs (5) to (13) above. More suitably, X 3 To X 6 As defined in paragraphs (7) to (8) above.

[0160] Suitably, Y is as defined in paragraph (14) above.

[0161] Appropriately, Z 1 As defined in any of paragraphs (15) to (20) above. More suitably, Z 1 As defined in paragraph (17) above.

[0162] Appropriately, Z 2 As defined in any of paragraphs (21) to (25) above. More suitably, Z 2 As defined in paragraph (22) or (25) above.

[0163] Suitably, R 1 and R 2 As defined in any of paragraphs (26) to (31) above. In an embodiment, R 1 and R 2 As defined in paragraph (31) above.

[0164] Suitably, R 3a to R 4b As defined in any of paragraphs (32) to (42) above. In an embodiment, R 3a to R 4b As defined in paragraphs (39) to (40) above.

[0165] Suitably, R 5 As defined in any of paragraphs (43) to (44) above. In an embodiment, R 5 As defined in paragraph (44) above.

[0166] Suitably, R 6 As defined in any of paragraphs (45) to (51) above. In an embodiment, R 6 As defined in paragraph (51) above.

[0167] Suitably, R 7 As defined in any of paragraphs (52) to (54) above. In an embodiment, R 7 As defined in paragraph (54) above.

[0168] Suitably, R 8 As defined in any of paragraphs (55) to (61) above. In an embodiment, R 8 As defined in paragraph (61) above.

[0169] Suitably, R 9 As defined in any of paragraphs (62) to (63) above. In an embodiment, R 9 As defined in paragraph (63) above.

[0170] Suitably, R 18 and R 19 As defined in any of paragraphs (64) to (65) above.

[0171] Suitably, R 20 and R 21 As defined in any of paragraphs (66) to (67) above.

[0172] In a convenient embodiment, the compound of Formula I is a compound according to Formula IA (a substructure of Formula I) below, or a pharmaceutically acceptable salt thereof:

[0173]

[0174] In another group of compounds, the compound has one of the structural formulas IB to IS (substructures of formula I) shown below:

[0175]

[0176]

[0177] where X 1 、X 2 、X 3 、X4 、X 5 、X 6 , Y, Z 1 , Z 2 、R 1 、R 2 、R 3a 、R 3b 、R 4a 、R 4b 、R 5 、R 6 、R 7 and R 8 As defined above.

[0178] In another group of compounds, the compound has one of the structural formulas IA to IS shown above, wherein X 1 As defined in any of paragraphs (1) to (2) above; X 2 As defined in any of paragraphs (3) to (4) above; X 3 To X 6 As defined in any of paragraphs (5) to (13) above; Y is as defined in paragraph (14) above; Z 1 As defined in any of paragraphs (15) to (20) above; Z 2 As defined in any of paragraphs (21) to (25) above; R 1 and R 2 As defined in any of paragraphs (26) to (31) above; R 3a to R 4b As defined in any of paragraphs (32) to (42) above; R 5 As defined in any of paragraphs (43) to (44) above; R 6 As defined in any of paragraphs (45) to (51) above; R 7 As defined in any of paragraphs (52) to (54) above; and R 8 As defined in any of paragraphs (55) to (61) above.

[0179] Specific compounds of the present invention include any of the following:

[0180] N-((S)-1-(4-((-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0181] (S)-N-(1-(4-((2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0182] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyloxazole-5-carboxamide;

[0183] 1-Acetyl-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide;

[0184] N-methyl-N-((S)-2,2,2-trifluoro-1-(4-(((1,2-cis)-1-methyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0185] N-methyl-N-((S)-2,2,2-trifluoro-1-(4-(((1,2-trans)-1-methyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0186] N-Methyl-N-((1S)-2,2,2-trifluoro-1-(4-((1-methoxy-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0187] N-((S)-1-(4-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylmorpholine-4-carboxamide;

[0188] N-((S)-1-(4-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylmorpholine-4-carboxamide;

[0189] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylthiomorpholine-4-carboxamide 1,1-dioxide;

[0190] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N,4-dimethylpiperidine-1-carboxamide;

[0191] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-4-carboxamide;

[0192] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide;

[0193] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylpiperidine-1-carboxamide;

[0194] 3-Acetamido-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpropionamide;

[0195] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyloxazole-4-carboxamide;

[0196] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2-methoxy-N-methylacetamide;

[0197] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2-hydroxy-N-methylacetamide;

[0198] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-methoxy-N-methylpropionamide;

[0199] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-hydroxy-N-methylpropionamide;

[0200] N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0201] N-((1S)-1-(4-((1,3-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0202] 2-Acetamido-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylacetamide;

[0203] 1-Acetyl-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,3-dimethylazetidine-3-carboxamide;

[0204] 1-Acetyl-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-fluoro-N-methylazetidine-3-carboxamide;

[0205] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-(2-oxopyrrolidin-1-yl)acetamide;

[0206] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(2-oxopyrrolidin-1-yl)acrylamide;

[0207] 5-(((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)amino)-5-oxopentanoic acid;

[0208] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1,2,5-oxadiazole-3-carboxamide;

[0209] 4-(((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)amino)-4-oxobutanoic acid;

[0210] N-Methyl-N-((1S)-2,2,2-trifluoro-1-(4-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0211] N-((1S)-1-(4-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0212] 1-Acetylazetidin-3-yl ((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamate;

[0213] tert-Butyl 3-((((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)oxy)azetidine-1-carboxylate;

[0214] ((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamic acid azetidin-3-yl ester hydrochloride;

[0215] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(N-methylsulfamoyl)acrylamide;

[0216] N-((1R)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0217] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(N-methylsulfamoyl)butanamide;

[0218] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2-(2,4-dioxoimidazolidin-1-yl)-N-methylacetamide;

[0219] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;

[0220] (S)-N-(1-(4-((2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide;

[0221] (S)-N-(1-(5-((2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0222] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide;

[0223] N3-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N3-dimethylazetidine-1,3-dicarboxamide;

[0224] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylazetidine-3-carboxamide;

[0225] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0226] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclopropanesulfonamide;

[0227] N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0228] N-(1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide;

[0229] N-(1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide;

[0230] N-(1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethylazetidine-3-carboxamide;

[0231] N-(1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N,1-dimethylazetidine-3-carboxamide;

[0232] N-(1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide;

[0233] N-(1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide;

[0234] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide;

[0235] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxooxazolidine-5-carboxamide;

[0236] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-(dimethylamino)-N-methylcyclobutane-1-carboxamide;

[0237] N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-trans-(dimethylamino)-N-methylcyclobutane-1-carboxamide;

[0238] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxopiperidine-4-carboxamide;

[0239] N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methylquinuclidine-3-carboxamide;

[0240] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide;

[0241] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-3-carboxamide;

[0242] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-4-carboxamide;

[0243] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxomorpholine-2-carboxamide;

[0244] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylquinuclidine-3-carboxamide;

[0245] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylthiomorpholine-4-carboxamide 1,1-dioxide;

[0246] N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-4-carboxamide;

[0247] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide;

[0248] N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide;

[0249] N-((1S)-1-(4-((6-chloro-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0250] N-((1S)-1-(4-((5-chloro-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0251] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide;

[0252] (4,6-trans)-N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-1-azaspiro[3.3]heptane-6-carboxamide;

[0253] (4,6-cis)-N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-1-azaspiro[3.3]heptane-6-carboxamide;

[0254] (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0255] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxomorpholine-3-carboxamide;

[0256] (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-4-oxoazetidine-2-carboxamide;

[0257] (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0258] (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylmorpholine-2-carboxamide dihydrochloride;

[0259] (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide;

[0260] (S)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide;

[0261] (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-2-carboxamide;

[0262] (R)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-2-carboxamide;

[0263] (1R,3S)-3-Acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide;

[0264] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide;

[0265] N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-7-oxo-6-oxa-8-azaspiro[3.5]nonane-2-carboxamide;

[0266] (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide;

[0267] N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0268] 3-Acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide;

[0269] (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,4-dimethylmorpholine-2-carboxamide;

[0270] (S)-4-Acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylmorpholine-2-carboxamide;

[0271] (1,3-cis)-3-acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide;

[0272] (2S,4R)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0273] (1R,3S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(2,2,2-trifluoroacetamido)cyclopentane-1-carboxamide;

[0274] N1-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N1,N3-dimethylbicyclo[1.1.1]pentane-1,3-dicarboxamide;

[0275] (1,3-trans)-3-acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide;

[0276] (1,3-cis)-3-acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide;

[0277] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-ethyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0278] N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0279] (R)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide;

[0280] (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylmorpholine-2-carboxamide;

[0281] (S)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-2-carboxamide;

[0282] (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,4-dimethylmorpholine-2-carboxamide;

[0283] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-N-methylacetamide;

[0284] N-((1S)-1-(5-((4-ethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0285] N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0286] N-((S)-1-(5-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0287] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-5-oxopiperazine-2-carboxamide;

[0288] N-((R)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-5-oxopiperazine-2-carboxamide;

[0289] N1-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N1,N3-dimethylbicyclo[1.1.1]pentane-1,3-dicarboxamide;

[0290] (1R,3S)-3-Acetamido-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide;

[0291] (1,3-cis)-3-acetamido-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide;

[0292] (1,3-trans)-3-acetamido-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide;

[0293] (2,4-cis)-N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide;

[0294] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)azetidine-3-carboxamide;

[0295] (S)-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0296] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,4-dioxoimidazolidin-1-yl)-N-methylacetamide;

[0297] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-thiabicyclo[3.1.0]hexane-6-carboxamide 3,3-dioxide;

[0298] (R)-N-((S)-1-(6-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide;

[0299] (S)-N-((S)-1-(6-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide;

[0300] (2S,4R)-1-acetyl-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide;

[0301] (1S,3R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide;

[0302] (1,3-trans)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)cyclobutane-1-carboxamide;

[0303] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)piperidine-4-carboxamide;

[0304] 1-Acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide;

[0305] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-5-oxopyrrolidine-2-carboxamide;

[0306] N 3 -((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -dimethylazetidine-1,3-dicarboxamide;

[0307] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide;

[0308] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)bicyclo[1.1.1]pentane-1-carboxamide;

[0309] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(1,1-dioxothiomorpholinyl)-N-methylacetamide;

[0310] 1-Acetyl-N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide;

[0311] N-((1S)-1-(5-((4-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0312] N 6-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 6 -dimethyl-1-azaspiro[3.3]heptane-1,6-dicarboxamide;

[0313] (1,3-cis)-N 1 -((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -dimethylcyclobutane-1,3-dicarboxamide;

[0314] (1,3-cis)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)cyclobutane-1-carboxamide;

[0315] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-(2-methoxyethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide;

[0316] (2S,4R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methyl-1-(methylsulfonyl)pyrrolidine-2-carboxamide;

[0317] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-(2-oxoimidazolidin-1-yl)acetamide;

[0318] (1,3-trans)-N 1 -((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -dimethylcyclobutane-1,3-dicarboxamide;

[0319] N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-(2-hydroxyethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide;

[0320] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-2-oxopiperidine-4-carboxamide;

[0321] N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-6-oxopiperidine-3-carboxamide;

[0322] N-((1S)-1-(5-((4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0323] N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0324] N-((1S)-1-(5-((4-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0325] N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0326] (S)-N-(1-(5-((5,6-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0327] N-((1S)-1-(5-((4,5-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0328] N-((1S)-1-(5-((4-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0329] N-((1S)-1-(5-((4-chloro-5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0330] (S)-N-(1-(5-((4,7-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0331] N-((1S)-1-(5-((4,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0332] N-((1S)-1-(5-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0333] (S)-N-(1-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0334] (S)-N-(1-(5-((4,7-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0335] N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0336] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0337] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0338] N-methyl-N-((1S)-2,2,2-trifluoro-1-(6-((4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0339] N-((1S)-1-(5-((4,6-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0340] N-((1S)-1-(5-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0341] N-((1S)-1-(5-((4-chloro-6-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0342] N-((1S)-1-(6-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0343] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonamido)cyclopropane-1-carboxamide;

[0344] N-((1S)-1-(5-((5-chloro-6-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0345] N 1 -((1S)-1-(5-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 4 -dimethylcubane-1,4-dicarboxamide;

[0346] N-((1S)-1-(5-((4-chloro-7-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0347] N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4,5,6-trifluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0348] (S)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide;

[0349] (S)-N-(1-(5-((5,6-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0350] N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)bicyclo[1.1.1]pentane-1-carboxamide;

[0351] (S)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0352] (R)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,3-dimethyl-2-oxoimidazolidine-4-carboxamide;

[0353] (S)-N-(1-(5-((4,7-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0354] N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxooxazolidine-5-carboxamide;

[0355] (R)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-2-carboxamide hydrochloride;

[0356] N-((1S)-1-(5-((5-chloro-4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0357] N-((1S)-1-(5-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0358] (R)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-2-carboxamide;

[0359] N-((1S)-1-(5-((5-bromo-6-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0360] N-((1S)-1-(5-((5-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0361] N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxopiperidine-4-carboxamide;

[0362] (S)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-2-carboxamide;

[0363] (3S)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0364] (3S)-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0365] (3S)-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide;

[0366] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)bicyclo[1.1.1]pentane-1-carboxamide;

[0367] N-((1S)-1-(5-((5-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0368] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)piperidine-4-carboxamide;

[0369] (3S)-N-((1S)-1-(5-((5-chloro-4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0370] (3S)-N-((1S)-1-(5-((5-chloro-4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide;

[0371] N-((1S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0372] N-((1S)-1-(5-((4-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0373] N 3 -((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -dimethylazetidine-1,3-dicarboxamide;

[0374] (3S)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide;

[0375] (3R)-N-((1S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0376] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide;

[0377] N-((1S)-1-(6-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0378] (3R)-N-((1S)-1-(6-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide;

[0379] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,2-dimethylpyrimidine-5-carboxamide;

[0380] 2-cyano-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylacetamide;

[0381] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(tetrahydrofuran-3-carbonyl)azetidine-3-carboxamide;

[0382] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylthietane-3-carboxamide 1,1-dioxide;

[0383] N-((1S)-1-(5-((5-chloro-4-(methoxymethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0384] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydrothiophene-3-carboxamide 1,1-dioxide;

[0385] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(1,1-dioxoanionylisothiazolidin-2-yl)-N-methylacetamide;

[0386] (1,3-trans)-N 1 -((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -dimethylcyclobutane-1,3-dicarboxamide;

[0387] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-3-carboxamide;

[0388] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-hydroxy-N-methylacetamide;

[0389] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,N′-dimethylcyclopropane-1,1-dicarboxamide;

[0390] N-((1S)-1-(5-((5-chloro-4-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0391] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(oxetane-3-carbonyl)azetidine-3-carboxamide;

[0392] N-((1S)-1-(5-((5-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide;

[0393] (1,3-trans)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-hydroxy-N-methylcyclobutane-1-carboxamide;

[0394] 1-Acetyl-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide;

[0395] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-(2-hydroxyacetyl)-N-methylazetidine-3-carboxamide;

[0396] N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-(methylsulfonamido)acetamide;

[0397] (1,3-cis)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-hydroxy-N-methylcyclobutane-1-carboxamide;

[0398] N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(oxetane-2-carbonyl)azetidine-3-carboxamide;

[0399] (3S)-N-((1S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide;

[0400] or a pharmaceutically acceptable salt thereof.

[0401] The various functional groups and substituents that make up the compounds of the invention are typically selected so that the molecular weight of the compound does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, eg, less than 700 or less than 650.

[0402] Suitable or preferred features of any compound of the invention may also be suitable features of any other aspect.

[0403] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic acid addition salts of the compounds of the present invention, for example, acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that 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 that provide physiologically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0404] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or in the arrangement of their atoms in space are called "isomers". Isomers whose atoms are arranged differently in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, the asymmetric center is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R and S ordering rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light and are designated as right- or left-handed (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as single enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0405] The compounds of the present invention typically have one or more asymmetric centers; such compounds can therefore be produced as single (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description and naming of specific compounds in this specification and claims are intended to include both single enantiomers, diastereomers, and mixtures (racemic or reverse) thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemic forms. Some compounds of the present invention may have geometric isomerization centers (E-isomers and Z-isomers). It should be understood that the present invention encompasses all optical, diastereoisomers, and geometric isomers and mixtures thereof having MALT1 inhibitory activity.

[0406] The present invention also encompasses compounds of the invention as defined herein that contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H(D) and3 H(T); C can be in any isotopic form, including 12 C. 13 C and 14 C; and O may be in any isotopic form, including 16 O and 18 O; and so on.

[0407] It will also be understood that certain compounds of the present invention may exist in solvated as well as unsolvated forms, for example hydrated forms. It is to be understood that the present invention encompasses all such solvated forms that possess MALT1 inhibitory activity.

[0408] It will also be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms that possess MALT1 inhibitory activity.

[0409] Compound of the present invention can exist in a variety of different tautomeric forms, and mentioning of the compounds of this invention includes all such forms. For avoidance of doubt, compound can exist in one of several tautomeric forms and only specifically elaborate or show a form of situation, compound of the present invention still encompasses all other forms.The example of tautomeric form includes keto form, enol form and enolate form, as for example in following tautomerism pair: keto / enol (hereinafter explained), imines / enamine, amides / imino alcohol, amidine / amidine, nitroso-group / oxime, thioketone / enethiol and nitro / acid nitro.

[0410]

[0411] The compounds of the present invention containing amine functional groups can also form N-oxides. References herein to compounds of formula I containing amine functional groups also include N-oxides. In the case where the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent (e.g., hydrogen peroxide or peracid (e.g., peroxycarboxylic acid)), for example, see Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, p. 14. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA), for example, in an inert solvent (e.g., dichloromethane).

[0412] The compounds of the present invention can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents to which modifying groups can be attached.

[0413] Thus, the present invention includes those compounds of formula I as defined above that are obtainable by organic synthesis and that are obtainable in the human or animal body by cleavage of a prodrug. Thus, the present invention includes those compounds of formula I produced by organic synthesis means as well as such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., the compounds of formula I may be synthetically produced compounds or metabolically produced compounds.

[0414] Suitable pharmaceutically acceptable prodrugs of the compounds of formula I are prodrugs that are suitable, based on sound medical judgment, for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

[0415] Various forms of prodrugs have been described, for example, in the following documents:

[0416] a) Methods in Enzymology , No. 42 K. Widder et al., eds., pp. 309-396.

[0417] (Academic Press, 1985);

[0418] b) Design of Pro-drugs, edited by H.Bundgaard, (Elsevier, 1985);

[0419] c) ATextbook of Drug Design and Development, Krogsgaard-Larsen and

[0420] H. Bundgaard, ed., Chapter 5 “Design and Application of Pro-drugs”, H. Bundgaard, pp. 113-191 (1991);

[0421] d)H.Bundgaard, Advanced Drug Delivery Reviews ,8,1-38(1992);

[0422] e) H. Bundgaard et al., Journal of Pharmaceutical Sciences ,77,285(1988);

[0423] f) N. Kakeya et al., Chem.Pharm.Bull. , 32,692(1984);

[0424] g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS

[0425] Symposium Series, Volume 14; and

[0426] h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0427] The in vivo effects of compounds of Formula I may be exerted in part through one or more metabolites formed in the human or animal body following administration of compounds of Formula I. As described above, the in vivo effects of compounds of Formula I may also be exerted through the metabolism of precursor compounds (prodrugs).

[0428] It will also be appreciated that compounds of Formula I may also be covalently linked (at any suitable position) to other groups, such as solubilizing moieties (e.g., PEG polymers), moieties that enable binding of the compound to a solid support (e.g., a biotin-containing moiety), and targeting ligands (e.g., antibodies or antibody fragments).

[0429] synthesis

[0430] In the descriptions of the synthetic methods set forth below and in the referenced synthetic methods for preparing starting materials, it is understood that all proposed reaction conditions (including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures) can be selected by one skilled in the art.

[0431] Those skilled in the art of organic synthesis will understand that the functional groups present on the various parts of the molecule must be compatible with the reagents and reaction conditions employed.

[0432] The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variations and in the accompanying examples. Alternatively, the necessary starting materials can be obtained by procedures analogous to those described herein that are familiar to those skilled in the art of organic chemistry.

[0433] It will be appreciated that 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 them from undesirable reactions. A skilled chemist will understand when such protection is necessary and how such protecting groups may be placed in place and subsequently removed.

[0434] For examples of protecting groups, see one of the various general texts on the subject, for example, "Protecting groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999)", T. Greene and P. Wuts. Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist to be suitable for removing the protecting group in question, such method being selected to achieve removal of the protecting group with minimal disturbance of groups elsewhere in the molecule.

[0435] Thus, if reactants include, for example, groups such as amino, carboxyl or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0436] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups, such as acetyl groups; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups; or aroyl groups, such as benzoyl groups. The deprotection conditions for the above protecting groups will necessarily vary depending on the choice of protecting group. Thus, for example, an acyl group (such as an alkanoyl group or alkoxycarbonyl group or aroyl group) can be removed, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide. Alternatively, an acyl group (such as tert-butoxycarbonyl) can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group (such as benzyloxycarbonyl) can be removed, for example, by hydrogenation over 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, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid. Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with an alkylamine (e.g. dimethylaminopropylamine) or with hydrazine.

[0437] Those skilled in the art will recognize that the compounds of the present invention can be prepared in a known manner and in a variety of ways. The compounds of formula I can be prepared by the methods given below, by the methods given in the experiments, or by similar methods. The approaches described are merely illustrative of some 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 will also be understood that the assignments of nucleophiles and electrophiles are not limited to those described herein, and in some cases, it may be appropriate to reverse the assignments. Different approaches to synthetic chemistry strategies are described in "Organic Synthesis: The Disconnection Approach", 2nd edition, S. Warren and P. Wyatt (2008).

[0438] Plan A

[0439]

[0440] Compounds of formula I, wherein R 1 、R 2 、R 3a 、R 3b 、R 4a 、R 4b 、R 5 、R 6 、R 7 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , Y, Z 1 , Z 2 and R 8 As previously defined, the intermediate (i) and the intermediate (ii) can be prepared by condensing the compounds using a suitable coupling reagent in step (a) (Scheme A). Suitable coupling reagents include, for example, propylphosphonic anhydride, phosphorus oxychloride, carbonyldiimidazole or 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide.

[0441] Plan B

[0442]

[0443] Compounds of formula I can also be prepared by condensing compounds of intermediate (i) and intermediate (iii) in step (b) in the presence of a suitable base (Scheme B). Suitable bases include, for example, pyridine, diisopropylethylamine or triethylamine.

[0444] Plan C

[0445]

[0446] Compounds of formula I can also be prepared by condensing intermediates (i) and (iv) in the presence of a suitable coupling reagent in step (c) (Scheme C). Suitable coupling reagents include, for example, phosgene, diphosgene, triphosgene, phenyl chloroformate, 4-nitrophenyl chloroformate or 1,1-carbonyldiimidazole.

[0447] Plan D

[0448]

[0449] Compounds of formula I can also be prepared by condensing intermediates (v) and (vi) in the presence of a suitable coupling reagent and a base in step (d) (Scheme D). Suitable coupling reagents include, for example, tBuBrettphosPdG3 in the presence of RuPhos, Pd2(dba)3, RuPhosPdG3, XPhosPdG2 in the presence of X-Phos, or BuBrettphosPdG1 in the presence of BrettPhos. Suitable bases include, for example, Cs2CO3, K3CO3, CsF, or sodium tert-butoxide. Suitable leaving groups (LG) include, for example, bromine, chloride, or triflate.

[0450] Intermediate (vi) can be prepared from intermediate (vii) as outlined above together with the appropriate intermediate (ii), (iii) or (iv), respectively.

[0451] Plan E

[0452]

[0453] The intermediate (i) compound can be prepared by removing a suitable protecting group (PG) (Scheme E). Suitable protecting groups include, for example, tert-butoxycarbonyl, pivaloyl or tert-butylsulfinyl. Removal of the protecting group can be carried out, for example, under alkaline, acidic or reducing conditions using methods such as those described in "Protecting groups in Organic Synthesis (3rd edition), John Wiley & Sons, NY (1999)", T. Greene and P. Wuts.

[0454] Plan F

[0455]

[0456] The compound of intermediate (viii) can be prepared by condensing the compound of intermediate (v) and intermediate (ix) in the presence of a suitable coupling reagent and a base in step (f) (Scheme F). Suitable coupling reagents include, for example, tBuBrettphosPdG3 in the presence of RuPhos, Pd2(dba)3, RuPhosPdG3, XPhosPdG2 in the presence of X-Phos, or BuBrettphosPdG1 in the presence of BrettPhos. Suitable bases include, for example, Cs2CO3, K3CO3, CsF or sodium tert-butoxide. Suitable leaving groups (LG) include, for example, bromine, chlorine or triflate.

[0457] Plan G

[0458]

[0459] Compounds of intermediate (viii) can also be prepared by condensing compounds of intermediate (x) and intermediate (xi) using reductive amination in step (g) (Scheme G). Suitable conditions include a suitable acid, such as acetic acid, and a suitable reducing agent, including, for example, sodium cyanoborohydride or sodium triacetoxyborohydride.

[0460] Compounds of formula I can also be prepared by condensing intermediates (x) and (xii) in step (g) using the conditions described in Scheme G (Scheme H). Intermediate (xii) can be prepared by removing the benzhydryl group of intermediate (xiii) under appropriate conditions (step h). Suitable conditions include, for example, hydrogenation in the presence of palladium on carbon. Intermediate (xiii) can be prepared as described in Scheme D from intermediate (xiv) as outlined above with the appropriate intermediate (ii), (iii) or (iv), respectively.

[0461] Plan H

[0462]

[0463] The compound of intermediate (xi) can be prepared by removing the benzhydryl group from intermediate (xv) in step (k) (Scheme I). Suitable reagents include, for example, formic acid and palladium on carbon or hydroxylamine. The compound of intermediate (xv) can be prepared by condensing the compound of intermediate (ix) with benzophenone imine in the presence of a suitable coupling reagent and a base in step (j) (Scheme I). Suitable coupling reagents include, for example, tBuBrettphosPdG3 in the presence of RuPhos, Pd2(dba)3 in the presence of X-Phos, RuPhosPdG3, XPhosPdG2 or BuBrettphosPdG1 in the presence of BrettPhos. Suitable bases include, for example, Cs2CO3, K2CO3, CsF or sodium tert-butoxide. Suitable leaving groups (LG) include, for example, bromine, chlorine or triflate. The compound of intermediate (xiv) can be prepared by simultaneously reducing the imine and removing the protecting group (PG) of intermediate (xv) in step (1). Suitable reagents for achieving this transformation include, for example, lithium aluminum hydride.

[0464] Plan I

[0465]

[0466] Plan J

[0467]

[0468] Compounds of intermediates (v) and (x) can be prepared as outlined in Scheme J. Suitable indan-2-ones as depicted by intermediates (xvi) or (xviii) can be converted to intermediates (xvii) or (xix), respectively, in a two-step process involving reduction of the ketone as in step (1) followed by elimination. Reduction of the ketone can be carried out, for example, using sodium borohydride or lithium aluminum hydride, and the elimination is carried out under acidic conditions, for example, by treatment with p-toluenesulfonic acid. Intermediate (x) can be prepared from (xix) or (xvii) by a suitable oxidation procedure (step m). An example of such an oxidation procedure would be a two-step process of dihydroxylation followed by acid treatment. A suitable oxidizing agent would be, for example, osmium tetroxide, and a suitable acid would be, for example, p-toluenesulfonic acid. A further oxidation procedure would be a two-step process of epoxidation followed by acid treatment. A suitable oxidizing agent would be, for example, meta-chloroperbenzoic acid, and a suitable acid would be, for example, silicon dioxide. Reaction of intermediate (x) with a suitable amine source and a suitable reducing agent under reductive amination conditions (as described in Scheme G) will provide the desired intermediate (v) (step n). Suitable amine sources include, for example, ammonium acetate or methylamine, and suitable reducing agents are, for example, sodium cyanoborohydride or sodium triacetoxyborohydride.

[0469] Plan K

[0470]

[0471] Compounds of intermediate (ix) can be prepared as outlined in Scheme K. Suitable protecting groups (including, for example, tert-butoxycarbonyl, pivaloyl or tert-butylsulfinyl) can be introduced in step (o) with intermediate (vii) using methods such as those described in "Protecting groups in Organic Synthesis (3rd edition), John Wiley & Sons, NY (1999)", T. Greene and P. Wuts.

[0472] Compounds of intermediate (vii) can be prepared as outlined in Scheme L. In step (p), intermediate (xx) is condensed with tert-butylsulfenamide to give imine (xxi). In step q, imine (xxi) is reacted with a series of nucleophiles to give intermediate (xxii). Suitable nucleophiles include, for example, organolithiums, organocuprates, Grignard reagents or in the presence of R 6 In the case of trifluoromethyl, it is trifluoromethyltrimethylsilane. In step (r), suitable base is utilized to deprotonate intermediate (xxii) and react with suitable electrophilic agent to generate intermediate (xxiii). Suitable base includes, for example, sodium hydride, LDA or lithium hexamethyldisilazide. Suitable electrophilic agent includes, for example, alkyl halide or trifluoromethanesulfonic acid alkyl ester. In step (s), the method described in " Protecting groups in Organic Synthesis (3rd edition), John Wiley & Sons, NY (1999) ", T.Greene and P.Wuts is used to remove tert-butylsulfinyl group and obtain intermediate (vii).

[0473] Plan L

[0474]

[0475] An alternative route to intermediate (vii) can be achieved as follows (Scheme L). In step (t), a suitable nucleophile is added to intermediate (xx) to give intermediate (xxiv). Suitable nucleophiles include, for example, organolithiums, organocuprates, Grignard reagents or in the presence of R 6 In the case of trifluoromethyl, it is trifluoromethyltrimethylsilane. In step (u), a suitable leaving group (LG) is introduced into intermediate (xxiv) to obtain intermediate (xxv). Suitable leaving groups include, for example, mesylate, tosylate or triflate. As in step (v), the reaction of intermediate (xxv) with a suitable amine nucleophile will obtain intermediate (vii).

[0476] Pharmaceutical composition

[0477] The compounds of the present invention are typically, but not necessarily, formulated into pharmaceutical compositions before being administered to a patient. Therefore, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0478] The pharmaceutical compositions of the present invention can be prepared and packaged in bulk form, from which a safe and effective amount of the compound of the present invention can be extracted and then administered to a patient in a form such as a powder or syrup. Alternatively, the pharmaceutical compositions of the present invention can be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of the compound of the present invention. When prepared in unit dosage form, the pharmaceutical compositions of the present invention typically contain 1 mg to 1000 mg.

[0479] The compositions of the present invention can be in a form suitable for oral use (e.g., as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets), topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams and gels), transdermal administration (e.g., via a transdermal patch), administration by inhalation (e.g., as dry powders, aerosols, suspensions and solutions), administration by insufflation (e.g., as a fine powder), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

[0480] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle that is involved in imparting the form or consistency of a pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed so that interactions that would substantially reduce the efficacy of the compounds of the invention when administered to a patient and that would render the resulting pharmaceutical composition pharmaceutically unacceptable are avoided. In addition, each excipient must be of sufficiently high purity to be pharmaceutically acceptable.

[0481] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected for the specific function they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be selected because they can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected because they can help produce a stable dosage form. Certain pharmaceutically acceptable excipients may be selected because they can help carry or transport one or more compounds of the present invention from one organ or part of the body to another organ or part of the body after administration to the patient. Certain pharmaceutically acceptable excipients may be selected because they can enhance patient compliance.

[0482] Suitable pharmaceutically acceptable excipients include excipients of the following types: diluents, fillers, adhesives, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants and buffers. It will be appreciated by those skilled in the art that some pharmaceutically acceptable excipients can perform more than one function and can perform alternative functions according to the amount of the excipient present in the preparation and other ingredients present in the preparation.

[0483] The knowledge and skills possessed by those skilled in the art enable them to select an appropriate amount of a suitable pharmaceutically acceptable excipient for use in the present invention. In addition, there are a variety of resources available to those skilled in the art that describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically 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).

[0484] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0485] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, 0.5 mg to 0.5 g of active agent (more suitably 0.5 to 100 mg, e.g., 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5% to about 98% by weight of the total composition.

[0486] According to well-known medical principles, the size of the dose of the compound of formula I for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0487] When the compound of the present invention is used for treatment or prevention purposes, it is usually used so that the daily dose range accepted is, for example, 0.1mg / kg to 75mg / kg body weight, if necessary, given in divided doses. Generally speaking, when adopting parenteral route, a lower dosage will be used. Therefore, for example, for intravenous or intraperitoneal administration, the dosage in the range of, for example, 0.1mg / kg to 30mg / kg body weight will be used. Similarly, for administration by inhalation, the dosage in the range of, for example, 0.05mg / kg to 25mg / kg body weight will be used. Oral administration can also be suitable, specifically in tablet form. Typically, a unit dosage form will contain the compound of this invention of about 0.5mg to 0.5g.

[0488] Route of administration

[0489] The compounds of the invention, or pharmaceutical compositions comprising the active compounds, may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, at the desired site of action).

[0490] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, an aerosol, e.g., through 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; by implantation of a reservoir, e.g., subcutaneous or intramuscular.

[0491] In a preferred embodiment, the compound of the invention as defined herein or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as defined herein is administered orally or via injection, eg conveniently by oral administration.

[0492] Therapeutic uses and applications

[0493] The compounds of the present invention are MALT1 inhibitors. Therefore, the compounds are potentially useful therapeutic agents for treating diseases or conditions mediated by MALT1.

[0494] Thus, in one aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0495] In another aspect, the present invention relates to a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition mediated by MALT1.

[0496] In another aspect, the present invention relates to a method of treating a disease or condition mediated by MALT1, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0497] Examples of specific diseases or conditions that the compounds of formula (I) and their pharmaceutically acceptable salts can be used to treat include, but are not limited to:

[0498] 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), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroid leukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), stomach 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, cheek cancer, oral cancer, or GIST (gastrointestinal stromal tumor); and

[0499] ii) immune 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 transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis (including atopic dermatitis), dermatomyositis, psoriasis, Behçet's disease, uveitis, Myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, blistering disorder, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorder, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung disease (including edema, embolism, fibrosis, sarcoidosis, hypertension, and emphysema), silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0500] In particular, the compounds of the present invention (including pharmaceutically acceptable salts) can 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).

[0501] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 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, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or ), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasma cell tumor, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroid leukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, Ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek 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 transplant rejection, chronic allograft rejection, acute or chronic allograft rejection, Plant-versus-host disease, dermatitis (including atopic dermatitis), dermatomyositis, psoriasis, Behçet's disease, uveitis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, blistering disorder, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorder, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung disease (including edema, embolism, fibrosis, sarcoidosis, hypertension, and emphysema), silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0502] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 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).

[0503] In another aspect, the present invention provides methods 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), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), and leukemia. ), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroid leukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), stomach 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 cell carcinoma, neuroblastoma, cervical cancer, kidney cancer, urothelial carcinoma, vulvar cancer, esophageal cancer, salivary gland cancer, nasopharyngeal cancer, cheek 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 transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis (including atopic dermatitis), dermatomyositis, psoriasis, Behçet's disease, uveitis, myasthenia gravis, Graves' disease A method for treating Steffen's disease, Hashimoto's thyroiditis, Sjögren's syndrome, blistering disorders, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung disease (including edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema), silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis or polymyositis, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0504] In another aspect, the present invention provides 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, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0505] In another aspect, the present invention provides a method of inhibiting MALT1 in vitro, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof.

[0506] In another aspect, the present invention provides a method of inhibiting MALT1 in vivo, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof.

[0507] In another aspect, the present invention provides a method of inhibiting MALT1 in vitro and / or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0508] Combination therapy

[0509] The compounds of the present invention may be administered alone as a monotherapy or in combination with one or more other therapeutic agents. The choice of the one or more other therapeutic agents will of course vary depending on the disease or condition to be treated and its severity.

[0510] It is common to use combination therapies to treat certain medical conditions.

[0511] According to a particular aspect of the invention there is provided a combination suitable for the treatment of a disease or condition in which MALT1 is implicated, comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0512] According to this aspect of the invention, there is provided a method for preventing or 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), Waldenstrom's macroglobulinemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia, Leukemia (CML), hairy cell leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroid leukemia, brain (glioma), glioblastoma, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer (including non-small cell lung cancer), gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head 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, cheek 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 transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis (including atopic dermatitis), dermatomyositis, psoriasis, Behçet's disease, uveitis, Myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, blistering disorders, antibody-mediated vasculitis syndrome, immune complex vasculitis, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, lung disease (including edema, embolism, fibrosis, sarcoidosis, hypertension and emphysema), silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis or polymyositis, the combination comprising a compound of the present invention as defined above or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents.

[0513] In another aspect of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0514] Where the term "combination" is used herein, it is understood that this refers to simultaneous, separate, or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. In the case of sequential or separate administration, delayed administration of the second component should not result in a loss of the beneficial effects of the combination.

[0515] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents, and a pharmaceutically acceptable diluent or carrier.

[0516] The one or more other therapeutic agents may comprise another compound of the invention.Thus, in an embodiment, a pharmaceutical composition is provided comprising two compounds of the invention, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable diluent or carrier.

[0517] According to a particular aspect of the invention, there is provided a combination useful for 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).

[0518] Examples of additional therapeutic agents that can be used as part of a combination therapy with the compounds of the invention (e.g., as one of two or more active agents, as part of a dual or triple combination) include, but are not limited to, the following:

[0519] (i) BTK (Bruton's tyrosine kinase) kinase) inhibitors, such as ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, evobrutinib, fenebrutinib, rilzabrutinib, tolebrutinib, MK1026 (ARQ-531), LOXO-305, elsubrutinib, poseltinib, branebrutinib, spebrutinib, luxeptinib, DTRM-555, JnJ64264681, BGB-3959, AS-1763, and remibrutinib;

[0520] (ii) SYK inhibitors, such as fostamatinib, entospletinib, HMPL-523, IC-265, SKI-O-703, cerdulatinib, PRT-2761, GSK-264264, SYHX-1901, MK-8457, HM-43239, R-348, and PUR-1800;

[0521] (iii) PKC inhibitors, such as darovasertib, MS-553, enzastaurin, safingol, ruboxistaurin, and AR-13503;

[0522] (iv) PI3K pathway inhibitors, such as alpelisib, duvelisib, copanlisib, idelalisib, umbralisib, serabelisib, CHF-6523, BDP-681, zandelisib, ART-001, buparlisib, OP-11, HMPL-689, dezapelisib, seletalisib, epivotide, IOA-244, and SHC-014 748M, LX-086, inavolisib, MEN-1611, eganelisib, leniolisib, 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;

[0523] (v) Bcl family inhibitors, such as ABT-737, HA14-1, BH3I-1, A-1155463, A-1331852, A-1210477, BDA-366, TW-37, S44563, S64315 (MIK665), S63845, BCL-201, AMG176, AZD-0466, AZD5991, UMI-77, navitoclax, pelcitoclax, obatoclax, sabutoclax, apogossypol, gossypol, antimycin A, gambogic acid, LP-118, FCN-338, BGB-11417, UBX-1325, LP-108, VOB-560, lisaftoclax, murizatoclax, venetoclax, ZN-d5, and ABBV-167;

[0524] (vi) JAK inhibitors, such as gusacitinib, delgocitinib, tofacitinib, abrocitinib, ruxolitinib, baricitinib, fedratinib, upadacitinib, filgotinib, peficitinib, TD-8236, TD-0903, CEE-321, lorpucitinib, WXSH-0150, SYHX-1901, seletinib, izencitinib, KL-130008, WP-1066, gusacitinib, INCB-52793, A C-1101, ATI-1777, SHR-0302, CPL-409116, momelotinib, brepocitinib, TTL-018, TD-5202, LP-0184, INCB-054707, jaktinib, TQ-05105, itacitinib, AZD-0449, GLPG-0555, LW-104, ARQ-252, WXFL-10203614, golidocitinib, deuruxolitinib, CJ-15314, CS-12192, ritlecitinib, R-348, ATI-2138, and ilginatinib;

[0525] (vii) PIM kinase inhibitors, such as uzansertib, TP-3654, MEN-1703, ETH-155008, abemaciclib, and SF-1126;

[0526] (viii) mTORC inhibitors, such as rapamycin, sirolimus, novolimus, umirolimus, zotarolimus, temsirolimus, everolimus, merilimus, eRapa, and ridaforolimus;

[0527] (ix) rituximab or other B cell antigen-binding antibodies and immune cell redirecting agents (e.g., blinatumomab or CAR-T cells);

[0528] (x) anti-PD-1 antibodies, such as nivolumab, pembrolizumab, lambrolizumab, pidilzumab, and BGB-A317;

[0529] (xi) anti-PD-L1 antibodies, such as atezolizemab, avelumab, durvalumab, MEDI-4736, and MPDL3280A;

[0530] (xii) antibodies that inhibit 4-1BB-ligand interactions, such as utomilumab; and

[0531] (xiii) Antibodies that inhibit the interaction of CTLA-4 with its ligand, such as ipilumab, tremelimumab, or those disclosed in WO2014 / 207063.

[0532] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

[0533] Such conjoint / combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0534] Such combination therapies employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within an approved dosage range and / or dosage described, for example, in the relevant publication references.

[0535] Examples

[0536] General procedure:

[0537] The following examples illustrate methods for preparing the compounds of the present invention. Starting materials were prepared according to procedures known in the art or as described herein, or were commercially available. Commercially available reagents were used without further purification. Where reaction temperatures are not specified, reactions were performed at ambient temperature, typically 17°C to 27°C.

[0538] Those skilled in the art will appreciate that reaction temperatures, reaction times, and amounts of reagents may vary from those set forth herein.

[0539] In passing 1 H NMR spectroscopy: For the characterization of the compounds described herein, spectra were recorded on a 400 MHz Bruker Avance III HD instrument and a 300 MHz Bruker Fourier HD instrument. Spectra were recorded at ambient temperature, unless temperature was included. 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.

[0540] In cases where compounds described in this invention were characterized by LCMS data, molecular weight was determined using the conditions listed below.

[0541] Method A: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 1.7 μm, 50 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B].

[0542] Method B: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: XBridge C18, 2.5 μm, 50 × 2.1 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B].

[0543] Method C: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 1.7 μm, 50 × 2.1 mm. Conditions: 0.05% formic acid in water [eluent A], 0.05% formic acid in MeCN [eluent B].

[0544] Method D: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Ascentis Express C18, 2.7 μm, 50×2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B].

[0545] Method E: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 1.7 μm, 50 × 2.1 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B].

[0546] Method F: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 3.5 μm, 50 × 4.6 mm. Conditions: 5 mM NH4HCO3 in water [eluent A], MeCN [eluent B].

[0547] Method G: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 1.7 μm, 50 × 2.1 mm. Conditions: 5 mM ammonium acetate in water [eluent A], MeCN [eluent B].

[0548] Method H: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 1.7 μm, 50×2.1 mm. Conditions: 0.1% TFA in water [eluent A], 0.1% TFA in MeCN [eluent B].

[0549] Method I: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 1.7 μm, 100×2.1 mm. Conditions: 0.1% TFA in water [eluent A], 0.1% TFA in MeCN [eluent B].

[0550] Method J: Shimadzu 2020 (SPD-M40 PDA 220 / 254 nm and MS detector). Column: Waters Acquity BEH C18, 1.7 μm, 100 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B].

[0551] Method K: Shimadzu 2020 (SPD-M40 PDA 254 / 280 nm and MS detector). Column: Waters Acquity BEH C18, 1.7 μm, 100 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B].

[0552] Method L: Waters Acquity I-Class Plus (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 1.7 μm, 100 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B].

[0553] Method M: Dionex UHPLC Ultimate 3000 (DAD 190-340 nm and Thermo Scientific ISQEC detector). Column: Kinetex XB-C18, 2.6 μm, 50 × 4.6 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B].

[0554] Method N: Dionex UHPLC Ultimate 3000 (DAD 190-340 nm and Thermo Scientific ISQEC detector). Column: Kinetex XB-C18, 2.6 μm, 50 × 4.6 mm. Conditions: 0.1% ammonia water [eluent A], MeCN [eluent B].

[0555] Method O: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: XBridge C18, 3.5 μm, 100 × 4.6 mm. Conditions: 10 mM NH4HCO3 in water [eluent A], MeCN [eluent B].

[0556] Method P: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: XBridge BEH C18, 2.5 μm, 50 × 2.1 mm. Conditions: 5 mM NH4HCO3 in water [eluent A], MeCN [eluent B].

[0557] Method Q: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: YMC-Triart C18, 1.9 μm, 50 × 2.1 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B].

[0558] Method R: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: YMC-Triart C18, 1.9 μm, 50 × 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], MeCN [eluent B].

[0559] Method S: Agilent 1260 (Waters Acquity PDA 210-400 nm and Waters Acquity SQ detector). Column: X-Select CSH C18, 5 μm, 100×4.6 mm. Conditions: 10 mM ammonium acetate in water [eluent A], MeCN [eluent B].

[0560] Method T: Dionex UHPLC Ultimate 3000 (DAD 190-340 nm and Thermo Scientific ISQEC detector). Column: Kinetex XB-C18, 2.6 μm, 50 × 4.6 mm. Conditions: Water [eluent A], MeCN [eluent B].

[0561] Preparative HPLC was performed using Shimadzu CBM-20A / SIL-10AP; Shimadzu Nexera; Waters Delta; Gilson GX-271; and Agilent 1260 Infinity II.

[0562] Preparative SFC was performed using Waters SFC-150-I; Water SFC-150-II; Waters SFC-200; Sepiatec-200.

[0563] Automated purification was performed using Interchim Puriflash XS 520: normal phase PF-50SIHP-JP; reverse phase PF-15C18HP.

[0564] abbreviation:

[0565]

[0566]

[0567]

[0568]

[0569] Intermediate synthesis

[0570] Intermediate 1: (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfenyl Amide

[0571] To a stirred solution of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (5.0 g, 14.0 mmol, CAS 336105-31-8) in 2-methyltetrahydrofuran (50 mL) was added LDA (2 M in THF, 21 mL, 42.0 mmol) at -78 °C, and the mixture was stirred for 1 h. Iodomethane (11.9 g, 83.7 mmol) was added, and the mixture was slowly allowed to reach room temperature and then stirred for 12 h. The mixture was cooled to 0 °C, then quenched with saturated aqueous NH4Cl, diluted with water, and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting with 10%-15% EtOAc in petroleum ether) to provide the title compound (2.5 g). LCMS (Method A): 372.2 [M+H] + .

[0572] Intermediate 2: (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride

[0573] To a stirred solution of intermediate 1 (3.3 g, 8.87 mmol) in EtOAc (5 mL) was added 4 M HCl in 1,4-dioxane (10 mL) at room temperature, and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure. The crude product was triturated in n-pentane and filtered to provide the title compound (2.7 g). LCMS (Method A): 268.0 [M+H] + .

[0574] Intermediate 3: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide Amine 1,1-dioxide

[0575] To a stirred solution of intermediate 2 (3.3 g, 8.87 mmol) in pyridine (2.0 mL, 24.6 mmol) was added To the mixture was added 1,1-dioxide (50% EtOAc, 26.1 g, 82.1 mmol) and tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (1.46 g, 8.21 mmol, CAS 64096-87-3), and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting with 50%-55% EtOAc in petroleum ether) to provide the title compound (2.87 g). LCMS (Method A): 428.2 [M+H] + .

[0576] Intermediate 4: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyloxazole-5-carboxamide

[0577] To a stirred solution of intermediate 2 (3.3 g, 8.87 mmol) in pyridine (5.0 mL, 24.6 mmol) was added oxazole-5-carboxylic acid (0.17 g, 1.48 mmol, CAS 118994-90-4) and DMAP (12 mg, 0.01 mmol) and stirred at room temperature for 10 min. The mixture was cooled at 0 ° C., POCl 3 (0.15 g, 0.99 mmol) was then added, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and then extracted with EtOAc. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (neutral alumina, eluted with 40% EtOAc in petroleum ether) to provide the title compound (0.38 g). LCMS (Method A): 363.0 [M+H] + .

[0578] Intermediate 5: (S)-1-acetyl-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylazetidine Alkane-3-carboxamide

[0579] The title compound (0.45 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (0.4 g, 1.30 mmol), 1-acetylazetidine-3-carboxylic acid (0.28 g, 0.15 mmol, CAS 97628-91-6), DMAP (10 mg, 0.01 mmol), and POCl (0.2 g, 0.13 mmol) in pyridine (10 mL) at room temperature for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 70%-100% EtOAc in petroleum ether). LCMS (Method A): 392.9 [M+H] + .

[0580] Intermediate 6: 1-Methyl-2,3-dihydro-1H-inden-2-amine hydrochloride

[0581] To a stirred solution of 1-methyl-1,3-dihydro-2H-inden-2-one (0.45 g, 3.08 mmol, CAS 35587-60-1) in ethanol (5.0 mL) was added ammonium acetate (3.56 g, 46.2 mmol) and sodium cyanoborohydride (0.23 g, 3.69 mmol) and stirred at 80° C. for 4 h. The mixture was cooled to 0° C., then 1 M aqueous HCl was added to adjust the pH to 3, and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (ATLANTIS T319, 19×250 mm×5 μm, flow rate: 18 mL / min, 0.05% HCl in water with MeCN from 10% to 35% over 7 min, held at 35% for 1 min, then ramped to 98% over 0.1 min and held for 6.9 min) to provide the title compound (0.32 g). LCMS (Method A): 148.2 [M+H] + .

[0582] Intermediate 7: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylmorpholine-4-carboxamide

[0583] To a stirred solution of triphosgene (0.39 g, 1.32 mmol) in DCM (5 mL) was added intermediate 2 (0.4 g, 1.30 mmol) at 0 ° C and stirred for 5 min. Triethylamine (0.6 mL, 3.93 mmol) was added followed by morpholine (0.12 mL, 1.32 mmol) and stirred at 0 ° C for 1 h. The mixture was quenched with ice-cold water and then extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 30%-70% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (method A): 381.0 [M+H] + .

[0584] Intermediate 8: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylthiomorpholine-4-carboxamide 1, 1-Dioxide

[0585] The title compound (0.35 g) was prepared in a similar manner to Intermediate 7 from Intermediate 2 (0.3 g, 0.99 mmol), thiomorpholine-1,1-dioxide (0.16 g, 1.19 mmol), triethylamine (0.43 mL, 2.97 mmol), triphosgene (0.32 g, 1.09 mmol) in DCM (5 mL) at 0° C. for 1 h. Purification was performed by flash chromatography (silica gel, eluting with 30%-70% EtOAc in petroleum ether). LCMS (Method A): 429.0 [M+H] + .

[0586] Intermediate 9: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N,4-dimethylpiperidin-1- Formamide

[0587] The title compound (0.35 g) was prepared in a similar manner to Intermediate 7 from Intermediate 2 (0.35 g, 1.15 mmol), 4-methylpiperidin-4-ol (0.14 g, 1.21 mmol), triethylamine (0.50 mL, 3.45 mmol), and triphosgene (0.37 g, 1.21 mmol) in DCM (5 mL) at 0° C. for 1 h. Purification was performed by flash chromatography (silica gel, eluting with 30%-70% EtOAc in petroleum ether). LCMS (Method A): 411.0 [M+H] + .

[0588] Intermediate 10: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,4-dimethyl-4-(trimethylsilyl)- 1-[4-[(1-[4-(2-methyl-1-thiazolyl)oxy)piperidine

[0589] To a stirred solution of intermediate 9 (0.35 g, 1.32 mmol) in DCM (5 mL) was added TFMTMS (0.19 g, 1.71 mmol), triethylamine (0.37 mL, 2.58 mmol) and DMAP (5 mg, 0.04 mmol) at 0 ° C. The mixture was stirred at room temperature for 3 h, then quenched with ice-cold water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 10%-50% EtOAc in petroleum ether) to provide the title compound (0.30 g). LCMS (Method A): 483.1 [M+H] + .

[0590] Intermediate 11: N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2, 2,2-trifluoroethyl)-N,4-dimethyl-4-((trimethylsilyl)oxy)piperidine-1-carboxamide

[0591] To a stirred solution of intermediate 10 (0.35 g, 1.32 mmol) and 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.12 g, 0.62 mmol, CAS 74413-86-8) in 1,4-dioxane (3 mL) was added CsCO (0.50 g, 1.55 mmol), and the mixture was degassed with nitrogen for 5 min. tBuBrettphosPdG (0.04 g, 0.04 mmol) and RuPhos (0.04 g, 0.09 mmol) were added, and the mixture was heated at 120° C. under microwave irradiation for 2 h. The mixture was allowed to cool, then diluted with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting with 10%-50% EtOAc in petroleum ether) to provide the title compound (0.15 g). LCMS (Method A): 562.4 [M+H] + .

[0592] Intermediate 12: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-4-carboxylate Amide

[0593] The title compound (0.18 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (0.7 g, 2.29 mmol), tetrahydro-2H-pyran-4-carboxylic acid (0.45 g, 3.45 mmol, CAS 5337-03-1), DMAP (5 mg, 0.04 mmol), and POCl (0.32 mL, 3.43 mmol) in pyridine (10 mL) at room temperature for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 70%-100% EtOAc in petroleum ether). LCMS (Method A): 382.0 [M+H] + .

[0594] Intermediate 13: (S)-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)benzene (2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfenamide

[0595] The title compound (0.17 g) was prepared in a similar manner to Intermediate 11 from Intermediate 1 (0.4 g, 1.07 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.21 g, 1.08 mmol, CAS 74413-86-8), Cs2CO3 (1.40 g, 4.30 mmol), tBuBrettphosPdG3 (0.18 g, 0.22 mmol) and RuPhos (0.2 g, 0.43 mmol) in 1,4-dioxane (10 mL) at 120° C. for 2 h. The crude product was used. LCMS (Method A): 453.2 [M+H] + .

[0596] Intermediate 14: 1,1-dimethyl-N-(4-((S)-2,2,2-trifluoro-1-(methylamino)ethyl)phenyl)-2,3- Dihydro-1H-inden-2-amine hydrochloride

[0597] To a stirred solution of intermediate 13 (0.17 g, 0.37 mmol) in EtOAc (5 mL) was added 4 M HCl in 1,4-dioxane (5 mL) at 0°C, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The crude product was triturated in diethyl ether and filtered to provide the title compound (0.12 g). LCMS (Method A): 349.6 [M+H] + .

[0598] Intermediate 15: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylpiperidin-1-yl amine

[0599] The title compound (0.3 g) was prepared in a similar manner to Intermediate 7 from Intermediate 2 (0.13 g, 0.30 mmol), piperidin-4-ol (0.03 g, 0.30 mmol), triethylamine (0.05 g, 0.30 mmol), and triphosgene (0.06 g, 0.21 mmol) in DCM (8 mL) at room temperature for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 40% EtOAc in petroleum ether). LCMS (Method A): 395.1 [M+H] + .

[0600] Intermediate 16: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4-((trimethylsilyl)oxy) 1-Methyl)piperidine-1-carboxamide

[0601] To a stirred solution of intermediate 15 (0.30 g, 0.76 mmol) in DCM (10 mL) was added DIPEA (0.37 mL, 2.58 mmol) at 0°C, followed by the addition of trimethylsilyl chloride (0.16 g, 1.52 mmol) after 10 min. The mixture was stirred at room temperature for 2 h, then quenched with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 5% EtOAc in petroleum ether) to provide the title compound (0.30 g). LCMS (Method B): 467.4 [M+H] + .

[0602] Intermediate 17: (S)-3-Acetamido-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylpropionamide

[0603] The title compound (0.35 g) was prepared in a similar manner to Intermediate 3 from Intermediate 2 (0.3 g, 0.99 mmol), pyridine (0.24 mL, 2.96 mmol), (50% EtOAc, 4.38 mL, 6.88 mmol) and 3-acetamidopropionic acid (0.19 g, 1.48 mmol, CAS 3025-95-4) were prepared at room temperature for 12 h. The crude product was purified by flash chromatography (silica gel, eluting with 40% EtOAc in petroleum ether). LCMS (Method A): 381.0 [M+H] + .

[0604] Intermediate 18: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyloxazole-4-carboxamide

[0605] The title compound (0.35 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (0.35 g, 1.15 mmol), oxazole-4-carboxylic acid (0.16 g, 1.38 mmol, CAS 23012-13-7), and POCl (0.17 mL, 0.172 mmol) in pyridine (3 mL) at room temperature for 3 h. Purification was performed by flash chromatography (silica gel, eluting with 50% EtOAc in petroleum ether). LCMS (Method A): 363.1 [M+H] + .

[0606] Intermediate 19: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methoxy-N-methylacetamide

[0607] The title compound (0.25 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (0.5 g, 1.64 mmol), 2-methoxyacetic acid (0.18 g, 1.97 mmol, CAS 625-45-6), DMAP (20 mg, 0.23 mmol), and POCl (0.37 g, 2.46 mmol) in pyridine (2.5 mL) at room temperature for 1 h. Purification was performed by flash chromatography (silica gel, eluting with 20%-25% EtOAc in petroleum ether). LCMS (Method A): 340.0 [M+H] + .

[0608] Intermediate 20: N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2, 2,2-trifluoroethyl)-2-methoxy-N-methylacetamide

[0609] The title compound (0.10 g) was prepared in a similar manner to Intermediate 11 from Intermediate 19 (0.3 g, 0.89 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.17 g, 0.89 mmol, CAS 74413-86-8), Cs2CO3 (1.15 g, 3.54 mmol), tBuBrettphosPdG3 (75 mg, 0.09 mmol) and RuPhos (82 mg, 0.18 mmol) in 1,4-dioxane (3 mL) at 120° C. for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 20% EtOAc in petroleum ether). LCMS (Method A): 421.2 [M+H] + .

[0610] Intermediate 21: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-methoxy-N-methylpropionamide

[0611] The title compound (0.30 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (0.40 g, 1.30 mmol), 3-methoxypropionic acid (0.27 g, 2.65 mmol, CAS 2544-06-1), DMAP (20 mg, 0.23 mmol), and POCl (0.20 g, 1.30 mmol) in pyridine (10 mL) at room temperature for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 50%-100% EtOAc in petroleum ether). LCMS (Method A): 354.0 [M+H] + .

[0612] Intermediate 22: N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2, 2,2-trifluoroethyl)-3-methoxy-N-methylpropionamide

[0613] The title compound (0.20 g) was prepared in a similar manner to Intermediate 11 from Intermediate 21 (0.3 g, 0.85 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.17 g, 0.89 mmol, CAS 74413-86-8), Cs2CO3 (0.83 g, 2.55 mmol), tBuBrettphosPdG3 (34 mg, 0.04 mmol) and RuPhos (40 mg, 0.09 mmol) in 1,4-dioxane (5 mL) at 120° C. for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 70%-100% EtOAc in petroleum ether). LCMS (Method A): 435.3 [M+H] + .

[0614] Intermediate 23: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate

[0615] To a stirred solution of 1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethan-1-ol (3.0 g, 16.0 mmol, CAS 1188477-81-7) in DCM (30 mL) was added trifluoromethanesulfonic anhydride (3.6 mL, 24.1 mmol) at -40 ° C., and the mixture was stirred at -40 ° C. for 1 h. The mixture was diluted with ice / water and then extracted with hexanes. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (3.5 g). LCMS (Method A): 387.9 [M+H] + .

[0616] Intermediate 24: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoro-N-methylethan-1-amine

[0617] A solution of intermediate 23 (3.0 g, 7.73 mmol) in methylamine in THF (2 M, 30 mL) was stirred at 60 ° C for 4 h. The mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography (silica gel, eluting with 10%-70% EtOAc in petroleum ether) to provide the title compound (2.5 g). LCMS (Method A): 269.2 [M+H] + .

[0618] Intermediate 25: 1-(6-bromopyridin-3-yl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride

[0619] To a stirred solution of intermediate 24 (2.5 g, 9.29 mmol) in 1,4-dioxane (25 mL) was added 4 M HCl in 1,4-dioxane (25 mL) at 0°C, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was triturated in diethyl ether and filtered to provide the title compound (2.5 g). LCMS (Method C): 269.0 [M+H] + .

[0620] Intermediate 26: N-(1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-5-(2,2,2-trifluoro-1-(methylamino)- (4-Methyl)ethyl)pyridin-2-amine

[0621] To a stirred solution of intermediate 25 (1.5 g, 4.91 mmol) and 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (1.32 g, 6.69 mmol, CAS 74413-86-8) in toluene (15 mL) was added sodium tert-butoxide (2.14 g, 22.3 mmol), and the mixture was degassed with argon for 5 min. Pd2(dba)3 (0.51 g, 0.56 mmol) and X-Phos (0.53 g, 1.12 mmol) were added, and the mixture was heated at 110 ° C. under microwave irradiation for 2 h. The mixture was poured into 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 chromatography (silica gel, eluting with 13%-15% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method A): 350.3 [M+H] + .

[0622] Intermediate 27: N-(1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-5-(2,2,2-trifluoro-1-(methylamino)- (4-[4-(2-amino-3-yl)ethyl)pyridin-2-amine hydrochloride)

[0623] To a stirred solution of intermediate 26 (0.45 g, 1.29 mmol) in 1,4-dioxane (2.5 mL) was added 4 M HCl in 1,4-dioxane (2.5 mL) at 0°C, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was triturated in EtOAc and filtered to provide the title compound (0.40 g). LCMS (Method A): 350.3 [M+H] + .

[0624] Intermediate 28: (S)-3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-3-methylamino Heterocyclobutane-1-carboxylic acid tert-butyl ester

[0625] The title compound (0.31 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (1.70 g, 6.51 mmol), 1-(tert-butoxycarbonyl)-3-methylazetidine-3-carboxylic acid (1.40 g, 6.51 mmol, CAS 887591-62-0), and POCl (0.73 mL, 7.80 mmol) in pyridine (15 mL) at room temperature for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 20%-50% EtOAc in petroleum ether). LCMS (Method A): 409.3 [M-tBu+H] + .

[0626] Intermediate 29: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,3-dimethylazetidine-3- Formamide hydrochloride

[0627] To a stirred solution of intermediate 28 (0.30 g, 0.64 mmol) in 1,4-dioxane (5 mL) was added 4 M HCl in 1,4-dioxane (5 mL) at 0°C, and the mixture was stirred at 0°C for 4 h. The mixture was concentrated under reduced pressure. The crude product was triturated in diethyl ether and filtered to provide the title compound (0.30 g). LCMS (Method A): 365.3 [M+H] + .

[0628] Intermediate 30: (S)-1-Acetyl-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,3-dimethylazepine Cyclobutane-3-carboxamide

[0629] To a stirred mixture of intermediate 29 (3.0 g, 7.73 mmol) in DCM (6 mL) was added triethylamine (0.32 mL, 2.25 mmol) and acetic anhydride (0.1 mL, 1.12 mmol) at 0°C and stirred for 3 h. The mixture was poured into ice water, basified with saturated aqueous NaHCO3 solution, and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 20%-50% EtOAc in petroleum ether) to provide the title compound (0.40 g). LCMS (Method A): 409.3 [M+H] + .

[0630] Intermediate 31: (S)-3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-3-fluoroazepine tert-Butyl cyclobutane-1-carboxylate

[0631] The title compound (1.38 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (2.20 g, 8.21 mmol), 1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-carboxylic acid (1.80 g, 8.21 mmol, CAS 1126650-67-6), and POCl (1.88 mL, 20.1 mmol) in pyridine (12 mL) at room temperature for 30 min. Purification was performed by flash chromatography (silica gel, eluting with 10%-15% EtOAc in petroleum ether). LCMS (Method A): 413.3 [M-tBu+H] + .

[0632] Intermediate 32: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-fluoro-N-methylazetidine-3- Formamide hydrochloride

[0633] To a stirred solution of intermediate 31 (1.38 g, 2.94 mmol) in EtOAc (20 mL) was added 4 M HCl in 1,4-dioxane (20 mL) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was triturated in diethyl ether and filtered to provide the title compound (1.10 g). LCMS (Method A): 369.0 [M+H] + .

[0634] Intermediate 33: (S)-1-acetyl-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-fluoro-N-methylazepine Cyclobutane-3-carboxamide

[0635] To a stirred mixture of intermediate 32 (1.10 g, 2.71 mmol) in DCM (8 mL) was added pyridine (8 mL), DMAP (0.03 g, 0.25 mmol) and acetic anhydride (0.56 g, 5.43 mmol) at room temperature and stirred for 2 h. The mixture was poured into ice water, basified with saturated aqueous NaHCO3 solution, and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 40%-50% EtOAc in petroleum ether) to provide the title compound (1.0 g). LCMS (Method A): 411.3 [M+H] + .

[0636] Intermediate 34: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-2-(2-oxopyrrolidine- 1-amino)acetamide

[0637] The title compound (0.40 g) was prepared in a similar manner to Intermediate 3 from Intermediate 2 (0.5 g, 1.87 mmol), DIPEA (1.30 mL, 7.46 mmol), Prepared by mixing 2-(2-oxopyrrolidin-1-yl)acetic acid (0.32 g, 2.24 mmol, CAS 53934-76-2) in THF (5 mL) at 80 ° C for 12 h. The crude product was purified by flash chromatography (silica gel, eluting with 80% EtOAc in petroleum ether). LCMS (Method A): 393.3 [M+H] + .

[0638] Intermediate 35: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(2-oxopyrrolidine- 1-amino)propionamide

[0639] The title compound (0.35 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 2 (0.4 g, 1.32 mmol), DIPEA (0.73 mL, 3.96 mmol), Prepared by mixing 2-[[(2-oxopyrrolidin-1-yl)propanoic acid]-1-[ ... + .

[0640] Intermediate 36: (S)-5-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)amino)-5-oxopentanoic acid ethyl esters

[0641] The title compound (0.59 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (0.75 g, 2.46 mmol), 5-ethoxy-5-oxopentanoic acid (0.16 g, 9.85 mmol, CAS 1070-62-8), and POCl (0.90 mL, 9.85 mmol) in pyridine (7.5 mL) at room temperature for 1 h. Purification was performed by flash chromatography (silica gel, eluting with 10%-15% EtOAc in petroleum ether). LCMS (Method A): 410.1 [M+H] + .

[0642] Intermediate 37: 5-(((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2, 2,2-Trifluoroethyl)(methyl)amino)-5-oxopentanoic acid ethyl ester

[0643] The title compound (0.24 g) was prepared in a similar manner to Intermediate 11 from Intermediate 36 (0.5 g, 1.22 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.24 g, 1.22 mmol, CAS 74413-86-8), Cs2CO3 (1.19 g, 3.66 mmol), tBuBrettphosPdG3 (104 mg, 0.12 mmol) and RuPhos (114 mg, 0.24 mmol) in 1,4-dioxane (4 mL) and DMF (1 mL) at 120° C. for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 20%-25% EtOAc in petroleum ether). LCMS (Method A): 491.3 [M+H] + .

[0644] Intermediate 38: (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)amino)-4-oxobutanoic acid ethyl esters

[0645] The title compound (1.2 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (1.0 g, 3.30 mmol), 4-ethoxy-4-oxobutanoic acid (0.87 g, 6.60 mmol, CAS 1070-34-4), and POCl (0.63 mL, 6.60 mmol) in pyridine (10 mL) at room temperature for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 70%-100% EtOAc in petroleum ether). LCMS (Method A): 396.3 [M+H] + .

[0646] Intermediate 39: 4-(((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2, 2,2-Trifluoroethyl)(methyl)amino)-4-oxobutanoic acid ethyl ester

[0647] The title compound (0.25 g) was prepared in a similar manner to Intermediate 11 from Intermediate 38 (0.8 g, 2.02 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.40 g, 2.02 mmol, CAS 74413-86-8), Cs2CO3 (1.64 g, 5.05 mmol), tBuBrettphosPdG3 (0.34 g, 0.40 mmol) and RuPhos (0.37 g, 0.81 mmol) in 1,4-dioxane (8 mL) at 120° C. for 4 h. Purification was performed by flash chromatography (silica gel, eluting with 70%-100% EtOAc in petroleum ether). LCMS (Method A): 477.5 [M+H] + .

[0648] Intermediate 40: (S)-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl chloride

[0649] To a stirred solution of intermediate 2 (1.50 g, 4.93 mmol) in DCM (15 mL) was added triphosgene (1.53 g, 5.17 mmol) portionwise at 0 ° C. and stirred for 30 min. Triethylamine (1.37 mL, 9.85 mmol) was added and stirred at room temperature for 2 h. The mixture was quenched with ice-cold water and then extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 20% EtOAc in petroleum ether) to provide the title compound (1.0 g). LCMS (Method A): 329.9 [M+H] + .

[0650] Intermediate 41: (S)-3-(((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)oxy)nitrogen Heterocyclobutane-1-carboxylic acid tert-butyl ester

[0651] To a stirred mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (0.63 g, 3.63 mmol, CAS 141699-55-0) in THF (15 mL) was added sodium hydride (60% in mineral oil, 0.24 g, 6.05 mmol) portionwise at 0°C and stirred at room temperature for 30 min. Intermediate 40 (1.0 g, 3.03 mmol) as a solution in THF (10 mL) was added at 0°C, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, eluted with 20% EtOAc in petroleum ether) to provide the title compound (0.7 g). LCMS (Method A): 411.3 [M-tBu+H] + .

[0652] Intermediate 42: (R)-N-(1-(4-bromophenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxo Chemical

[0653] The title compound (1.0 g) was prepared in a similar manner to Intermediate 3 from (R)-1-(4-bromophenyl)-N-methylethan-1-amine hydrochloride (1.2 g, 5.05 mmol, CAS 2366996-95-2), pyridine (1.22 mL, 15.2 mmol), Prepared by adding 1,1-dioxide (50% EtOAc, 15.2 mL, 50.5 mmol) and tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (0.90 g, 5.05 mmol, CAS 64096-87-3) at room temperature for 16 h. The crude product was purified by flash chromatography (silica gel, eluting with 50%-55% EtOAc in petroleum ether). LCMS (Method A): 374.0 [M+H] + .

[0654] Intermediate 43: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)nitrile Heterocyclobutane-3-carboxamide

[0655] The title compound (0.45 g) was prepared in a similar manner to Intermediate 4 from Intermediate 2 (0.50 g, 1.64 mmol), 1-(methylsulfonyl)azetidine-3-carboxylic acid (0.38 g, 2.13 mmol, CAS 1219828-27-9), and POCl (0.30 mL, 3.28 mmol) in pyridine (5 mL) at room temperature for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 25%-30% EtOAc in petroleum ether). LCMS (Method A): 430.0 [M+H] + .

[0656] Intermediate 44: (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidin-1-carboxylate tert-Butyl ester

[0657] The title compound (2.1 g) was prepared in a similar manner to Intermediate 3 from Intermediate 2 (2.0 g, 6.56 mmol), pyridine (2.11 mL, 26.3 mmol), Prepared by mixing 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.31 g, 1.98 mmol, CAS 84358-13-4) (50% EtOAc, 29.3 mL, 45.97 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid at room temperature for 12 h. The crude product was purified by flash chromatography (silica gel, eluting with 30% EtOAc in petroleum ether). LCMS (Method A): 425.1 [M-tBu+H] + .

[0658] Intermediate 45: (S)-4-((1-(4-((2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl tert-Butyl(methyl)carbamoyl)piperidine-1-carboxylate

[0659] The title compound (1.17 g) was prepared in a similar manner to Intermediate 11 from Intermediate 44 (2.1 g, 4.38 mmol), 2,3-dihydro-1H-inden-2-amine hydrochloride (0.74 g, 4.38 mmol, CAS 2975-41-9), Cs2CO3 (5.70 g, 17.5 mmol), tBuBrettphosPdG3 (0.37 g, 0.43 mmol) and RuPhos (0.40 g, 0.87 mmol) in 1,4-dioxane (42 mL) at 130° C. for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 50% EtOAc in petroleum ether). LCMS (Method A): 532.3 [M+H] + .

[0660] Intermediate 46: 1-(5-bromopyridin-2-yl)-2,2,2-trifluoro-N-methylethan-1-amine

[0661] The title compound (3.9 g) was prepared in a similar manner to Intermediate 24 from 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (7.0 g, 18.0 mmol, CAS 1374038-21-7) and methylamine in THF (2 M, 35 mL) at 60° C. for 2 h. The crude product was purified by flash chromatography (silica gel, eluting with 10%-15% EtOAc in petroleum ether). LCMS (Method A): 269.1 [M+H] + .

[0662] Intermediate 47: 1-(5-bromopyridin-2-yl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride

[0663] To a stirred solution of intermediate 46 (2.0 g, 7.43 mmol) in EtOAc (10 mL) was added 4 M HCl in 1,4-dioxane (10 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure to provide the title compound (2.0 g). LCMS (Method A): 269.1 [M+H] + .

[0664] Intermediate 48: N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxylate Amide 1,1-dioxide

[0665] The title compound (5.8 g) was prepared in a similar manner to Intermediate 3 from Intermediate 47 (6.0 g, 19.8 mmol), pyridine (60 mL), Prepared by heating 1,1-dioxane (50% EtOAc, 31.5 g, 99.0 mmol) and tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (4.30 g, 23.8 mmol, CAS 64096-87-3) at 60° C. for 5 h. The crude product was purified by flash chromatography (silica gel, eluting with 35%-40% EtOAc in petroleum ether). LCMS (Method A): 431.0 [M+H] + .

[0666] Intermediate 49: (S)-3-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)azetidine tert-Butyl 1-oxanecarboxylate

[0667] The title compound (2.8 g) was prepared in a similar manner to Intermediate 3 from Intermediate 2 (2.0 g, 6.56 mmol), pyridine (2.11 mL, 26.3 mmol), Prepared by adding 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (50% EtOAc, 29.3 mL, 46.0 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1.98 g, 9.85 mmol, CAS 142253-55-2) at room temperature for 12 h. The crude product was purified by flash chromatography (silica gel, eluting with 30% EtOAc in hexanes). LCMS (Method A): 397.0 [M-tBu+H] + .

[0668] Intermediate 50: 3-(((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2, tert-Butyl 2,2-trifluoroethyl)(methyl)carbamoyl)azetidine-1-carboxylate

[0669] The title compound (0.45 g) was prepared in a similar manner to Intermediate 11 from Intermediate 49 (0.9 g, 1.99 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.39 g, 1.99 mmol, CAS 74413-86-8), Cs2CO3 (2.59 g, 7.97 mmol), tBuBrettphosPdG3 (0.20 g, 0.24 mmol) and RuPhos (0.23 g, 0.49 mmol) in 1,4-dioxane (27 mL) at 160° C. for 1 h. Purification was performed by flash chromatography (silica gel, eluting with 40% EtOAc in petroleum ether). LCMS (Method A): 532.3 [M+H] + .

[0670] Intermediate 51: (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide

[0671] The title compound (1.9 g) was prepared in a similar manner to Intermediate 3 from Intermediate 2 (1.75 g, 6.02 mmol), pyridine (1.46 mL, 18.1 mmol), (50% EtOAc, 38.3 g, 60.2 mmol) and tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (1.07 g, 6.02 mmol, CAS 64096-87-3) at room temperature for 16 h. The crude product was purified by flash chromatography (silica gel, eluting with 40% EtOAc in hexanes). LCMS (Method A): 416.2 [M+H] + .

[0672] Intermediate 52: 3-((1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)azetidine tert-Butyl 1-oxanecarboxylate

[0673] The title compound (1.1 g) was prepared in a similar manner to Intermediate 3 from Intermediate 47 (1.0 g, 3.27 mmol), pyridine (10 mL), Prepared by adding 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.79 g, 3.92 mmol, CAS 142253-55-2) (50% EtOAc, 10 mL, 15.7 mmol) and THF (10 mL) for 16 h at room temperature. The crude product was purified by flash chromatography (silica gel, eluting with 25% EtOAc in petroleum ether). LCMS (Method A): 396.0 [M-tBu+H] + .

[0674] Intermediate 53: 3-((1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2, tert-Butyl 2,2-trifluoroethyl)(methyl)carbamoyl)azetidine-1-carboxylate

[0675] The title compound (0.6 g) was prepared in a similar manner to Intermediate 11 from Intermediate 52 (1.0 g, 1.10 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.21 g, 1.10 mmol, CAS 74413-86-8), Cs2CO3 (1.08 g, 3.31 mmol) and RuPhosPdG3 (0.09 g, 0.11 mmol) in toluene (10 mL) at 110° C. for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 40% EtOAc in petroleum ether). LCMS (Method A): 533.5 [M+H] + .

[0676] Intermediate 54: 3-((1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2, tert-Butyl 2,2-trifluoroethyl)(methyl)carbamoyl)azetidine-1-carboxylate

[0677] The title compound (0.3 g) was prepared in a similar manner to Intermediate 3 from Intermediate 26 (0.5 g, 1.43 mmol), pyridine (5 mL), Prepared by adding 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (50% EtOAc, 4.5 mL, 7.16 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.58 g, 2.86 mmol, CAS 142253-55-2) in THF (5 mL) for 16 h at room temperature. The crude product was purified by flash chromatography (silica gel, eluting with 70% EtOAc in petroleum ether). LCMS (Method A): 533.5 [M+H] + .

[0678] Intermediate 55: N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpalmitamide

[0679] To a stirred mixture of intermediate 47 (1.0 g, 3.27 mmol) in DCM (15 mL) was added triethylamine (2.28 mL, 16.4 mmol) at 0 ° C and stirred for 5 min. Trimethylacetyl chloride (1.2 mL, 9.82 mmol) was added, the reaction tube was sealed, and the mixture was stirred at 40 ° C for 8 h. The mixture was poured into water and then extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (neutral alumina, eluted with 5% EtOAc in petroleum ether) to provide the title compound (1.1 g). LCMS (Method A): 353.2 [M+H] + .

[0680] Intermediate 56: N-(1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2, 2,2-trifluoroethyl)-N-methylpalmitamide

[0681] The title compound (0.7 g) was prepared in a similar manner to Intermediate 11 from Intermediate 55 (1.1 g, 3.12 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.62 g, 3.12 mmol, CAS 74413-86-8), Cs2CO3 (3.04 g, 9.34 mmol) and RuPhosPdG3 (0.26 g, 0.31 mmol) in toluene (10 mL) at 110° C. for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 20% EtOAc in petroleum ether). LCMS (Method A): 434.4 [M+H] + .

[0682] Intermediate 57: N-(1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-6-(2,2,2-trifluoro-1-(methylamino)- (4-[3-[(1-amino-4-yl)ethyl)pyridin-3-amine] hydrochloride

[0683] Intermediate 56 (0.50 g, 7.43 mmol) was suspended in 6 M HCl (10 mL), and the mixture was stirred at 110 ° C for 16 h. The mixture was diluted with water and washed with diethyl ether. The aqueous layer was basified with saturated aqueous NaHCO 3 solution, then extracted with EtOAc. The organics were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was diluted with EtOAc, 2 M HCl in diethyl ether was added at 0 ° C, and then concentrated under reduced pressure to provide the title compound (0.35 g). LCMS (Method A): 350.3 [M+H] + .

[0684] Intermediate 58: (S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoro-N-methylethan-1-amine

[0685] The title compound (3.86 g) was prepared from intermediate 46 (9.0 g, 33.5 mmol) by preparative SFC (LUXAMYLOSE-i3, 30×250 mm×5 μm, temperature 30° C., back pressure 100 bar, flow rate: 95 g / min, 93% CO 2 with 7% MeCN modifier). LCMS (Method A): 269.1 [M+H] + , 98% ee by chiral SFC.

[0686] Intermediate 59: (S)-N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpalmitamide

[0687] The title compound (1.0 g) was prepared in a similar manner to Intermediate 55 from Intermediate 58 (1.0 g, 3.72 mmol), trimethylacetyl chloride (1.37 mL, 11.2 mmol), and triethylamine (2.68 mL, 18.6 mmol) in DCM (10 mL) at room temperature for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 2%-4% EtOAc in petroleum ether). LCMS (Method A): 353.2 [M+H] + .

[0688] Intermediate 60: N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- (2,2,2-trifluoroethyl)-N-methylpalmitamide

[0689] The title compound (0.65 g) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (1.0 g, 2.83 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.84 g, 4.25 mmol, CAS 74413-86-8), Cs2CO3 (2.77 g, 8.49 mmol) and RuPhosPdG3 (0.24 g, 0.28 mmol) in toluene (10 mL) at 110° C. for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 4%-8% EtOAc in petroleum ether). LCMS (Method A): 434.4 [M+H] + .

[0690] Intermediate 61: N-(1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-3-amine

[0691] To a stirred solution of intermediate 60 (0.65 g, 1.50 mmol) in THF (6 mL) was slowly added LiAlH4 (2 M in THF, 1.5 mL, 3.0 mmol) at -15 ° C. such that the temperature did not exceed 0 ° C. The mixture was stirred at -10 ° C for 30 min. The mixture was quenched with ice-cold aqueous NH4Cl solution and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 15%-20% EtOAc in petroleum ether) to provide the title compound (0.25 g). LCMS (Method A): 350.3 [M+H] + .

[0692] Intermediate 62: (S)-1-(6-bromopyridin-3-yl)-2,2,2-trifluoro-N-methylethan-1-amine

[0693] The title compound (8.5 g) was prepared from intermediate 24 (28 g) by preparative SFC (LUX Cellulose-i-A3, 30×250 mm×5 μm, temperature 30° C., back pressure 100 bar, flow rate: 95 g / min, 90% CO 2 with 7% MeOH modifier). LCMS (Method A): 269.0 [M+H] + , 95.7% ee by chiral SFC.

[0694] Intermediate 63: N-(1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-5-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-2-amine

[0695] The title compound (0.55 g) was prepared in a similar manner to Intermediate 26 from Intermediate 62 (1.0 g, 3.71 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.73 g, 3.71 mmol, CAS 74413-86-8), sodium tert-butoxide (1.07 g, 11.2 mmol), Pd2(dba)3 (0.34 g, 0.37 mmol), and X-Phos (0.35 g, 0.74 mmol) in toluene (10 mL) at 110° C. for 2 h under microwave irradiation. Purification was performed by flash chromatography (silica gel, eluting with 25% EtOAc in petroleum ether). LCMS (Method A): 350.3 [M+H] + .

[0696] Intermediate 64: N-(1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-5-((S)-2,2,2-trifluoro-1-(methyl) (amino)ethyl)pyridin-2-amine hydrochloride

[0697] To a stirred solution of intermediate 63 (0.80 g, 2.29 mmol) in EtOAc (8 mL) was added 4 M HCl in 1,4-dioxane (4 mL) at 0°C, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude product was triturated in n-pentane and filtered to provide the title compound (0.60 g). LCMS (Method C): 350.5 [M+H] + .

[0698] Intermediate 65: 3-(((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- tert-Butyl (methyl)-2,2,2-trifluoroethyl (methyl)carbamoyl)piperidine-1-carboxylate

[0699] The title compound (0.55 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 61 (0.30 g, 0.85 mmol), pyridine (1.5 mL), Prepared by adding 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (0.40 g, 1.71 mmol, CAS 84358-12-3) (50% EtOAc, 3.8 mL, 6.01 mmol) and 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid at room temperature for 16 h. The crude product was purified by flash chromatography (silica gel, eluting with 20%-25% EtOAc in petroleum ether). LCMS (Method A): 561.5 [M+H] + .

[0700] Intermediate 66: methyl 3-((2,4-dimethoxybenzyl)amino)-2-hydroxypropanoate

[0701] To a stirred solution of methyl 3-amino-2-hydroxypropanoate hydrochloride (9.0 g, 57.9 mmol, CAS 186393-00-0) in methanol (90 mL) was added triethylamine (16 mL, 115 mmol) and 2,4-dimethoxybenzaldehyde (10.6 g, 63.6 mmol) at 0 ° C., and the mixture was then heated at 60 ° C. for 16 h. The mixture was cooled to 0 ° C., then sodium borohydride (4.38 g, 116 mmol) was added, and then the mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated aqueous NH4Cl solution and then extracted with EtOAc. The organic layer was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting with EtOAc and 0.1% triethylamine) to provide the title compound (5.0 g). LCMS (Method C): 270.3 [M+H] + .

[0702] Intermediate 67: 4-(2,4-dimethoxybenzyl)-5-oxomorpholine-2-carboxylic acid

[0703] To a stirred solution of intermediate 66 (2.5 g, 9.28 mmol) in 3.7 M NaOH (25 mL) was added chloroacetyl chloride (1.25 g, 11.1 mmol) at 0 ° C, and the mixture was stirred at room temperature for 30 min. The mixture was adjusted to pH 13 by adding 50% NaOH aqueous solution (10 mL), and then stirred at room temperature for 16 h. The mixture was quenched with 2M HCl aqueous solution until pH 2 and then extracted with EtOAc. The organic layer was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 10% MeOH and 0.1% triethylamine in DCM) to provide the title compound (0.1 g). LCMS (Method C): 296.4 [M+H] + .

[0704] Intermediate 68: 5-Oxomorpholine-2-carboxylic acid

[0705] A stirred solution of intermediate 67 (0.2 g, 0.54 mmol) in TFA (1.0 mL) was heated at 70° C. for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.09 g). LCMS (Method C): 146.1 [M+H] + .

[0706] Intermediate 69: N-(1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2, 2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide

[0707] To a stirred mixture of intermediate 53 (0.60 g, 1.12 mmol) in DCM (12 mL) was added TFA (3 mL) at 0 ° C and stirred at room temperature for 16 h. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM NH4HCO3 aqueous solution with MeCN 10% to 50% in 7 min, maintained at 50% for 8 min, then ramped to 98% in 0.5 min and maintained for 3.5 min) to provide the title compound (0.11 g). LCMS (Method G): 431.6 [MH] - .

[0708] Intermediate 70: N-(1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2, 2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide

[0709] To a stirred mixture of intermediate 54 (0.35 g, 0.66 mmol) in DCM (3.5 mL) was added TFA (1.75 mL) at 0 ° C and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, then diluted with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18, 19×250 mm×5 μm, flow rate: 18 mL / min, 10 mM NH4HCO3 aqueous solution with MeCN 10% to 50% in 7 min, maintained at 50% for 8 min, then ramped to 98% in 0.5 min and maintained for 3.5 min) to provide the title compound (0.17 g). LCMS (Method G): 431.6 [MH] - .

[0710] Intermediate 71: N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- (2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide

[0711] To a stirred solution of intermediate 65 (0.55 g, 0.98 mmol) in DCM (5.5 mL) was added TFA (0.44 mL, 3.92 mmol) at 0 ° C., followed by stirring at room temperature for 16 h. The mixture was concentrated under reduced pressure, then diluted with DCM and washed with saturated aqueous NaHCO 3 solution, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC (X-Select C18, 25×250 mm×5 μm, flow rate: 18 mL / min, 10 mM aqueous NH 4 HCO 3 solution with MeCN from 45% to 70% in 13 min, ramped to 98% in 0.1 min and held for 4.9 min) to provide the title compound (0.13 g). LCMS (Method C): 461.5 [M+H] + .

[0712] Intermediate 72: 4-(((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- tert-Butyl (methyl)-2,2,2-trifluoroethyl (methyl)carbamoyl)piperidine-1-carboxylate

[0713] The title compound (0.15 g) was prepared in a similar manner to Intermediate 3 from Intermediate 61 (0.10 g, 0.28 mmol), pyridine (0.5 mL), Prepared by the reaction of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.20 g, 0.85 mmol, CAS 84358-13-4) (50% EtOAc, 0.64 g, 2.00 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.20 g, 0.85 mmol, CAS 84358-13-4) at room temperature for 16 h. The crude product was purified by flash chromatography (silica gel, eluting with 25% EtOAc in petroleum ether). LCMS (Method C): 561.6 [M+H] + .

[0714] Intermediate 73: 4-(((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-3- tert-Butyl (methyl)-2,2,2-trifluoroethyl (methyl)carbamoyl)piperidine-1-carboxylate

[0715] The title compound (0.10 g) was prepared in a similar manner to Intermediate 3 from Intermediate 64 (0.30 g, 0.78 mmol), pyridine (1.5 mL), Prepared by adding 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.54 g, 2.34 mmol, CAS 84358-13-4) (50% EtOAc, 2.5 mL, 3.93 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid) at room temperature for 16 h. The crude product was purified by flash chromatography (silica gel, eluting with 70% EtOAc in petroleum ether). LCMS (Method A): 561.5 [M+H] + .

[0716] Intermediate 74: 5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-one / 6-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-one Hydro-1H-inden-1-one

[0717] To a stirred solution of 3-methyl-2-butenoic acid (15 g, 0.15 mol, CAS 541-47-9) in chlorobenzene (80 mL) was added aluminum chloride (50 g, 0.45 mol) portionwise at 0 ° C., and the mixture was then stirred at 80 ° C. for 12 h. The mixture was cooled, then quenched with cold 5M aqueous HCl, and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 10%-20% EtOAc in petroleum ether) to provide the title compound (19 g) as a mixture. LCMS (Method A): 195.2 [M+H] + .

[0718] Intermediate 75: 5-chloro-3,3-dimethyl-2,3-dihydro-1H-indene-1-ol / 6-chloro-3,3-dimethyl-2,3-dihydro-1H-indene-1-ol Hydrogen-1H-inden-1-ol

[0719] To a stirred solution of intermediate 74 (10 g, 51.4 mmol) in ethanol (100 mL) was added sodium borohydride (3.89 g, 103 mmol) portionwise at 0°C, and the mixture was then stirred at room temperature for 1 h. The mixture was cooled, then quenched with saturated aqueous NH4Cl, and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound (8.89 g) as a mixture. LCMS (Method A): 179.2 [M-18+H] + .

[0720] Intermediate 76: 6-chloro-1,1-dimethyl-1H-indene / 5-chloro-1,1-dimethyl-1H-indene

[0721] To a stirred solution of intermediate 75 (8.7 g, 44.2 mmol) in toluene (80 mL) was added pTSA (4.21 g, 22.1 mmol) at 0° C., and the mixture was then stirred at 120° C. for 1 h. The mixture was allowed to cool, then diluted with water and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting with 1%-5% EtOAc in petroleum ether) to provide the title compound (5.0 g) as a mixture. 1 H NMR (400 MHz; CDCl 3 ) δ: 7.11-7.29 (m, 6H), 6.55 (t, 2H), 6.41-6.44 (m, 1H), 6.35 (d, 1H), 1.29 (d, 12H) - total for both compounds.

[0722] Intermediate 77: 6-chloro-1,1-dimethyl-1,3-dihydro-2H-inden-2-one / 5-chloro-1,1-dimethyl-1,3-dihydro-2H-inden-2-one Hydro-2H-inden-2-one

[0723] To a stirred solution of intermediate 76 (2.0 g, 11.2 mmol) in acetone / tert-butanol / water (5:1:1, 14 mL) was added osmium tetroxide (4% in water, 2.8 mL, 0.45 mmol) and NMMO (2.27 g, 16.8 mmol) at 0 ° C., and the mixture was stirred at room temperature for 16 h. The mixture was then diluted with 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 chromatography (silica gel, eluted with 8%-15% EtOAc in petroleum ether). The residue was dissolved in benzene (10 mL) and pTSA (0.29 g, 1.5 mmol) was added, and the mixture was stirred at 80 ° C for 1 h. The mixture was diluted with 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 chromatography (silica gel, eluting with 1%-5% EtOAc in petroleum ether) to provide the title compound (1.0 g) as a mixture. LCMS (Method A): 193.2 [MH] - .

[0724] Intermediate 78a: 6-Chloro-1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

[0725] Intermediate 78b: 5-Chloro-1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

[0726] To a stirred solution of intermediate 77 (0.2 g, 1.03 mmol) in ethanol (10 mL) was added ammonium acetate (1.18 g, 15.3 mmol) and sodium cyanoborohydride (77 mg, 1.23 mmol), and the mixture was stirred at 100 ° C for 1 h. The mixture was cooled, 4M HCl in 1,4-dioxane was added, and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO 3 solution. The organic layer was treated with 4M HCl in 1,4-dioxane, dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide the title compound (1.0 g) as a mixture. LCMS (Method A): 196.2 [M+H] + .

[0727] Intermediate 79a / Intermediate 79b: 6-(((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino tert-Butyl (methyl)pyridin-2-yl)-2,2,2-trifluoroethyl (methyl)carbamoyl)-1-azaspiro[3.3]heptane-1-carboxylate

[0728] In a similar manner to Intermediate 3, intermediate 61 (0.62 g, 1.77 mmol), pyridine (3.1 mL), 79a (0.57 g, diastereomer 1) and intermediate 79b (0.38 g, diastereomer 2). LCMS (Method A) for 79a: 573.6 [M+H] + ; 79b LCMS (Method A): 573.5 [M+H] + .

[0729] Intermediate 80: (S)-1,1-Dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

[0730] Intermediate 114: (R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

[0731] 1,1-Dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (3.8 g, 17.9 mmol, CAS 74413-86-8) was added to a saturated aqueous NaHCO solution and extracted with DCM containing 10% MeOH. The organic layer was dried over MgSO, filtered and concentrated under reduced pressure. The product was purified by preparative SFC ( Chiral purification was performed using a 1G, 30×250 mm×5 μm, temperature 30° C., back pressure 100 bar, flow rate: 60 g / min, 50% CO 2 with 50% (MeCN containing 0.2% diethylamine) modifier. After drying the separated peaks, 4 M HCl in diethyl ether was added, followed by concentration to provide intermediate 80 (1.15 g) as peak 2 and intermediate 114 (1.0 g) as peak 1. Intermediate 80: 1 H NMR (400 MHz; DMSO-d6) δ: 8.44 (br s, 3H), 7.26-7.17 (m, 4H), 3.55 (dd, 1H), 3.24 (dd, 1H), 2.99 (dd, 1H), 1.36 (s, 3H), 1.18 (s, 3H). Intermediate 114: 1 H NMR(400MHz; DMSO-d6)δ:8.12(br s,3H),7.25-7.16(m,4H),3.51(dd,1H),3.21(dd,1H),2.98(dd,1H),1.36(s,3H),1.17(s,3H).

[0732] Intermediate 81: N-((1S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine- 2-aminoethyl)-2,2,2-trifluoroethyl)-N-methylpalmitamide

[0733] The title compound (1.58 g) was prepared from Intermediate 59 (1.6 g, 4.53 mmol), Intermediate 80 (1.16 g, 5.89 mmol), Cs2CO3 (4.43 g, 3.0 mmol) and RuPhosPdG3 (0.55 g, 0.14 mmol) in toluene (22.7 mL) at 110° C. for 16 h in a similar manner to Intermediate 11. Purification was performed by automated column chromatography (silica gel 120 g, eluting with 0-40% EtOAc in hexanes). 1 H NMR(300MHz; DMSO-d6)δ:8.15(d,1H),7.23-7.13(m,5H),7.07(d,1H),6.45(dd,1H),6.21(d,1H),4 .10-3.99(m,1H),3.20(dd,1H),3.02(s,3H),2.75(dd,1H),1.33(s,3H),1.25(s,9H),1.10(s,3H).

[0734] Intermediate 82: N-((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1- (Methylamino)ethyl)pyridin-3-amine

[0735] The title compound (0.10 g) was prepared in a similar manner to Intermediate 61 from Intermediate 81 (0.20 g, 0.46 mmol) and LiAlH4 (1 M in THF, 0.92 mL, 0.92 mmol) in THF (12.7 mL) at -13°C for 30 min. The crude product was purified by automated column chromatography (silica gel, 40 g, eluting with 0-50% EtOAc in hexanes). LCMS (Method J): 350.2 [M+H] + .

[0736] Intermediate 83: (S)-2-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino) Tert-butyl (pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)morpholine-4-carboxylate

[0737] The title compound (0.10 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.20 g, 0.57 mmol), pyridine (1.9 mL), Prepared by adding (50% EtOAc, 1.05 mL, 1.72 mmol) and (2S)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid (0.54 g, 2.34 mmol, CAS 868689-63-8) at room temperature for 16 h. The crude product was purified by automated column chromatography (silica gel 40 g, eluted with 5%-50% EtOAc in hexanes). LCMS (Method J): 563.4 [M+H] + .

[0738] Intermediate 84: (S)-3-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino) tert-Butyl (pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate

[0739] The title compound (0.19 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.15 g, 0.43 mmol), pyridine (2.1 mL), Prepared by evaporating 4-(4-(4-(4-(4-(4-(4-thiazolyl)pyrrolidine)-1-yl)-1-[4-(4-(4-thiazolyl)pyrrolidine)-3-carboxylic acid (50% in MeTHF, 0.80 mL, 1.3 mmol) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (0.14 g, 0.64 mmol, CAS 140148-70-5) at room temperature for 16 h. The crude product was purified by preparative TLC (eluting with 24:1 DCM / MeOH). LCMS (Method K): 547.1 [M+H] + .

[0740] Intermediate 85: ((1S,3R)-3-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl) tert-Butyl (amino)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclopentyl)carbamate

[0741] The title compound (0.19 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.10 g, 0.29 mmol), pyridine (4.3 mL), Prepared by evaporating 1% paraformaldehyde (50% in MeTHF, 0.53 mL, 0.87 mmol) and (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (72 mg, 0.32 mmol, CAS 161660-94-2) at room temperature for 16 h. LCMS (Method K): 561.3 [M+H] + .

[0742] Intermediate 86: (1R,3S)-3-amino-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-indene- (2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide TFA salt

[0743] A solution of intermediate 85 (0.14 g, 0.24 mmol) in TFA (0.2 mL) and DCM (1.5 mL) was stirred at room temperature for 1 h. The mixture was poured into water and extracted with EtOAc. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.09 g). LCMS (Method K): 461.2 [M+H] + .

[0744] Intermediate 87: 6-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine- tert-Butyl (2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0745] The title compound (0.23 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.20 g, 0.57 mmol), pyridine (1.9 mL), Prepared by adding 2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid (50% in EtOAc, 1.10 mL, 1.7 mmol) and 2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid (0.21 g, 0.86 mmol, CAS 1211526-53-2) at room temperature for 16 h. The crude product was purified by automated column chromatography (silica gel 12 g, eluting with 0-50% EtOAc in isohexane). LCMS (Method L): 573.6 [M+H] + .

[0746] Intermediate 88: 6-(((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-3- tert-Butyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0747] The title compound (18 mg) was prepared in a similar manner to Intermediate 3 from Intermediate 63 (0.10 g, 0.25 mmol), pyridine (1.0 mL), Prepared by adding 2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid (50% in EtOAc, 1.49 mL, 0.75 mmol) and 2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid (0.09 g, 0.37 mmol, CAS 1211526-53-2) at room temperature for 16 h. The crude product was purified by automated column chromatography (silica gel 12 g, eluting with 0-40% EtOAc in hexanes). LCMS (Method K): 573.6 [M+H] + .

[0748] Intermediate 89: (R)-3-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino) tert-Butyl (pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate

[0749] The title compound (0.21 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.15 g, 0.43 mmol), pyridine (2.1 mL), Prepared by adding (50% in EtOAc, 0.80 mL, 1.3 mmol) and (3R)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (0.14 g, 0.64 mmol, CAS 72925-16-7) at room temperature for 16 h. The crude product was purified by automated column chromatography (silica gel 12 g, eluting with 0-20% EtOAc in hexanes). LCMS (Method K): 547.1 [M+H] + .

[0750] Intermediate 90: (S)-N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran- 4-Formamide 1,1-dioxide

[0751] To a stirred solution of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (1.54 g, 8.64 mmol, CAS 64096-87-3) in DCM (5 mL) was added oxalyl chloride (0.15 mL, 1.73 mmol) and DMF (0.1 mL) at 0°C, and the mixture was then stirred at room temperature for 2 h. A solution of intermediate 58 (0.50 g, 1.73 mmol) and triethylamine (0.24 mL, 1.72 mmol) in DCM (5 mL), which had been premixed for 30 min at room temperature, was cooled at 0°C, and the acid chloride mixture was then added, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and 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 chromatography (silica gel, eluting with 0-45% EtOAc in petroleum ether) to provide the title compound (0.45 g). LCMS (Method A): 431.2 [M+H] + .

[0752] Intermediate 91: (3-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine tert-Butyl (methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0753] The title compound (0.12 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.10 g, 0.29 mmol), pyridine (1.4 mL), Prepared by adding 1-[(tert-butyloxycarbonylamino)-1-cyclohexane-1-carboxylic acid (50% in EtOAc, 0.53 mL, 0.86 mmol) and 3-(tert-butoxycarbonylamino)bicyclo[1.1.1]pentane-1-carboxylic acid (68 mg, 0.30 mmol, CAS 303752-38-7) at room temperature for 16 h. The crude product was purified by automated column chromatography (silica gel 40 g, eluting with 0-50% EtOAc in hexanes). LCMS (Method J): 559.4 [M+H] + .

[0754] Intermediate 92: 3-amino-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino (2-(2-Yl)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide dihydrochloride

[0755] To a stirred solution of intermediate 91 (0.11 g, 0.19 mmol) in 1,4-dioxane (1.8 mL) was added 4M HCl in 1,4-dioxane (0.29 μL) and stirred at room temperature for 16 h. Additional 4M HCl in 1,4-dioxane (0.29 μL) was added and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and triturated in diethyl ether to provide the title compound (0.11 g). 1H NMR (300MHz; DMSO-d6-D2O oscillation) δ:8.14(s,1H),7.25-7.10(m,6H),6.30(dd,1H),4.03(dd,1H),3.22 -3.12(m,1H),3.01(s,3H),2.80-2.68(m,1H),2.42(d,1H),2.35(s,5H),1.31(s,3H),1.08(s,3H).

[0756] Intermediate 93: (R)-2-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino) Tert-butyl (pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)morpholine-4-carboxylate

[0757] The title compound (0.16 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.15 g, 0.41 mmol), pyridine (1.4 mL), (50% in EtOAc, 0.81 mL, 1.27 mmol) and (2R)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid (99 mg, 0.43 mmol, CAS 884512-77-0) were prepared at room temperature for 16 h. The crude product was purified by automated column chromatography (silica gel 25 g, eluting with 5%-50% EtOAc in hexanes). 1 H NMR(300MHz; DMSO-d6)δ:8.16(s,1H),7.33-7.09(m,6H),6.27(dd,2H),4.35-4.22(m,1H),4.09-4.03(m,2H),3.9 3-3.67(m,3H),3.53(t,1H),3.19(dd,1H),3.00(s,3H),2.80-2.68(m,2H),1.42(s,9H),1.33(s,3H),1.10(s,3H).

[0758] Intermediate 94: (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine (2-pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylmorpholine-2-carboxamide dihydrochloride

[0759] To a stirred solution of intermediate 93 (0.15 g, 0.26 mmol) in 1,4-dioxane (2.6 mL) was added 4 M HCl in 1,4-dioxane (0.39 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and triturated in diethyl ether to provide the title compound (70 mg). LCMS (Method M): 463.3 [M+H] + .

[0760] Intermediate 95: (S)-2-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino) Tert-butyl (pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)morpholine-4-carboxylate

[0761] The title compound (0.26 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.20 g, 0.57 mmol), pyridine (1.9 mL), Prepared by adding (50% in EtOAc, 1.05 mL, 1.71 mmol) and (2S)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid (0.14 g, 0.60 mmol, CAS 868689-63-8) at room temperature for 16 h. The crude product was purified by automated column chromatography (silica gel 40 g, eluting with 5%-50% EtOAc in hexanes). LCMS (Method J): 563.4 [M+H] + .

[0762] Intermediate 96: (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine (2-pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylmorpholine-2-carboxamide dihydrochloride

[0763] To a stirred solution of intermediate 95 (0.15 g, 0.26 mmol) in 1,4-dioxane (1.5 mL) was added 4 M HCl in 1,4-dioxane (1.38 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and triturated in diethyl ether to provide the title compound (0.17 g). LCMS (Method M): 463.3 [M+H] + .

[0764] Intermediate 97: ((1,3-cis)-3-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-indene-2- tert-Butyl) (methyl)carbamoyl)cyclobutyl)carbamate

[0765] The title compound (0.16 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.10 g, 0.57 mmol), pyridine (4.3 mL), Prepared by reacting 4-[[(tert-butyloxycarbonylamino)cyclobutanecarboxylic acid]-4-[ ... + .

[0766] Intermediate 98: (1,3-cis)-3-amino-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H- (inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide TFA salt

[0767] To a stirred mixture of intermediate 97 (0.17 g, 0.30 mmol) in DCM (1.5 mL) was added TFA (0.23 mL) at 0° C. and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.14 g). 1HNMR (300 MHz; DMSO-d6) δ: 8.14 (d, 1H), 7.27-7.00 (m, 6H), 6.35 (q, 1H), 6.21 (d, 1H), 3.26-3.14 (m, 2H), 2.86 (s, 3H), 2.81-2.63 (m, 2H), 2.44-2.22 (m, 1H), 1.91-1.64 (m, 3H), 1.32 (s, 3H), 1.10 (s, 3H) - NH was not observed.

[0768] Intermediate 99: (2S,4R)-1-acetyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid

[0769] To a stirred solution of (2S,4R)-1-acetyl-4-hydroxypyrrolidine-2-carboxylic acid (0.20 g, 1.15 mmol, CAS 33996-33-7) in MeCN (1.4 mL) was added DBU (0.37 mL, 2.48 mmol) and TBDMS-Cl (0.37 g, 2.48 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated in diethyl ether to provide the title compound (0.15 g). 1 H NMR(300MHz; DMSO-d6)δ:12.56(br s,1H),4.56-4.45(m,1H),4.20(t,1H),3.70(dd,1H),2.22-1.98(m,2H),1.95(s,3H),1.85(s,1H),0.85(d,9H),0.12-0.00(m,6H).

[0770] Intermediate 100: (2S,4R)-1-acetyl-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(5- (((S)-1,1-Dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyridine Pyrrolidine-2-carboxamide

[0771] The title compound (0.10 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.10 g, 0.29 mmol), pyridine (2.1 mL), (50% in MeTHF, 0.53 mL, 0.86 mmol) and intermediate 99 (91 mg, 0.32 mmol) were prepared at room temperature for 16 h. Purification was performed by preparative TLC (eluting with DCM 4% MeOH). LCMS (Method K): 619.3 [M+H] + .

[0772] Intermediate 101: 3-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine methyl)-2,2,2-trifluoroethyl(methyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate

[0773] The title compound (0.16 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.10 g, 0.29 mmol), pyridine (4.3 mL), Prepared by adding 1-[4-(4-(4-nitro-2-oxo-1-pyrrolidone)-1-yl]-1-thiazolinone (50% in MeTHF, 0.53 mL, 0.87 mmol) and 3-methoxycarbonylbicyclo[1.1.1]pentane-1-carboxylic acid (54 mg, 0.32 mmol, CAS 83249-10-9) at room temperature for 16 h. LCMS (Method K): 4.01 min, 502.3 [M+H] + .

[0774] Intermediate 102: ((1,3-trans)-3-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-indene-2- tert-Butyl) (methyl)carbamoyl)cyclobutyl)carbamate

[0775] The title compound (0.15 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.10 g, 0.29 mmol), pyridine (1.9 mL), Prepared by reacting 4-[[(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid]-4-[ ... + .

[0776] Intermediate 103: (1,3-trans)-3-amino-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H- (inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide

[0777] To a stirred solution of intermediate 102 (0.15 g, 0.28 mmol) in 1,4-dioxane (1.2 mL) was added 2 M HCl in diethyl ether (0.49 mL) at 0 ° C, and the mixture was stirred at room temperature for 16 h. The mixture was poured into 1 M aqueous NaOH and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.13 g). LCMS (Method K): 447.0 [M+H] + .

[0778] Intermediate 104: ((1R,3S)-3-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl) tert-Butyl (amino)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclopentyl)carbamate

[0779] The title compound (0.15 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.10 g, 0.29 mmol), pyridine (2.1 mL), Prepared by evaporating 15% methyl parathionyl (50% in MeTHF, 0.53 mL, 0.87 mmol) and (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (69 mg, 0.30 mmol, CAS 261165-05-3) at room temperature for 16 h. LCMS (Method K): 561.3 [M+H] + .

[0780] Intermediate 105: (1S,3R)-3-amino-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-indene- (2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide

[0781] To a stirred solution of intermediate 104 (0.15 g, 0.27 mmol) in DCM (1.7 mL) was added 2 M HCl in diethyl ether (0.75 mL) at 0° C., and the mixture was stirred at room temperature for 16 h. The mixture was poured into a 1 M aqueous NaOH solution and extracted with DCM. The combined organics were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to provide the title compound (0.11 g). LCMS (Method K): 461.2 [M+H] + .

[0782] Intermediate 106: (S)-1-(5-bromopyridin-2-yl)-N-ethyl-2,2,2-trifluoroethan-1-amine

[0783] The title compound (2 g) was prepared in a similar manner to intermediate 24 from 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (7.0 g, 18.0 mmol, CAS 1374038-21-7) and ethylamine in THF (2 M, 90 mL) at 60 ° C for 2 h. Purification was carried out by flash chromatography (silica gel, eluting with 8%-10% EtOAc in petroleum ether). The product was purified by preparative SFC ( -IG, 30 × 250 mm × 5 μm, temperature 30 ° C, back pressure 100 bar, flow rate: 95 g / min, 95% CO2 with 5% IPA modifier) ​​for chiral purification as peak 2. LCMS (method A): 283.1 [M + H] + .

[0784] Intermediate 107: (S)-N-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-N-ethyltetrahydro-2H-thiophene Phenylacetamide 1,1-dioxide

[0785] The title compound (0.65 g) was prepared in a similar manner to Intermediate 90 from Intermediate 106 (1.20 g, 4.15 mmol), pyridine (1.68 mL, 20.8 mmol) and tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (2.22 g, 12.5 mmol, CAS 64096-87-3) in THF (12 mL), oxalyl chloride (1.75 mL, 20.77 mmol) and DMF (0.03 mL) in DCM (12 mL) at 0° C., then at 40° C. for 16 h. Purification by flash chromatography (silica gel, eluting with 40%-50% EtOAc in petroleum ether) provided the title compound (0.45 g). LCMS (Method A): 443.2 [M+H] + .

[0786] Intermediate 108: (E)-2-(Hydroxyimino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one

[0787] To a stirred solution of 4-(trifluoromethyl)indan-1-one (1.0 g, 5.00 mmol, CAS 68755-42-0) and acetyl chloride (0.14 mL, 2.00 mmol) in MeOH (0.5 mL), heptane (6 mL) and DCM (7 mL) was added isoamyl nitrite (1.01 mL, 7.49 mmol) dropwise at 0° C., and the mixture was stirred at 0° C. for 2 h. Heptane was added, and the solid was filtered and dried under reduced pressure to provide the title compound (0.50 g). LCMS (Method A): 230.1 [M+H] + .

[0788] Intermediate 109: 4-(Trifluoromethyl)-2,3-dihydro-1H-inden-2-amine hydrochloride

[0789] To a stirred solution of intermediate 108 (0.50 g, 2.12 mmol) in AcOH (15 mL) was slowly added sulfuric acid (2 mL, 37.5 mmol), and the mixture was stirred at room temperature for 15 min. Palladium on carbon (10%, 0.50 g) was added, and the mixture was stirred under a hydrogen atmosphere for 16 h. The mixture was filtered through celite, washed with EtOAc, and the filtrate was carefully basified with Na2CO3 and extracted with EtOAc. The organic layer was acidified with 4M HCl in 1,4-dioxane and concentrated under reduced pressure to provide the title compound (0.39 g). LCMS (Method A): 202.2 [M+H] + .

[0790] Intermediate 110: (E)-4-ethyl-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one

[0791] To a stirred solution of 4-ethyldihydroindan-1-one (5.5 g, 29.5 mmol, CAS 79780-68-0) in MeOH (55 mL) was added isoamyl nitrite (3.86 mL, 32.5 mmol) at 40 ° C, and the mixture was stirred at 40 ° C for 1 h. Hydrochloric acid (12 M, 5.5 mL) was added, and the mixture was stirred at 60 ° C for 16 h. The mixture was cooled and ice / water was added, and the solid was filtered and dried under reduced pressure. The crude product was purified by flash chromatography (neutral silica gel, eluted with 5%-10% MeOH in DCM) to provide the title compound (2.50 g). LCMS (Method A): 190.1 [M+H] + .

[0792] Intermediate 111: 4-Ethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

[0793] The title compound (1.10 g) was prepared in a similar manner to intermediate 109 from intermediate 110 (2.0 g, 9.51 mmol), sulfuric acid (4.5 mL, 84.4 mmol), palladium on carbon (10%, 2.20 g) in AcOH (45 mL) under a hydrogen atmosphere at 450 psi for 16 h, acidified with 4 M HCl in 1,4-dioxane. LCMS (Method O): 162.0 [M+H] + .

[0794] Intermediate 112: N-((1S)-1-(5-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2, 2,2-trifluoroethyl)-N-methylpalmitamide

[0795] The title compound (0.40 g) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (1.0 g, 2.63 mmol), 5-chloro-2,3-dihydro-1H-inden-2-amine hydrochloride (0.44 g, 2.63 mmol, CAS 73536-86-4), Cs2CO3 (2.57 g, 7.90 mmol) and RuPhosPdG3 (0.22 g, 0.26 mmol) in toluene (20 mL) at 110° C. for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 20%-25% EtOAc in petroleum ether). LCMS (Method C): 440.4 [M+H] + .

[0796] Intermediate 113: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1-(methylamino) ethyl)pyridin-3-amine

[0797] The title compound (0.25 g) was prepared in a similar manner to Intermediate 61 from Intermediate 112 (0.40 g, 0.45 mmol) and LiAlH (2 M in THF, 0.98 mL, 1.96 mmol) in THF (8.0 mL) at -0°C for 30 min. The crude product was purified by flash chromatography (silica gel, eluting with 25%-30% EtOAc in petroleum ether). LCMS (Method A): 356.3 [M+H] + .

[0798] Intermediate 115: N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine- 2-aminoethyl)-2,2,2-trifluoroethyl)-N-methylpalmitamide

[0799] The title compound (1.29 g) was prepared from Intermediate 59 (1.5 g, 4.25 mmol), Intermediate 114 (0.90 g, 5.58 mmol), Cs2CO3 (4.15 g, 12.7 mmol) and RuPhosPdG3 (0.51 g, 0.14 mmol) in toluene (14.2 mL) at 110° C. for 20 h in a similar manner to Intermediate 11. Purification was performed by automated column chromatography (silica gel 120 g, eluting with 0-40% EtOAc in hexanes). 1 H NMR(300MHz; DMSO-d6)δ:8.16(d,1H),7.26-7.13(m,5H),7.12-7.02(d,1H),6.45(dd,1H),6.20(d,1H ),4.19-3.95(m,1H),3.21(dd,1H),3.03(s,3H),2.75(dd,1H),1.33(s,3H),1.26(s,9H),1.12(s,3H).

[0800] Intermediate 116: N-((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1- (Methylamino)ethyl)pyridin-3-amine

[0801] The title compound (0.88 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 115 (1.29 g, 2.97 mmol) and LiAlH4 (2 M in THF, 3.00 mL, 6.00 mmol) in THF (30 mL) at -15°C for 30 min. The crude product was purified by automated column chromatography (silica gel 80 g, eluting with 0-50% EtOAc in hexanes). 1H NMR(300MHz; DMSO-d6)δ:8.12(d,1H),7.25-7.08(m,6H),6.06(d,1H),4.06(dq,2H),3 .20(dd,1H),2.75(dd,1H),2.67-2.59(m,1H),2.24(d,3H),1.32(s,3H),1.10(s,3H).

[0802] Intermediate 117: 3-(((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine methyl)-2,2,2-trifluoroethyl(methyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate

[0803] The title compound (0.17 g) was prepared in a similar manner to Intermediate 3 from Intermediate 116 (0.10 g, 0.29 mmol), pyridine (1.4 mL), Prepared by adding 1-methoxy-1,1-dihydro-2-nitro-2-thiazolyl-1-ol (50% in MeTHF, 0.53 mL, 0.87 mmol) and 3-methoxycarbonylbicyclo[1.1.1]pentane-1-carboxylic acid (54 mg, 0.32 mmol, CAS 83249-10-9) at room temperature for 16 h. LCMS (Method K): 502.4 [M+H] + .

[0804] Intermediate 118: ((1S,3R)-3-(((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl) tert-Butyl (amino)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclopentyl)carbamate

[0805] The title compound (0.19 g) was prepared in a similar manner to Intermediate 3 from Intermediate 116 (0.10 g, 0.29 mmol), pyridine (1.4 mL), Prepared by evaporating 1% paraformaldehyde (50% in MeTHF, 0.55 mL, 0.87 mmol) and (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (72 mg, 0.32 mmol, CAS 161660-94-2) at room temperature for 16 h. LCMS (Method J): 561.3 [M+H] + .

[0806] Intermediate 119: (1R,3S)-3-amino-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-indene- (2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide dihydrochloride

[0807] To a stirred solution of intermediate 118 (0.19 g, 0.27 mmol) in 1,4-dioxane (1.8 mL) was added 4 M HCl in 1,4-dioxane (0.81 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and triturated in n-pentane to provide the title compound (0.20 g). 1H NMR (300MHz; DMSO-d6 2 drops of D2O)δ:8.19-8.02(m,2H),7.29-7.08(m,6H),6.40(q,1H),4.04(t,1H),3.51(dd,1H),3.3 0-3.10(m,2H),2.98(s,3H),2.82-2.65(m,1H),2.37-1.46(m,6H),1.31(s,3H),1.08(s,3H).

[0808] Intermediate 120: ((1,3-cis)-3-(((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-indene-2- tert-Butyl) (methyl)carbamoyl)cyclobutyl)carbamate

[0809] The title compound (0.11 g) was prepared in a similar manner to Intermediate 3 from Intermediate 116 (0.10 g, 0.29 mmol), pyridine (1.4 mL), Prepared by (50% in MeTHF, 0.55 mL, 0.86 mmol) and cis-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (68 mg, 0.31 mmol, CAS 1008773-79-2) at room temperature for 16 h. 1 H NMR(300MHz; DMSO-d6)δ:8.58(d,1H),8.14(d,1H),7.79(t,1H),7.39(dd,1H),7.31-7.04(m,5H),6.39(d,1H),6.20( d,1H),4.14-3.88(m,2H),3.20(dd,1H),2.92-2.63(m,4H),2.40-2.07(m,4H),1.38(s,9H),1.32(s,3H),1.10(s,3H).

[0810] Intermediate 121: (1,3-cis)-3-amino-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H- (inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide dihydrochloride

[0811] To a stirred solution of intermediate 120 (0.10 g, 0.19 mmol) in diethyl ether (0.9 mL) was added 2M HCl in diethyl ether (0.93 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (90 mg). LCMS (Method K): 447.8 [M+H] + .

[0812] Intermediate 122: ((1,3-trans)-3-(((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-indene-2- tert-Butyl) (methyl)carbamoyl)cyclobutyl)carbamate

[0813] The title compound (0.18 g) was prepared in a similar manner to Intermediate 3 from Intermediate 116 (0.10 g, 0.29 mmol), pyridine (1.4 mL), Prepared by reacting 4-[4-(tert-butyloxycarbonylamino)cyclobutanecarboxylic acid (50% in MeTHF, 0.55 mL, 0.86 mmol) and trans-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (68 mg, 0.31 mmol, CAS 939400-34-7) at room temperature for 16 h. LCMS (Method K): 547.8 [M+H] + .

[0814] Intermediate 123: (1,3-trans)-3-amino-N-((S)-1-(5-((R)-1,1-dimethyl-2,3-dihydro-1H- (inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide dihydrochloride

[0815] To a stirred solution of intermediate 122 (0.16 g, 0.29 mmol) in diethyl ether (0.9 mL) was added 2 M HCl in diethyl ether (1.43 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (90 mg). LCMS (Method K): 447.6 [M+H] + .

[0816] Intermediate 124: N-((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)-5-((S)-2,2,2-trifluoro-1- (Methylamino)ethyl)pyridin-2-amine

[0817] The title compound (0.34 g) was prepared in a similar manner to Intermediate 26 from Intermediate 62 (0.90 g, 3.35 mmol), Intermediate 80 (0.64 g, 4.01 mmol), sodium tert-butoxide (0.97 g, 10.0 mmol), Pd2(dba)3 (0.31 g, 0.33 mmol) and X-Phos (0.32 g, 0.70 mmol) in toluene (33 mL) at 110°C for 16 h. Purification was performed by automated column chromatography (silica gel, 40 g, eluting with 0-40% EtOAc in hexanes). LCMS (Method K): 350.6 [M+H] + .

[0818] Intermediate 125: (2S,4R)-1-acetyl-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(5- (((R)-1,1-Dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyridine Pyrrolidine-2-carboxamide

[0819] The title compound (0.11 g) was prepared in a similar manner to Intermediate 3 from Intermediate 116 (75 mg, 0.21 mmol), pyridine (1.4 mL), (50% in MeTHF, 0.39 mL, 0.64 mmol) and intermediate 99 (68 mg, 0.24 mmol) at room temperature for 16 h. LCMS (Method K): 619.3 [M+H] + .

[0820] Intermediate 126: (1,3-cis)-3-amino-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H- (inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide dihydrochloride

[0821] To a stirred solution of intermediate 97 (0.23 g, 0.42 mmol) in 1,4-dioxane (2.9 mL) was added 4 M HCl in 1,4-dioxane (1.26 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and triturated with pentane to provide the title compound (0.22 g). LCMS (Method K): 447.1 [M+H] + .

[0822] Intermediate 127: 4-(((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine tert-Butyl (methyl)piperidin-2-yl)-2,2,2-trifluoroethyl (methyl)carbamoyl)piperidine-1-carboxylate

[0823] The title compound (0.47 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.30 g, 0.86 mmol), pyridine (1.7 mL), (0.77 mL, 2.58 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.22 g, 0.94 mmol, CAS 84358-13-4) at room temperature for 16 h. The crude product was purified by automated column chromatography (silica gel 40 g, eluting with 0-100% EtOAc in hexanes). 1 H NMR(400MHz; DMSO-d6)δ:8.20-8.09(m,1H),7.25-7.04(m,6H),6.38(q,1H),6.22(d,1H),4.16-3.92(d,4H),3.20 (dd,1H),3.02(s,3H),2.93(t,1H),2.90-2.67(m,3H),1.84-1.50(m,3H),1.40(d,9H),1.33(s,3H),1.11(s,3H).

[0824] Intermediate 128: N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine- 2-aminoethyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride

[0825] To a stirred solution of intermediate 127 (0.47 g, 0.59 mmol) in 1,4-dioxane (1.2 mL) was added 4 M HCl in 1,4-dioxane (0.74 mL) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (0.24 g). LCMS (Method K): 461.2 [M+H] + .

[0826] Intermediate 129: 3-(((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- tert-Butyl)-2,2,2-trifluoroethyl(methyl)carbamoyl)azetidine-1-carboxylate

[0827] The title compound (0.35 g) was prepared in a similar manner to Intermediate 3 from Intermediate 61 (0.25 g, 0.67 mmol), pyridine (0.3 mL), Prepared from 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (50% in MeTHF, 2.12 mL, 6.65 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.21 g, 0.99 mmol, CAS 142253-55-2) at room temperature for 16 h. Purified by flash chromatography (silica gel, eluting with 0-60% EtOAc in petroleum ether). LCMS (Method A): 533.6 [M+H] + .

[0828] Intermediate 130: N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- (2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide TFA salt

[0829] A solution of intermediate 129 (0.35 g, 0.54 mmol) in TFA (0.23 mL) and DCM (5 mL) was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure to provide the title compound (0.32 g). LCMS (Method A): 433.5 [M+H] + .

[0830] Intermediate 131: Methyl (1,3-cis)-3-(methylcarbamoyl)cyclobutane-1-carboxylate

[0831] To a stirred solution of cis-3-(methoxycarbonyl)cyclobutanecarboxylic acid (50 mg, 0.32 mmol, CAS 142733-61-7) in DCM (1.6 mL) was added oxalyl chloride (32 μL, 0.38 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. Methylamine (1 M in THF, 1.58 mL, 1.58 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (75 mg). 1 H NMR (300MHz; DMSO-d6) δ: 7.71 (br s, 1H), 3.58 (s, 3H), 3.11-2.99 (m, 1H), 2.97-2.73 (m, 1H), 2.54 (d, 3H), 2.25-2.05 (m, 4H).

[0832] Intermediate 132: (1,3-cis)-3-(methylcarbamoyl)cyclobutane-1-carboxylic acid

[0833] To a stirred solution of intermediate 131 (75 mg, 0.44 mmol) in THF (3 mL) and MeOH (1.4 mL) was added lithium hydroxide (21 mg, 0.88 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and dissolved in MeOH and washed with (IR 120H form) and filtration to provide the title compound (69 mg). 1H NMR (300 MHz; DMSO-d6) δ: 7.67 (s, 1H), 2.99-2.72 (m, 2H), 2.54 (d, 3H), 2.27-2.10 (m, 4H) - no OH observed.

[0834] Intermediate 133: (2S,4R)-1-(tert-Butoxycarbonyl)-4-((tert-Butyldimethylsilyl)oxy)pyrrolidine- 2-Formic acid

[0835] The title compound (0.62 g) was prepared in an analogous manner to Intermediate 99 using (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.50 g, 2.16 mmol, CAS 13726-69-7), DBU (0.68 mL, 4.54 mmol) and TBDMS-Cl (0.36 g, 2.38 mmol) in MeCN (4.3 mL) at room temperature for 18 h. 1 H NMR(300MHz; DMSO-d6)δ:12.67(br s,1H),4.42(t,1H),4.12(q,1H),3.43(ddd,1H),3.20(dt,1H),2.13-1.95(m,2H),1.37(d,9H),0.85(s,9H),0.06(d,6H).

[0836] Intermediate 134: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((S)-1-(5-(((S)-1,1- (dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrole tert-Butyl 1-oxanecarboxylate

[0837] The title compound (0.35 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 82 (0.20 g, 0.57 mmol), pyridine (0.3 mL), (50% in MeTHF, 1.09 mL, 1.72 mmol) and Intermediate 133 (0.22 g, 0.63 mmol) were prepared at room temperature for 16 h. Purification was performed by automated column chromatography (silica gel 40 g, eluting with 0-40% EtOAc in hexanes). LCMS (Method J): 677.2 [M+H] + .

[0838] Intermediate 135: (2S,4R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amine (2-(2-Yl)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide dihydrochloride

[0839] To a stirred solution of intermediate 134 (0.21 g, 0.31 mmol) in 1,4-dioxane (1.6 mL) was added 4 M HCl in 1,4-dioxane (0.78 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.17 g). LCMS (Method J): 463.5 [M+H] + .

[0840] Intermediate 136: Methyl (1,3-trans)-3-(methylcarbamoyl)cyclobutane-1-carboxylate

[0841] To a stirred solution of methyl trans-3-(methylcarbamoyl)cyclobutane-1-carboxylate (100 mg, 0.63 mmol, CAS 1401103-71-6) in DCM (3.2 mL) was added oxalyl chloride (64 μL, 0.76 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. Methylamine (1 M in THF, 3.16 mL, 3.16 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.20 g). 1 H NMR (300MHz; DMSO-d6) δ: 7.73 (br s, 1H), 3.61 (s, 3H), 3.15-2.93 (m, 2H), 2.56 (d, 3H), 2.33-2.16 (m, 4H).

[0842] Intermediate 137: (1,3-trans)-3-(methylcarbamoyl)cyclobutane-1-carboxylic acid

[0843] To a stirred solution of intermediate 136 (0.20 g, 1.17 mmol) in THF (2.2 mL) and MeOH (1.1 mL) was added lithium hydroxide (56 mg, 2.34 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and dissolved in MeOH and washed with (IR 120H form) and filtration to provide the title compound (0.19 g). 1 HNMR (300 MHz; DMSO-d6) δ: 7.65 (br d, 1H), 2.99-2.80 (m, 2H), 2.55 (dd, 3H), 2.30-2.14 (m, 4H) - no OH observed.

[0844] Intermediate 138: N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- (2,2,2-trifluoroethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide TFA salt

[0845] To a stirred mixture of intermediate 79a (0.48 g, 0.72 mmol) in DCM (9.6 mL) was added TFA (2.5 mL) at 0°C and stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and triturated in pentane to provide the title compound (0.60 g). LCMS (Method A): 473.2 [M+H] + .

[0846] Intermediate 139: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N-((1S)-1-(5-((1,1-dimethyl (2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-azaspiro[3.3]heptyl) Alkane-6-carboxamide

[0847] To a stirred solution of intermediate 138 (0.60 g, 0.93 mmol) in DMF (6 mL) was added DIPEA (0.49 mL, 2.79 mmol), followed by the addition of a solution of (2-bromoethoxy)-tert-butyl-dimethylsilane (0.89 g, 3.72 mmol, CAS 86864-60-0) in DMF (6 mL) over 5 min. The mixture was stirred at 70 ° C for 16 h. The mixture was diluted in 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 chromatography (silica gel, eluting with 100% EtOAc) to provide the title compound (0.20 g). LCMS (Method A): 631.7 [M+H] + .

[0848] Intermediate 140: 4-Bromo-2,3-dihydro-1H-inden-2-amine hydrochloride

[0849] The title compound (1.40 g) was prepared in a similar manner to Intermediate 6 using 4-bromoindan-2-one (10 g, 47.4 mmol, CAS 846032-36-8), ammonium acetate (54.8 g, 0.71 mol) and sodium cyanoborohydride (3.57 g, 56.9 mmol) in ethanol (0.2 L) at 100 °C for 3 h. The reaction mixture was quenched with 4 M HCl in 1,4-dioxane. LCMS (Method A): 1.05 min, 214.2 [M+H] + .

[0850] Intermediate 141: tert-Butyl (4-bromo-2,3-dihydro-1H-inden-2-yl)carbamate

[0851] To a stirred solution of intermediate 140 (1.40 g, 4.84 mmol) in DCM (30 mL) was added triethylamine (2.03 mL, 14.5 mmol) and di-tert-butyl dicarbonate (1.27 g, 5.82 mmol) at 0°C and stirred at room temperature for 3 h. The mixture was poured into water and then extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting with 3%-10% EtOAc in isohexane) to provide the title compound (1.80 g). LCMS (Method A): 256.1 [M-tBu+H] + .

[0852] Intermediate 142: tert-Butyl (4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)carbamate

[0853] To a stirred solution of intermediate 141 (0.51 g, 1.60 mmol) in toluene (5 mL) and water (1 mL) was added potassium cyclopropyltrifluoroborate (0.36 g, 2.40 mmol), and the mixture was degassed with argon. Palladium acetate (36 mg, 0.16 mmol) and tricyclohexylphosphine (90 mg, 0.32 mmol) were added and degassed with argon. K 3 PO 4 (1.02 g, 4.81 mmol) was added, and the mixture was stirred at 100 ° C for 16 h. The mixture was poured into water and then extracted with EtOAc. The organic layer was washed with water, brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by automated column chromatography (silica gel, eluted with 0-20% EtOAc in petroleum ether) to provide the title compound (0.36 g). LCMS (Method P): 218.2 [M-tBu+H] + .

[0854] Intermediate 143: 4-Cyclopropyl-2,3-dihydro-1H-inden-2-amine hydrochloride

[0855] To a stirred solution of intermediate 142 (0.35 g, 1.08 mmol) in DCM (3 mL) was added 4 M HCl in 1,4-dioxane (5 mL) and stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.26 g). LCMS (Method C): 174.5 [M+H] + .

[0856] Intermediate 144: N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((5-(trifluoromethyl)-2,3-dihydro-1H- (inden-2-yl)amino)pyridin-2-yl)ethyl)palmitamide

[0857] The title compound (1.80 g) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (1.0 g, 2.63 mmol), 5-(trifluoromethyl)dihydroindan-2-amine hydrochloride (0.73 g, 2.90 mmol, CAS 2851992-32-8), Cs2CO3 (2.57 g, 7.90 mmol) and RuPhosPdG3 (0.22 g, 0.26 mmol) in toluene (20 mL) at 110°C for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 15%-25% EtOAc in petroleum ether). LCMS (Method A): 474.5 [M+H] + .

[0858] Intermediate 145: 6-((S)-2,2,2-trifluoro-1-(methylamino)ethyl)-N-(5-(trifluoromethyl)-2,3-difluoro- Hydrogen-1H-inden-2-yl)pyridin-3-amine

[0859] The title compound (1.50 g) was prepared in a similar manner to Intermediate 61 from Intermediate 144 (1.80 g, 3.19 mmol) and LiAlH (2 M in THF, 5.0 mL, 10.0 mmol) in THF (18 mL) at 0° C. for 30 min. The crude product was purified by flash chromatography (silica gel, eluting with 25%-30% EtOAc in petroleum ether). LCMS (Method A): 390.4 [M+H] + .

[0860] Intermediate 146: 2-Amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride

[0861] To a stirred solution of tert-butyl (4-cyano-2,3-dihydro-1H-inden-2-yl)carbamate (0.11 g, 0.40 mmol, CAS 2116717-24-7) in 1,4-dioxane (1.1 mL) was added 4 M HCl in 1,4-dioxane (2 mL) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to provide the title compound (80 mg). LCMS (Method A): 159.2 [M+H] + .

[0862] Intermediate 147: (S)-N-(1-(5-((5,6-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2-yl) (2,2,2-trifluoroethyl)-N-methylpalmitamide

[0863] The title compound (0.12 g) was prepared from intermediate 59 (0.21 g, 0.60 mmol), 5,6-dimethylindan-2-amine (0.10 g, 0.62 mmol, CAS 162752-07-0), CsCO (0.58 g, 1.78 mmol) and RuPhosPdG (75 mg, 1.78 mmol) in toluene (3.1 mL) at 110° C. for 14 h in an analogous manner to intermediate 11. Purification was achieved by flash chromatography (silica gel, eluting with 15%-25% EtOAc in petroleum ether). 1 H NMR(300MHz; DMSO-d6)δ:8.01(d,1H),7.16-6.93(m,4H),6.50-6.32(m,2H),4. 22(q,1H),3.24(dd,2H),3.02(s,3H),2.72(dd,2H),2.18(s,6H),1.25(s,9H).

[0864] Intermediate 148: (S)-N-(5,6-dimethyl-2,3-dihydro-1H-inden-2-yl)-6-(2,2,2-trifluoro-1-(methyl)- (amino)ethyl)pyridin-3-amine

[0865] The title compound (47 mg) was prepared from Intermediate 147 (0.12 g, 0.27 mmol) and LiAlH (2 M in THF, 0.27 mL, 0.53 mmol) in THF (1.3 mL) at -15°C for 30 min in an analogous manner to Intermediate 61. The crude product was purified by automated column chromatography (silica gel 12 g, eluting with 0-50% EtOAc in hexanes). 1 H NMR(300MHz; DMSO-d6)δ:7.98(d,1H),7.23(d,1H),7.03-6.96(m,3H),6.27(d,1H),4.29-4.08(m,2H),3.24(dd,2H),2.72(dd,2H),2.63(br s,1H),2.23(s,3H),2.18(s,6H).

[0866] Intermediate 149: N-((1S)-1-(5-((4-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2, 2,2-trifluoroethyl)-N-methylpalmitamide

[0867] The title compound (0.80 g) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (0.70 g, 1.94 mmol), 4-chloroindan-2-amine hydrochloride (0.45 g, 2.14 mmol, CAS 2408959-26-0), Cs2CO3 (1.90 g, 5.83 mmol) and RuPhosPdG3 (0.32 g, 0.39 mmol) in toluene (7 mL) at 110° C. for 16 h. Purification was performed by automated column chromatography (silica gel 40 g, eluting with 50% EtOAc in petroleum ether). LCMS (Method A): 441.6 [M+H] + .

[0868] Intermediate 150: N-(4-chloro-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1-(methylamino) ethyl)pyridin-3-amine

[0869] The title compound (0.54 g) was prepared in a similar manner to Intermediate 61 from Intermediate 149 (0.75 g, 2.07 mmol) and LiAlH4 (1 M in THF, 3.0 mL, 3.00 mmol) in THF (7.5 mL) at -15°C, then at room temperature for 1 h. The crude product was purified by flash chromatography (silica gel, eluting with 55% EtOAc in petroleum ether). LCMS (Method A): 356.1 [M+H] + .

[0870] Intermediate 151: 7-Chloro-6-fluoro-2,3-dihydro-1H-inden-1-ol

[0871] To a stirred solution of 7-chloro-6-fluoro-indan-1-one (5.0 g, 27.1 mmol, CAS 881190-95-0) in ethanol (50 mL) was added sodium borohydride (2.06 g, 54.2 mmol) portionwise at 0°C, and the mixture was then stirred at room temperature for 3 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 to provide the title compound (4.9 g). 1 H NMR (400MHz; DMSO-d6) δ: 7.27-7.22(m,2H),5.27(d,1H),5.15-5.13(m,1H),3.10-3.02(m,1H),2.79-2.72(m,1H),2.33-2.24(m,1H),1.89(m,1H).

[0872] Intermediate 152: 4-Chloro-5-fluoro-1H-indene

[0873] To a stirred solution of intermediate 151 (4.9 g, 26.6 mmol) in toluene (200 mL) was added pTSA (1.00 g, 5.26 mmol) at 0° C., and the mixture was then stirred at 120° C. for 3 h. The mixture was allowed to cool, then diluted with water and extracted with TBDME. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted in petroleum ether) to provide the title compound (3.8 g). 1 H NMR(400MHz; DMSO-d6)δ:7.28-7.17(m,2H),7.01-6.96(m,2H),3.44(s,2H).

[0874] Intermediate 153: 4-Chloro-5-fluoro-1,3-dihydro-2H-inden-2-one

[0875] Intermediate 152 (3.30 g, 19.6 mmol) was added to a stirred solution of formic acid (13.3 mL) and hydrogen peroxide (30% aqueous solution, 2.14 mL, 27.4 mmol) at 50 ° C, and the mixture was then stirred at 60 ° C for 16 h. Sodium bisulfite (0.94 g) was added and stirred at 60 ° C for 1 h. The mixture was concentrated, then diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in toluene (35 mL) and pTSA (0.96 g, 5.03 mmol) was added and stirred at 120 ° C for 3 h. The mixture was diluted with water and extracted into EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted in petroleum ether) to provide the title compound (0.48 g). LCMS (Method C): 183.0 [MH] - .

[0876] Intermediate 154: (S)-(1-((1-(5-(Benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)(Methyl tert-Butyl)carbamoyl)cyclopropyl)carbamate

[0877] The title compound (0.19 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (0.20 g, 0.54 mmol), pyridine (2.7 mL), Prepared by mixing 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (50% in EtOAc, 3.30 mL, 5.34 mmol) and 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (0.16 g, 0.81 mmol, CAS 88950-64-5) at room temperature for 16 h. Purification was performed by automated flash chromatography (silica gel 25 g, eluting with 0-50% EtOAc in cyclohexane). LCMS (Method K): 555.6 [M+H] + .

[0878] Intermediate 155: (S)-N-(1-(5-((4,7-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2-yl) (2,2,2-trifluoroethyl)-N-methylpalmitamide

[0879] The title compound (55 mg) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (0.21 g, 0.60 mmol), 4,7-dimethylindan-2-amine (0.10 g, 2.90 mmol, CAS 162752-12-7), Cs2CO3 (0.58 g, 1.78 mmol) and RuPhosPdG3 (75 mg, 0.09 mmol) in toluene (2.8 mL) at 110°C for 14 h. Purification was performed by flash chromatography (silica gel, eluting with 15%-25% EtOAc in petroleum ether). LCMS (Method J): 434.2 [M+H] + .

[0880] Intermediate 156: (S)-N-(4,7-dimethyl-2,3-dihydro-1H-inden-2-yl)-6-(2,2,2-trifluoro-1-(methyl)- (amino)ethyl)pyridin-3-amine

[0881] The title compound (29 mg) was prepared in an analogous manner to Intermediate 61 from Intermediate 155 (55 mg, 0.13 mmol) and LiAlH4 (2 M in THF, 0.13 mL, 0.25 mmol) in THF (0.6 mL) at -15°C for 20 min. LCMS (Method A): 350.3 [M+H] + .

[0882] Intermediate 157: N-((1S)-1-(5-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2-yl) (2,2,2-trifluoroethyl)-N-methylpalmitamide

[0883] The title compound (0.25 g) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (0.50 g, 1.39 mmol), 6-chloro-4-fluoroindan-2-amine hydrochloride (0.38 g, 1.53 mmol, CAS 2755418-45-0), Cs2CO3 (1.36 g, 4.16 mmol) and RuPhosPdG3 (0.12 g, 0.14 mmol) in toluene (10 mL) at 110°C for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 20%-25% EtOAc in petroleum ether). LCMS (Method C): 458.5 [M+H] + .

[0884] Intermediate 158: N-(6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-3-amine

[0885] The title compound (0.19 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 157 (0.25 g, 0.45 mmol) and LiAlH4 (2 M in THF, 1.12 mL, 2.24 mmol) in THF (5 mL) at -10°C for 15 min. LCMS (Method C): 374.5 [M+H] + .

[0886] Intermediate 159: N-((1S)-1-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2-yl) (2,2,2-trifluoroethyl)-N-methylpalmitamide

[0887] The title compound (0.25 g) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (70 mg, 0.20 mmol), 5,6-difluoroindan-2-amine (35 mg, 0.21 mmol, CAS 173996-48-0), CsCO (0.19 g, 0.60 mmol), and RuPhosPdG (25 mg, 0.03 mmol) in toluene (0.7 mL) at 110° C. for 14 h. Purification was performed by automated column chromatography (silica gel 25 g, eluting with 0-40% EtOAc in hexanes). LCMS (Method J): 442.2 [M+H] + .

[0888] Intermediate 160: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-3-amine

[0889] The title compound (10 mg) was prepared in a similar manner to Intermediate 61 from Intermediate 159 (32 mg, 0.07 mmol) and LiAlH4 (2 M in THF, 0.07 mL, 0.15 mmol) in THF (0.4 mL) at -15°C for 30 min. Purification was performed by preparative TLC (eluting with 30% EtOAc in hexanes). LCMS (Method J): 358.1 [M+H] + .

[0890] Intermediate 161: N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- (2,2,2-trifluoroethyl)-N-methylpalmitamide

[0891] The title compound (0.25 g) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (0.50 g, 1.39 mmol), 5-chloro-4-fluoroindan-2-amine hydrochloride (0.37 g, 1.53 mmol, CAS 2740843-37-0), Cs2CO3 (1.36 g, 4.16 mmol) and RuPhosPdG3 (0.12 g, 0.14 mmol) in toluene (10 mL) at 90° C. for 16 h. Purification was performed by automated column chromatography (silica gel, eluting with 0-30% EtOAc in hexanes). LCMS (Method C): 458.5 [M+H] + .

[0892] Intermediate 162: N-(5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-3-amine

[0893] The title compound (0.20 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 161 (0.25 g, 0.44 mmol) and LiAlH4 (2 M in THF, 0.77 mL, 1.54 mmol) in THF (5 mL) at -10°C for 15 min. LCMS (Method C): 374.4 [M+H] + .

[0894] Intermediate 163: (S)-N-(1-(5-((diphenylmethylene)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- N-Methylpalmitamide

[0895] The title compound (5.0 g) was prepared in a similar manner to Intermediate 26 from Intermediate 59 (4.3 g, 15.7 mmol), benzophenone imine (3.94 mL, 23.5 mmol), Cs2CO3 (15.3 g, 47.0 mmol), Pd2(dba)3 (1.43 g, 1.57 mmol) and X-Phos (1.49 g, 0.74 mmol) in toluene (40 mL) at 110°C for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 0-100% EtOAc in petroleum ether). LCMS (Method C): 454.6 [M+H] + .

[0896] Intermediate 164: (S)-N-Benzhydryl-6-(2,2,2-trifluoro-1-(methylamino)ethyl)pyridin-3-amine

[0897] The title compound (4.0 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 163 (5.21 g, 11.0 mmol) and LiAlH4 (2 M in THF, 11.0 mL, 22.1 mmol) in THF (50 mL) at -10°C for 30 min. LCMS (Method C): 372.4 [M+H] + .

[0898] Intermediate 165: (S)-N-(1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl Tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[0899] The title compound (4.5 g) was prepared in a similar manner to Intermediate 3 from Intermediate 164 (4.25 g, 10.8 mmol), pyridine (12 mL), Prepared by mixing 1,1-dioxide (50% in EtOAc, 32.1 mL, 107 mmol) and tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (5.76 g, 32.3 mmol, CAS 64096-87-3) at room temperature for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 10% to 50% EtOAc in isohexane). LCMS (Method C): 532.6 [M+H] + .

[0900] Intermediate 166: (S)-N-(1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiol Phenylacetamide 1,1-dioxide

[0901] To a stirred solution of intermediate 165 (4.55 g, 2.12 mmol) in MeOH (50 mL) was added palladium on carbon (10%, 2.70 g), and the mixture was stirred under a hydrogen atmosphere for 4 h. The mixture was filtered through celite, washed with EtOAc and concentrated under reduced pressure to provide the title compound (3.0 g). LCMS (Method C): 366.4 [M+H] + .

[0902] Intermediate 167: 5-((S)-2,2,2-trifluoro-1-(methylamino)ethyl)-N-(4-(trifluoromethyl)-2,3-difluoro- Hydrogen-1H-inden-2-yl)pyridin-2-amine

[0903] The title compound (1.0 g) was prepared in a similar manner to Intermediate 26 from Intermediate 62 (1.02 g, 3.72 mmol), 4-(trifluoromethyl)-dihydroindan-2-amine hydrochloride (1.35 g, 5.58 mmol, CAS 1916506-14-3), sodium tert-butoxide (1.07 g, 11.2 mmol), Pd2(dba)3 (0.34 g, 0.37 mmol), and X-Phos (0.18 g, 0.37 mmol) in toluene (20 mL) at 110° C. for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 0-100% EtOAc in petroleum ether). LCMS (Method C): 390.2 [M+H] + .

[0904] Intermediate 168: 4-Chloro-6-fluoro-1,3-dihydro-2H-inden-2-one

[0905] The title compound (0.6 g) was prepared in a similar manner to Intermediate 153 from 7-chloro-5-fluoro-1H-indene (8.0 g, 42.7 mmol, CAS 1215279-93-8) and hydrogen peroxide (30% aqueous solution, 8.0 mL, 70.6 mmol) in formic acid (37.7 mL) at 60° C. for 16 h. The mixture was quenched with sodium bisulfite (2.05 g) at 60° C. for 1 h. The mixture was then treated with pTSA (0.47 g, 2.47 mmol) in toluene (100 mL) at 80° C. for 7 h. The crude product was purified by flash chromatography (silica gel, eluting with 5% EtOAc in petroleum ether). LCMS (Method A): 183.1 [MH] - .

[0906] Intermediate 169: N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-5-((S)-2,2,2-trifluoro-1-(methylamino) ethyl)pyridin-2-amine

[0907] The title compound (0.32 g) was prepared in a similar manner to Intermediate 26 from Intermediate 62 (0.50 g, 1.82 mmol), 5-chloroindan-2-amine hydrochloride (0.51 g, 2.18 mmol, CAS 73536-86-4), sodium tert-butoxide (0.88 g, 9.11 mmol), Pd2(dba)3 (0.17 g, 0.18 mmol) and X-Phos (0.17 g, 0.36 mmol) in toluene (5 mL) at 110°C for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 20%-30% EtOAc in petroleum ether). LCMS (Method C): 356.5 [M+H] + .

[0908] Intermediate 170: (S)-1-amino-N-(1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethane (4-Methyl)-N-methylcyclopropane-1-carboxamide dihydrochloride

[0909] To a stirred solution of intermediate 154 (0.19 g, 0.33 mmol) in 1,4-dioxane (17 mL) was added 4 M HCl in 1,4-dioxane (1 mL) and stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to provide the title compound (0.15 g). LCMS (Method K): 455.2 [M+H] + .

[0910] Intermediate 171: 6-Chloro-5-(difluoromethoxy)-2,3-dihydro-1H-inden-1-one

[0911] To a stirred solution of 6-chloro-5-hydroxy-2,3-dihydro-1H-inden-1-one (0.60 g, 3.29 mmol, CAS 1260012-31-4) in MeCN (16.5 mL) was added CsCO (2.14 g, 6.57 mmol) and chlorodifluoroacetic acid (0.56 mL, 6.61 mmol), and the mixture was heated at 120 ° C. for 30 min under microwave irradiation. The mixture was filtered and washed with DCM. The filtrate was washed with water, brine, dried over NaSO, filtered and concentrated under reduced pressure to provide the title compound (0.72 g). 1 H NMR (300MHz; DMSO-d6)δ:7.81(s,1H),7.60(t,1H),7.48(t,1H)3.20-3.01(m,2H),2.77-2.60(m,2H).

[0912] Intermediate 172: 6-Chloro-5-(difluoromethoxy)-2,3-dihydro-1H-inden-1-ol

[0913] The title compound (0.74 g) was prepared in an analogous manner to Intermediate 151 from Intermediate 171 (0.72 g, 0.86 mmol) and sodium borohydride (0.16 g, 1.21 mmol) in THF (14 mL) and MeOH (3.5 mL) at room temperature for 1.5 h. 1 H NMR(300MHz; DMSO-d6)δ:7.45(d,1H),7.24(t,1H),7.23(d,1H),5.39(d,1H),5.0 4(q,1H),3.00-2.84(m,1H),2.72(dt,1H),2.42-2.29(m,1H),1.88-1.71(m,1H).

[0914] Intermediate 173: 5-chloro-6-(difluoromethoxy)-1H-indene

[0915] The title compound (0.63 mg) was prepared in an analogous manner to Intermediate 152 using Intermediate 172 (0.71 g, 3.02 mmol) and pTSA (0.10 g, 0.60 mmol) and MgSO 4 (0.36 g, 3.01 mmol) in toluene (29 mL) at 80° C. for 1 h. 1 H NMR (400MHz; CDCl3) δ: 7.64 (s, 1H), 7.52 (s, 1H), 7.23 (t, 1H), 6.94-6.89 (m, 1H), 6.74 (dt, 1H), 3.48 (s, 2H).

[0916] Intermediate 174: 5-Chloro-6-(difluoromethoxy)-1,3-dihydro-2H-inden-2-one

[0917] The title compound (0.32 g) was prepared in a similar manner to Intermediate 153 from Intermediate 173 (0.63 g, 2.89 mmol) and hydrogen peroxide (35% aqueous solution, 0.35 mL, 4.05 mmol) in formic acid (1.9 mL) at 60° C. for 16 h, quenched with sodium bisulfite (0.12 g) at 55° C. for 1 h. This was followed by treatment with pTSA (0.12 g, 0.58 mmol) in toluene (4.2 mL) at 115° C. for 2 h. The crude product was purified by automated column chromatography (silica gel, eluted with 4%-38% EtOAc in cyclohexane). 1 H NMR (400MHz; CDCl3) δ: 7.56 (s, 1H), 7.36 (s, 1H), 7.26 (t, 1H), 3.58 (s, 2H), 3.56 (s, 2H).

[0918] Intermediate 175: Methyl 4-(methylcarbamoyl)cubane-1-carboxylate

[0919] To a stirred solution of 4-methoxycarbonylcubane-1-carboxylic acid (50 mg, 0.24 mmol, CAS 24539-28-4) in DCM (1.2 mL) was added oxalyl chloride (25 μL, 0.29 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. Methylamine (1 M in THF, 1.21 mL, 1.58 mmol) was added, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (53 mg). 1 HNMR (300MHz; DMSO-d6) δ: 7.61 (br s, 1H), 4.10 (s, 6H), 3.62 (s, 3H), 2.58 (d, 3H).

[0920] Intermediate 176: 4-(Methylcarbamoyl)cubane-1-carboxylic acid

[0921] To a stirred solution of intermediate 175 (0.11 g, 0.51 mmol) in THF (2 mL) and water (1.3 mL) was added lithium hydroxide (24 mg, 1.00 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and dissolved in MeOH and washed with (IR 120H form) and filtration to provide the title compound (0.19 g). 1 H NMR (300 MHz; DMSO-d6) δ: 7.55 (d, 1H), 3.91 (dd, 3H), 3.85-3.75 (m, 3H), 2.57 (dd, 3H) - no OH observed.

[0922] Intermediate 177: (E)-5,6,7-Trifluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one

[0923] To a stirred solution of 5,6,7-trifluoroindan-1-one (2.0 g, 10.5 mmol, CAS 1257844-57-7) in MeOH (20 mL) was added butyl nitrite (1.35 mL, 11.6 mmol) at 40 ° C, and the mixture was stirred at 40 ° C for 16 h. Hydrochloric acid (0.28 mL, 11.6 mmol) was added, and the mixture was stirred at 40 ° C for 3 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 Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to provide the title compound (1.10 g). LCMS (Method C): 213.9 [MH] - .

[0924] Intermediate 178: 4,5,6-Trifluoro-2,3-dihydro-1H-inden-2-amine hydrochloride

[0925] The title compound (0.42 g) was prepared in a similar manner to Intermediate 109 from Intermediate 177 (2.2 g, 9.00 mmol), sulfuric acid (0.48 mL, 9.00 mmol), palladium on carbon (10%, 1.92 g) in AcOH (14 mL) under a hydrogen atmosphere at 450 psi for 16 h, acidified with 4 M HCl in 1,4-dioxane. LCMS (Method C): 188.2 [M+H] + .

[0926] Intermediate 179: N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4,5,6-trifluoro-2,3-dihydro-1H-indene- 2-yl)amino)pyridin-2-yl)ethyl)palmitamide

[0927] To a stirred solution of intermediate 178 (0.26 g, 0.88 mmol) in 1,4-dioxane (3 mL) was added intermediate 59 (0.45 g, 2.31 mmol) and Cs2CO3 (0.53 g, 1.61 mmol), and the mixture was degassed with argon for 10 min. Pd-PEPPSI-iHeptCl (39 mg, 0.04 mmol) was added, and the mixture was heated at 110 ° C for 5 h. The mixture was poured into 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 chromatography (silica gel, eluted with 0-30% EtOAc in hexanes) to provide the title compound (0.25 g). LCMS (Method C): 460.6 [M+H] + .

[0928] Intermediate 180: 6-((S)-2,2,2-trifluoro-1-(methylamino)ethyl)-N-(4,5,6-trifluoro-2,3-dihydro- 1H-inden-2-yl)pyridin-3-amine

[0929] The title compound (0.13 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 179 (0.20 g, 0.34 mmol) and LiAlH4 (2 M in THF, 0.52 mL, 1.03 mmol) in THF (2 mL) at 0°C for 30 min. LCMS (Method C): 376.5 [M+H] + .

[0930] Intermediate 181: 7-(difluoromethoxy)-1H-indene

[0931] The title compound (0.95 g) was prepared in an analogous manner to Intermediate 152 using 4-(difluoromethoxy)-2,3-dihydro-1H-inden-1-ol (0.98 g, 4.90 mmol, CAS 1304084-59-0) and pTSA (0.19 g, 0.98 mmol) in toluene (24 mL) at 80 °C for 3 h. 1H NMR (300MHz; CDCl3) δ: 7.29(d,1H),7.27(s,1H),6.99-6.92(m,1H),6.88(dt,1H),6.63-6.60(m,1H),6.59(t,1H),3.45(t,2H).

[0932] Intermediate 182: (S)-N-(1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl 1-(methylsulfonamido)cyclopropane-1-carboxamide

[0933] The title compound (0.36 g) was prepared from Intermediate 170 (0.51 g, 0.97 mmol), triethylamine (0.40 mL, 2.90 mmol) and methanesulfonyl chloride (0.13 g, 1.16 mmol) in DCM (32 mL) at room temperature for 16 h in a manner analogous to Example 169. Purification was by flash chromatography (silica gel, eluting with 0-100% EtOAc in hexanes). 1 H NMR (300MHz; DMSO-d6)δ:8.15-8.04(m,1H),7.44-7.31(m,9H),7.25(t,2H),7.06(br s,1H),7.00(d,2H),6.16(dd,1H),5.72(d,1H),3.06(br s,3H),2.85(s,3H),1.25-1.05(m,4H).

[0934] Intermediate 183: (S)-N-(1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)- amido)cyclopropane-1-carboxamide

[0935] The title compound (0.28 g) was prepared in a similar manner to Intermediate 206 from Intermediate 182 (0.45 g, 0.84 mmol), formic acid (0.32 mL, 8.40 mmol) and palladium on carbon (10%, 0.25 g) in MeOH (8.4 mL) at 50° C. for 5 h. Purification was performed by automated flash chromatography (12 g silica gel, eluting with 0-10% MeOH in DCM). LCMS (Method M): 367.1 [M+H] + .

[0936] Intermediate 184: (S)-tert-Butyl (5-chloro-2,3-dihydro-1H-inden-2-yl)carbamate

[0937] The title compound (12 g) was prepared in an analogous manner to Intermediate 141 using 5-chloroindan-2-amine hydrochloride (25.0 g, 123 mmol, CAS 73536-86-4), triethylamine (51.2 mL, 368 mmol) and di-tert-butyl dicarbonate (32.1 g, 147 mmol) in DCM (250 mL) for 3 h at room temperature. The product was purified by flash chromatography (silica gel, eluting with 0-10% EtOAc in isohexane) followed by preparative SFC ( -AD-H, 30×250 mm×5 μm, temperature 30°C, back pressure 100 bar, flow rate: 100 g / min, 90% CO2 with 10% 1:1 MeCN / IPA modifier) ​​for purification - title compound peak 1. LCMS (Method C): 212.2 [M-tBu+H] + .

[0938] Intermediate 185: (S)-5-chloro-2,3-dihydro-1H-inden-2-amine hydrochloride

[0939] To a stirred solution of intermediate 184 (12.0 g, 44.4 mmol) in 1,4-dioxane (60 mL) was added 4 M HCl in 1,4-dioxane (120 mL) and stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and triturated in pentane to provide the title compound (10.0 g). LCMS (Method C): 168.2 [M+H] + .

[0940] Intermediate 186: N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)- 2,2,2-trifluoroethyl)-N-methylpalmitamide

[0941] The title compound (9.0 g) was prepared in a similar manner to Intermediate 11 from Intermediate 59 (9.0 mg, 25.2 mmol), Intermediate 185 (5.2 g, 25.2 mmol), Cs2CO3 (25.7 g, 75.7 mmol) and RuPhosPdG3 (2.11 g, 2.52 mmol) in toluene (180 mL) at 100° C. for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 20%-25% EtOAc in petroleum ether). LCMS (Method J): 440.5 [M+H] + .

[0942] Intermediate 187: N-((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-3-amine

[0943] The title compound (7.0 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 186 (9.0 g, 18.4 mmol) and LiAlH4 (2M in THF, 25 mL, 50.0 mmol) in THF (90 mL) at 0°C for 30 min. 1 H NMR (400 MHz; DMSO-d6) δ: 7.98 (d, 1H), 7.31-7.19 (m, 4H), 7.01 (dd, 1H), 6.33 (d, 1H), 4.32-4.23 (m, 1H), 4.18-4.08 (m, 1H), 2.84-2.73 (m, 2H), 2.63 (br s, 1H), 2.25-2.19 (m, 4H) - one H is obscured by the water peak.

[0944] Intermediate 188: (3-(((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- tert-Butyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0945] The title compound (0.10 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 187 (60 mg, 0.17 mmol), 3-(tert-butoxycarbonylamino)-bicyclo[1.1.1]pentane-1-carboxylic acid (42 mg, 0.18 mmol, CAS 303752-38-7), pyridine (0.8 mL), (50% in EtOAc, 0.30 mL, 0.51 mmol) Prepared at room temperature for 16 h. LCMS (Method K): 565.1 [M+H] + .

[0946] Intermediate 189: 3-amino-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridine (2-pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide

[0947] To a stirred solution of intermediate 188 (0.10 g, 0.18 mmol) in 1,4-dioxane (1.4 mL) was added 4 M HCl in 1,4-dioxane (0.44 mL) and stirred at room temperature for 17 h. The mixture was concentrated under reduced pressure and basified with saturated aqueous NaHCO 3 solution and extracted with diethyl ether. The organics were dried over MgSO 4 , filtered and concentrated under reduced pressure to provide the title compound (77 mg). LCMS (Method K): 465.0 [M+H] + .

[0948] Intermediate 190: (R)-2-(((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridine- tert-Butyl (2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-5-oxopyrrolidine-1-carboxylate

[0949] The title compound (14 mg) was prepared in a similar manner to Intermediate 3 from Intermediate 187 (50 mg, 0.14 mmol), (2R)-1-tert-butoxycarbonyl-5-oxo-pyrrolidine-2-carboxylic acid (40 mg, 0.15 mmol, CAS 160347-90-0), pyridine (0.7 mL), (50% in EtOAc, 0.25 mL, 0.42 mmol) was prepared at room temperature for 16 h. Purification was performed by preparative HPLC (Gemini NX-C18, 21.2×250 mm×5 μm, flow rate: 30 mL / min, 0.1% aqueous formic acid and MeCN 27% isocratic for 6 min, ramped to 95% in 0.2 min and held for 2.2 min). 1 H NMR(300MHz; CDCl3)δ:8.04(d,1H),7.23-7.13(m,4H),6.92(dd,1H),6.42(dd,1H),5.02(dd,1H),4.39-4.30(m,1H),3.36(dt,2H),3 .12(s,3H),2.93-2.81(m,2H),2.80-2.59(m,1H),2.49-2.40(m,1H),2.34-2.18(m,1H),2.00(s,1H),1.95-1.89(m,1H),1.49(s,9H).

[0950] Intermediate 191: 7-Bromo-6-chloro-1H-indene

[0951] The title compound (1.75 g) was prepared in an analogous manner to Intermediate 152 using 4-bromo-5-chloro-2,3-dihydro-1H-inden-1-ol (1.93 g, 7.81 mmol, CAS 2153981-78-1) and pTSA (0.30 g, 1.56 mmol) in toluene (26 mL) at 80° C. for 1 h. 1 H NMR (300MHz; CDCl3) δ: 7.38 (d, 1H), 7.26 (d, 1H), 6.88 (dt, 1H), 6.62 (dt, 1H), 3.43 (s, 2H).

[0952] Intermediate 192: 4-Bromo-5-chloro-1,3-dihydro-2H-inden-2-one

[0953] The title compound (0.79 g) was prepared in a similar manner to Intermediate 153 from Intermediate 191 (1.75 g, 7.60 mmol) and hydrogen peroxide (35% aqueous solution, 0.93 mL, 10.6 mmol) in formic acid (5.0 mL) at 60° C. for 16 h, quenched with sodium bisulfite (0.32 g) at 55° C. for 1 h. This was followed by treatment with pTSA (0.29 g, 1.52 mmol) in toluene (9.5 mL) at 80° C. for 2 h. The crude product was purified by automated column chromatography (silica gel 120 g, eluted with 0-90% EtOAc in hexanes). 1 H NMR (300MHz; CDCl3) δ: 7.38 (d, 1H), 7.20 (d, 1H), 3.65 (s, 2H), 3.59 (s, 2H).

[0954] Intermediate 193: 5-Chloro-4-cyclopropyl-1,3-dihydro-2H-inden-2-one

[0955] To a stirred solution of intermediate 192 (0.25 g, 0.87 mmol) in toluene (4.8 mL) and water (0.8 ml) was added potassium cyclopropyltrifluoroborate (0.26 g, 2.00 mmol, CAS 1065010-87-8), and the mixture was degassed with argon for 10 min. Pd(dppf)Cl (64 mg, 0.10 mmol) and KPO (0.55 g, 3.00 mmol) were added, and the mixture was heated at 90° C. for 16 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by automated column chromatography (silica gel 80 g, eluting with 0-20% EtOAc in cyclohexane) to provide the title compound (0.65 g). 1 H NMR(300MHz; DMSO-d6)δ:7.32(d,1H),7.20(d,1H),3.65(s,2H),3.53(s,2H),1.88-1.74(m,1H),1.05-0.88(m,2H),0.72-0.65(m,2H).

[0956] Intermediate 194: (R)-6-Oxo-1-(trimethylsilyl)piperidine-2-carboxylic acid

[0957] To a stirred solution of (R)-6-oxopiperidine-2-carboxylic acid (0.10 g, 0.70 mmol, CAS 72002-30-3) and triethylamine (0.11 mL, 0.77 mmol) in toluene (3.9 mL) was added chlorotrimethylsilane (0.09 mL, 0.77 mmol), and the mixture was heated at 110° C. for 16 h. The mixture was concentrated under reduced pressure to provide the title compound (0.15 g). 1H NMR (300MHz; CDCl3) δ: 11.99 (d, 1H), 4.06 (dd, 1H), 2.50-2.18 (m, 3H), 1.98-1.86 (m, 1H), 1.83-1.60 (m, 2H), 0.05 (s, 9H).

[0958] Intermediate 195: 5-Bromo-6-fluoro-1H-indene

[0959] The title compound (2.55 g) was prepared in an analogous manner to Intermediate 152 using 6-bromo-5-fluoro-2,3-dihydro-1H-inden-1-ol (2.52 g, 10.9 mmol, CAS 2089649-48-7) and pTSA (0.31 g, 1.09 mmol) in toluene (57 mL) at 90° C. for 2 h. 1 H NMR (300MHz; DMSO-d6) δ: 7.76 (dd, 1H), 7.42 (d, 1H), 6.93-6.89 (m, 1H), 6.81-6.74 (m, 1H), 3.43 (s, 2H).

[0960] Intermediate 196: 5-Bromo-6-fluoro-1,3-dihydro-2H-inden-2-one

[0961] The title compound (0.79 g) was prepared in an analogous manner to Intermediate 153 from Intermediate 195 (2.25 g, 10.6 mmol) and hydrogen peroxide (35% aqueous solution, 1.29 mL, 14.8 mmol) in formic acid (7.0 mL) at 60° C. for 16 h, quenched with sodium bisulfite (0.44 g) at 55° C. for 1 h, and then treated with pTSA (0.40 g, 2.11 mmol) in toluene (53 mL) at 80° C. for 1.5 h. 1 H NMR (300MHz; DMSO-d6) δ: 7.65 (d, 1H), 7.35 (d, 1H), 3.54 (s, 4H).

[0962] Intermediate 197: 5-Chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol

[0963] The title compound (2.2 g) was prepared in a similar manner to Intermediate 151 from 5-chloro-4-(trifluoromethyl)indan-1-one (2.70 g, 8.98 mmol, CAS 1273661-11-2) and sodium borohydride (0.51 g, 13.5 mmol) in ethanol (30 mL) at room temperature for 3 h. Purification was performed by flash chromatography (silica gel, eluting with 0-10% EtOAc in petroleum ether). LCMS (Method C): 219.2 [M-H2O+H] + .

[0964] Intermediate 198: 6-Chloro-7-(trifluoromethyl)-1H-indene

[0965] The title compound (2.20 g) was prepared in an analogous manner to Intermediate 152 using Intermediate 197 (2.70 g, 6.73 mmol) and pTSA (0.26 g, 1.34 mmol) in toluene (30 mL) at 90 °C for 3 h. 1 H NMR (400MHz; CDCl3) δ: 7.43 (dd, 2H), 6.85 (d, 1H), 6.66 (dd, 1H), 3.65-3.62 (m, 2H).

[0966] Intermediate 199: 5-Chloro-4-(trifluoromethyl)-1,3-dihydro-2H-inden-2-one

[0967] The title compound (0.35 g) was prepared in a similar manner to Intermediate 153 from Intermediate 198 (1.10 g, 5.03 mmol) and hydrogen peroxide (30% aqueous solution, 0.55 mL, 7.04 mmol) in formic acid (3.4 mL) at 60° C. for 16 h, quenched with sodium bisulfite (0.28 g) at 60° C. for 2 h. It was then treated with pTSA (0.18 g, 0.95 mmol) in toluene (25 mL) at 90° C. for 3 h. LCMS (Method C): 235.1 [M+H] + .

[0968] Intermediate 200: (S)-2-(((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridine- tert-Butyl (2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)-5-oxopyrrolidine-1-carboxylate

[0969] The title compound (20 mg) was prepared in a similar manner to Intermediate 3 from Intermediate 187 (70 mg, 0.20 mmol), (2S)-1-(tert-butoxycarbonyl)-5-oxo-pyrrolidine-2-carboxylic acid (80 mg, 0.29 mmol, CAS 53100-44-0), pyridine (1.0 mL), (50% in EtOAc, 1.17 mL, 2.95 mmol) was prepared at room temperature for 16 h. Purification was performed by preparative HPLC (X Bridge C18, 19×150 mm×5 μm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN from 10% to 60% over 6 min, held at 60% for 7 min, ramped to 95% over 0.2 min and held for 1.8 min). LCMS (Method K): 567.4 [M+H] + .

[0970] Intermediate 201: (S)-N-((S)-1-(5-(diphenylmethylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N- Methyl-5-oxopyrrolidine-3-carboxamide

[0971] The title compound (0.39 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (0.40 g, 1.03 mmol), (3S)-5-oxopyrrolidine-3-carboxylic acid (0.14 g, 1.08 mmol, CAS 30948-17-5), pyridine (5.2 mL), (50% in EtOAc, 3.0 mL, 4.90 mmol) Prepared at room temperature for 40 h. Purified by flash chromatography (silica gel, eluting with 0-10% MeOH in DCM). LCMS (Method K): 483.2 [M+H] + .

[0972] Intermediate 202: (S)-N-((S)-1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyridin-2-yl 3-Hydrrolidine-3-carboxamide

[0973] To a stirred solution of intermediate 201 (0.39 g, 0.81 mmol) in MeOH (4 mL) was added formic acid (0.09 mL, 2.41 mmol), ammonium formate (0.31 g, 4.84 mmol) and palladium on carbon (10%, 0.17 g), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO3 and 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 chromatography (silica gel, eluted with 0-20% MeOH in DCM) to provide the title compound (0.14 g). LCMS (Method M): 317.2 [M+H] + .

[0974] Intermediate 203: 6-chloro-7-fluoro-1H-indene

[0975] The title compound (4.00 g) was prepared in an analogous manner to Intermediate 152 using 4-fluoro-5-chloro-2,3-dihydro-1H-inden-1-ol (5.00 g, 26.8 mmol, CAS 1597134-92-3) and pTSA (1.02 g, 5.37 mmol) in toluene (134 mL) at 80° C. for 1 h. 1 H NMR (300MHz; CDCl3) δ: 7.30 (dd, 1H), 7.11 (d, 1H), 6.85-6.80 (m, 1H), 6.61-6.58 (m, 1H), 3.48 (t, 2H).

[0976] Intermediate 204: 5-Chloro-4-fluoro-1,3-dihydro-2H-inden-2-one

[0977] The title compound (0.52 g) was prepared in a similar manner to Intermediate 153 from Intermediate 203 (2.0 g, 11.6 mmol) and hydrogen peroxide (35% aqueous solution, 1.43 mL, 16.3 mmol) in formic acid (7.7 mL) at 60° C. for 16 h, quenched with sodium bisulfite (0.48 g) at 55° C. for 1 h. This was followed by treatment with pTSA (0.44 g, 0.20 mmol) in toluene (60 mL) at 90° C. for 2 h. Purification was achieved by flash chromatography (silica gel, eluting with 0-20% EtOAc in cyclohexane). 1 H NMR (300MHz; CDCl3) δ: 7.32 (dt, 1H), 7.05 (d, 1H), 3.60 (s, 2H), 3.57 (s, 2H).

[0978] Intermediate 205: (S)-N-((S)-1-(5-(diphenylmethylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N- Methyl-6-oxopiperidine-3-carboxamide

[0979] The title compound (1.12 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (1.11 g, 2.89 mmol), (3S)-6-oxopiperidine-3-carboxylic acid (0.50 g, 1.20 mmol, CAS 1426408-56-1), pyridine (15.8 mL), (50% in EtOAc, 8.8 mL, 14.4 mmol) Prepared at room temperature for 72 h. Purified by flash chromatography (silica gel, eluting with 0-20% MeOH in DCM). LCMS (Method K): 497.3 [M+H] + .

[0980] Intermediate 206: (S)-N-((S)-1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxo- 3-Hydroxypiperidine-3-carboxamide

[0981] To a stirred solution of intermediate 205 (1.11 g, 1.79 mmol) in MeOH (18 mL) was added formic acid (0.68 mL, 17.9 mmol) and palladium on carbon (10%, 0.57 g), and the mixture was stirred at 50 ° C for 2 h. The mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO 3 solution and extracted with DCM. The organic layer was washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 0-10% MeOH in DCM) to provide the title compound (0.47 g). LCMS (Method K): 331.1 [M+H] + .

[0982] Intermediate 207: (S)-(3-((1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl tert-Butyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0983] The title compound (0.60 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (0.40 g, 1.08 mmol), 3-(tert-butoxycarbonylamino)bicyclo[1.1.1]pentane-1-carboxylic acid (0.30 g, 1.30 mmol, CAS 303752-38-7), pyridine (6.0 mL), (50% in EtOAc, 2.0 mL, 3.27 mmol) Prepared at room temperature for 16 h. Purified by flash chromatography (silica gel, eluting with 0-50% EtOAc in cyclohexane). LCMS (Method L): 581.3 [M+H] + .

[0984] Intermediate 208: (S)-3-amino-N-(1-(5-(diphenylmethylamino)pyridin-2-yl)-2,2,2-trifluoroethyl 1-Methyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide

[0985] A solution of intermediate 207 (0.60 g, 0.98 mmol) in TFA (0.60 mL) and DCM (9.8 mL) was stirred at room temperature for 6 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with DCM. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.50 g). LCMS (Method K): 481.2 [M+H] + .

[0986] Intermediate 209: (S)-N-(1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl 3-(methylsulfonamido)bicyclo[1.1.1]pentane-1-carboxamide

[0987] To a solution of intermediate 208 (0.50 g, 0.94 mmol) and triethylamine (0.39 mL, 2.80 mmol) in DCM (9.4 mL) was added methanesulfonyl chloride (0.09 mL, 1.12 mmol) at 0°C, and the mixture was then 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 chromatography (silica gel, eluting with 0-3% MeOH in DCM) to provide the title compound (0.41 g). LCMS (Method K): 559.1 [M+H] + .

[0988] Intermediate 210: (S)-N-(1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonyl)- Amide)bicyclo[1.1.1]pentane-1-carboxamide

[0989] The title compound (0.26 g) was prepared in an analogous manner to Intermediate 206 from Intermediate 209 (0.41 g, 0.73 mmol), formic acid (0.27 mL, 7.16 mmol) and palladium on carbon (10%, 0.23 g) in MeOH (6.9 mL) at 50° C. for 2 h. LCMS (Method K): 393.0 [M+H]+ .

[0990] Intermediate 211: 5-(difluoromethoxy)-1,3-dihydro-2H-inden-2-one

[0991] The title compound (0.18 g) was prepared in a similar manner to Intermediate 153 from Intermediate 247 (0.80 g, 3.07 mmol) and hydrogen peroxide (35% aqueous solution, 0.38 mL, 4.32 mmol) in formic acid (2.0 mL) at 60° C. for 16 h, quenched with sodium bisulfite (0.40 g) at 55° C. for 1 h. This was followed by treatment with pTSA (0.12 g, 0.62 mmol) in toluene (18 mL) at 90° C. for 2 h. Purification was achieved by flash chromatography (silica gel, eluting with 0-40% EtOAc in cyclohexane). 1 H NMR (300MHz; CDCl3) δ: 7.30 (d, 1H), 7.11-7.02 (d, 2H), 6.51 (t, 1H) 3.58 (s, 2H), 3.55 (s, 2H).

[0992] Intermediate 212: (S)-N-(1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl 1-(methylsulfonyl)piperidine-4-carboxamide

[0993] The title compound (0.60 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (0.20 g, 0.52 mmol), 1-(methylsulfonyl)piperidine-4-carboxylic acid (0.14 g, 0.68 mmol, CAS 280772-00-1), pyridine (2.6 mL), (50% in MeTHF, 0.96 mL, 1.57 mmol) Prepared at room temperature for 16 h. Purified by flash chromatography (silica gel, eluting with 0-50% EtOAc in cyclohexane). 1 HNMR(300MHz; DMSO-d6)δ:8.12-8.03(m,1H),7.45-7.31(m,8H),7.30-7.12(m,2H),7.11-6.93(m,3H),6.35(d d,1H),5.77-5.67(m,1H),3.64-3.47(m,2H),2.99(s,3H),2.86(s,3H),2.81-2.67(m,3H),1.92-1.47(m,4H).

[0994] Intermediate 213: (S)-N-(1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)- acyl)piperidine-4-carboxamide

[0995] The title compound (92 mg) was prepared from Intermediate 212 (0.22 g, 0.39 mmol), formic acid (0.22 g, 4.71 mmol) and palladium on carbon (10%, 0.13 g) in MeOH (1.3 mL) at 50° C. for 3 h in an analogous manner to Intermediate 206. Purification was by flash chromatography (silica gel, eluting with 0-10% MeOH in DCM). 1 H NMR(300MHz; DMSO-d6)δ:7.99-7.90(m,1H),7.19-6.90(m,2H),6.36(dd,1H),5.65-5.53( m,2H),3.67-3.52(m,2H),2.99(s,3H),2.89(s,3H),2.83-2.69(m,2H),1.95-1.46(m,5H).

[0996] Intermediate 214: (S)-N-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-N-methylpalmitamide

[0997] To a stirred solution of intermediate 62 (0.20 g, 0.74 mmol) and triethylamine (0.51 mL, 3.68 mmol) in DCM (4 mL) was added pivaloyl chloride (0.54 mL, 4.42 mmol) at 10 ° C, and the mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with DCM. The organics were washed with saturated aqueous NaHCO 3 solution, brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 0-8% EtOAc in hexanes) to provide the title compound (0.20 g). LCMS (Method C): 353.3 [M+H] + .

[0998] Intermediate 215: N-((1S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-3- (2,2,2-trifluoroethyl)-N-methylpalmitamide

[0999] The title compound (92 mg) was prepared in a similar manner to Intermediate 179 from Intermediate 214 (0.26 g, 0.88 mmol), 5-chloro-4-fluoro-indan-2-amine hydrochloride (0.45 g, 2.31 mmol, CAS 2740843-37-0), Cs2CO3 (0.79 g, 2.42 mmol) and Pd-PEPPSI-iHeptCl (55 mg, 0.08 mmol) in 1,4-dioxane (6 mL) at 100° C. for 16 h. Purification by flash chromatography (silica gel, eluting with 0-100% EtOAc in petroleum ether) provided the title compound (0.11 g). LCMS (Method C): 458.3 [M+H] + .

[1000] Intermediate 216: N-(5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)-5-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-2-amine

[1001] The title compound (0.15 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 215 (0.16 g, 0.31 mmol) and LiAlH4 (2 M in THF, 0.92 mL, 1.84 mmol) in THF (5 mL) at 0°C for 30 min. LCMS (Method C): 374.2 [M+H] + .

[1002] Intermediate 217: 5-(Difluoromethoxy)-1a,6a-dihydro-6H-indeno[1,2-b]oxetine

[1003] To a stirred solution of intermediate 181 (0.75 g, 3.29 mmol) in DCM (16.5 mL) was added NaHCO (0.41 g, 4.90 mmol) and MCPBA (1.22 g, 4.94 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with DCM. The organic matter was washed with water, brine, dried over NaSO, filtered and concentrated under reduced pressure. The crude product was purified by automated column chromatography (silica gel 25 g, 0-10% EtOAc in cyclohexane) to provide the title compound (0.54 g). 1 H NMR (300MHz; CDCl3) δ: 7.38(dd,1H),7.21(dt,1H),7.04(dt,1H),6.50(t,1H),4.29(dd,1H),4.16(t,1H),3.27(dd,1H),2.97(dd,1H).

[1004] Intermediate 218: 4-(Difluoromethoxy)-1,3-dihydro-2H-inden-2-one

[1005] To a stirred solution of intermediate 217 (0.53 g, 2.67 mmol) in toluene (13 mL) was added silica gel (1.2 g), and the mixture was stirred at reflux for 1 h. The mixture was filtered and concentrated under reduced pressure to provide the title compound (0.40 g). 1 H NMR (300MHz; CDCl3) δ:7.33-7.27(m,1H),7.18(dd,1H),7.07-7.03(m,1H),6.56(t,1H),3.60(s,2H),3.57(s,2H).

[1006] Intermediate 219: (S)-3-((1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl) tert-Butyl (carbamoyl)azetidine-1-carboxylate

[1007] The title compound (0.43 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (0.40 g, 1.08 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.17 g, 0.85 mmol, CAS 142253-55-2), pyridine (4.1 mL), (50% in MeTHF, 1.99 mL, 3.23 mmol) was prepared at room temperature for 2 h. 1 H NMR(400MHz; DMSO-d6)δ:8.07(d,1H),7.44-7.22(m,10H),7.11(d,1H),7.05-6.9 7(m,2H),6.31(dd,1H),5.71(d,1H),4.09-3.74(m,5H),2.78(s,3H),1.39(d,9H).

[1008] Intermediate 220: (S)-N-(1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl Azetidine-3-carboxamide

[1009] A solution of intermediate 219 (0.42 g, 0.75 mmol) in TFA (0.58 mL) and DCM (5 mL) was stirred at room temperature for 17 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with DCM. The organics were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound (0.30 g). 1 HNMR(400MHz; DMSO-d6)δ:8.06(d,1H),7.44-7.32(m,10H),7.28-6.96(m,5H),6.32(d d,1H),5.71(d,1H),3.79(q,1H),3.64(q,1H),3.54(t,1H),3.46(t,1H),2.74(s,3H).

[1010] Intermediate 221: (S)-N 3 -(1-(5-(diphenylmethylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 - Dimethylazetidine-1,3-dicarboxamide

[1011] To a stirred solution of intermediate 220 (0.28 g, 0.62 mmol) and triethylamine (0.26 mL, 1.85 mmol) in DCM (3.4 mL) was added methylcarbamoyl chloride (53.5 μL, 0.68 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with DCM. The organics were dried over MgSO 4 , filtered and concentrated under reduced pressure to provide the title compound (0.30 g). LCMS (Method K): 512.5 [M+H] + .

[1012] Intermediate 222: (S)-N 3 -(1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -Dimethylazepine Cyclobutane-1,3-dicarboxamide

[1013] The title compound (0.15 g) was prepared in an analogous manner to Intermediate 206 from Intermediate 221 (0.28 g, 0.47 mmol), formic acid (0.17 mL, 4.61 mmol) and palladium on carbon (10%, 0.15 g) in MeOH (5 mL) at 50° C. for 2 h. LCMS (Method L): 346.2 [M+H] + .

[1014] Intermediate 223: (S)-N-(1-(5-(Benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl 6-Oxo-5-azaspiro[3.4]octane-2-carboxamide

[1015] The title compound (0.34 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (0.30 g, 0.81 mmol), 6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (0.24 g, 1.05 mmol, CAS 2166848-89-9), pyridine (8.1 mL), (50% in MeTHF, 1.50 mL, 2.45 mmol) Prepared at room temperature for 16 h. Purified by flash chromatography (silica gel, eluting with 0-50% EtOAc in cyclohexane). LCMS (Method K): 523.3 [M+H] + .

[1016] Intermediate 224: (S)-N-(1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxo-5- Azaspiro[3.4]octane-2-carboxamide

[1017] The title compound (0.23 g) was prepared in an analogous manner to Intermediate 206 from Intermediate 223 (0.39 g, 0.70 mmol), formic acid (0.27 mL, 7.04 mmol) and palladium on carbon (10%, 0.23 g) in MeOH (7 mL) at 50° C. for 2 h. LCMS (Method L): 357.2 [M+H] + .

[1018] Intermediate 225: N-((1S)-1-(6-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-3-yl)- (2,2,2-trifluoroethyl)-N-methylpalmitamide

[1019] The title compound (0.35 g) was prepared in a similar manner to Intermediate 26 from Intermediate 214 (0.50 g, 1.26 mmol), 4,5-dichloro-2,3-dihydro-1H-inden-2-amine hydrochloride (0.40 g, 1.26 mmol, CAS 2755418-27-8), Cs2CO3 (1.23 g, 3.78 mmol), Pd2(dba)3 (0.12 g, 0.13 mmol) and Xantphos (0.15 g, 0.25 mmol) in 1,4-dioxane (20 mL) at 100° C. for 16 h. Purification was performed by flash chromatography (silica gel, eluting with 0-30% EtOAc in petroleum ether). LCMS (Method C): 474.4 [M+H] + .

[1020] Intermediate 226: N-(4,5-dichloro-2,3-dihydro-1H-inden-2-yl)-5-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-2-amine

[1021] The title compound (0.14 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 225 (0.36 g, 0.45 mmol) and LiAlH4 (2 M in THF, 0.45 mL, 0.90 mmol) in THF (10 mL) at 0°C for 15 min. LCMS (Method C): 390.3 [M+H] + .

[1022] Intermediate 227: N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2-yl) (2,2,2-trifluoroethyl)-N-methylpalmitamide

[1023] The title compound (1.0 g) was prepared in a similar manner to Example 265 from Intermediate 59 (0.95 g, 3.12 mmol), 4,5-dichloro-1,3-dihydro-2H-inden-2-one (0.99 g, 4.68 mmol, CAS 69392-70-7), AcOH (0.18 mL, 3.13 mmol) in MeOH (24 mL) at 60° C. for 6 h, followed by sodium cyanoborohydride (0.39 g, 6.24 mmol) at room temperature for 8 h. Purification was performed by flash chromatography (silica gel, eluting with 0-15% MeOH in DCM). LCMS (Method C): 474.3 [M+H] + .

[1024] Intermediate 228: N-(4,5-dichloro-2,3-dihydro-1H-inden-2-yl)-6-((S)-2,2,2-trifluoro-1-(methyl) amino)ethyl)pyridin-3-amine

[1025] The title compound (0.85 g) was prepared in an analogous manner to Intermediate 61 from Intermediate 227 (1.1 g, 2.09 mmol) and LiAlH4 (2 M in THF, 2.09 mL, 4.17 mmol) in THF (10 mL) at 0°C for 15 min. LCMS (Method C): 390.2 [M+H] + .

[1026] Intermediate 229: N-((1S)-1-(5-((4-bromo-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2-yl) (2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[1027] The title compound (0.59 g) was prepared in a similar manner to Example 265 from Intermediate 166 (0.50 g, 1.37 mmol), Intermediate 192 (0.67 g, 2.74 mmol), AcOH (41 mg, 0.68 mmol) in MeOH (6.8 mL) at 50° C. for 3 h, followed by sodium cyanoborohydride (1.72 g, 27.4 mmol) at room temperature for 90 h. Purification was performed by flash chromatography (silica gel, eluting with 0-100% EtOAc in hexanes). LCMS (Method J): 596.0 [M+H] + .

[1028] Intermediate 230: (1,3-trans)-3-(((S)-1-(5-(diphenylmethylamino)pyridin-2-yl)-2,2,2-trifluoro Methyl ethyl (methyl)carbamoyl)cyclobutane-1-carboxylate

[1029] The title compound (0.29 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (0.30 g, 0.81 mmol), trans-3-(methylcarbamoyl)cyclobutane-1-carboxylate (0.19 g, 1.21 mmol, CAS 1401103-71-6), pyridine (2.7 mL), (50% in MeTHF, 2.47 mL, 4.04 mmol) Prepared at room temperature for 16 h. Purified by automated flash chromatography (silica gel 80 g, eluting with 0-100% EtOAc in hexanes). LCMS (Method K): 512.2 [M+H] + .

[1030] Intermediate 231: (1,3-trans)-3-(((S)-1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)(methyl methyl)carbamoyl)cyclobutane-1-carboxylate

[1031] The title compound (0.11 g) was prepared in an analogous manner to Intermediate 206 from Intermediate 230 (0.23 g, 0.45 mmol), formic acid (0.17 mL, 4.50 mmol) and palladium on carbon (10%, 0.14 g) in MeOH (4.5 mL) at 50° C. for 3 h. 1H NMR(400MHz; DMSO-d6)δ:7.93(d,1H),7.06(d,1H),6.94(dd,1H),6.34(dd,1H),5.57(s, 2H),3.63(s,3H),3.59-3.42(m,1H),3.17-3.00(m,1H),2.80(s,3H),2.43-2.34(m,4H).

[1032] Intermediate 232: (1,3-trans)-3-(((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino (2-(methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid methyl ester

[1033] The title compound (62 mg) was prepared in a similar manner to Example 265 from Intermediate 231 (0.14 g, 0.39 mmol), 4,5-dichloro-1,3-dihydro-2H-inden-2-one (0.16 g, 0.78 mmol, CAS 69392-70-7), AcOH (26 mg, 0.43 mmol) in MeOH (2 mL) at 50° C. for 6 h, followed by sodium cyanoborohydride (98 mg, 1.56 mmol) at room temperature for 8 h. Purification was performed by flash chromatography (silica gel, eluting with 0-100% EtOAc in hexanes). LCMS (Method J): 529.9 [M+H] + .

[1034] Intermediate 233: (1,3-trans)-3-(((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino (2-(methyl)pyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid

[1035] To a stirred solution of intermediate 232 (62 mg, 0.12 mmol) in THF (1 mL) and MeOH (0.5 mL) was added lithium hydroxide (8.4 mg, 0.35 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was diluted with 1 M aqueous sodium dihydrogen phosphate solution until pH 4, then extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (41 mg). LCMS (Method J): 515.9 [M+H] + .

[1036] Intermediate 234: 2-(tert-Butyloxy)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl) (amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylacetamide

[1037] The title compound (0.15 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 162 (0.25 g, 0.56 mmol), 2-tert-butoxyacetic acid (0.22 g, 1.66 mmol, CAS 13211-32-0), pyridine (3.0 mL), (50% in EtOAc, 1.76 mg, 5.55 mmol) Prepared at room temperature for 16 h. Purified by flash chromatography (silica gel, eluting with 0-100% EtOAc in petroleum ether). LCMS (Method J): 488.4 [M+H] + .

[1038] Intermediate 235: (S)-N-(1-(5-(diphenylmethylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,N'- Dimethylcyclopropane-1,1-dicarboxamide

[1039] The title compound (0.33 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 164 (0.25 g, 0.67 mmol), 1-(methylcarbamoyl)cyclopropanecarboxylic acid (0.10 g, 0.71 mmol, CAS 1250809-34-7), pyridine (2.7 mL), (50% in MeTHF, 1.65 mL, 2.69 mmol) was prepared at room temperature for 17 h. 1 H NMR(400MHz; DMSO-d6)δ:8.08(d,1H),7.63(d,1H),7.44-7.39(m,5H),7.37-7.32(m,4H),7.28-7.22(m,2H),7.16(d,1H),7.0 3-7.01(m,1H),6.25(dd,1H),5.73(d,1H),2.85(s,3H),2.57(d,3H),1.38-1.30(m,1H),1.27-1.20(m,1H),1.16-1.03(m,2H).

[1040] Intermediate 236: (S)-N-(1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N,N'-dimethylcyclopropane Alkane-1,1-dicarboxamide

[1041] The title compound (0.23 g) was prepared in an analogous manner to Intermediate 206 from Intermediate 235 (0.31 g, 0.62 mmol), formic acid (0.23 mL, 6.19 mmol) and palladium on carbon (10%, 0.20 g) in MeOH (3.9 mL) at 50° C. for 2 h. LCMS (Method K): 331.2 [M+H] + .

[1042] Intermediate 237: (S)-3-((1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)(methyl)carbamoyl) tert-Butyl azetidine-1-carboxylate

[1043] The title compound (0.40 g) was prepared in an analogous manner to Intermediate 206 from Intermediate 219 (0.50 g, 0.90 mmol), formic acid (0.34 mL, 8.93 mmol) and palladium on carbon (10%, 0.29 g) in MeOH (5.9 mL) at 50° C. for 2 h. LCMS (Method K): 389.1 [M+H] + .

[1044] Intermediate 238: 3-(((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2- tert-Butyl)-2,2,2-trifluoroethyl(methyl)carbamoyl)azetidine-1-carboxylate

[1045] The title compound (0.14 g) was prepared in a similar manner to Example 265 from Intermediate 237 (0.14 g, 0.39 mmol), Intermediate 204 (0.20 g, 0.98 mmol), AcOH (0.14 mL, 0.25 mmol) in MeOH (6.2 mL) at 50° C. for 2 h, followed by sodium cyanoborohydride (0.16 g, 2.47 mmol) at room temperature for 2 h. Purification was performed by flash chromatography (silica gel, eluting with 20% to 100% EtOAc in hexanes). LCMS (Method K): 557.1 [M+H] + .

[1046] Intermediate 239: N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridine-2-yl) (2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide

[1047] A solution of intermediate 238 (0.35 g, 0.54 mmol) in TFA (0.17 mL) and DCM (1.3 mL) was stirred at room temperature for 17 h. The mixture was poured into saturated aqueous NaHCO3 and extracted into DCM. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound (0.10 g). LCMS (Method L): 457.2 [M+H] + .

[1048] Intermediate 240: (1,3-trans)-3-((tert-butyldimethylsilyl)oxy)-N-((1S)-1-(5-((5-chloro- (4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide amine

[1049] The title compound (0.21 g) was prepared in a similar manner to Intermediate 3 from Intermediate 162 (0.20 g, 0.48 mmol), (1,3-trans)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-carboxylic acid (0.11 g, 0.48 mmol, CAS 1431285-79-8), triethylamine (0.67 mL, 4.82 mmol), (50% in MeTHF, 1.53 mL, 2.41 mmol) Prepared at room temperature for 4 h. LCMS (Method C): 586.6 [M+H] +.

[1050] Intermediate 241: (S)-N-(1-(5-(benzhydrylamino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl Thietane-3-carboxamide 1,1-dioxide

[1051] The title compound (0.15 g) was prepared in a similar manner to Intermediate 3 from Intermediate 164 (0.12 g, 0.31 mmol), thietane-3-carboxylic acid 1,1-dioxide (56 mg, 0.37 mmol, CAS 13129-21-0), pyridine (3.1 mL), (50% in MeTHF, 0.57 mL, 0.93 mmol) Prepared at room temperature for 17 h. Purified by automated flash chromatography (25 g silica gel, eluting with 0-50% EtOAc in hexanes). LCMS (Method L): 504.3 [M+H] + .

[1052] Intermediate 242: (S)-N-(1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylthietan Alkane-3-carboxamide 1,1-dioxide

[1053] The title compound (60 mg) was prepared in a similar manner to Intermediate 206 from Intermediate 241 (0.15 g, 0.27 mmol), formic acid (0.10 mL, 2.65 mmol) and palladium on carbon (10%, 85 mg) in MeOH (2.7 mL) at 50° C. for 1 h. Purification was performed by automated flash chromatography (40 g silica gel, eluting with 0-10% MeOH in DCM). LCMS (Method K): 337.8 [M+H] + .

[1054] Intermediate 243: 1-(2-(tert-Butoxy)acetyl)-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H- (inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide

[1055] The title compound (0.15 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 228 (0.21 g, 0.49 mmol), 1-(2-tert-butoxyacetyl)azetidine-3-carboxylic acid (0.17 g, 0.73 mmol, CAS 1564594-27-9), pyridine (0.2 mL), (50% in MeTHF, 2.92 mL, 4.90 mmol) Prepared at room temperature for 2 h. Purified by flash chromatography (silica gel, eluting with 0-80% EtOAc in hexanes). LCMS (Method C): 587.5 [M+H] + .

[1056] Intermediate 244: (1,3-cis)-3-((tert-butyldimethylsilyl)oxy)-N-((1S)-1-(5-((5-chloro- (4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide amine

[1057] The title compound (0.17 g) was prepared in a similar manner to Intermediate 3 from Intermediate 162 (0.20 g, 0.48 mmol), (1,3-cis)-3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-carboxylic acid (0.44 g, 1.90 mmol, CAS 1431285-80-1), triethylamine (0.93 mL, 6.67 mmol), (50% in MeTHF, 1.92 mL, 3.33 mmol) was prepared in DCM (0.5 mL) for 16 h at room temperature. Purification was performed by flash chromatography (silica gel, eluting with 0-30% EtOAc in petroleum ether). LCMS (Method C): 586.9 [M+H] + .

[1058] Intermediate 245: (5S)-5-(((1S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridine tert-Butyl (methyl)-2-oxopiperidine-1-carboxylate

[1059] The title compound (0.12 g) was prepared in an analogous manner to Intermediate 3 from Intermediate 216 (0.10 g, 0.26 mmol), (3S)-1-tert-butoxycarbonyl-6-oxo-piperidine-3-carboxylic acid (0.31 g, 1.28 mmol, CAS 1629681-71-5), pyridine (0.2 mL), (50% in MeTHF, 1.59 mL, 2.57 mmol) Prepared at room temperature for 16 h. Purified by flash chromatography (silica gel, eluting with 50%-70% EtOAc in hexanes). LCMS (Method A): 499.3 [M-Boc+H] + .

[1060] Intermediate 246: 5-(Difluoromethoxy)-2,3-dihydro-1H-inden-1-ol

[1061] The title compound (0.82 g) was prepared in an analogous manner to Intermediate 151 from 5-(difluoromethoxy)indan-1-one (0.87 g, 4.39 mmol, CAS 1273599-48-6) and sodium borohydride (0.18 g, 4.84 mmol) in MeOH (4.4 mL) and THF (18 mL) at room temperature for 1 h. 1H NMR (300 MHz; CDCl 3 ) δ: 7.43-7.33 (m, 1H), 7.04-6.92 (m, 2H), 6.49 (t, 1H), 5.23 (dd, 1H), 3.18-2.96 (m, 1H), 2.82 (dt, 1H), 2.61-2.42 (m, 1H), 2.04-1.92 (m, 1H), 1.66 (br s, 1H).

[1062] Intermediate 247: 7-Bromo-6-chloro-1H-indene

[1063] The title compound (0.80 g) was prepared in an analogous manner to Intermediate 152 using Intermediate 246 (0.82 g, 4.07 mmol) and pTSA (0.15 g, 0.81 mmol) in toluene (20 mL) at 80 °C for 0.5 h. 1 H NMR (300MHz; CDCl3) δ:7.35(d,1H),7.17(d,1H),7.05(dd,1H),6.88-6.82(m,1H),6.57(dt,1H),6.50(t,1H),3.42-3.40(m,2H).

[1064] Synthesis of examples

[1065] Example 1: N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2- (Trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide-isomer 1

[1066]

[1067] Example 2: N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2- (Trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide-isomer 2

[1068]

[1069] The title compound was prepared in an analogous manner to Intermediate 11 from Intermediate 3 (0.5 g, 1.17 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.23 g, 1.17 mmol, CAS 74413-86-8), Cs2CO3 (1.52 g, 4.68 mmol), tBuBrettphosPdG3 (0.20 g, 0.23 mmol) and RuPhos (0.22 g, 0.47 mmol) in 1,4-dioxane (10 mL) at 120°C for 1 h. Purification was performed by flash chromatography (silica gel, eluting with 45%-50% EtOAc in petroleum ether) and preparative HPLC (X Bridge C18, 19×250 mm×5 μm, flow rate: 17 mL / min, 10 mM aqueous NH 4 HCO 3 with MeCN from 30% to 65% over 6 min, held at 65% for 8 min, then ramped to 100% over 0.1 min and held for 2.4 min). Chiral purification was performed by preparative SFC (Chiralcel-OJ-H, 20×250 mm×5 μm, temperature 30° C., back pressure 100 bar, flow rate: 60 g / min, 70% CO 2 with 30% 1:1 MeCN / MeOH modifier) ​​to provide Example 1 (56 mg) as Peak 1 and Example 2 (50 mg) as Peak 2. Example 1: 1H NMR (400 MHz; DMSO-d6) δ: 7.21-7.12 (m, 6H), 6.78 (d, 2H), 5.94-5.83 (m, 2H), 3.99 (q, 1H), 3.67-3.51 (m, 4H), 3.20-3.06 (m, 5H), 2.77-2.68 (d, 1H), 2.11-1.95 (m, 4H), 1.32 (s, 3H), 1.09 (s, 3H). LCMS (Method A): 509.4 [M+H] + Example 2: 1 H NMR(400MHz; DMSO-d6)δ:7.20-7.12(m,4H),7.50(d,2H),6.79(d,2H),6.34(dd,1H),6.01-5.94(m,1H), 3.99(q,1H),3.28-3.08(m,6H),2.89(s,3H),2.73(dd,1H),2.11-1.95(m,4H),1.31(s,3H),1.09(s,3H). LCMS (Method A): 509.4[M+H] + .

[1070] Example 3: (S)-N-(1-(4-((2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- Methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[1071]

[1072] The title compound (40 mg) was prepared in a similar manner to Intermediate 11 from Intermediate 3 (0.2 g, 0.47 mmol), 2,3-dihydro-1H-inden-2-amine hydrochloride (79 mg, 0.47 mmol, CAS 2975-41-9), Cs2CO3 (0.61 g, 1.87 mmol), tBuBrettphosPdG3 (80 mg, 0.01 mmol) and RuPhos (87 mg, 0.19 mmol) in 1,4-dioxane (10 mL) at 120° C. for 1 h. Purification was performed by preparative HPLC (X-Select C18, 19×250 mm×5 μm, flow rate: 17 mL / min, 10 mM aqueous NH4HCO3 with MeCN from 30% to 65% over 8 min, held at 65% for 7 min, then ramped to 98% over 0.1 min and held for 2.9 min). 1H NMR(400MHz; DMSO-d6)δ:7.28-7.21(m,2H),7.17-7.14(m,2H),7.07(d,2H),6.66(d,2H),6.35(dd,1H), 6.26-6.21(m,1H),4.23-4.18(m,1H),3.23-3.08(m,7H),2.88(s,3H),2.79(dd,2H),2.11-1.95(m,4H). LCMS (Method D): 481.3[M+H] + .

[1073] Example 4: N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2- (Trifluoroethyl)-N-methyloxazole-5-carboxamide-isomer 1

[1074]

[1075] Example 5: N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2- (Trifluoroethyl)-N-methyloxazole-5-carboxamide-isomer 2

[1076]

[1077] The title compound was prepared in a similar manner to Intermediate 11 from Intermediate 4 (0.38 g, 0.96 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.23 g, 1.15 mmol, CAS 74413-86-8), Cs2CO3 (1.25 g, 3.84 mmol), tBuBrettphosPdG3 (0.16 g, 0.19 mmol) and RuPhos (0.18 g, 0.38 mmol) in 1,4-dioxane (7 mL) at 120° C. for 1 h. Purification was performed by preparative HPLC (X Bridge C18, 19×250 mm×5 μm, flow rate: 17 mL / min, 5 mM aqueous NH4HCO3 with MeCN from 35% to 75% over 28 min, then ramped to 98% over 0.1 min and held for 2.4 min). Chiral purification was performed by preparative SFC (Chiralcel OJ-H, 30×250 mm×5 μm, temperature 30° C., back pressure 100 bar, flow rate: 100 g / min, 70% CO 2 with 30% MeOH modifier) ​​to provide Example 4 (18 mg) as Peak 1 and Example 5 (22 mg) as Peak 2. Example 4: 11H NMR (400 MHz; DMSO-d6) δ: 8.59 (s, 1H), 7.90 (br s, 1H), 7.22 - 7.15 (m, 6H), 6.82 (d, 2H), 6.40 (br s, 1H), 6.01 (d, 1H), 4.01 (t, 1H), 3.17 (dd, 1H), 3.07 (br s, 3H), 2.74 (dd, 1H), 1.32 (s, 3H), 1.09 (s, 3H). LCMS (Method A): 444.2 [M+H] + Example 5: 1 1H NMR (400 MHz; DMSO-d6) δ: 8.64 (s, 1H), 7.92 (br s, 1H), 7.21 - 7.13 (m, 6H), 6.81 (d, 2H), 6.40 (br s, 1H), 6.01 (d, 1H), 4.01 (dd, 1H), 3.17 (dd, 1H), 3.05 (br s, 3H), 2.74 (dd, 1H), 1.31 (s, 3H), 1.09 (s, 3H). LCMS (Method A): 444.2 [M+H] + .

[1078] Example 6: 1-Acetyl-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)benzene (2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide-isomer 1

[1079]

[1080] Example 7: 1-Acetyl-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)benzene (2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide-isomer 2

[1081]

[1082] The title compound was prepared in an analogous manner to Intermediate 11 from Intermediate 5 (0.40 g, 1.03 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.20 g, 1.03 mmol, CAS 74413-86-8), Cs2CO3 (1.04 g, 3.09 mmol), tBuBrettphosPdG3 (44 mg, 0.05 mmol) and RuPhos (48 mg, 0.10 mmol) in 1,4-dioxane (7 mL) at 120°C for 2 h. Purification was performed by preparative HPLC (X Bridge C18, 19×250 mm×5 μm, flow rate: 17 mL / min, 5 mM aqueous NH 4 HCO 3 with MeCN from 10% to 50% in 0.1 min, to 67% in 16.9 min, ramped to 98% in 0.1 min and held for 2.9 min). Chiral purification was performed by preparative SFC (Chiralcel OJ-H, 30×250 mm×5 μm, temperature 30° C., back pressure 100 bar, flow rate: 90 g / min, 90% CO 2 with 10% MeOH / MeCN 1:1 modifier) ​​to provide Example 6 (18 mg) as Peak 1 and Example 7 (22 mg) as Peak 2. Example 6: 1 H NMR(400MHz; DMSO-d6)δ:7.22-7.05-7.22(m,6H),6.79(d,2H),6.33(dd,1H),5.96(d,1H),4.36-4.16(m,2H), 4.10-3.97(m,2H),3.92-3.80(m,2H),3.16(dd,1H),2.76-2.71(m,4H),1.76(d,3H),1.32(s,3H),1.09(s,3H). LCMS (Method A): 474.3[M+H] + Example 7: 1 H NMR(400MHz; DMSO-d6)δ:7.22-7.05(m,6H),6.79(d,2H),6.33(dd,1H),5.96(d,1H),4.36-4.16(m,2H),4.1 0-3.97(m,2H),3.95-3.81(m,2H),3.17(dd,1H),2.76-2.71(m,4H),1.76(d,3H),1.31(s,3H),1.09(s,3H). LCMS (Method A): 474.3[M+H] + .

[1083] Example 8: N-methyl-N-((S)-2,2,2-trifluoro-1-(4-(((1,2-cis)-1-methyl-2,3-dihydro-1H- (inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[1084]

[1085] Example 9: N-methyl-N-((S)-2,2,2-trifluoro-1-(4-(((1,2-trans)-1-methyl-2,3-dihydro-1H- (inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[1086]

[1087] The title compound was prepared in a similar manner to Intermediate 11 from Intermediate 3 (0.74 g, 1.74 mmol), Intermediate 6 (0.32 g, 1.74 mmol), Cs2CO3 (2.27 g, 6.97 mmol), tBuBrettphosPdG3 (0.30 g, 0.05 mmol) and RuPhos (0.33 g, 0.70 mmol) in 1,4-dioxane (10 mL) at 120°C for 2 h. Purification was performed by preparative HPLC (X Bridge C18, 19×250 mm×5 μm, flow rate: 17 mL / min, 5 mM aqueous NH4HCO3 with MeCN from 35% to 75% in 28 min, ramped to 98% in 0.1 min and held for 2.4 min). Chiral purification was performed by preparative SFC (Chiralcel IE, 30×250 mm×5 μm, temperature 30° C., back pressure 100 bar, flow rate: 110 g / min, 67% CO 2 with 33% IPA modifier) ​​to provide Example 8 (36 mg) as Peak 1 and Example 9 (10 mg) as Peak 2. Example 8: 1 H NMR(400MHz; DMSO-d6)δ:7.26-7.11(m,4H),7.07(d,2H),6.77-6.67(m,2H),6.35(dd,1H),6.28-6. 13(m,1H),4.27-4.17(m,1H),3.50-3.06(m,7H),2.94-2.85(m,4H),2.11-1.96(m,4H),0.98(d,3H). LCMS (Method A): 495.3[M+H] + Example 9: 1 H NMR(400MHz; DMSO-d6)δ:7.24-7.13(m,4H),7.07(d,2H),6.74-6.67(m,2H),6.35(dd,1H),6.28-6.23(m,1 H),3.76-3.69(m,1H),3.41-3.15(m,7H),2.89(s,3H),2.67-2.55(m,1H),2.11-1.96(m,4H),1.30(d,3H). LCMS (Method A): 495.3[M+H] + .

[1088] Example 10: N-methyl-N-((S)-2,2,2-trifluoro-1-(4-(((1,2-trans)-1-methoxy-2,3-dihydro- 1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide-isomer 1

[1089] Example 11: N-methyl-N-((S)-2,2,2-trifluoro-1-(4-(((1,2-trans)-1-methoxy-2,3-dihydro- 1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide-isomer 2

[1090]

[1091] The title compound was prepared in an analogous manner to Intermediate 11 from Intermediate 3 (0.23 g, 0.54 mmol), 1-methoxy-2,3-dihydro-1H-inden-2-amine hydrochloride (0.13 g, 0.64 mmol, CAS 2702474-20-0), Cs2CO3 (0.70 g, 2.16 mmol), tBuBrettphosPdG3 (23 mg, 0.03 mmol) and RuPhos (25 mg, 0.05 mmol) in 1,4-dioxane (5 mL) at 120°C for 1 h. Purification was performed by preparative HPLC (X-Select C18, 19×250 mm×5 μm, flow rate: 17 mL / min, 5 mM aqueous NH 4 HCO 3 with MeCN from 10% to 45% in 0.1 min, then to 61% in 15.9 min, ramped to 95% in 0.1 min and held for 0.1 min). Diastereomer purification was performed by preparative SFC (Chiralcel OD-H, 30×250 mm×5 μm, temperature 30° C., back pressure 100 bar, flow rate: 110 g / min, 70% CO 2 with 30% MeOH modifier) ​​to provide Example 10 (32 mg) as Peak 1 and Example 11 (30 mg) as Peak 2. Example 10: 1 HNMR(400MHz; DMSO-d6)δ:7.39(d,1H),7.32-7.16(m,3H),7.09(d,2H),6.75-6.67(m,2H),6.36(dd,1H),6.32-6.24(m,1H) ,4.66(d,1H),4.10-4.02(m,1H),3.46-3.32(m,4H),3.24-3.06(m,5H),2.89(s,3H),2.70-2.64(m,1H),2.11-1.96(m,4H). LCMS (Method A): 511.2[M+H] + Example 11: 1H NMR(400MHz; DMSO-d6)δ:7.39(d,1H),7.32-7.16(m,3H),7.11(d,2H),6.75-6.67(m,2H),6.36(dd,1H),6.32-6.24(br m,1H),4.66(d,1H),4.10-4.02(m,1H),3.46-3.32(m,4H),3.24-3.06(m,5H),2.90(s,3H),2.71-2.64(m,1H),2.11-1.96(m,4H). LCMS (Method A): 511.2[M+H] + .

[1092] Example 12: N-((S)-1-(4-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2, 2,2-trifluoroethyl)-N-methylmorpholine-4-carboxamide

[1093]

[1094] Example 13: N-((S)-1-(4-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2, 2,2-trifluoroethyl)-N-methylmorpholine-4-carboxamide

[1095]

[1096] The title compound was prepared in an analogous manner to Intermediate 11 from Intermediate 7 (0.40 g, 1.05 mmol), 1,1-dimethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (0.20 g, 1.05 mmol, CAS 74413-86-8), Cs2CO3 (1.24 g, 3.15 mmol), tBuBrettphosPdG3 (45 mg, 0.05 mmol) and RuPhos (49 mg, 0.1 mmol) in 1,4-dioxane (5 mL) at 120°C for 2 h. Purification was performed by prepa...

Claims

1. A compound according to formula I or a pharmaceutically acceptable salt thereof: in: X 1 and X 2 Independently selected from CR 9 or N; X 3 , X 4 , X 5 and X 6 Independently selected from CR 10 or N, provided that X is 3 , X 4 , X 5 and X 6 No more than two of them are N; Y is Z 1 Does not exist, Z 2 Does not exist or is C 1-4 An alkylene linker group, which is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, cyano, hydroxyl and C 3-7 and optionally spiro-attached to a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl ring, wherein the cycloalkyl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxyl, C 1-4 Alkoxy, C 3-6 Substitution of cycloalkyl, halogen and cyano substituents; R 1 and R 2 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, halogen, cyano, hydroxyl, C 3-7 Cycloalkyl and S(O)2C 1-4 alkyl; R 3a , R 3b , R 4a and R 4b are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, halogen, cyano, NR 13 R 14 、C(O)OR 15 、C(O)NR 16 R 17 OR 18 ; R 5 is hydrogen or C 1-3 alkyl; R 6 C 1-3 Alkyl, C 1-3 Haloalkyl or C 3-5 Cycloalkyl; R 7 For hydrogen, C 1-3 Alkyl or CD3; R 8 Selected from OR 19 NR 20 R 21 、C(O)R 22 、S(O)2NR 23 R 24 , cyano, C 3-8 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and phenyl, wherein the C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl and phenyl are optionally substituted with one or more radicals of formula C 0-3 Alkylene-R 25 Substituents, where each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 and NR 32 S(O)2R 33 ;and Wherein C 3-8 Cycloalkyl and 4- to 10-membered heterocyclic groups R 8 Groups can: iii) is a monocyclic or polycyclic ring system, wherein the rings in the polycyclic ring system are fused, bridged or spiro-connected; and iv) Except for optional C 0-3 Alkylene-R 25 In addition to the substituents, it may also be optionally substituted with one or more oxo groups; R 9 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, halogen, cyano, hydroxyl, C 3-7 Cycloalkyl and S(O)2C 1-4 alkyl; R 10 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, halogen, cyano and hydroxyl; R 11 and R 12 are independently selected from hydrogen, C 1-4 Alkyl and halogen; R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from hydrogen and C 1-4 alkyl; R 18 and R 19 are independently selected from hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocyclyl, and 5- or 6-membered heteroaryl, wherein the C 1-4 Alkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl are optionally substituted by one or more selected from C 1-4 Alkyl, halogen, OH, C 1-4 Alkoxy, C 3-7 Cycloalkyl, NR 34 R 35 、C(O)OR 36 and C(O)NR 37 R 38 Substituents are substituted; R 20 and R 21 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C(O)C 1-4 Alkyl, C(O)NR 39 R 40 and S(O)2R 41 ; R 22 Selected from hydroxyl, C 1-4 Alkoxy and NR 42 R 43 ; R 23 and R 24 are independently selected from hydrogen and C 1-4 alkyl; R 26 and R 27 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-7 Cycloalkyl; R 28 is hydrogen or C 1-4 alkyl; R 29 C 1-4 Alkyl, C 1-4 Halogenated alkyl or NR 44 R 45 ; R 30 Selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, NR 46 R 47 and a 4- to 6-membered heterocyclic group; R 31 C 1-4 Alkyl or NR 48 R 49 ;and R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 and R 49 are independently selected from hydrogen and C 1-4 Alkyl; or R 34 and R 35 ; R 37 and R 38 ; R 39 and R 40 ; R 42 and R 43 ; R 44 and R 45 ; R 46 and R 47 ; or R 48 and R 49 Together with the corresponding nitrogen atom to which it is attached, it forms a 4- to 7-membered heterocyclic ring.

2. The compound according to claim 1, wherein the compound has a structure according to Formula IA: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein: aX 1 and X 2 One of is CH and the other is N; BxF 1 and X 2 Both are CR 9 ;or X 1 and X 2 Both are CH.

4. A compound according to any one of claims 1 to 3, wherein: aX 3 , X 4 , X 5 and X 6 are independently selected from CH or N, provided that X 3 , X 4 , X 5 and X 6 No more than two of them are N; BxF 3 , X 4 , X 5 and X 6 One of them is N and the other three are CH; or X 3 , X 4 , X 5 and X 6 All are CH.

5. A compound according to any one of claims 1 to 4, wherein Y is 6. A compound according to any one of claims 1 to 5, wherein Z 1 Does not exist.

7. A compound according to any one of claims 1 to 6, wherein Z 2 Does not exist or is C 1-3 Alkylene.

8. A compound according to any one of claims 1 to 7, wherein R 1 and R 2 Independently selected from: a. Hydrogen, C 1-2 Alkyl, C 1-4 Alkoxy, C 1-2 haloalkyl, halogen and cyano; or b. Hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluorine, chlorine and cyano.

9. A compound according to any one of claims 1 to 8, wherein R 3a , R 3b , R 4a and R 4b are independently selected from hydrogen, C 1-4 Alkyl and OR 18 .

10. The compound according to claim 9, wherein R 3a and R 3b Both are C 1-4 Alkyl groups, such as all methyl groups.

11. A compound according to any one of claims 1 to 10, wherein R 5 For hydrogen.

12. A compound according to any one of claims 1 to 11, wherein R 6 C 1-3 Haloalkyl, such as trifluoromethyl.

13. A compound according to any one of claims 1 to 12, wherein R 7 C 1-3 Alkyl groups, such as methyl.

14. A compound according to any one of claims 1 to 13, wherein R 8 Selected from OR 19 NR 20 R 21 、C(O)R 22 、S(O)2NR 23 R 24 , cyano, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally substituted with one or more of the formula C 0-3 Alkylene-R 25 Substituents, where each R 25 Independently selected from C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, NR 26 R 27 NR 28 C(O)R 29 、C(O)R 30 、S(O)2R 31 and NR 32 S(O)2R 33 ;and Wherein C 3-8 Cycloalkyl and 4- to 10-membered heterocyclic groups R 8 Groups can: is a monocyclic or polycyclic ring system, wherein the rings in the polycyclic ring system are fused, bridged or spiro-connected; and Except optional C 0-3 Alkylene-R 25 In addition to the substituents, it may also be optionally substituted by one or more oxo groups.

15. The compound according to claim 1, wherein the compound is selected from one of the following compounds or a pharmaceutically acceptable salt thereof: N-((S)-1-(4-((-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(4-((2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyloxazole-5-carboxamide; 1-Acetyl-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide; N-methyl-N-((S)-2,2,2-trifluoro-1-(4-(((1,2-cis)-1-methyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N-((S)-2,2,2-trifluoro-1-(4-(((1,2-trans)-1-methyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N-((1S)-2,2,2-trifluoro-1-(4-((1-methoxy-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((S)-1-(4-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylmorpholine-4-carboxamide; N-((S)-1-(4-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylmorpholine-4-carboxamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylthiomorpholine-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N,4-dimethylpiperidine-1-carboxamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-4-carboxamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylpiperidine-1-carboxamide; 3-Acetamido-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpropanamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyloxazole-4-carboxamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2-methoxy-N-methylacetamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2-hydroxy-N-methylacetamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-methoxy-N-methylpropanamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-hydroxy-N-methylpropanamide; N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((1,3-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; 2-Acetamido-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylacetamide; 1-Acetyl-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,3-dimethylazetidine-3-carboxamide; 1-Acetyl-N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-fluoro-N-methylazetidine-3-carboxamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-(2-oxopyrrolidin-1-yl)acetamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(2-oxopyrrolidin-1-yl)acrylamide; 5-(((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)amino)-5-oxopentanoic acid; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1,2,5-oxadiazole-3-carboxamide; 4-(((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)amino)-4-oxobutanoic acid; N-methyl-N-((1S)-2,2,2-trifluoro-1-(4-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; 1-Acetylazetidin-3-yl ((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamate; tert-butyl 3-((((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)oxy)azetidine-1-carboxylate; ((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamic acid azetidin-3-yl ester hydrochloride; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(N-methylsulfamoyl)acrylamide; N-((1R)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(N-methylsulfamoyl)butanamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-2-(2,4-dioxoimidazolidin-1-yl)-N-methylacetamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)azetidine-3-carboxamide; (S)-N-(1-(4-((2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; (S)-N-(1-(5-((2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide; N3-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N3-dimethylazetidine-1,3-dicarboxamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylazetidine-3-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclopropanesulfonamide; N-((1S)-1-(4-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-(1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide; N-(1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide; N-(1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethylazetidine-3-carboxamide; N-(1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N,1-dimethylazetidine-3-carboxamide; N-(1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide; N-(1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxooxazolidine-5-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-(dimethylamino)-N-methylcyclobutane-1-carboxamide; N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-trans-(dimethylamino)-N-methylcyclobutane-1-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxopiperidine-4-carboxamide; N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methylquinuclidine-3-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-3-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-4-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxomorpholine-2-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylquinuclidine-3-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylthiomorpholine-4-carboxamide 1,1-dioxide; N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-4-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; N-((1S)-1-(4-((6-chloro-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((5-chloro-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide; (4,6-trans)-N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-1-azaspiro[3.3]heptane-6-carboxamide; (4,6-cis)-N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-1-azaspiro[3.3]heptane-6-carboxamide; (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxomorpholine-3-carboxamide; (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-4-oxoazetidine-2-carboxamide; (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylmorpholine-2-carboxamide dihydrochloride; (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide; (S)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide; (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-2-carboxamide; (R)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-2-carboxamide; (1R,3S)-3-acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide; N-((1S)-1-(6-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-7-oxo-6-oxa-8-azaspiro[3.5]nonane-2-carboxamide; (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide; N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; 3-Acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylbicyclo[1.1.1]pentane-1-carboxamide; (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,4-dimethylmorpholine-2-carboxamide; (S)-4-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylmorpholine-2-carboxamide; (1,3-cis)-3-acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide; (2S,4R)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (1R,3S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(2,2,2-trifluoroacetamido)cyclopentane-1-carboxamide; N1-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N1,N3-dimethylbicyclo[1.1.1]pentane-1,3-dicarboxamide; (1,3-trans)-3-acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide; (1,3-cis)-3-acetamido-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-ethyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (R)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide; (R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylmorpholine-2-carboxamide; (S)-1-acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-2-carboxamide; (S)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,4-dimethylmorpholine-2-carboxamide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-N-methylacetamide; N-((1S)-1-(5-((4-ethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((S)-1-(5-(((R)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-5-oxopiperazine-2-carboxamide; N-((R)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-5-oxopiperazine-2-carboxamide; N1-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N1,N3-dimethylbicyclo[1.1.1]pentane-1,3-dicarboxamide; (1R,3S)-3-acetamido-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclopentane-1-carboxamide; (1,3-cis)-3-acetamido-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide; (1,3-trans)-3-acetamido-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide; (2,4-cis)-N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)azetidine-3-carboxamide; (S)-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(2,4-dioxoimidazolidin-1-yl)-N-methylacetamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-thiabicyclo[3.1.0]hexane-6-carboxamide 3,3-dioxide; (R)-N-((S)-1-(6-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide; (S)-N-((S)-1-(6-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide; (2S,4R)-1-acetyl-N-((S)-1-(5-(((R)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylpyrrolidine-2-carboxamide; (1S,3R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide; (1,3-trans)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)cyclobutane-1-carboxamide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)piperidine-4-carboxamide; 1-Acetyl-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-5-oxopyrrolidine-2-carboxamide; N 3 -((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -Dimethylazetidine-1,3-dicarboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)bicyclo[ 1.1.1]pentane-1-carboxamide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(1,1-dioxothiomorpholinyl)-N-methylacetamide; 1-Acetyl-N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide; N-((1S)-1-(5-((4-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N 6 -((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 6 -dimethyl-1-azaspiro[3.3]heptane-1,6-dicarboxamide; (1,3-cis)-N 1 -((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -Dimethylcyclobutane-1,3-dicarboxamide; (1,3-cis)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)cyclobutane-1-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-(2-methoxyethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide; (2S,4R)-N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methyl-1-(methylsulfonyl)pyrrolidine-2-carboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-(2-oxoimidazolidin-1-yl)acetamide; (1,3-trans)-N 1 -((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -Dimethylcyclobutane-1,3-dicarboxamide; N-((1S)-1-(5-((1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-(2-hydroxyethyl)-N-methyl-1-azaspiro[3.3]heptane-6-carboxamide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-2-oxopiperidine-4-carboxamide; N-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,1-dimethyl-6-oxopiperidine-3-carboxamide; N-((1S)-1-(5-((4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(5-((5,6-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4,5-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4-chloro-5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(5-((4,7-dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(5-((4,7-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N-((1S)-2,2,2-trifluoro-1-(6-((4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4,6-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4-chloro-6-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(6-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonamido)cyclopropane-1-carboxamide; N-((1S)-1-(5-((5-chloro-6-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N 1 -((1S)-1-(5-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 4 -Dimethylcubane-1,4-dicarboxamide; N-((1S)-1-(5-((4-chloro-7-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-methyl-N-((1S)-2,2,2-trifluoro-1-(5-((4,5,6-trifluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide; (S)-N-(1-(5-((5,6-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)bicyclo[ 1.1.1]pentane-1-carboxamide; (S)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; (R)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,3-dimethyl-2-oxoimidazolidine-4-carboxamide; (S)-N-(1-(5-((4,7-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxooxazolidine-5-carboxamide; (R)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-2-carboxamide hydrochloride; N-((1S)-1-(5-((5-chloro-4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (R)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-2-carboxamide; N-((1S)-1-(5-((5-bromo-6-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((5-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-oxopiperidine-4-carboxamide; (S)-N-((S)-1-(5-(((S)-5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-2-carboxamide; (3S)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; (3S)-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; (3S)-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-3-(methylsulfonamido)bicyclo[ 1.1.1]pentane-1-carboxamide; N-((1S)-1-(5-((5-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(methylsulfonyl)piperidine-4-carboxamide; (3S)-N-((1S)-1-(5-((5-chloro-4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; (3S)-N-((1S)-1-(5-((5-chloro-4-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide; N-((1S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N 3 -((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -Dimethylazetidine-1,3-dicarboxamide; (3S)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide; (3R)-N-((1S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide; N-((1S)-1-(6-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (3R)-N-((1S)-1-(6-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,2-dimethylpyrimidine-5-carboxamide; 2-cyano-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylacetamide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(tetrahydrofuran-3-carbonyl)azetidine-3-carboxamide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylthietane-3-carboxamide 1,1-dioxide; N-((1S)-1-(5-((5-chloro-4-(methoxymethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydrothiophene-3-carboxamide 1,1-dioxide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-(1,1-dioxoisothiazolidin-2-yl)-N-methylacetamide; (1,3-trans)-N 1 -((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N 1 ,N 3 -Dimethylcyclobutane-1,3-dicarboxamide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-3-carboxamide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-hydroxy-N-methylacetamide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N,N'-dimethylcyclopropane-1,1-dicarboxamide; N-((1S)-1-(5-((5-chloro-4-isopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(oxetane-3-carbonyl)azetidine-3-carboxamide; N-((1S)-1-(5-((5-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (1,3-trans)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-hydroxy-N-methylcyclobutane-1-carboxamide; 1-Acetyl-N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methylazetidine-3-carboxamide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-(2-hydroxyacetyl)-N-methylazetidine-3-carboxamide; N-((1S)-1-(5-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-2-(methylsulfonamido)acetamide; (1,3-cis)-N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-hydroxy-N-methylcyclobutane-1-carboxamide; N-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-N-methyl-1-(oxetane-2-carbonyl)azetidine-3-carboxamide; and (3S)-N-((1S)-1-(6-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-N-methyl-6-oxopiperidine-3-carboxamide.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

17. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use in therapy.

18. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use in treating a disease or condition mediated by MALT1.

19. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, 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; multiple myeloma; chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); Waldenstrom's macroglobulinemia; lymphoblastic T-cell leukemia; chronic myeloid leukemia (CML); hairy cell leukemia; acute lymphoblastic T-cell leukemia; plasmacytoma; immunoblastic large cell leukemia; megakaryoblastic leukemia; acute megakaryocytic leukemia; promyelocytic leukemia; erythroid leukemia; brain (glioma); glioblastoma; breast cancer; colorectal / colon cancer; prostate cancer; lung cancer, including non-small cell lung cancer; gastric cancer; endometrial cancer; melanoma; pancreatic cancer; liver cancer; kidney cancer; squamous cell carcinoma; ovarian cancer; sarcoma; osteosarcoma; thyroid cancer; bladder cancer; head 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; cheek 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 transplant rejection; chronic allograft rejection; acute or chronic graft-versus-host disease; dermatitis, including atopic dermatitis; dermatomyositis; psoriasis; Behcet's disease; uveitis; myasthenia gravis; Graves' disease; Hashimoto's thyroiditis; Sjögren's syndrome; blistering disorder; antibody-mediated vasculitis syndrome; immune complex vasculitis; allergic disorders; asthma; bronchitis; chronic obstructive pulmonary disease (COPD); cystic fibrosis; pneumonia; lung disease, including edema, embolism, fibrosis, sarcoidosis, hypertension, and emphysema; silicosis; Respiratory failure; acute respiratory distress syndrome; BENTA disease; berylliosis; or polymyositis.

20. A method of treating a disease or condition mediated by MALT1, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16.

21. A method of treating the following diseases: 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); Waldenstrom's macroglobulinemia; lymphoblastic T-cell leukemia; chronic myeloid leukemia (CML); hairy cell leukemia; acute lymphoblastic leukemia Baculoblastic T-cell leukemia; plasmacytoma; immunoblastic large-cell leukemia; megakaryoblastic leukemia; acute megakaryocytic leukemia; promyelocytic leukemia; erythroid leukemia; brain (glioma); glioblastoma; breast cancer; colorectal / colon cancer; prostate cancer; lung cancer, including non-small cell lung cancer; stomach 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; cheek 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 transplant rejection; chronic allograft rejection; acute or chronic graft-versus-host disease; dermatitis, including atopic dermatitis; dermatomyositis; psoriasis; Behcet's disease; uveitis; myasthenia gravis; Graves' disease; Hashimoto's thyroiditis; Sjögren's syndrome; blistering disorder; antibody-mediated vasculitis syndrome; immune complex vasculitis; allergic disorders; asthma; bronchitis; chronic obstructive pulmonary disease (COPD); cystic fibrosis; pneumonia; lung disease, including edema, embolism, fibrosis, sarcoidosis, hypertension, and emphysema; silicosis; Respiratory failure; acute respiratory distress syndrome; BENTA disease; berylliosis; or polymyositis, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16.

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