Therapeutic compounds

Abstract

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

Description

THERAPEUTIC COMPOUNDSINTRODUCTION

[0001] The present invention relates to compounds that are MALT1 inhibitors. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with MALT1.BACKGROUND OF THE INVENTION

[0002] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular protein which plays a key role in antigen receptor-induced NF-kB pathway activation in T and B lymphocytes, via both a scaffolding function and a protease function. Antigen receptor triggering leads to formation of the CBM complex, comprising a CARMA or CARD protein, BCL10 and MALT1 , that subsequently 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 translate to the nucleus and initiate transcription of target genes (doi.org / 10.1038 / ni1568; doi:10.1007 / s00018-015-2059-z). Additionally, MALT1 proteolytically cleaves a variety of substrates involved in NF-kB 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 be expansion of the amplitude and duration of the NF-kB response (doi: 10.1016 / j. biochi.2015.09.018).

[0003] Several lines of genetic evidence suggest a key role of MALT 1 in the immune response. Mice lacking MALT1 protein were viable, but showed impairment in the generation and activation of Treg cells and less activated T cells in the periphery. MALT1 KO mice were protected in inflammatory models for MS (EAE) and rheumatoid arthritis (doi: 10.4049 / jimmunol.1201351). Mice expressing proteolytically inactive MALT1 show defects in multiple immune cell types including mature T- and B- cells and Treg cells, and develop progressive multiorgan inflammatory pathology (doi: 10.4049 / jimmunol.1402254; doi: 10.3389 / fimmu.2020.00745). A small cohort of human patients with defective MALT1 expression and / or function have presented with 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) is dependent on NF-kB activation via constitutive activation of theCARMA1-BCL10-MALT1 pathway for its survival and proliferation (doi.org / 10.1038 / nature04687). This constitutive NF-kB activation occurs often due to a variety of oncogenic mutations in pathway genes, including CARD11 , MYD88, CD79A / B and A20 (doi:10.1038 / nature07968; doi:10.1016 / j.ccr.2012.11.003). Pre-clinical studies have suggested that MALT 1 protease inhibition may be an effective treatment rationale for ABC-DLBCL, as treatment with the MALT1 inhibitor z-VRPR-fmk decreased the expression of NF-kB target genes with concomitant reduction in cell growth and viability (doi:10.1073 / pnas.0907511106; doi:10.1084 / jem.20091167), and small-molecule MALT1 inhibitors have also been shown to be active in xenograft models of ABC-DLBCL (doi:10.1016 / j.ccr.2012.11.002; doi:10.1016 / j.ccr.2012.11.003). Chronic activation of the BCR-mediated CBM-NF-kB pathway has been identified in a subset of mantle cell lymphoma (MCL) lines, suggesting that a subset of MCL may also be responsive to MALT 1 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-kB pathway, and these patients may also benefit from treatment with MALT1 inhibitors (doi 10.1074 / jbc.M605116200). MALT 1 inhibition may play a role in the treatment of some solid tumour types such as glioblastoma, breast cancer, melanoma, lung cancer, prostate cancer, pancreatic cancer and osteosarcoma (doi: 10.1038 / s41388-019-0958-4; doi:10.15252 / embj.2019102030; doi: 10.1111 / jcmm.15383; doi:10.1038 / oncsis.2017.68; doi: 10.1038 / onc.2015.146; doi: 10.3390 / biomedicines9030250; doi: 10.1002 / ijc.32567).

[0005] BTK inhibitors such as ibrutinib are important therapies for cancers such as MCL and chronic lymphocytic leukemia (CLL), but effectiveness is limited due to primary or acquired resistance (doi: 10.3390 / cancersl 2051328). MALT1 sits downstream of BTK in the NF-kB activation pathway and therefore may be an effective target either in combination with BTK inhibitors, or in BTKi-refractive tumours. MALT 1 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). MALT1 inhibition has also been shown to be synergistic with the mTORCI inhibitor, rapamycin, in ABC-DLBCL cell lines, PDX and in vivo models, opening further possibilities for combination treatment and mitigation strategies for MALTIi resistance (doi: 10.1182 / blood.2019004713). Combinations of MALT1 inhibitors together with inhibitors of the Bcl-2 family protein have also been demonstrated to show a synergistic benefit in animal models of B-cell lymphoma (W02023 / 016995).

[0006] MALT 1 inhibitors have also been proposed to be effective therapies for a range of cancers, independent of dysregulation of the NF-kB pathway, as an immunomodulatory therapy (doi:10.1038 / s41586-019-1215-2; WO2018 / 226150 & WO2018 / 141749). Geneticevidence from MALT1 -deficient mice suggests that MALT 1 promotes development of Treg cells in vivo, which in turn inhibit several types of immune cells, suppressing the antitumour immune response. Further studies targeting the CBM complex (by either MALT1 inhibition or CARMA1 deletion in Treg cells) led to a gain of effector activity by Treg cells and enhanced control of tumour growth. A MALT1 inhibitor synergized with anti-PD1 therapy in both poorly immunogenic and immunogenic murine melanoma models (doi:10.1038 / s41586-019-1215-2), suggesting a possible combinatorial role of MALT1 inhibitors with immunotherapies, including anti-PD1 , anti-PD-L1 and anti-CTLA4.

[0007] As well as having a use in oncology indications, small-molecule MALT 1 inhibitors may also be effective therapies in inflammatory disorders, for example multiple sclerosis, psoriasis, ulcerative colitis and rheumatoid arthritis. MI-2 has been shown to suppress the differentiation of monocytes into osteoclasts in the presence or absence of TN Fa, and to ameliorate the pathologic bone erosion and synovitis in a mouse collagen-induced arthritis (CIA) model, suggesting a role for MALT 1 inhibitors in the treatment of rheumatoid arthritis (doi:10.1038 / s41598-017-12349-9). The scaffold protein CARD14 forms a signalling complex with BCL10 and MALT1 in keratinocytes and this process is enhanced upon pathogenic CARD14 mutation which as in turn been linked to 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 suppress endothelial activation through increasing MCPIP1 expression, inhibiting TNFa-induced VCAM-1 expression in HUVECs and LPS-induced VCAM-1 expression in mice, suggesting a possible role for MALT 1 inhibitors in the treatment of vascular inflammatory diseases such as atherosclerosis (doi: 10.1016 / j. cellsig.2018.05.009).

[0008] Homozygous MALT 1 W580S mutations have been determined in patients with combined immunodeficieny (CID). This was associated with low MALT1-W580S protein levels leading to reduced amplitude but extended duration of NF-kB due to impaired negative feedback through reduced HOIL1 cleavage, manifesting clinically in increased dermal and Gl inflammation and increased susceptibility to infection (doi.org / 10.1016 / j.jaci.2013.10.045). Small-molecule ligands known to bind to the MALT1 wild-type allosteric site have been shown to also bind to the W580S mutant leading to enzyme stabilization and reconstitution of protein levels, even after ligand washout. Both scaffolding and protease functions were restored; thus allosteric MALT 1 inhibitors may be able to serve as ‘molecular correctors’ in cases of W80S MALT1 mutations (doi . org / 10.1038 / s41589-018-0222- 1 ) .

[0009] Clinical and pre-clinical studies are ongoing with a variety of MALT1 inhibitors. JNJ-67856633 is a small molecule MALT 1 inhibitor currently in Phi studies in patients with NHL and CLL. A review of MALT1 inhibitor patents has recently been published (doi: 10.1080 / 13543776.2021 .1951703) .

[0010] Therefore, there is an ongoing need for agents capable of MALT 1 inhibition, given the role of MALT1 in multiple indications.SUMMARY OF THE INVENTION

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

[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 present 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 invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of diseases or disorders mediated by MALT1.

[0015] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by MALT 1 , 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 disorders mediated by MALT 1 include: i) lymphomas, leukaemias, carcinomas, and sarcomas; 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, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblasticlarge cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, or GIST (gastrointestinal stromal tumour); and ii) immunological diseases including autoimmune and inflammatory disorders; such as 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, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0017] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, 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 leukaemia (CLL), or small lymphocytic lymphoma (SLL).

[0018] In another aspect, the present invention provides a method of treating nonHodgkin'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 leukaemia (CLL), or small lymphocytic lymphoma(SLL), said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0019] The present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0020] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0021] In another aspect, the present invention provides novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.

[0022] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0023] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0024] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, / .e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, / .e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

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

[0026] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for thestraight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For example, “(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl. A similar convention applies to other radicals, for example “phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0027] In this specification the term “alkylene” includes both straight and branched chain divalent alkyl groups. For example, “Ci.4alkylene” includes methylene (-CH2-), ethylene (- CH2CH2-), propylene and butylene.

[0028] In this specification the term “alkoxy” includes both straight and branched chain alkyl groups singularly bonded to oxygen. For example, “Ci.4alkoxy” includes methoxy, ethoxy, / so-propoxy and t-butoxy.

[0029] The term "Cm-n" or used alone or as a prefix, refers to any group having m to n carbon atoms.

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

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

[0032] The term “haloalkyl” is used herein to refer to an alkyl group respectively in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms. Examples of haloalkyl groups include fluoroalkyl groups such as -CHF2, -CH2CF3, or perfluoroalkyl / alkoxy groups such as -CF3, or -CF2CF3.

[0033] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2 / 7-thiopyran, andhexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, dihydroisoxazolyl (such as 4,5-dihydroisoxazolyl), dihydropyridinyl (such as 1 ,2-dihydropyridinyl or 1 ,6- dihydropyridinyl), tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1-dioxide and thiomorpholinyl 1 ,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 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 spiro bicyclic 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 the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. Suitably, the term “heterocyclyl”, “heterocyclic” or “heterocycle” will refer to 4, 5, 6 or 7 membered monocyclic rings as defined above.

[0034] The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of anindole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Suitably, the term “heteroaryl” or “heteroaromatic” will refer to 5 or 6 membered monocyclic heteroaryl rings as defined above.

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

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

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

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

[0039] Particular non-limiting examples of bicyclic heteroaryl groups containing two fused six 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 groups.

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

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

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

[0043] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0044] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.Compounds of the Invention

[0045] In a first aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:wherein:R1and R2are independently selected from hydrogen and halo;R3and R4are independently selected from hydrogen, Ci-4alkyl, Ci.4alkoxy, Ci.4haloalkyl, Ci-4haloalkoxy, halo, cyano, hydroxy, Cs-ecycloalkyl, S(O)2Ci-4alkyl, and 3-, 4-, or 5- membered heterocyclyl;R5a, R5b, R6a, and R6bare independently selected from hydrogen and Ci-4alkyl;X1, X2, and X3are independently selected from CH or N;Ring A is a 5- or 6-membered heterocyclic ring: i) optionally comprising one or more additional heteroatoms selected from N, O and S(O)n, wherein n is 0, 1 , or 2; ii) optionally substituted with one or more substituents independently selected from 5- or 6-membered heterocyclyl and Y1a-R7a; wherein Y1ais Ci.3alkylene, C(O), NR8a, S(O)2, or NR8aS(O)2, and R7ais Ci-4alkyl, NR9aR10aor C3.6cycloalkyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring optionally substituted with one or more substituents independently selected from oxo and Y1 b-R7b; wherein Y1 bis Ci.3alkylene, C(O), NR8b, S(O)2or NR8bS(O)2, and R7bis Ci- 4alkyl, NR9bR10bor Cs-ecycloalkyl;R8a, R8b, R10a, and R10bare independently selected from hydrogen and Ci-4alkyl;R9aand R9bare independently selected from hydrogen, Ci-4alkyl, and C3.6cycloalkyl;X4is CR11R12, NR13, O, S(O)m, or S(O)NHR14, wherein m is 0, 1 , or 2;R11and R12are independently selected from hydrogen, Y1c-R7cand 4-, 5- or 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from Ci.3alkyl, oxo, and Ci.3alkylene-C3.6cycloalkyl; wherein Y1cis S(O)2, NR8cC(O), or NR8cS(O)2, and R7cis Ci-4alkyl, NR9cR10c, or C3. ecycloalkyl; ORR11and R12, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring optionally substituted with one or more substituents independently selected from oxo and Y1d-R7d; wherein Y1dis Ci.3alkylene, C(O), NR8d, S(O)2or NR8dS(O)2, and R7dis Ci-4alkyl, Ci.4alkoxy, NR9dR10dor C3.6cycloalkyl; andR13is hydrogen, Ci-3alkyl, 5- or 6-membered heteroaryl, or 4-, 5- or 6-membered heterocyclyl, wherein said heteroaryl or heterocyclyl group is optionally substituted with one or more substituents independently selected from Ci-3alkyl, oxo, and Ci.3alkylene-C3. ecycloalkyl; andR8c, R8d, R9c, R9d, R10c, and R10dare independently selected from hydrogen and Ci-4alkyl.

[0046] Particular compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated,each of R1, R2, R3, R4, R5a, R5b, R6a, R6b, Ring A, R11, R12, R13, X1, X2, X3, X4, and n has any of the meanings defined hereinbefore or in any of paragraphs (1) to (68) hereinafter. 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 substituent definitions defined herein may be combined with any of the other substituent definitions also defined herein:(1) R1and R2are independently selected from hydrogen, fluoro and chloro;(2) R1is hydrogen;(3) R2is hydrogen;(4) R1and R2are both hydrogen;(5) R3and R4are independently selected from hydrogen, methyl, methoxy, trifluoromethyl, fluoro, chloro, cyano, hydroxy, and cyclopropyl;(6) R3and R4are independently selected from hydrogen, methyl, fluoro, chloro, cyano, and cyclopropyl;(7) R3and R4are independently selected from hydrogen, fluoro, chloro, and cyclopropyl;(8) R3is selected from hydrogen, methyl, methoxy, trifluoromethyl, fluoro, chloro, cyano, hydroxy, and cyclopropyl;(9) R3is selected from hydrogen, fluoro, chloro, and cyclopropyl;(10) R3is hydrogen or chloro;(11) R3is chloro;(12) R4is selected from hydrogen, methyl, methoxy, trifluoromethyl, fluoro, chloro, cyano, hydroxy, and cyclopropyl;(13) R4is selected from hydrogen, fluoro, chloro, and cyclopropyl;(14) R4is fluoro or chloro;(15) R4is fluoro;(16) R5a, R5b, R6a, and R6bare independently selected from hydrogen, methyl and ethyl;(17) R5a, R5b, R6a, and R6bare independently selected from hydrogen and methyl;(18) R5aand R5bare independently selected from hydrogen and methyl;(19) R5aand R5bare both hydrogen;(20) R5aand R5bare both methyl;(21) R6aand R6bare both hydrogen;(22) R6aand R6bare both methyl;(23) R5a, R5b, R6a, and R6bare all hydrogen;(24) R5aand R5bare both methyl, and R6aand R6bare both hydrogen;(25) X1, X2, and X3are independently selected from CH or N, provided that at least one is N;(26) One or two of X1, X2, and X3are N, and the others are CH;(27) One of X1, X2, and X3is N, and the other two are CH;(28) Two of X1, X2, and X3are N, and the other one is CH;(29) X1is N, and X2and X3are CH;(30) X3is N, and X1and X2are CH;(31) X1and X2are N, and X3is CH;(32) Ring A is a 5- or 6-membered heterocyclic ring: i) optionally comprising one additional heteroatom selected from N, O and S(O)n, wherein n is 0, 1 , or 2; ii) optionally substituted with one or two substituents independently selected from 5- or 6-membered heterocyclyl and Y1a-R7a; wherein Y1ais Ci-salkylene, C(O), NR8a, S(O)2, or NR8aS(O)2, and R7ais Ci-4alkyl, NR9aR10aor Cs-ecycloalkyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or two substituents independently selected from oxo and Y1 b-R7b; wherein Y1 bis Ci-3alkylene, C(O), NR8b, S(O)2or NR8bS(O)2, and R7bis Ci-4alkyl, NR9bR10bor Cs-ecycloalkyl;(33) Ring A is a 5- or 6-membered heterocyclic ring: i) optionally comprising one additional heteroatom selected from N, O and S(O)2; ii) optionally substituted with a substituent selected from 5- or 6-membered heterocyclyl and Y1a-R7a; wherein Y1ais Ci^alkylene, C(O), NR8a, S(O)2or NR8aS(O)2, and R7ais Ci-4alkyl, NR9aR10aor Cs-ecycloalkyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or two substituents independently selected from oxo and Y1 b-R7b; wherein Y1 bis Ci^alkylene and R7bis Cs-ecycloalkyl;(34) Ring A is a 5- or 6-membered heterocyclic ring:i) optionally comprising one additional heteroatom selected from N and O; ii) optionally substituted with one or more substituents independently selected from 6-membered heterocyclyl and Y1a-R7a; wherein Y1ais CH2, C(O), or S(O)2, and R7ais methyl, NR9aR10aor cyclopropyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with oxo;(35) Ring A is a 6-membered heterocyclic ring: i) optionally comprising one additional heteroatom selected from N, O and S(O)n, wherein n is 0, 1 , or 2; ii) optionally substituted with one or two substituents independently selected from5- or 6-membered heterocyclyl and Y1a-R7a; wherein Y1ais Ci^alkylene, C(O), NR8a, S(O)2, or NR8aS(O)2, and R7ais Ci-4alkyl, NR9aR10aor C3-6cycloalkyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or two substituents independently selected from oxo and Y1 b-R7b; wherein Y1 bis Ci-3alkylene, C(O), NR8b, S(O)2or NR8bS(O)2, and R7bis Ci-4alkyl, NR9bR10bor Cs-ecycloalkyl;(36) Ring A is a 6-membered heterocyclic ring: i) optionally comprising one additional heteroatom selected from N, O and S(O)2; ii) optionally substituted with a substituent selected from 5- or 6-membered heterocyclyl and Y1a-R7a; wherein Y1ais Ci-salkylene, C(O), NR8a, S(O)2 or NR8aS(O)2, and R7ais Ci-4alkyl, NR9aR10aor Cs-ecycloalkyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or two substituents independently selected from oxo and Y1 b-R7b; wherein Y1 bis Ci-salkylene and R7bis Cs-ecycloalkyl;(37) Ring A is a 6-membered heterocyclic ring: i) optionally comprising one additional heteroatom selected from N and O; ii) optionally substituted with one or more substituents independently selected from6-membered heterocyclyl and Y1a-R7a; wherein Y1ais CH2, C(O), or S(O)2, and R7ais methyl, NR9aR10aor cyclopropyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with oxo;(38) Ring A is selected from:are as defined herein; R15and R16are independently selected from hydrogen, S(0)2Me, and 5- or 6-membered heterocyclyl; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs-ecycloalkyl; and R17is hydrogen, 5- or 6-membered heterocyclyl ring, or Y2-R18, wherein Y2is Ci^alkylene, C(0), or S(0)2, and R18is Ci- 4alkyl, NR9aR10aor Cs-ecycloalkyl; m and n are independently 0, 1 , or 2; provided that: (i) if X4is NR13, O, S(0)n, or S(O)NHR14, then X5is CR15R16; and (ii) if X5is NR17, O, or S(0)m, then X4is CR11R12and X6is CR15R16;(39) Ring A is selected from:whereinX5and X6are independently selected fromCR15R16, NR17, and O, wherein R11, R12and R13are as defined herein; R15and R16are independently selected from hydrogen, S(0)2Me, and 5- or 6-membered heterocyclyl; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs- ecycloalkyl; and R17is hydrogen, a 6-membered heterocyclyl ring, or Y2-R18, wherein Y2is Ci-salkylene, C(0), or S(0)2, and R18is Ci-4alkyl, NR9aR10aor Cs-ecycloalkyl; provided that: (i) if X4is NR13, then X5is CR15R16; and (ii) if X5is NR17, or O, then X4is CR11R12and X6is CR15R16;(40) Ring A is selected from:wherein X4is CR11R12, or NR13; and X5and X6are independently selected from CR15R16, NR17, and O, wherein R11, R12and R13are as defined herein; R15and R16are both hydrogen; or R15is S(0)2Me and R16is hydrogen; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6- membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs-ecycloalkyl; and R17is hydrogen, a 6-membered heterocyclyl ring, or Y2-R18, wherein Y2is CH2, C(O), or S(O)2, and R18is methyl, NHcyclopropyl, or cyclopropyl; provided that: (i) if X4is NR13, then X5is CR15R16; and (ii) if X5is NR17, or O, then X4is CR11R12and X6isCR15R16;(41) Ring A is selected from:wherein R11and R12are independently selected from hydrogen, Y1c-R7cand and 4-, 5- or 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and Ci-salkylene-cyclopropyl, and wherein Y1cis S(O)2, NHC(O), or NHS(O)2, and R7cis methyl, NR9cR10c, or cyclopropyl; or R11and R12taken together with the carbon atom to which they are attached form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d- R7d; wherein Y1dis Ci.2alkylene, C(O), or S(O)2, and R7dis methyl, methoxy, NMe2 or cyclopropyl; R13is hydrogen, Ci-salkyl, 5- or 6-membered heteroaryl, or 4-, 5- or 6-membered heterocyclyl, wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from Ci-salkyl, oxo, and Ci-salkylene-Cs-6cycloalkyl; R15and R16are both hydrogen; or R15is S(O)2Me and R16is hydrogen; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs- ecycloalkyl; and R17is hydrogen, a 6-membered heterocyclyl ring or Y2-R18, wherein Y2is CH2, C(O), or S(O)2, and R18is methyl, NHcyclopropyl, or cyclopropyl;(42) Ring A is selected from:wherein R11and R12are independently selected from hydrogen, Y1c-R7c, and 4-, 5- or 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and Ci-salkylene- cyclopropyl, and wherein Y1cis S(O)2, NHC(O), or NHS(O)2, and R7cis methyl, NR9cR10c, or cyclopropyl; or R11and R12taken together with the carbon atom to whichthey are attached form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d- R7d; wherein Y1dis CH2, C(O), or S(O)2, and R7dis methyl, methoxy, NMe2 or cyclopropyl; R13is hydrogen, methyl, 5-membered heteroaryl, or 4-, 5- or 6- membered heterocyclyl, wherein said heteroaryl or heterocyclyl group is optionally substituted with one or more substituents independently selected from methyl, oxo, and Ci-3alkylene-C3-6cycloalkyl; and R17is hydrogen, a 6-membered heterocyclyl ring or Y2-R18, wherein Y2is CH2, C(O), or S(O)2, and R18is methyl, NHcyclopropyl, or cyclopropyl;(43) Ring A is selected from:wherein R11and R12are independently selected from hydrogen, NHS(O)2Me, NHS(O)2cyclopropyl, NHC(O)NMe2, S(0)2Me, and 1 ,1-dioxido-tetrahydro- thiopyranyl; or R11and R12taken together with the carbon atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydropyranyl or tetrahydrothiopyranyl ring, optionally substituted with one or more substituents independently selected from oxo, CH2cyclopropyl, S(0)2Me, S(O)2cyclopropyl, C(O)cyclopropyl, C(0)NMe2, and CF^CFWMe; R13is methyl, triazolyl, pyrazolyl, pyrrolidinyl, oxetanyl, or tetrahydropyranyl, optionally substituted with methyl, oxo, or CH2cyclopropyl; and R17is hydrogen, tetrahydropyranyl, CH2cyclopropyl, S(0)2Me, S(O)2cyclopropyl, C(O)cyclopropyl, or C(O)NHcyclopropyl;(44) Ring A is selected from:wherein R11and R12are independently selected from hydrogen, NHS(O)2Me, NHS(O)2cyclopropyl, NHC(O)NMe2, S(0)2Me, and 1 ,1-dioxido-tetrahydro- thiopyranyl; or R11and R12taken together with the carbon atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydropyranyl or tetrahydrothiopyranyl ring, optionally substituted with one or more substituents independently selected from oxo, CH2cyclopropyl, S(0)2Me, S(O)2cyclopropyl, C(O)cyclopropyl, C(0)NMe2, and CF^CFWMe; and R13is methyl, triazolyl, pyrazolyl, pyrrolidinyl, oxetanyl, or tetrahydropyranyl, optionally substituted with methyl, oxo, or CH2cyclopropyl;(45) X4is CR11R12, O, or NR13;(46) X4is CR11R12;(47) X4is NR13;(48) X4is O;(49) R11and R12are independently selected from hydrogen, Y1c-R7cand 4-, 5- or 6- membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and Ci-salkylene-Cs- ecycloalkyl; wherein Y1cis S(O)2, NR8cC(O), or NR8cS(O)2, and R7cis Ci-4alkyl, NR9cR10c, or Cs-ecycloalkyl;(50) R11and R12are independently selected from hydrogen, Y1c-R7cand 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and CH2cyclopropyl; wherein Y1cis S(O)2, NHC(O), or NHS(O)2, and R7cis methyl, NR9cR10c, or cyclopropyl;(51) R11and R12are independently selected from hydrogen, NHS(O)2Me, NHS(O)2cyclopropyl, NHC(O)NMe2, S(O)2Me, and 1 ,1-dioxido-tetrahydro- thiopyranyl;(52) R11is hydrogen and R12is Y1c-R7cor 4-, 5- or 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and Ci-salkylene-Cs-ecycloalkyl; and wherein Y1cis S(O)2, NR8cC(O), or NR8CS(O)2, and R7cis Ci-4alkyl, NR9cR10c, or Cs-ecycloalkyl;(53) R11is hydrogen and R12is Y1 c-R7cor 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and CH2cyclopropyl; and wherein Y1cis S(O)2, NHC(O), or NHS(O)2, and R7cis methyl, NR9cR10c, or cyclopropyl;(54) R11is hydrogen and R12is selected from NHS(O)2Me, NHS(O)2cyclopropyl, NHC(O)NMe2, S(O)2Me, and 1 ,1-dioxido-tetrahydro-thiopyranyl;(55) R11and R12are both hydrogen;(56) R11and R12, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d-R7d; wherein Y1dis Ci- 3alkylene, C(O), NR8d, S(O)2or NR8dS(O)2, and R7dis Ci-4alkyl, Ci-4alkoxy, NR9dR10dor Cs-ecycloalkyl;(57) R11and R12, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d-R7d; wherein Y1dis Ci- salkylene, C(O), or S(O)2, and R7dis Ci-4alkyl, Ci.4alkoxy, NR9dR10dor Cs-ecycloalkyl;(58) R11and R12, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d-R7d; wherein Y1dis CH2, C(O), or S(O)2, and R7cis methyl, methoxy, NMe2 or cyclopropyl;(59) R11and R12, taken together with the carbon atom to which they are attached, form a oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d-R7d; wherein Y1dis CH2, C(O), or S(O)2, and R7cis methyl, methoxy, NMe2 or cyclopropyl;(60) R11and R12, taken together with the carbon atom to which they are attached, form a oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl ring, optionally substituted with one or more substituents independently selected from oxo, CH2cyclopropyl, S(O)2Me, S(O)2cyclopropyl, C(O)cyclopropyl, C(O)NMe2, and CF^CFWMe;(61) R11and R12, taken together with the carbon atom to which they are attached, form a oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or tetrahydrothiopyranyl ring, optionally substituted with one or two substituentsindependently selected from oxo, CH2cyclopropyl, S(O)2Me, S(O)2cyclopropyl, C(O)cyclopropyl, C(O)NMe2, and CF^CFWMe;(62) R13is hydrogen, methyl, 5- or 6-membered heteroaryl, or 4-, 5- or 6-membered heterocyclyl, wherein said heteroaryl or heterocyclyl group is optionally substituted with one or more substituents independently selected from methyl, oxo, and CH2cyclopropyl;(63) R13is methyl, 5- or 6-membered heteroaryl, or 4-, 5- or 6-membered heterocyclyl, wherein said heteroaryl or heterocyclyl group is optionally substituted with one or more substituents independently selected from methyl, oxo, and CH2cyclopropyl;(64) R13is triazolyl, pyrazolyl, pyrrolidinyl, oxetanyl, or tetrahydropyranyl, optionally substituted with one or more substituents independently selected from oxo, and CH2cyclopropyl;(65) R13is methyl, triazolyl, pyrazolyl, pyrrolidinyl, oxetanyl, or tetrahydropyranyl, optionally substituted with methyl, oxo, or CH2cyclopropyl;(66) n is 0;(67) n is i ;(68) n is 2.

[0047] Suitably, R1and R2are as defined in any one of paragraphs (1) to (4) above.

[0048] Suitably, R3and R4are as defined in any one of paragraphs (5) to (7) above. Suitably, R3is as defined in any one of paragraphs (8) to (11) above. Suitably, R4is as defined in any one of paragraphs (12) to (15) above.

[0049] Suitably, R5a, R5b, R6a, and R6bare as defined in any one of paragraphs (16) to(17), or (23) to (24) above. Suitably, R5aand R5bare as defined in any one of paragraphs(18) to (20) above. Suitably R6aand R6bare as defined in any one of paragraphs (21) to (22) above.

[0050] Suitably, X1, X2, and X3are as defined in any one of paragraphs (25) to (31 ) above.

[0051] Suitably, Ring A is as defined in any one of paragraphs (32) to (44) above. More suitably, Ring A is as defined in paragraph (43) or (44) above.

[0052] Suitably, X4is as defined in any one of paragraphs (45) to (48) above.

[0053] Suitably, R11and R12are as defined in any one of paragraphs (49) to (61) above. In an embodiment, R11and R12are as defined in paragraph (54) or paragraph (61) above.

[0054] Suitably, R13is as defined in any one of paragraphs (62) to (65) above. In an embodiment, R13is as defined in paragraph (65) above.

[0055] Suitably, n is as defined in any one of paragraphs (66) to (68) above.

[0056] In a convenient embodiment, the compound of formula I is a compound according to formula IA (sub-structure of formula I) below, or a pharmaceutically acceptable salt thereof:

[0057] In a further group of compounds, the compounds have one of the structural formulae IB to IL (sub-structures of formula I) shown below:wherein X1, X2, X3, X4, R1, R2, R3, R4, R5a, R5b, R6a, and R6bare as defined hereinbefore; and X5and X6are independently selected from CR15R16, NR17, O, and S(O)n; wherein R15and R16are both hydrogen; or R15is S(O)2Me and R16is hydrogen; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs-ecycloalky; and R17is hydrogen, 5- or 6-membered heterocyclyl ring, or Y2-R18, wherein Y2is Ci-salkylene, C(O), or S(O)2, and R18is Ci-4alkyl, NR9aR10aor Cs-ecycloalkyl; and n is 0, 1 , or 2; provided that: (i) if X4is NR13, O, S(O)n, or S(O)NHR14, then X5is CR15R16; and (ii) if X5is NR17, O, or S(O)m, then X4is CR11R12and X6is CR15R16.

[0058] In a further group of compounds, the compounds have one of the structural formulae I A to IL shown above, wherein R1and R2are as defined in any one of paragraphs (1) to (4) above; R3and R4are as defined in any one of paragraphs (5) to (15) above; R5a, R5b, R6a, and R6bare as defined in any one of paragraphs (16) to (24) above; X1, X2, and X3are as defined in any one of paragraphs (25) to (31) above; X4is as defined in any one of paragraphs (45) to (48) above; X5and X6are independently selected from CR15R16, NR17, and O; wherein R15and R16are both hydrogen; or R15is S(O)2Me and R16is hydrogen; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs-ecycloalkyl; and R17is hydrogen, a 6-membered heterocyclyl ring or Y2-R18, wherein Y2is CH2, C(O), or S(O)2, and R18is methyl, NHcyclopropyl, or cyclopropyl; provided that: (i) if X4is NR13, then X5is CR15R16; and (ii) if X5is NR17, or O, then X4is CR11R12and X6is CR15R16.

[0059] In a further group of compounds, the compounds have one of the structural formulae I A to IL shown above, wherein R1and R2are as defined in paragraph (4) above; R3and R4are as defined in paragraph (7) above; R5a, R5b, R6a, and R6bare as defined in any one of paragraphs (23) to (24) above; X1, X2, and X3are as defined in paragraph (26) above; X4is NR13or CR11R12; X5and X6are independently selected from CR15R16, NR17, and O; wherein R11and R12are independently selected from hydrogen, Y1c-R7c, and 4-, 5- or 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and Ci-salkylene-cyclopropyl, and wherein Y1cis S(O)2, NHC(O), or NHS(O)2, and R7cis methyl, NR9cR10c, or cyclopropyl; or R11and R12taken together with the carbon atom to which they are attached form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d-R7d; wherein Y1dis CH2, C(O), or S(O)2, and R7dis methyl, methoxy, NMe2 or cyclopropyl; R13is 4- or 5-membered heterocyclyl, optionallysubstituted with one or more substituents independently selected from Ci-salkyl, oxo, and Ci.salkylene-Cs-ecycloalkyl; R15and R16are both hydrogen; or R15is S(O)2Me and R16is hydrogen; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs-ecycloalkyl; and R17is hydrogen, a 6-membered heterocyclyl ring or Y2-R18, wherein Y2is CH2, C(O), or S(O)2, and R18is methyl, NHcyclopropyl, or cyclopropyl; provided that: (i) if X4is NR13, then X5is CR15R16; and (ii) if X5is NR17, or O, then X4is CR11R12and X6is CR15R16.

[0060] In a further group of compounds, the compounds have one of the structural formulae I Ba to I La (sub-structures of formula I) shown below:hereinbefore.

[0061] Particular compounds of the present invention include any one of the following compounds:A / -((S)-1-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxopyrrolidin-3-yl)methanesulfonamide; 2-(( / ?)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one; 2-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one; 2-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one; 2-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-A / ,A / -dimethyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide; 1-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)piperazin-2-one; 8-(Cyclopropanecarbonyl)-2-((S)-1-(5-(((S)-1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one;8-(Cyclopropylsulfonyl)-2-((S)-1-(5-(((S)-1 , 1-dimethyl-2,3-dihydro-1 H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one;1-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-(methylsulfonyl)piperazin-2-one;4-(Cyclopropanecarbonyl)-1-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one;4-(Cyclopropylmethyl)-1-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)piperazin-2-one;8-(Cyclopropylmethyl)-2-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one;4-(Cyclopropylsulfonyl)-1-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)piperazin-2-one;A / -Cyclopropyl-4-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-oxopiperazine-1 -carboxamide;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3- methylimidazolidin-2-one;3-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)oxazolidin-2-one;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3- methyltetrahydropyrimidin-2(1 / 7)-one;3-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)- 1 ,3-oxazinan-2-one;4-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)morpholin-3-one;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-8- oxa-2-azaspiro[4.5]decan-1-one;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)pyrrolidin-2-one;3-((3S)-1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxopyrrolidin-3-yl)-1 ,1 -dimethylurea;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-2-one;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-(2- methyl-2H-1 ,2,3-triazol-4-yl)tetrahydropyrimidin-2(1 / 7)-one;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-8- thia-2-azaspiro[4.5]decan-1-one 8,8-dioxide;9-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3- oxa-9-azaspiro[5.5]undecan-8-one;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-9- oxa-2-azaspiro[5.5]undecan-3-one;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-9- oxa-2-azaspiro[5.5]undecan-1-one;N-((3S)-1-((1 S)-1-(5-((5-chloro-4-cyclopropyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)methanesulfonamide;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-(1- methyl-1 H-pyrazol-4-yl)tetrahydropyrimidin-2(1 / 7)-one;1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(1 ,1-dioxidotetrahydro-2 / 7-thiopyran-4-yl)tetrahydropyrimidin-2(1 / 7)-one;1-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-3-(1 ,1-dioxidotetrahydro-2 / 7-thiopyran-4-yl)tetrahydropyrimidin-2(1 / 7)-one;2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]decan-1-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-9-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-1-one;6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxa-6-azaspiro[3.4]octan-5-one;6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxa-6-azaspiro[3.4]octan-7-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,7-diazaspiro[4.4]nonane-1 , 8-dione;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-7-(cyclopropylmethyl)-2,7-diazaspiro[4.4]nonan-1-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-7-(cyclopropylmethyl)-2,7-diazaspiro[4.4]nonan-3-one;8-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,8-diazaspiro[4.5]decane-3, 7-dione;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]decan-1-one;N-((3R)-1-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-2-oxopyrrolidin-3-yl)methanesulfonamide;N-((3R)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxopiperidin-3-yl)methanesulfonamide;1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-((R)-1-(cyclopropylmethyl)pyrrolidin-3-yl)tetrahydropyrimidin-2(1 / 7)-one;6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-5-one;6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-5-one;1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(oxetan-3-yl)tetrahydropyrimidin-2(1 / 7)-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]decan-1-one;7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,7-diazaspiro[4.5]decane-1 , 6-dione;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,7-diazaspiro[4.4]nonane-1 , 6-dione;7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1 ,7-diazaspiro[4.5]decane-2, 6-dione;N-((3S)-1-((1 S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-2-oxopyrrolidin-3-yl)methanesulfonamide;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(cyclopropylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(2-methoxyethyl)-2,8-diazaspiro[4.5]decan-1-one;4-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1-oxa-9-thia-4-azaspiro[5.5]undecan-5-one 9,9-dioxide;A / -((3S)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxopiperidin-3-yl)cyclopropanesulfonamide;N-((3S)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxopiperidin-3-yl)methanesulfonamide;7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1 ,7-diazaspiro[4.4]nonane-2, 6-dione;N-((3S)-1-((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-2-oxopyrrolidin-3-yl)cyclopropanesulfonamide;2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-9-thia-2-azaspiro[5.5]undecan-1-one 9,9-dioxide;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one;2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-9-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-1-one;4-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-9-(cyclopropylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one; and A / -((3S)-1-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-2-oxopiperidin-3-yl)methanesulfonamide; or a pharmaceutically acceptable salt thereof.

[0062] The various functional groups and substituents making up the compounds of the present invention are typically chosen such that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650.

[0063] Suitable or preferred features of any compounds of the present invention may also be suitable features of any other aspect.

[0064] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0065] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e.,as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0066] The compounds of this invention typically possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers, diastereoisomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see 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 a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess MALT1 inhibitory activity.

[0067] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D) and3H (T); C may be in any isotopic form including12C,13C, and14C; and O may be in any isotopic form, including16O and18O; and the like.

[0068] It is also to be understood that certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess MALT 1 inhibitory activity.

[0069] It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms that possess MALT1 inhibitory activity.

[0070] Compounds of the invention may exist in a number of different tautomeric forms and references to compounds of the invention include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by compounds of the invention. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci- nitro.keto enol enolate

[0071] Compounds of the invention containing an amine function may also form / V- oxides. A reference herein to a compound of the formula I that contains an amine function also includes the / V-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an / V-oxide. Particular examples of / V-oxides are the / V-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. / V-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, / V-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0072] The compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.

[0073] Accordingly, the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I may be a synthetically-produced compound or a metabolically-produced compound.

[0074] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0075] Various forms of pro-drug have been described, for example in the following documents:a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0076] The in vivo effects of a compound of the formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I. As stated hereinbefore, the in vivo effects of a compound of the formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0077] It shall also be appreciated that compounds of the formula I may also be covalently linked (at any suitable position) to other groups such as, for example, solubilising moieties (for example, PEG polymers), moieties that enable them to be bound to a solid support (such as, for example, biotin-containing moieties), and targeting ligands (such as antibodies or antibody fragments).

[0078] In the description of the synthetic methods described below and in the referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0079] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0080] Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with thefollowing representative process variants and within the accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

[0081] 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 substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0082] For examples of protecting groups see one of the many general texts on the subject, for example, “Protecting groups in Organic Synthesis (3rdEd), John Wiley & Sons, NY (1999)”, T. Greene & P. Wuts. Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0083] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0084] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert- butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a terf-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example BF3.OEt2. A suitable protecting group for an amino or alkylamino group is, for example, a substituted benzyl group such as 4-methoxybenzyl or 2,4-dimethoxybenzyl. Such a protecting group may be removed by, for example, by treatment with by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl groupwhich may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0085] The person skilled in the art will recognise that the compounds of the invention may be prepared, in known manner, in a variety of ways. Compounds of Formula I can be prepared by the methods given below, by the methods given in the experimental or by analogous methods. The routes described are merely illustrative of some of the methods that can be employed for the synthesis of compounds of Formula I and the person skilled in the art will appreciate that the order of the reaction steps is not limited to those described. It will also be appreciated that the assignment of nucleophile and electrophile is not limited to that described herein and in some cases it may be appropriate for the assignment to be reversed. Different approaches to synthetic chemistry strategy are described in “Organic Synthesis: The Disconnection Approach”, 2ndedition, S. Warren and P. Wyatt (2008).Scheme A

[0086] Compounds of Formula I, wherein R1, R2, R3, R4, R5a, R5b, R6a, R6b, X1, X2, X3, X4and Ring A are as previously defined, can be prepared by the condensation of compounds of Formula II and Formula III in step (a) in the presence of suitable coupling reagent and base (Scheme A). A suitable coupling reagent includes, for example, tBuBrettphosPdG3 in the presence of RuPhos, Pd2(dba)s in the presence of X-Phos, RuPhosPdG3, XPhosPdG2 or BuBrettphosPdGI in the presence of BrettPhos. A suitable base includes, for example, CS2CO3, K2CO3, CsF or sodium t-butoxide. A suitable leaving group (LG) includes, for example, bromide, chloride or triflate.Scheme B

[0087] Compounds of Formula II can be prepared as outlined in Scheme B. A suitable indan-2-one, as depicted by Formula IV or VII can be converted to a compound of Formula V or VIII respectively in a two-step process involving reduction of the ketone followed by elimination as in step (b). The reduction of the ketone can be performed, for example, using sodium borohydride or lithium aluminium hydride with the elimination occurring under acidic conditions, for example, treatment with para-toluenesulfonic acid. Compounds of Formula VI can be prepared by a suitable oxidation procedure (step c) from compounds of Formula V or VIII. An example of such an oxidation procedure would by the two-step process of dihydroxylation followed by acid treatment. A suitable oxidant, for example, would be osmium tetroxide with a suitable acid, for example, being para-toluenesulfonic acid. A further oxidation procedure would be the two-step process of epoxidation followed by acid treatment. A suitable oxidant, for example, would be meta-chloroperoxybenzoic acid with a suitable acid, for example, being silica. The reaction of a compound of Formula VI with a suitable amine source and suitable reducing agent under reductive amination conditions would furnish the required compound of Formula II (step d). A suitable amine source includes, for example, ammonium acetate with a suitable reducing agent, for example, sodium cyanoborohydride or sodium triacetoxyborohydride.Scheme C

[0088] Compounds of Formula III can be prepared as outlined in Scheme C. Addition of a suitable nucleophile to a compound of Formula IX affords Formula X in step (e). A suitable nucleophile includes trifluoromethyltrimethylsilane. The introduction of a suitable leaving group (LG1) to the compound of Formula X in step (f) affords Formula XI. A suitable leaving group includes, for example, a mesylate, tosylate or triflate. The reaction of the compound of Formula XI with a suitable cyclic amine nucleophile will afford Formula XII as in step (g). The oxidation of the compound of Formula XII with a suitable oxidizing agent may afford a compound of Formula III in step (h). A suitable oxidizing agent includes, for example, sodium chlorite.Scheme D(XI) (XIII) (III)

[0089] Compounds of Formula III can also be prepared as outlined in Scheme D. The reaction of a compound of Formula XI with a suitable acyclic amine, in which X4is NR13or O, in step (i) would afford Formula XIII. The cyclisation of the compound of Formula XIII with a suitable cyclising reagent may afford a compound of Formula III as shown in step (j). A suitable cyclising reagent includes, for example, diphosgene, triphosgene or carbonyl diimidazole.Scheme E

[0090] Compounds of Formula III can also be prepared as outlined in Scheme E. Condensation of a compound of Formula IX with t-butylsulfinamide in step (k) may afford the imine of Formula XIV. Reaction of an imine of Formula XIV with a range of nucleophiles would afford a compound of Formula XV in step I with a suitable nucleophile being, for example, trifluoromethyltrimethylsilane. Removal of the t-butylsulfinyl group from a compound of Formula XV using methods as described in “Protecting groups in Organic Synthesis (3rdEd), John Wiley & Sons, NY (1999)”, T. Greene & P. Wuts affords a compound of Formula XVI in step (m). Reacting the compound of Formula XVI with lactam A in step (n) under Lewis acid conditions may afford a compound of Formula XVII. A suitable Lewis acid includes, for example, trimethylaluminium. Finally, cyclisation of a compound of Formula XVII with a suitable dehydrating reagent, step (o), may afford the compound of Formula III. A suitable dehydrating agent includes, for example, di-terf-butyl azodicarboxylate.Scheme F

[0091] Compounds of Formula III can also be prepared as outlined in Scheme F. The reductive amination of a compound of Formula XVI with aldehyde A, step (p), using a suitable reducing agent may furnish a compound of Formula XVIII. A suitable reducing agent, for example, would be sodium cyanoborohydride or sodium triacetoxyborohydride.Finally, cyclisation of a compound of Formula XVIII under thermal conditions, step (q), would afford a compound of Formula III.Scheme G

[0092] Compounds of Formula I can also be prepared as outlined in Scheme G. The oxidation of a compound of Formula X with a suitable oxidizing agent may furnish a compound of Formula XIX in step (r). A suitable oxidizing agent, for example, would be manganese (IV) oxide. The condensation of a compound of Formula II, from Scheme B, with a compound of Formula XIX in the presence of suitable coupling reagent and base as in step (s) would furnish a compound of Formula XX. A suitable coupling reagent includes, for example, tBuBrettphosPdG3 in the presence of RuPhos, Pd2(dba)s in the presence of X-Phos, RuPhosPdG3, XPhosPdG2 or BuBrettphosPdGI in the presence of BrettPhos. A suitable base includes, for example, CS2CO3, K2CO3, CsF or sodium t-butoxide. A suitable leaving group (LG) includes, for example, bromide, chloride or triflate. A compound of Formula XXII can be prepared in a two-step process from a compound of Formula XX, via imine formation with amine (XXI) in step (t) using an appropriate Lewis acid followed by reduction of the imine in step (u) with a suitable reducing agent. A suitable Lewis acid includes, for example, titanium isopropoxide whilst an appropriate reducing agent includes, for example, sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride. The oxidation of a compound of Formula XXII with a suitable oxidizing agent may afford a compound of Formula I in step (h). A suitable oxidizing agent includes, for example, sodium chlorite.Pharmaceutical Compositions

[0093] The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Therefore, according to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluent or carrier.

[0094] The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.

[0095] The compositions of the invention may be in a form suitable for oral use (for example as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets), for topical use (for example as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels), for transdermal administration such as via transdermal patches, for administration by inhalation (for example as a dry powders, aerosols, suspensions, and solutions), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0096] As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must be of sufficiently high purity to render it pharmaceutically-acceptable.

[0097] Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for theirability to facilitate the production of uniform dosage forms. Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

[0098] Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The person skilled in the art will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

[0099] Persons skilled in the art possess the knowledge and skill to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting 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).

[0100] The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0101] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0102] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well- known principles of medicine.

[0103] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.Routes of Administration

[0104] The compounds of the invention or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e. at the site of desired action).

[0105] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0106] In a preferred embodiment, a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, is administered orally or via injection, such as conveniently by oral administration.Therapeutic Uses and Applications

[0107] The compounds of the invention are inhibitors of MALT1. As a consequence, they are potentially useful therapeutic agents for the treatment of diseases or conditions mediated by MALT 1 .

[0108] Thus, in one aspect, the present 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.

[0109] In another aspect, the present 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 the treatment of diseases or disorders mediated by MALT1.

[0110] In another aspect, the present invention relates to a method of treating a disease or disorders 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.

[0111] Examples of particular diseases or conditions that the compounds of formula (I) and their pharmaceutically acceptable salts may be used to treat include, but are not limited to: i) lymphomas, leukaemias, carcinomas, and sarcomas; 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, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngealcancer, buccal cancer, cancer of the mouth, or GIST (gastrointestinal stromal tumour); and ii) immunological diseases including autoimmune and inflammatory disorders; such as 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, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0112] In particular, the compounds of the invention (including pharmaceutically acceptable salts) may be used in the treatment of 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 leukaemia (CLL), or small lymphocytic lymphoma (SLL).

[0113] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, 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 leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small- cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma,rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), 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, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody- mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

[0114] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, 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 leukaemia (CLL), or small lymphocytic lymphoma (SLL).

[0115] In another aspect, the present invention provides a method of treating nonHodgkin'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 leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer,oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), 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, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0116] In another aspect, the present invention provides a method of treating nonHodgkin'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 leukaemia (CLL), or small lymphocytic lymphoma (SLL), said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0117] In another aspect, the present invention provides a method of inhibiting MALT1 in vitro, said method comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof.

[0118] In another aspect, the present invention provides a method of inhibiting MALT1 in vivo, said method comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof.

[0119] In another aspect, the present invention provides a method of inhibiting MALT1 in vitro and / or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.Combination Therapies

[0120] The compounds of the invention may be administered alone as a monotherapy or may administered in combination with one or more additional therapeutic agents. Theselection of the one or more additional therapeutic agents will of course vary depending on the disease or condition to be treated and its severity.

[0121] It is commonplace to use combination therapies to treat certain medical conditions.

[0122] According to a particular aspect of the invention there is provided a combination suitable for use in the treatment of a disease or condition in which MALT1 is implicated, comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0123] According to this aspect of the invention there is provided a combination suitable for use in the prevention or treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small- cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), 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, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody- mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis, the combination comprising a compound of theinvention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0124] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0125] Herein, where the term “combination” is used it is to be 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 a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0126] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents in association with a pharmaceutically acceptable diluent or carrier.

[0127] The one or more additional therapeutic agents may comprise a further compound of the present invention. Therefore, in an embodiment, there is provided a pharmaceutical composition which comprises two compounds of the invention, or pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0128] According to a particular aspect of the invention there is provided a combination suitable for use in the prevention or treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukaemia (CLL), or small lymphocytic lymphoma (SLL).

[0129] Examples of other therapeutic agents that may be used as part of a combination therapy with a compound of the present invention (e.g. as one of two or more active agents as part of double or triple combinations) include, but are not limited to, the following:

[0130] (i) BTK (Bruton’s tyrosine 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;

[0131] (ii) SYK inhibitors such as fostamatinib, entospletinib, HM PL-523, IC-265, SKI-O- 703, cerdulatinib, PRT-2761, GSK-264264, SYHX-1901 , MK-8457, HM-43239, R-348 and PUR-1800;

[0132] (iii) PKC inhibitors such as darovasertib, MS-553, enzastaurin, safingol, ruboxistaurin and AR-13503;

[0133] (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, SHC-014748M, 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;

[0134] (v) Bel 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;

[0135] (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 , cerdulatinib, izencitinib, KL-130008, WP- 1066, gusacitinib, INCB-52793, AC-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;

[0136] (vii) PIM kinase inhibitors such as uzansertib, TP-3654, MEN-1703, ETH-155008, abemaciclib and SF-1126;

[0137] (viii) mTORC inhibitors such as rapamycin, sirolimus, novolimus, umirolimus zotarolimus, temsirolimus, everolimus, merilimus, eRapa, ridaforolimus;

[0138] (ix) Rituximab or other B cell antigen-binding antibodies as well as immune cell redirection agents (e.g. blinatumomab or CAR-T cells);

[0139] (x) Anti-PD1 antibodies such as nivolumab, pembrolizumab, lambrolizumab, pidilzumab, BGB-A317;

[0140] (xi) Anti-PD-L1 antibodies such as atezolizemab, avelumab, durvalumab, MEDI- 4736 and MPDL3280A;

[0141] (xii) Antibodies that inhibit the 4-1 BB - ligand interaction such as utomilumab; and

[0142] (xiii) Antibodies that inhibit the interaction of CTLA-4 and its ligands such as ipilumumab, tremelimumab, or those disclosed in W02014 / 207063.

[0143] 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.

[0144] Such conjoint / combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0145] Such combination therapies employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges and / or the dosage such as described in the relevant publication reference.EXAMPLESGeneral Procedures:

[0146] Methods for preparing the compounds of this invention are illustrated in the following Examples. Starting materials are made according to procedures known in the art or as illustrated herein or are available commercially. Commercial reagents were used without further purification. Where no reaction temperature is included, the reaction was performed at ambient temperature which is typically 17 - 27 °C.

[0147] A person skilled in the art will appreciate that reaction temperatures, reaction times & reagent quantities may be varied from those stated herein.

[0148] Where compounds described in the invention are characterized by1H NMR spectroscopy, spectra were recorded on 400 MHz Bruker Avance III HD instrument and 300 MHz Bruker Fourier HD instrument. Where no temperature is included, the spectra were recorded at ambient temperature. Chemical shift values are expressed in parts per million (ppm). The following abbreviations are used for the multiplicity of the NMR signals: s=singlet, br=broad, t=triplet, q=quartet, m=multiplet, d=doublet.

[0149] Where compounds described in the invention are characterized by LCMS data, molecular weight is determined using the conditions listed below.Method A: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 50 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method B: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 50 x 2.1 mm. Conditions: 0.05% formic acid in water [eluent A], 0.05% formic acid in MeCN [eluent B],Method C: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 50 x 2.1 mm. Conditions: 0.1% TFA in water [eluent A], 0.1% TFA in MeCN [eluent B],Method D: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.1% TFA in water [eluent A], 0.1% TFA in MeCN [eluent B],Method E: Shimadzu 2020 (SPD-M40 PDA 220 I 254 nm and MS detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method F: Shimadzu 2020 (SPD-M40 PDA 254 I 280 nm and MS detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method G: Waters Acquity l-Class Plus (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.1 % formic acid in water [eluent A], 0.1 % formic acid in MeCN [eluent B],Method H: Dionex LIHPLC Ultimate 3000 (DAD 190 - 340 nm and Thermo Scientific ISQ EC detector). Column: Kinetex XB-C18, 110 A, 2.6 pm, 50 x 4.6 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method I: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: XBridge C18, 130 A, 3.5 pm, 100 x 4.6 mm. Conditions: 5 mM NH4HCO3 in water [eluent A], MeCN [eluent B],Method J: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: XBridge BEH C18, 130 A, 2.5 pm, 50 x 2.1 mm. Conditions: 5 mM NH4HCO3 in water [eluent A], MeCN [eluent B],Method K: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: YMC-Triart C18, 120 A, 1.9 pm, 50 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], MeCN [eluent B],Method L: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: X-Select CSH C18, 1.7 pm, 30 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method M: Dionex LIHPLC Ultimate 3000 (DAD 190 - 340 nm and Thermo Scientific ISQ EC detector). Column: Kinetex XB-C18, 110 A, 2.6 pm, 50 x 4.6 mm. Conditions: water [eluent A], MeCN [eluent B],Method N: Shimadzu 2020 (SPD-M40 PDA 205 I 254 nm and MS detector). Column: Waters Acquity BEH C18, 130 A, 1.7 pm, 100 x 2.1 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method O: Agilent 1260 (Waters Acquity PDA 210 - 400 nm and Waters Acquity SQ detector). Column: XBridge C18, 130 A, 3.5 pm, 150 x 4.6 mm. Conditions: 10 mM NH4HCO3 in water [eluent A], MeCN [eluent B],Method P: Vanquish Flex UHPLC (DAD 190 - 340 nm and Thermo Scientific ISQ EM detector). Column: Kinetex XB-C18, 110 A, 2.6 pm, 50 x 4.6 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],Method Q: Vanquish Flex UHPLC (DAD 190 - 340 nm and Thermo Scientific ISQ EM detector). Column: Gemini NX-C18, 110 A, 3 pm, 50 x 4.6 mm. Conditions: 0.05% ammonia in water [eluent A], MeCN [eluent B],Method R: Vanquish Flex UHPLC (DAD 190 - 340 nm and Thermo Scientific ISQ EM detector). Column: Gemini NX-C18, 110 A, 3 pm, 150 x 4.6 mm. Conditions: 0.1% formic acid in water [eluent A], 0.1% formic acid in MeCN [eluent B],

[0150] Preparative HPLC was performed using Shimadzu CBM-20A I SIL-10AP; Shimadzu Nexera; Waters Delta; Gilson GX-271 ; Agilent 1260 Infinity II.

[0151] Preparative SFC was performed using Waters SFC-150-1; Water SFC-150-II; Waters SFC-200; Sepiatec-200.

[0152] Automated purification was carried out using Interchim Puriflash XS 520: Normalphase PF-50SIHP-JP; Reverse-phase PF-15C18HP.Abbreviations:Intermediate SynthesisIntermediate 1 : tert-Butyl ((S)-1-(((S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)amino)- 4-hydroxy-1-oxobutan-2-yl)carbamate

[0153] To a stirred solution of (S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-amine (0.30 g, 1.12 mmol, CAS 1213534-94-1) in DCM (8 mL) was added trimethylaluminium (2 M in toluene, 1.1 mL, 2.2 mmol) at 0 °C and stirred for 15 min before addition of terf-butyl A / -[(3S)-2-oxotetrahydrofuran-3-yl]carbamate (0.25 g, 1.23 mmol, CAS 40856-59-5) then the mixture was stirred at RT for 18 h. Additional terf-butyl A / -[(3S)-2-oxotetrahydrofuran- 3-yl]carbamate (0.11 g, 0.56 mmol) was added and stirred at RT for 18 h. Additional trimethylaluminium (2 M in toluene, 1.1 mL, 2.2 mmol) was added and stirred at RT for 18 h. The mixture was poured into 10% aqueous citric acid and extracted with DCM. The organics were washed with saturated aqueous NaHCOs, water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, eluting 0-5% MeOH in DCM) to provide the title compound (0.30 g).1H NMR (300 MHz; DMSO-d6) 5: 8.97 - 8.60 (m, 2H), 8.21 (dd, 1 H), 7.73 (d, 1 H), 7.06 (d, 1 H), 6.07 - 5.86 (m, 1 H), 4.63 - 4.46 (m, 1 H), 4.24 - 4.05 (m, 1 H), 3.44 (d, 2H), 1.90 - 1.60 (m, 2H), 1.35 (s, 9H).Intermediate 2: (S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-amine hydrochloride

[0154] 1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (3.8 g, 17.9 mmol, CAS 74413-86-8) was added to saturated aqueous NaHCOs and extracted with DCM containing 10% MeOH. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Chiral purification was carried out by preparative SFC (Chiralpak®-IG, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 60 g / min, 50% CO2 with 50% (MeCN with 0.2% diethylamine) modifier). After drying the separated peaks, 4M HCI in diethyl ether was added then concentrated to provide the title compound (1.15 g) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.44 (br s, 3H), 7.26 - 7.17 (m, 4H), 3.55 (dd, 1 H), 3.24 (dd, 1 H), 2.99 (dd, 1 H), 1.36 (s, 3H), 1.18 (s, 3H).Intermediate 3: tert-Butyl ((S)-1-((S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2- oxopyrrolidin-3-yl)carbamate

[0155] To a stirred solution of DBAD (0.53 g, 2.30 mmol) in THF (7.4 mL) was added tri- n-butylphosphine (1.45 mL, 5.81 mmol) at RT for 15 min then Intermediate 1 (0.55 g, 1.16 mmol) was added at 0 °C and the mixture was stirred at RT for 18 h. The mixture waspoured into saturated aqueous NaHCOs and extracted with DCM. The combined organics were washed with water, brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (120 g silica gel, eluting 0-30% EtOAc in hexane) to provide the title compound (0.19 g).1H NMR (300 MHz; DMSO-d6) 5: 8.80 (d, 1 H), 8.18 (dd, 1 H), 7.56 (d, 1 H), 7.27 (d, 1 H), 6.03 (dd, 1 H),4.17 (dd, 1 H), 3.49 (t, 1 H), 3.24 - 3.12 (m, 1 H), 2.21 - 2.13 (m, 1 H), 1.87 (t, 1 H), 1.39 (s, 9H).Intermediate 4: tert- Butyl ((S)-1-((S)-1-(5-(((S)-1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)carbamate

[0156] To a stirred solution of Intermediate 3 (0.19 g, 0.42 mmol) and Intermediate 2 (87 mg, 0.54 mmol) in toluene (3 mL) was added CS2CO3 (0.41 g, 1.26 mmol) and the mixture was degassed with nitrogen for 5 min. RuPhosPdG3 (53 mg, 63 pmol) was added and the mixture was heated at 110 °C for 16 h. The mixture was allowed to cool, filtered through Celite® then concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, eluting 0-50% EtOAc in hexane) to provide the title compound (0.13 g). LCMS (Method F): 519.2 [M+H]+.Intermediate 5: (S)-3-Amino-1-((S)-1-(5-(((S)-1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)pyrrolidin-2-one hydrochloride

[0157] To a stirred solution of Intermediate 4 (0.13 g, 0.25 mmol) in 1 ,4-dioxane (1.7 mL) was added 4 M HCI in 1 ,4-dioxane (0.75 mL) and stirred at RT for 18 h. The mixture was concentrated under reduced pressure and triturated in pentane to provide the title compound (0.12 g).1H NMR (300 MHz; DMSO-d6- D2O shake) 5: 8.14 (d, 1 H), 7.32 - 7.03 (m, 7H), 5.75 (dd, 1 H), 4.14 - 3.94 (m, 2H), 3.73 - 3.64 (m, 1 H), 3.37 - 3.24 (m, 1 H),3.17 (dd, 1 H), 2.74 (dd, 1 H), 2.45 - 2.34 (m, 1 H), 2.08 - 1.82 (m, 1 H), 1.31 (s, 3H), 1.08 (s, 3H).Intermediate 6: l-(tert-Butyl) 4-ethyl 4-(2-oxoethyl)piperidine-1 ,4-dicarboxylate

[0158] To a stirred solution of ethyl A / -Boc-4-allylpiperidine-4-carboxylate (0.30 g, 1.01 mmol, CAS 146603-99-8) in 1 ,4-dioxane (16 mL) and water (4 mL) was added 2 ,6-lutidine (0.24 mL, 2.02 mmol), osmium tetroxide (4% in water, 13 pL, 0.05 mmol) and sodium periodate (0.86 g, 4.04 mmol) and stirred at RT for 2 h. The mixture was diluted with water and extracted with DCM. The combined organics were dried over Na2SC>4, filtered and concentrated under reduced pressure, to provide the title compound (0.29 g).1H NMR (300 MHz; DMSO-d6) 5: 9.62 (s, 1 H), 4.09 (q, 2H), 3.49 (ddd, 2H), 3.18 (t, 2H), 2.77 (d, 2H), 1.97 - 1.80 (m, 2H), 1.51 (ddd, 2H), 1.39 (s, 9H), 1.16 (t, 3H).Intermediate 7: tert- Butyl 2-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1-oxo-2,8- diazaspiro[4.51decane-8-carboxylate

[0159] To a stirred solution of (S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-amine (0.58 g, 2.26 mmol, CAS 1213534-94-1) and Intermediate 6 (0.71 g, 2.37 mmol) in DCE (23.5 mL) was added STAB (2.87 g, 13.5 mmol) and AcOH (0.26 mL, 4.51 mmol) at RT then the mixture was stirred at 50 °C for 18 h, followed by 80 °C for 24 h. The mixture was diluted with DCM then washed with saturated aqueous NaHCOs, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, eluting 0-50% EtOAc in isohexane) to provide the title compound (0.88 g).1H NMR (300 MHz; DMSO-d6) 5: 8.80 (d, 1 H), 8.17 (dd, 1 H), 7.53 (d, 1 H), 6.06 (d, 1 H), 3.80 (dd, 2H), 3.55 - 3.38 (m, 2H), 2.95 (d, 2H), 2.09 - 1.87 (m, 2H), 1.53 (dt, 2H), 1.40 (s, 9H), 1.46 - 1.27 (m, 2H).Intermediate 8: tert-Butyl 2-(1-(5-(((S)-1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1-oxo-2,8-diazaspirof4.51decane-8-carboxylate

[0160] The title compound (0.50 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 7 (0.69 g, 1.41 mmol), Intermediate 2 (0.25 g, 1.55 mmol), CS2CO3 (1.38 g, 4.23 mmol) and RuPhosPdG3 (0.18 g, 0.21 mmol) in toluene (7 mL) at 110 °C for 20 h. Purified by flash chromatography (80 g silica gel, eluting 0-50% EtOAc in hexane). LCMS (Method E): 573.4 [M+H]+.Intermediate 9: tert-Butyl (2-((1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)amino)ethyl)- carbamate

[0161] To a stirred solution of 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1- trifluoromethanesulfonate (6.60 g, 22.9 mmol, CAS 1374038-21-7) in THF (50 mL) was added / V-Boc-ethylenediamine (3.67 g, 22.9 mmol, CAS 57260-73-8) at RT then stirred at 60 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-20% EtOAc in petroleum ether) to provide the title compound (7.0 g). LCMS (Method A): 400.1 [M+H]+.Intermediate 10: tert-Butyl (2-( / V-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2- chloroacetamido)ethyl)carbamate

[0162] To a stirred solution of Intermediate 9 (7.0 g, 15.3 mmol) in THF (50 mL) was added DI PEA (6.40 mL, 45.9 mmol) and chloroacetyl chloride (1.83 mL, 22.9 mmol) at RT then the mixture was stirred at 60 °C for 16 h. The mixture was diluted with water then extracted into EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purifiedby flash chromatography (silica gel, eluting 0-15% EtOAc in petroleum ether) to provide the title compound (4.10 g). LCMS (Method A): 476.3 [M+H]+.Intermediate 11 : A / -(2-aminoethyl)-A / -(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2- chloroacetamide hydrochloride

[0163] To a stirred solution of Intermediate 10 (4.1 g, 6.13 mmol) in diethyl ether (20 mL) was added 2 M HCI in diethyl ether (3.05 mL) and stirred at RT for 6 h. The mixture was concentrated under reduced pressure and triturated in diethyl ether to provide the title compound (3.50 g). LCMS (Method A): 376.2 [M+H]+.Intermediate 12a: tert-Butyl 4-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3- oxopiperazine-1 -carboxylateIntermediate 12b: tert-Butyl 4-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3- oxopiperazine-1 -carboxylate

[0164] To a stirred suspension of Intermediate 11 (3.5 g, 6.47 mmol) in DCM (35 mL) was added triethylamine (2.71 mL, 19.4 mmol) at RT and stirred for 3 h. Boc anhydride (2.12 g, 9.71 mmol) was added and the mixture stirred at RT for 1 h. The mixture was diluted with water then extracted into DCM. The combined 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 0-20% EtOAc in petroleum ether). Chiral purification was carried out by preparative SFC (Chiralpak®-AD- H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% (MeCN with 0.2% 7 M ammonia MeOH in 1 :1 MeCN I MeOH) modifier) to provide Intermediate 12a (0.85 g) as Peak 1 and Intermediate 12b (0.75 g) as Peak 2. Intermediate 12a LCMS (Method A): 440.4 [M+H]+; Intermediate 12b LCMS (Method A): 440.2 [M+H]+.Intermediate 13: tert-Butyl 4-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-oxopiperazine-1-carboxylate

[0165] The title compound (0.24 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 12a (0.35 g, 0.82 mmol), 1 ,1-dimethyl-2,3-dihydro-1 / 7- inden-2-amine hydrochloride (0.17 g, 0.82 mmol, CAS 74413-86-8), CS2CO3 (0.80 g, 2.46 mmol) and RuPhosPdG3 (69 mg, 0.08 mmol) in toluene (10 mL) at 110 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-30% EtOAc in petroleum ether). LCMS (Method J): 517.4 [M-H]’.Intermediate 14: tert-Butyl 4-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-oxopiperazine-1-carboxylate

[0166] The title compound (0.30 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 12b (0.50 g, 1.12 mmol), 1 ,1-dimethyl-2,3-dihydro-1 / 7- inden-2-amine hydrochloride (0.23 g, 1.12 mmol, CAS 74413-86-8), CS2CO3 (1.09 g, 3.35 mmol) and RuPhosPdG3 (94 mg, 0.11 mmol) in toluene (5 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-30% EtOAc in petroleum ether). LCMS (Method A): 519.7 [M+H]+.Intermediate 15: tert-Butyl (2-((1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)amino)ethyl)- (methyl)carbamate

[0167] The title compound (4.0 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (5.0 g, 12.9 mmol, CAS 1374038-21-7) and / V-Boc- / V-methylethylenediamine (5.66 g, 32.5 mmol, CAS 121492-06-6) in THF (50 mL) at 65 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method B): 414.5 [M+H]+.Intermediate 16: A / 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-A / 2-methylethane-1 ,2- diamine

[0168] To a stirred solution of Intermediate 15 (4.0 g, 9.65 mmol) in DCM (40 mL) was added 4 M HCI in 1 ,4-dioxane (18.5 mL) and stirred at RT for 8 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (3.2 g). LCMS (Method B): 314.0 [M+H]+.Intermediate 17: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-methylimidazolidin-2- one

[0169] To a stirred solution of Intermediate 16 (3.2 g, 10.3 mmol) in DCM (40 mL) was added triethylamine (8.13 mL, 58.3 mmol) and triphosgene (2.77 g, 9.33 mmol) at 0 °C then the mixture was stirred at RT for 16 h. The mixture was diluted with water then extracted into DCM. The combined organics were washed with water, brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-40% EtOAc in petroleum ether) then chiral purification was carried out by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier) to provide the title compound (0.90 g) as Peak 1. LCMS (Method B): 340.1 [M+H]+.Intermediate 18: 1-(5-Bromopyridin-2-yl)-A / -(2-((terf-butyldimethylsilyl)oxy)ethyl)-2,2,2- trifluoroethan-1-amine

[0170] The title compound (4.5 g) was prepared in an analogous manner to Intermediate9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (5.62 g, 12.9 mmol, CAS 1374038-21-7) and 2-[terf-butyl(dimethyl)silyl]oxyethanamine (6.70 mL, 32.5 mmol, CAS 101711-55-1) in THF (60 mL) at 65 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method B): 415.0 [M+H]+.Intermediate 19: 2-((1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)amino)ethan-1-ol

[0171] To a stirred solution of Intermediate 18 (4.12 g, 9.68 mmol) in DCM (40 mL) was added 4 M HCI in 1 ,4-dioxane (18.5 mL) and stirred at RT for 8 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (2.5 g). LCMS (Method A): 299.2 [M+H]+.Intermediate 20: 3-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)oxazolidin-2-one

[0172] The title compound (0.80 g) was prepared in an analogous manner to Intermediate 17 using Intermediate 19 (1.95 g, 6.26 mmol), triethylamine (4.36 mL, 31.3 mmol) and triphosgene (1.49 g, 1.39 mmol) in DCM (14 mL) at 0 °C then RT for 16 h. Purified by preparative HPLC (X Bridge C18, 19 x 250 mm x 5 pm, flow rate: 18 mL / min,10 mM aqueous NH4HCO3 with MeCN 35% to 63% over 10 min, held at 63% for 2 min then ramped to 100% over 0.1 min and held for 3.3 min). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 90% CO2 with 10% MeOH modifier) to provide the title compound as Peak 1. LCMS (Method B): 327.1 [M+H]+.Intermediate 21 : tert-Butyl (3-((1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)amino)propyl)- (methyl)carbamate

[0173] The title compound (5.0 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (6.0 g, 14.2 mmol, CAS 1374038-21-7) and terf-butyl / V-(3-aminopropyl)- / V-methylcarbamate (2.68 g, 14.2 mmol, CAS 150349-36-3) in THF (60 mL) at 65 °C for 16 h. Purified by flash chromatography (80 g silica gel, eluting 25% EtOAc in petroleum ether). LCMS (Method A): 428.4 [M+H]+.Intermediate 22: A / 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-A / 3-methylpropane-1 ,3- diamine hydrochloride

[0174] To a stirred solution of Intermediate 21 (5.0 g, 10.6 mmol) in DCM (15 mL) was added 4 M HCI in 1 ,4-dioxane (25 mL) and stirred at RT for 2 h. The mixture wasconcentrated under reduced pressure and triturated in pentane to provide the title compound (3.5 g). LCMS (Method A): 326.1 [M+H]+.Intermediate 23: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-methyltetrahydro- pyrimidin-2(1 / 7)-one

[0175] The title compound (0.42 g) was prepared in an analogous manner to Intermediate 17 using Intermediate 22 (2.50 g, 5.52 mmol), triethylamine (3.84 mL, 27.6 mmol) and triphosgene (1.31 g, 4.41 mmol) in DCM (25 mL) at 0 °C then RT for 2 h. Purified by flash chromatography (40 g silica gel, eluting 20% EtOAc in petroleum ether). Chiral purification by preparative SFC (Chiralpak®-IC, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide the title compound as Peak 1. LCMS (Method A): 352.4 [M+H]+.Intermediate 24: / V-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-((tert- butyldimethylsilyl)oxy)propan-1 -amine

[0176] The title compound (3.5 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (4.3 g, 9.97 mmol, CAS 1374038-21-7) and 3-[terf-butyl(dimethyl)silyl]oxypropan-1 -amine (2.83 g, 15.0 mmol, CAS 115306-75-7) in THF (43 mL) at 65 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method B): 427.4 [M+H]+.Intermediate 25: 3-((1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)amino)propan-1-ol

[0177] To a stirred solution of Intermediate 24 (3.65 g, 7.94 mmol) in DCM (35 mL) was added 4 M HCI in 1 ,4-dioxane (2 mL) and stirred at RT for 8 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (2.9 g). LCMS (Method B): 313.2 [M+H]+.Intermediate 26: 3-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1 ,3-oxazinan-2-one

[0178] Prepared in an analogous manner to Intermediate 17 using Intermediate 25 (1.50 g, 4.50 mmol), triethylamine (3.14 mL, 22.5 mmol) and triphosgene (1.07 g, 3.60 mmol) in DCM (15 mL) at 0 °C then RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-40% EtOAc in petroleum ether). Chiral purification by preparative SFC (LUX i-Amylose, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% MeOH modifier) to provide the title compound (0.24 g) as Peak 2. LCMS (Method B): 341.1 [M+H]+.Intermediate 27: 4-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)morpholine

[0179] The title compound (4.1 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (5.0 g, 12.9 mmol, CAS 1374038-21-7) and morpholine (2.45 g, 25.8 mmol) in THF (50 mL) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-20% EtOAc in petroleum ether). LCMS (Method B): 327.2 [M+H]+.Intermediate 28: 4-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)morpholin-3-one

[0180] To a stirred solution of Intermediate 27 (4.1 g, 11.5 mmol) in MeCN (40 mL) at 60 °C under CO2 was added sodium chlorite (2.60 g, 23.0 mmol) in water (3 mL) dropwise over 30 min and stirred at 60 °C under CO2 for 8 h. The mixture was poured into aqueous sodium sulfite and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Chiral purification was carried out by preparative SFC ((R,R) Whelk-O1 , 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 90% CO2 with 10% MeOH modifier) to provide the title compound (1.2 g) as Peak 2. LCMS (Method A): 341.1 [M+H]+.Intermediate 29: 2-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-8-oxa-2- azaspirof4.51decan-1-one

[0181] The title compound (0.10 g) was prepared in an analogous manner to Intermediate 7 using ethyl 4-(2-oxoethyl)tetrahydro-2 / 7-pyran-4-carboxylate (0.25 g, 0.94 mmol, CAS 1429014-68-5) and (S)-1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (0.25 g, 0.86 mmol, CAS 1391567-85-3), STAB (1.09 g, 5.16 mmol) and AcOH (98 pL, 1.72 mmol) in DCE (8.6 mL) at 50 °C for 18 h, followed by 80 °C for 24 h. Purified by flash chromatography (80 g silica gel, eluting 0-50% EtOAc in isohexane).1H NMR (300 MHz; DMSO-d6) 5: 8.80 (d, 1 H), 8.17 (dd, 1 H), 7.53 (d, 1 H), 6.07 (q, 1 H), 3.84 - 3.76 (m, 2H), 3.54 - 3.38 (m, 4H), 2.14 - 1 .89 (m, 2H), 1.80 - 1.61 (m, 2H), 1.36 (d, 1 H), 1.26 (d, 1 H).Intermediate 30: A / 1-(1-(5-Bromopyridin-2-yl)-2, 2, 2-trifluoroethyl)ethane-1 ,2-diamine

[0182] To a stirred solution of Intermediate 9 (5.0 g, 10.4 mmol) in DCM (50 mL) was added 4 M HCI in 1 ,4-dioxane (50 mL) and stirred at RT for 2 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (4.0 g). LCMS (Method B): 300.3 [M+H]+.Intermediate 31 : A / 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-A / 2-(tetrahvdro-2 / 7- pyran-4-yl)ethane-1 ,2-diamine

[0183] To a stirred solution of tetrahydropyran-4-one (6.38 g, 63.7 mmol, CAS 29943- 42-8) and Intermediate 30 (4.0 g, 11.7 mmol) in DMSO (27.5 mL) and THF (55 mL) wasadded triethylamine (11.5 mL, 82.5 mmol) and stirred at RT for 5 h. To this was added STAB (13.5 g, 63.7 mmol) at 0 °C then the mixture was stirred at RT for 18 h. The mixture was diluted with water then extracted with EtOAc. The organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting 0-2% MeOH in DCM) to provide the title compound (4.0 g). LCMS (Method B): 382.3 [M+H]+.Intermediate 32: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-(tetrahvdro-2 / 7-pyran- 4-yl)imidazolidin-2-one

[0184] Prepared in an analogous manner to Intermediate 17 using Intermediate 31 (1.50 g, 3.77 mmol), triethylamine (1.58 mL, 11.3 mmol) and triphosgene (0.89 g, 3.01 mmol) in DCM (8 mL) at 0 °C then RT for 1 h. Purified by flash chromatography (silica gel, eluting 0-70% EtOAc in petroleum ether). Chiral purification by preparative SFC (LUX i- Amylose, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide the title compound (0.51 g) as Peak 1. LCMS (Method B): 408.4 [M+H]+.Intermediate 33: 5-Bromo-2-(2,2,2-trifluoro-1-(pyrrolidin-1-yl)ethyl)pyridine

[0185] The title compound (3.5 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (5.0 g, 11.6 mmol, CAS 1374038-21-7) and pyrrolidine (1.91 g, 23.2 mmol) in THF (50 mL) at 60 °C for 6 h. Purified by flash chromatography (silica gel, eluting 0-15% EtOAc in petroleum ether). LCMS (Method B): 309.2 [M+H]+.Intermediate 34: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)pyrrolidin-2-one

[0186] Prepared in an analogous manner to Intermediate 28 using Intermediate 33 (3.18 g, 10.2 mmol) in MeCN (31 mL) and sodium chlorite (0.92 g, 10.2 mmol) in water (7 mL) dropwise at 60 °C over 30 min and stirred at 80 °C under CO2 for 6 h. Purified by flash chromatography (silica gel, 0-25% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 110 g / min, 75% CO2 with 25% MeOH modifier) to provide the title compound (0.54 g) as Peak 2. LCMS (Method B): 323.2 [M+H]+.Intermediate 35: tert-Butyl ((3S)-1-((1 S)-1-(5-((5-chloro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)carbamate

[0187] The title compound (57 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 3 (0.15 g, 0.33 mmol), 5-chloro-2,3-dihydro-1 / 7-inden- 2-amine hydrochloride (80 mg, 0.39 mmol, CAS 73536-86-4), CS2CO3 (0.32 g, 0.98 mmol) and RuPhosPdG3 (42 mg, 0.15 mmol) in toluene (1.1 mL) at 110 °C for 20 h. Purified byflash chromatography (25 g silica gel, eluting 0-40% EtOAc in hexane). LCMS (Method F): 525.2 [M+H]+.Intermediate 36: (3S)-3-Amino-1-((1 S)-1-(5-((5-chloro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)pyrrolidin-2-one hydrochloride

[0188] To a stirred solution of Intermediate 35 (66 mg, 90 pmol) in 1 ,4-dioxane (0.6 mL) was added 2 M HCI in 1 ,4-dioxane (0.54 mL) and stirred at RT for 18 h. The mixture was concentrated under reduced pressure and triturated in pentane to provide the title compound (55 mg). LCMS (Method F): 425.1 [M+H]+.Intermediate 37: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one hydrochloride

[0189] To a stirred solution of Intermediate 12b (1.40 g, 2.59 mmol) in DCM (13 mL) was added 4 M HCI in 1 ,4-dioxane (13.5 mL) and stirred at RT for 2 h. The mixture was concentrated under reduced pressure and triturated in diethyl ether to provide the title compound (1.1 g). LCMS (Method B): 340.4 [M+H]+.Intermediate 38: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-4-(tetrahvdro-2 / 7-pyran- 4-yl)piperazin-2-one

[0190] Prepared in an analogous manner to Intermediate 31 using tetrahydropyran-4- one (0.65 g, 6.47 mmol, CAS 29943-42-8), Intermediate 37 (0.92 g, 1.62 mmol) and triethylamine (1.13 mL, 8.08 mmol) in DMSO (10 mL) and THF (20 mL) at RT for 3 h, then STAB (1.37 g, 6.47 mmol) at RT for 18 h. Purified by flash chromatography (silica gel, eluting 0-70% EtOAc in petroleum ether). Chiral purification by preparative SFC (LUX i- Amylose, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% 1 :1 MeOH I MeCN modifier) to provide the title compound (0.30 g) as Peak 2. LCMS (Method B): 424.4 [M+H]+.Intermediate 39: Benzyl (3-((2-methyl-2 / 7-1 ,2,3-triazol-4-yl)amino)propyl)carbamate

[0191] Prepared in an analogous manner to Intermediate 31 using 3- [(benzyloxycarbonyl)amino]propionaldehyde (6.0 g, 28.1 mmol, CAS 65564-05-8), 2- methyltriazol-4-amine (0.92 g, 1.62 mmol, CAS 936940-63-5) and AcOH (4.3 mL, 68.2 mmol) in DCE (0.10 L) at RT for 4 h, then STAB (11.9 g, 56.2 mmol) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 30-60% EtOAc in hexane) to provide the title compound (5.0 g). LCMS (Method A): 290.2 [M+H]+.Intermediate 40: A / 1-(2-Methyl-2 / 7-1 ,2,3-triazol-4-yl)propane-1 ,3-diamine

[0192] To a stirred solution of Intermediate 39 (7.14 g, 17.3 mmol) in MeOH (0.10 L), was added palladium on carbon (10%, 4.0 g) and the mixture stirred under a hydrogen atmosphere for 4 h. The mixture was filtered through Celite®, washed with MeOH and thefiltrate was concentrated under reduced pressure to provide the title compound (1.50 g).1H NMR (400 MHz; DMSO-d6) 5: 6.89 (s, 1 H), 5.46 (br s, 1 H) 3.88 (s, 3H), 3.07 - 3.04 (m, 2H), 2.61 - 2.50 (m, 2H), 1 .60 - 1 .54 (m, 2H) - NH2 observed as very broad swell between 2 and 3 ppm.Intermediate 41 : A / 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-A / 3-(2-methyl-2 / 7-1,2,3- triazol-4-yl)propane-1 ,3-diamine

[0193] The title compound (1.5 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (3.5 g, 8.30 mmol, CAS 1374038-21-7) and Intermediate 40 (1.29 g, 8.30 mmol) in THF (40 mL) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 10-50% EtOAc in petroleum ether). LCMS (Method B): 395.4 [M+H]+.Intermediate 42: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-(2-methyl-2 / 7-1 ,2,3- triazol-4-yl)tetrahvdropyrimidin-2(1 / 7)-one

[0194] Prepared in an analogous manner to Intermediate 17 using Intermediate 41 (1.60 g, 4.07 mmol), triethylamine (0.13 L, 0.90 mol) and triphosgene (42.7 g, 0.14 mol) in DCM (35 mL) at 0 °C then RT for 2 h. Purified by flash chromatography (silica gel, eluting 10-50% EtOAc in isohexane). Chiral purification by preparative SFC (LUX i-Amylose, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 90% CO2 with 10% (10 mM NH4HCO3 in MeOH) modifier) to provide the title compound (0.45 g) as Peak 1. LCMS (Method A): 421.2 [M+H]+.Intermediate 43: Methyl 4-allyltetrahvdro-2 / 7-thiopyran-4-carboxylate

[0195] To a stirred solution of methyl tetrahydrothiopyran-4-carboxylate (1.0 g, 6.24 mmol, CAS 128094-82-6) in THF (31 mL) at -60 °C was added LDA (2 M in THF, 3.43 mL, 6.86 mmol) and stirred for 30 min before addition of allyl bromide (0.59 mL, 6.87 mmol) slowly keeping the temp below -55 °C then the mixture was stirred at RT for 10 min. The mixture was poured into saturated aqueous NH4CI and extracted with EtOAc. The organics were washed with 10% H2SO4, water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, eluting 0-20% EtOAc in cyclohexane) to provide the title compound (1.03 g).1H NMR (300 MHz; CDCI3) 6: 5.72 - 5.58 (m, 1 H), 5.13 - 4.99 (m, 2H), 3.72 (s, 3H), 2.74 - 2.66 (m, 2H), 2.58 - 2.49 (m, 2H), 2.45 - 2.34 (m, 2H), 2.26 (dt, 2H), 1.63 (ddd, 2H).Intermediate 44: Methyl 4-allyltetrahvdro-2 / 7-thiopyran-4-carboxylate 1 ,1-dioxide

[0196] To a stirred solution of Intermediate 43 (0.40 g, 2.00 mmol) in MeOH (9.6 mL) and water (10 mL) was added Oxone® (1.82 g, 12.0 mmol) and the mixture was stirred at RT for 18 h. The mixture was diluted with water and extracted with EtOAc. The organicswere washed with water, brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to provide the title compound (0.45 g).1H NMR (300 MHz; CDCh) 6: 5.75 - 5.54 (m, 1 H), 5.22 - 5.05 (m, 2H), 3.78 (s, 3H), 3.11 - 2.92 (m, 4H), 2.59 - 2.47 (m, 2H), 2.35 (dt, 2H), 2.16 - 2.03 (m, 2H).Intermediate 45: Methyl 4-(2-oxoethyl)tetrahvdro-2 / 7-thiopyran-4-carboxylate 1 ,1-dioxide

[0197] Prepared in an analogous manner to Intermediate 6 using Intermediate 44 (0.30 g, 1.16 mmol), 2,6-lutidine (0.27 mL, 2.33 mmol), osmium tetroxide (4% in water, 0.37 mL, 0.06 mmol) and sodium periodate (0.99 g, 4.65 mmol) in 1 ,4-dioxane (19 mL) and water (4.5 mL) at RT for 16 h. Purified by flash chromatography (40 g silica gel, 20-100% EtOAc in cyclohexane) to provide the title compound (0.15 g).1H NMR (300 MHz; CDCh) 6: 9.70 (t, 1 H), 3.79 (s, 3H), 3.39 - 3.25 (m, 2H), 3.01 - 2.89 (m, 2H), 2.83 (d, 2H), 2.65 - 2.50 (m, 2H), 2.27 - 2.09 (m, 2H).Intermediate 46: 2-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-8-thia-2- azaspirof4.51decan-1-one 8,8-dioxide

[0198] The title compound (0.11 g) was prepared in an analogous manner to Intermediate 7 using Intermediate 45 (0.20 g, 0.85 mmol) and (S)-1-(5-bromopyridin-2- yl)-2,2,2-trifluoroethan-1-amine hydrochloride (0.25 g, 0.86 mmol, CAS 1391567-85-3), STAB (1.09 g, 5.12 mmol) and AcOH (98 pL, 1.71 mmol) in DCE (4.3 mL) at 50 °C for 18 h, followed by 80 °C for 24 h. Purified by reverse-phase chromatography (C18, eluting 60- 70% MeCN in pH 7 buffer).1H NMR (300 MHz; DMSO-d6) 5: 8.80 (dd, 1 H), 8.18 (dd, 1 H), 7.56 (d, 1 H), 6.09 (q, 1 H), 3.46 (d, 2H), 3.27 - 3.05 (m, 4H), 2.19 - 2.00 (m, 4H), 1.98 - 1.77 (m, 2H).Intermediate 47: 9-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-oxa-9- azaspirof5.51undecane

[0199] The title compound (3.5 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (5.0 g, 12.0 mmol, CAS 1374038-21-7) and 3-oxa-9-azaspiro[5.5]undecane (2.79 g, 18.0 mmol, CAS 311-21-7) in THF (50 mL) at 65 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method B): 395.4 [M+H]+.Intermediate 48: 9-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-oxa-9- azaspirof5.51undecan-8-one

[0200] Prepared in an analogous manner to Intermediate 28 using Intermediate 47 (2.68 g, 6.18 mmol) in 1 ,4-dioxane (30 mL) and sodium chlorite (1.68 g, 18.6 mmol) in water (11 mL) dropwise at 60 °C over 30 min and stirred at 65 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane). Chiral purificationby preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier) to provide the title compound (0.55 g) as Peak 2. LCMS (Method B): 409.2 [M+H]+. in-2-yl)-2,2,2-trifluoroethyl)-9-oxa-2-

[0201] The title compound (4.5 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (5.0 g, 12.0 mmol, CAS 1374038-21-7) and 9-oxa-2-azaspiro[5.5]undecane (3.16 g, 20.4 mmol, CAS 57289-77-7) in THF (50 mL) at 65 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method B): 395.4 [M+H]+.Intermediate 50: 2-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-9-oxa-2- i-3-oneIntermediate 51 : 2-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-9-oxa-2- azaspiro[5.5lundecan-1-one

[0202] Prepared in an analogous manner to Intermediate 28 using Intermediate 49 (4.0 g, 9.26 mmol) in 1 ,4-dioxane (44 mL) and sodium chlorite (2.51 g, 27.8 mmol) in water (18 mL) dropwise at 60 °C over 30 min and stirred at 65 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane) to give rac-lntermediate 50 (1.57 g) and rac-lntermediate 51 (1.22 g). Chiral purification of rac-lntermediate 50 was carried out by preparative SFC (LUX i-Amylose, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% I PA modifier) to provide Intermediate 50 (0.55 g) as Peak 2. LCMS (Method B): 409.2 [M+H]+. Chiral purification of rac-lntermediate 51 was carried out by preparative SFC (Chiralpak®-IK, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier) to provide Intermediate 51 (0.35 g) as Peak 2. LCMS (Method B): 409.4 [M+H]+.Intermediate 52: terf-Butyl ((S)-1-((S)-1-(5-aminopyridin-2-yl)-2,2,2-trifluoroethyl)-2- oxopvrrolidin-3-vl)carbamate

[0203] To a stirred solution of Intermediate 3 (0.55 g, 1.00 mmol) in ethanol (5.5 mL) and water (1 .4 mL) was added sodium azide (0.24 g, 3.69 mmol), sodium L-ascorbate (20 mg, 0.10 mmol), copper (I) iodide (40 mg, 0.21 mmol) and (F?,F?)-A / ,A / '-dimethyl-1 ,2- cyclohexanediamine (40 mg, 0.28 mmol) and the mixture was degassed with nitrogen for 5 min. The mixture was heated at 70 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (80 g silica gel, eluting 0-10% MeOH in DCM) to provide the titlecompound (0.13 g).1H N MR (300 MHz; CDCh) 6: 8.15 (d, 1 H), 7.22 (d, 1 H), 7.04 (dd, 1 H), 5.83 (q, 1 H), 5.13 (s, 1 H), 4.26 (s, 1H), 3.72 (t, 1 H), 3.54 - 3.25 (m, 2H), 2.65 (s, 1 H), 2.13 - 1.79 (m, 2H), 1.47 (d, 9H).Intermediate 53: 7-Bromo-6-chloro-1 / 7-indene

[0204] To a stirred solution of 4-bromo-5-chloro-2,3-dihydro-1 / 7-inden-1-ol (1.93 g, 7.81 mmol, CAS 2153981-78-1) in toluene (26 mL) at 0 °C was added pTSA (0.30 g, 1.56 mmol) then the mixture was stirred at 80 °C for 1 h. The mixture was cooled then diluted with water and extracted with TBDME. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting in petroleum ether) to provide the title compound (1.75 g).1H NMR (300 MHz; CDCh) 6: 7.38 (d, 1 H), 7.26 (d, 1 H), 6.88 (dt, 1 H), 6.62 (dt, 1 H), 3.43 (s, 2H).Intermediate 54: 4-Bromo-5-chloro-1 ,3-dihydro-2 / 7-inden-2-one

[0205] Intermediate 53 (1.75 g, 7.60 mmol) was added to a stirred solution of formic acid (5 mL) and hydrogen peroxide (30% aqueous, 0.93 mL, 10.6 mmol) at 50 °C then the mixture was stirred at 60 °C for 16 h. Sodium bisulfite (0.32 g) was added and stirred at 55 °C for 1 h. The mixture was concentrated then diluted with water and extracted with DCM. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in toluene (35 mL) and pTSA (0.29 g, 1.52 mmol) added and stirred at 80 °C for 2 h. The mixture was diluted with water and extracted into EtOAc. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluting in 0-90% EtOAc in hexane) to provide the title compound (0.79 g).1H NMR (300 MHz; CDCh) 6: 7.38 (d, 1 H), 7.20 (d, 1 H), 3.65 (s, 2H), 3.59 (s, 2H).Intermediate 55: 5-Chloro-4-cvclopropyl-1 ,3-dihydro-2 / 7-inden-2-one

[0206] To a stirred solution of Intermediate 54 (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)Ch (64 mg, 0.10 mmol) and K3PO4 (0.55 g, 3.00 mmol) were added then the mixture was heated at 90 °C for 16 h. The mixture was poured into water and extracted with EtOAc. The organic layer washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by automated column chromatography (silica gel 80 g, eluting 0-20% EtOAc in cyclohexane) to provide the title compound (0.65 g).1H NMR (300 MHz; DMSO-d6) 5: 7.32 (d, 1 H), 7.20 (d, 1 H), 3.65 (s, 2H), 3.53 (s, 2H), 1.88 - 1.74 (m, 1 H), 1.05 - 0.88 (m, 2H), 0.72 - 0.65 (m, 2H).Intermediate 56: tert- Butyl ((3S)-1-((1 S)-1-(5-((5-chloro-4-cvclopropyl-2,3-dihvdro-1 / 7- inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)carbamate

[0207] To a stirred solution of Intermediate 55 (0.19 g, 0.92 mmol) and Intermediate 52 (0.18 g, 0.46 mmol) in ethanol (10 mL) was added AcOH (14 mg, 0.23 mmol) then the mixture was stirred at 50 °C for 3 h. Sodium cyanoborohydride (0.12 g, 1.83 mmol) was added and stirred at RT for 24 h. The mixture was diluted 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 automated column chromatography (silica gel 40 g, eluting 0-100% EtOAc in cyclohexane) to provide the title compound (40 mg). LCMS (Method F): 565.2 [M+H]+.Intermediate 57: (3S)-3-Amino-1-((1 S)-1-(5-((5-chloro-4-cvclopropyl-2,3-dihvdro-1 / 7- inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)pyrrolidin-2-one

[0208] A solution of Intermediate 56 (38 mg, 47 pmol) in TFA (35 pL) and DCM (0.5 mL) was stirred at RT for 6 h. The mixture was poured into saturated aqueous NaHCCh and extracted with DCM. The combined organics were washed with water, brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to provide the title compound (30 mg). LCMS (Method F): 465.1 [M+H]+.Intermediate 58: Benzyl (3-((1-methyl-1 / 7-pyrazol-4-yl)amino)propyl)carbamate

[0209] Prepared in an analogous manner to Intermediate 31 using 3- [(benzyloxycarbonyl)amino]propionaldehyde (3.0 g, 14.5 mmol, CAS 65564-05-8), 1- methylpyrazol-4-amine (1.55 g, 15.9 mmol, CAS 69843-13-6) and AcOH (2.2 mL, 35.2 mmol) in DCE (0.20 L) at RT for 1 h, then STAB (6.14 g, 29.0 mmol) at RT for 16 h. Repeated twice and combined and purified by flash chromatography (silica gel, eluting 2- 10% MeOH in DCM) to provide the title compound (6.0 g). LCMS (Method B): 289.2 [M+H]+.Intermediate 59: A / 1-(1-Methyl-1 / 7-pyrazol-4-yl)propane-1 ,3-diamine

[0210] To a stirred solution of Intermediate 58 (3.50 g, 6.92 mmol) in MeOH (68 mL), was added palladium on carbon (10%, 3.0 g) and the mixture stirred under a hydrogen atmosphere for 4 h. The mixture was filtered through Celite®, washed with MeOH and the filtrate was concentrated under reduced pressure. The crude product purified by flash chromatography (silica gel, eluting 10-12% MeOH in DCM) to provide the title compound (1.0 g). LCMS (Method B): 155.1 [M+H]+.Intermediate 60: A / 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-A / 3-(1-methyl-1 / 7- pyrazol-4-yl)propane-1 ,3-diamine

[0211] The title compound (0.84 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (3.5 g, 8.39 mmol, CAS 1374038-21-7) and Intermediate 59 (2.43 g, 12.6 mmol) in THF (30 mL) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 2-10% MeOH in EtOAc). LCMS (Method B): 394.3 [M+H]+.Intermediate 61 : 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-(1-methyl-1 / 7-pyrazol- 4-yl)tetrahydropyrimidin-2(1 / 7)-one

[0212] Prepared in an analogous manner to Intermediate 17 using Intermediate 60 (0.28 g, 0.66 mmol), triethylamine (0.54 mL, 3.85 mmol) and triphosgene (0.18 g, 0.62 mmol) in DCM (10 mL) at 0 °C then RT for 1 h. Purified by flash chromatography (silica gel, eluting 50-60% EtOAc in hexane). Chiral purification by preparative SFC (( , ) Whelk- 01 , 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% MeOH modifier) to provide the title compound (0.35 g) as Peak 2. LCMS (Method B): 420.2 [M+H]+.1 ,1-dioxide

[0213] The title compound (2.1 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (2.5 g, 5.73 mmol, CAS 1374038-21-7) and 4-((3-aminopropyl)amino)tetrahydro-2 / 7-thiopyran 1 ,1-dioxide (1.66 g, 8.03 mmol, CAS 1178854-73-3) with DIPEA (3.0 ml, 17.2 mmol) in MeCN (41 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 2-10% MeOH in EtOAc). LCMS (Method A): 446.4 [M+H]+.Intermediate 63: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-(1 ,1-dioxidotetrahydro- 2 / 7-thiopyran-4-yl)tetrahydropyrimidin-2(1 / 7)-one

[0214] Prepared in an analogous manner to Intermediate 17 using Intermediate 62 (0.48 g, 1.07 mmol), triethylamine (0.87 mL, 6.21 mmol) and triphosgene (0.29 g, 0.99 mmol) in DCM (20 mL) at 0 °C then RT for 1 h. Repeated twice and combined to purify by flash chromatography (silica gel, eluting 60-70% EtOAc in isohexane). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide the title compound (0.40 g) as Peak 1. LCMS (Method B): 472.3 [M+H]+. n-3-yl)-2,2,2-•-2 / 7-thiopyran 1 ,1-dioxide

[0215] The title compound (2.1 g) was prepared in an analogous manner to Intermediate 9 using [1-(6-bromo-3-pyridyl)-2,2,2-trifluoro-ethyl] trifluoromethanesulfonate (2.5 g, 5.05mmol, CAS 2565622-62-8) and 4-((3-aminopropyl)amino)tetrahydro-2 / 7-thiopyran 1 ,1- dioxide (1.44 g, 6.57 mmol, CAS 1178854-73-3) with DIPEA (2.64 ml, 15.2 mmol) in MeCN (41 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-5% MeOH in DCM). LCMS (Method B): 446.3 [M+H]+.Intermediate 65: 1-(1-(6-Bromopyridin-3-yl)-2,2,2-trifluoroethyl)-3-(1,1-dioxidotetrahydro- 2 / 7-thiopyran-4-yl)tetrahydropyrimidin-2(1 / 7)-one

[0216] Prepared in an analogous manner to Intermediate 17 using Intermediate 64 (2.1 g, 3.78 mmol), triethylamine (3.06 mL, 21.9 mmol) and triphosgene (0.95 g, 3.51 mmol) in DCM (60 mL) at 0 °C then RT for 1 h. Repeated twice and combined to purify by flash chromatography (silica gel, eluting 60-70% EtOAc in isohexane). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% MeOH modifier) to provide the title compound (0.40 g) as Peak 1. LCMS (Method B): 472.3 [M+H]+.Intermediate 66: terf-Butyl 2-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-1-oxo-2,8->-8-i

[0217] The title compound (0.75 g) was prepared in an analogous manner to Intermediate 7 using Intermediate 6 (0.44 g, 1.47 mmol) and [1-(6-bromo-3-pyridyl)- 2,2,2-trifluoro-ethyl] trifluoromethanesulfonate (0.50 g, 1.47 mmol, CAS 2565622-62-8), STAB (1.97 g, 8.82 mmol) and AcOH (0.17 mL, 2.94 mmol) in DCE (9.8 mL) at 80 °C for 24 h. Purified by flash chromatography (40 g silica gel, eluting 0-60% EtOAc in isohexane). LCMS (Method E): 394.9 [M-Boc+H]+.Intermediate 67: terf-Butyl 2-(1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-

[0218] The title compound (0.20 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 66 (0.30 g, 0.61 mmol), 5-chloro-4-fluoro-2,3-dihydro- 1 / 7-inden-2-amine (0.13 g, 0.67 mmol, CAS 1934610-84-0), CS2CO3 (0.60 g, 1.84 mmol) and RuPhosPdG3 (77 mg, 0.15 mmol) in toluene (6 mL) at 90 °C for 12 h. Purified by flash chromatography (40 g silica gel, eluting 0-50% EtOAc in hexane). LCMS (Method F): 597.3 [M+H]+.Intermediate 68: 2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5ldecan-1-one

[0219] To a stirred solution of Intermediate 67 (0.19 g, 0.28 mmol) in 1 ,4-dioxane (3.3 mL) was added 4 M HCI in 1 ,4-dioxane (0.8 mL) and stirred at RT for 6 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer waswashed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to provide the title compound (0.17 g). LCMS (Method F): 497.0 [M+H]+.Intermediate 69: tert-Butyl 2-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,9- diazaspirof5.51undecane-9-carboxylate

[0220] The title compound (4.5 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (5.0 g, 12.0 mmol, CAS 1374038-21-7) and terf-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate (4.57 g, 18.0 mmol, CAS 1023595-19-8) with triethylamine (5.01 mL, 36.0 mmol) in THF (50 mL) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-10% EtOAc in petroleum ether). LCMS (Method B): 494.3 [M+H]+.Intermediate 70: tert-Butyl 2-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1-oxo-2,9- diazaspirof5.51undecane-9-carboxylate

[0221] Prepared in an analogous manner to Intermediate 28 using Intermediate 69 (4.5 g, 10.1 mmol) in MeCN (25 mL) and sodium chlorite (2.75 g, 27.8 mmol) in water (3.4 mL) dropwise at 60 °C over 30 min and stirred at 65 °C under CO2 for 4 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane) to provide the title compound (2.3 g). LCMS (Method B): 506.3 [M+H]+.Intermediate 71 : 2-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,9- diazaspirof5.51undecan-1-one

[0222] To a stirred solution of Intermediate 70 (2.30 g, 3.54 mmol) in DCM (1 .2 mL) was added 4 M HCI in 1 ,4-dioxane (25 mL) and stirred at RT for 4 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (1.8 g). LCMS (Method F): 406.2 [M+H]+.Intermediate 72: 2-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-9-(cvclopropylmethyl)- 2,9-diazaspirof5.51undecan-1-one

[0223] Prepared in an analogous manner to Intermediate 31 using Intermediate 71 (1.20 g, 2.95 mmol), cyclopropanecarbaldehyde (0.31 g, 4.43 mmol) and AcOH (0.19 mL, 2.95 mmol) in MeOH (30 mL) at RT for 1 h, then sodium cyanoborohydride (0.56 g, 8.86 mmol) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 1-3% MeOH in DCM). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% (10 mM NH4HCO3 in MeOH) modifier) to provide the title compound (0.18 g) as Peak 2. LCMS (Method I): 460.4 [M+H]+.-2-oxa-6-

[0224] The title compound (0.54 g) was prepared in an analogous manner toIntermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (0.60 g, 1.55 mmol, CAS 1374038-21-7) and 2-oxa-6- azaspiro[3.4]octane (0.21 g, 1.86 mmol, CAS 220290-68-6) with DI PEA (0.40 mL, 2.32 mmol) in MeCN (7.7 mL) at RT for 2 h. LCMS (Method F): 352.8 [M+H]+.Intermediate 74: 6-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxa-6- i-5-oneIntermediate 75: 6-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxa-6- azaspiro[3.41octan-7-one

[0225] Prepared in an analogous manner to Intermediate 28 using Intermediate 73 (0.54 g, 1.54 mmol), sodium chlorite (0.28 g, 3.08 mmol) in MeCN (7.7 mL) at 60 °C under CO2 for 4 h. Purified by flash chromatography (silica gel, 3-47% EtOAc in cyclohexane) to provide Intermediate 74 (0.20 g) and Intermediate 75 (77 mg). Intermediate 74:1H NMR (400 MHz; DMSO-d6) 5: 8.79 (d, 1 H), 8.18 (dd, 1 H), 7.57 (d, 1 H), 6.12 (q, 1 H), 4.65 (dd, 2H), 4.53 (d, 1 H), 4.43 (d, 1 H), 3.47 - 3.35 (m, 2H), 2.49 - 2.30 (m, 2H). Intermediate 75:1H NMR (400 MHz; DMSO-d6) 5: 8.82 (dd, 1 H), 8.19 (dd, 1 H), 7.56 (d, 1 H), 6.10 (q, 1 H), 4.58 (d,1 H), 4.50 (d, 2H), 4.41 (d, 1 H), 3.79 (s, 2H), 2.85 - 2.69 (m, 2H).Intermediate 76: 7-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,7- diazaspiro[4.4]nonan-3-one

[0226] The title compound (0.80 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (2.36 g, 5.35 mmol, CAS 1374038-21-7) and 2,7- diazaspiro[4.4]nonan-3-one (0.50 g, 3.57 mmol, CAS 1226550-00-0) with triethylamine (1.49 mL, 10.7 mmol) in THF (25 mL) at 70 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method B): 380.3 [M+H]+.Intermediate 77: 2-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,7- diazaspiro[4.4lnonane-1 ,8-dione

[0227] Prepared in an analogous manner to Intermediate 28 using Intermediate 76 (2.90 g, 6.60 mmol) in MeCN (30 mL) and sodium chlorite (1.79 g, 19.8 mmol) in water (2.5 mL) dropwise at 60 °C over 30 min and stirred at 60 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane) to provide the title compound (1.1 g). LCMS (Method B): 394.2 [M+H]+.Intermediate 78a: tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3,6-dioxo-2,7- diazaspiro[4.41nonane-2-carboxylateIntermediate 78b: tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3,6-dioxo-2,7- diazaspiro[4.41nonane-2-carboxylate

[0228] Prepared in an analogous manner to Intermediate 12a / 12b using Intermediate 77 (2.1 g, 4.55 mmol), Boc anhydride (0.99 g, 4.55 mmol), triethylamine (0.63 mL, 4.55 mmol) and DMAP (0.56 g, 4.55 mmol) in DCM (30 mL) at RT for 2 h. Purified by flash chromatography (silica gel, eluting 0-30% EtOAc in petroleum ether). Chiral purification by preparative SFC (Chiralpak®-IG, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 95% CO2 with 5% MeOH modifier) to provide Intermediate 78a (0.40 g) as Peak 1 ; and final peak further purified by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% MeOH modifier) to provide Intermediate 78b (0.42 g) as Peak 3. Intermediate 78a LCMS (Method I): 492.2 [M-H]’; Intermediate 78b LCMS (Method I): 492.2 [M-H]’.Intermediate 79a: tert-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3,6-dioxo-2,7-diazaspirof4.41nonane-2- carboxylate

[0229] The title compound (86 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 78a (0.20 g, 0.40 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.11 g, 0.48 mmol, CAS 2740843-37-0), CS2CO3 (0.39 g, 1.19 mmol) and RuPhosPdG3 (33 mg, 0.04 mmol) in toluene (10 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-70% EtOAc in hexane). LCMS (Method B): 597.6 [M+H]+.Intermediate 79b: tert-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3,6-dioxo-2,7-diazaspirof4.41nonane-2- carboxylate

[0230] The title compound (0.13 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 78b (0.25 g, 0.50 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.13 g, 0.60 mmol, CAS 2740843-37-0), CS2CO3 (0.49 g, 1.51 mmol) and RuPhosPdG3 (42 mg, 0.05 mmol) in toluene (8 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-70% EtOAc in hexane). LCMS (Method I): 597.3 [M+H]+.Intermediate 80: tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,7- diazaspirof4.41nonane-2-carboxylate

[0231] The title compound (1.04 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1-trifluoromethanesulfonate (1.0 g, 2.58 mmol, CAS 1374038-21-7) and terf-butyl 2,7- diazaspiro[4.4]nonane-2-carboxylate (0.70 g, 3.09 mmol, CAS 236406-49-8) with DI PEA (0.90 mL, 5.17 mmol) in MeCN (13 mL) at RT for 16 h. Purified by flash chromatography (40 g silica gel, eluting 0-35% EtOAc in petroleum ether). LCMS (Method F): 465.8 [M+H]+.Intermediate 81 : tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-6-oxo-2,7- diazaspirof4.41nonane-2-carboxylateIntermediate 82: tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-8-oxo-2,7- diazaspirof4.41nonane-2-carboxylate

[0232] Prepared in an analogous manner to Intermediate 28 using Intermediate 80 (2.04 g, 3.95 mmol), sodium chlorite (0.71 g, 7.90 mmol) in MeCN (13 mL), 1 ,4-dioxane (6.5 mL) and water (6.5 mL) at 60 °C under CO2 for 72 h. Purified by flash chromatography (silica gel, 0-30% EtOAc in cyclohexane) to provide Intermediate 81 (1.14 g) and Intermediate 82 (0.46 g). Intermediate 81 :1H NMR (300 MHz; DMSO-d6) 5: 8.84 - 8.75 (m, 1 H), 8.18 (dd, 1 H), 7.56 (dd, 1 H), 6.08 (q, 1 H), 3.57 - 3.33 (m, 4H), 3.32 - 3.11 (m, 1 H), 2.20 - 1 .68 (m, 5H), 1.41 - 1.36 (m, 9H). Intermediate 82:1H NMR (300 MHz; DMSO- d6) 5: 8.80 (dd, 1 H), 8.18 (dd, 1 H), 7.55 (d, 1 H), 6.08 (q, 1 H), 3.56 - 3.33 (m, 4H), 3.30 - 3.19 (m, 2H), 2.15 - 1.66 (m, 4H), 1.40 (s, 9H).Intermediate 83: tert-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-6-oxo-2,7-diazaspirof4.41nonane-2-carboxylate

[0233] The title compound (0.17 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 81 (0.51 g, 1.01 mmol), 5-chloro-4-fluoro-2,3-dihydro- 1 / 7-inden-2-amine (0.24 g, 1.18 mmol, CAS 1934610-84-0), CS2CO3 (0.99 g, 3.03 mmol) and RuPhosPdG3 (0.13 g, 0.15 mmol) in toluene (10 mL) at 90 °C for 12 h. Purified by flash chromatography (40 g silica gel, eluting 0-100% EtOAc in cyclohexane). LCMS (Method F): 583.2 [M+H]+.Intermediate 84: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,7-diazaspirof4.41nonan-1-one

[0234] To a stirred solution of Intermediate 83 (0.17 g, 0.27 mmol) in DCM (2.2 mL) was added 4 M HCI in 1 ,4-dioxane (0.7 mL) and stirred at RT for 6 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.14 g). LCMS (Method G): 483.2 [M+H]+.Intermediate 85: tert-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-8-oxo-2,7-diazaspirof4.41nonane-2-carboxylate

[0235] The title compound (0.10 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 82 (0.25 g, 0.47 mmol), 5-chloro-4-fluoro-2,3-dihydro- 1 / 7-inden-2-amine (87 mg, 0.47 mmol, CAS 1934610-84-0), CS2CO3 (0.46 g, 1.41 mmol) and BrettPhosPdG3 (85 mg, 0.09 mmol) in toluene (3.1 mL) at 90 °C for 3 h. Purified by flash chromatography (25 g silica gel, eluting 0-70% EtOAc in cyclohexane). LCMS (Method N): 583.3 [M+H]+.Intermediate 86: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,7-diazaspirof4.41nonan-3-one

[0236] To a stirred solution of Intermediate 85 (0.10 g, 0.14 mmol) in DCM (0.9 mL) was added 4 M HCI in 1 ,4-dioxane (0.35 mL) and stirred at RT for 6 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (88 mg). LCMS (Method N): 483.0 [M+H]+.Intermediate 87: 8-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,8- diazaspirof4.51decan-3-one

[0237] The title compound (4.08 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (9.18 g, 22.7 mmol, CAS 1374038-21-7) and 2,8- diazaspiro[4.5]decan-3-one (2.50 g, 16.2 mmol, CAS 561314-57-6) with triethylamine (4.52 mL, 32.4 mmol) in THF (50 mL) at 60 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 70-80% EtOAc in isohexane). LCMS (Method A): 394.3 [M+H]+.Intermediate 88: 8-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,8- diazaspirof4.51decane-3, 7-dione

[0238] Prepared in an analogous manner to Intermediate 28 using Intermediate 87 (4.08 g, 10.1 mmol) in MeCN (50 mL) and sodium chlorite (3.65 g, 40.4 mmol) in water (10 mL) dropwise at 60 °C over 30 min and stirred at 60 °C under CO2 for 8 h. Purified by flash chromatography (silica gel, 0-10% EtOAc in petroleum ether) to provide the title compound (1.3 g). LCMS (Method B): 408.3 [M+H]+.Intermediate 89a: tert-Butyl 8-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3,7-dioxo-2,8- diazaspirof4.51decane-2-carboxylateIntermediate 89b: tert-Butyl 8-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3,7-dioxo-2,8- diazaspirof4.51decane-2-carboxylate

[0239] Prepared in an analogous manner to Intermediate 12a / 12b using Intermediate 88 (1.5 g, 3.32 mmol), Boc anhydride (1.09 g, 4.99 mmol), triethylamine (1.39 mL, 9.97 mmol) and DMAP (81 mg, 0.67 mmol) in DCM (50 mL) at RT for 1 h. Purified by flashchromatography (silica gel, eluting 10-20% EtOAc in hexane). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% 1 :1 MeOH I MeCN modifier) to provide Intermediate 89a (0.30 g) as Peak 2 and Intermediate 89b (0.28 g) as Peak 3. Intermediate 89a LCMS (Method I): 408.2 [M-Boc+H]+; Intermediate 89b LCMS (Method A): 508.4 [M+H]+.Intermediate 90: terf-Butyl 8-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- idin-2- i-2,2,2-tri i-3,7-dioxo-2,8-di >-2-

[0240] The title compound (0.17 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 89a (0.30 g, 0.59 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.17 g, 0.76 mmol, CAS 2740843-37-0), CS2CO3 (0.57 g, 1.76 mmol) and RuPhosPdG3 (98 mg, 0.12 mmol) in toluene (10 mL) at 95 °C for 16 h. Purified by flash chromatography (silica gel, eluting 60-70% EtOAc in isohexane). LCMS (Method K): 611.5 [M+H]+.Intermediate 91 : terf-Butyl 8-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- idin-2-yl)-2,2,2-tri i-3,7-dioxo-2,8-di >-2-

[0241] The title compound (0.16 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 89b (0.28 g, 0.57 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.17 g, 0.75 mmol, CAS 2740843-37-0), CS2CO3 (0.57 g, 1.73 mmol) and RuPhosPdG3 (97 mg, 0.12 mmol) in toluene (10 mL) at 95 °C for 16 h. Purified by flash chromatography (silica gel, eluting 60-70% EtOAc in isohexane). LCMS (Method B): 611.5 [M+H]+.Intermediate 92: terf-Butyl 2-(1-(5-((5-chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-1-oxo-2,8-diazaspiro[4.5ldecane-8-carboxylate

[0242] The title compound (0.50 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 7 (0.20 g, 0.41 mmol), 5-chloroindan-2-amine (75 mg, 0.45 mmol, CAS 73536-83-1), CS2CO3 (0.40 g, 1.22 mmol) and BrettPhosPdG3 (74 mg, 0.08 mmol) in toluene (4 mL) at 100 °C for 4 h. Purified by flash chromatography (25 g silica gel, eluting 0-40% EtOAc in cyclohexane). LCMS (Method E): 579.1 [M+H]+.Intermediate 93: 2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- i-2,8-diazaspiro[4.5ldecan-1-one

[0243] To a stirred solution of Intermediate 92 (0.18 g, 0.31 mmol) in 1 ,4-dioxane (1.4 mL) was added 4 M HCI in 1 ,4-dioxane (0.9 mL) and stirred at RT for 2 h. The mixture waspoured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.11 g). LCMS (Method E): 479.2 [M+H]+.Intermediate 94: tert-Butyl ((3 )-1-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin- 3-yl) carbarn ate

[0244] The title compound (1.01 g) was prepared in an analogous manner to Intermediate 9 using ( )-3-(Boc-amino)pyrrolidine (0.56 g, 3.03 mmol, CAS 122536-77- 0) and [1-(6-bromo-3-pyridyl)-2,2,2-trifluoro-ethyl] trifluoromethanesulfonate (1.00 g, 2.53 mmol, CAS 2565622-62-8), with DIPEA (0.88 mL, 5.05 mmol) in MeCN (13 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-30% EtOAc in cyclohexane). LCMS (Method N): 423.8 [M+H]+.Intermediate 95: tert-Butyl ((3 )-1-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2- oxopyrrolidin-3-yl)carbamate

[0245] Prepared in an analogous manner to Intermediate 28 using Intermediate 94 (1.01 g, 2.38 mmol) in MeCN (9.2 mL) and sodium chlorite (0.43 g, 4.76 mmol) in water (2.7 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 18 h. Purified by flash chromatography (silica gel, 0-50% EtOAc in cyclohexane) to provide the title compound (0.50 g). LCMS (Method N): 439.6 [M+H]+.Intermediate 96: tert-Butyl ((3 )-1-(1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)carbamate

[0246] The title compound (54 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 95 (0.24 g, 0.22 mmol), 5-chloro-4-fluoro-2,3-dihydro- 1 / 7-inden-2-amine (49 mg, 0.27 mmol, CAS 1934610-84-0), CS2CO3 (0.22 g, 0.67 mmol) and BrettPhosPdG3 (30 mg, 0.03 mmol) in toluene (1.5 mL) at 90 °C for 4 h. Purified by flash chromatography (25 g silica gel, eluting 0-40% EtOAc in cyclohexane). LCMS (Method N): 543.2 [M+H]+.Intermediate 97: (3 )-3-Amino-1-(1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-2-one

[0247] To a stirred solution of Intermediate 96 (54 mg, 0.08 mmol) in 1 ,4-dioxane (0.5 mL) was added 4 M HCI in 1 ,4-dioxane (0.2 mL) and stirred at RT for 6 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (31 mg). LCMS (Method N): 443.0 [M+H]+.Intermediate 98: tert-Butyl ((3 )-1-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)piperidin- 3-yl) carbarn ate

[0248] The title compound (2.11 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (2.0 g, 4.63 mmol, CAS 1374038-21-7) and terf-butyl A / -[(3R)-3- piperidinyl]carbamate (1.11 g, 5.57 mmol, CAS 309956-78-3) in THF (21 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-20% EtOAc in cyclohexane). LCMS (Method N): 437.8 [M+H]+.Intermediate 99: tert-Butyl ((3 )-1-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2- oxopiperidin-3-yl)carbamate

[0249] Prepared in an analogous manner to Intermediate 28 using Intermediate 98 (2.14 g, 4.63 mmol) in MeCN (18 mL) and sodium chlorite (0.84 g, 9.26 mmol) in water (5.3 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-50% EtOAc in cyclohexane) to provide the title compound (0.47 g). LCMS (Method N): 451.8 [M+H]+.Intermediate 100: tert-Butyl ((3 )-1-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopiperidin-3-yl)carbamate

[0250] The title compound (0.25 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 99 (0.47 g, 1.03 mmol), 5-chloro-4-fluoro-2,3-dihydro- 1 / 7-inden-2-amine (0.19 g, 1.03 mmol, CAS 1934610-84-0), CS2CO3 (1.01 g, 3.10 mmol) and BrettPhosPdG3 (0.14 g, 0.16 mmol) in toluene (5.2 mL) at 90 °C for 2 h. Purified by flash chromatography (40 g silica gel, eluting 0-60% EtOAc in cyclohexane). LCMS (Method N): 557.0 [M+H]+.Intermediate 101 : (3 )-3-Amino-1-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperidin-2-one

[0251] To a stirred solution of Intermediate 100 (0.25 g, 0.35 mmol) in 1 ,4-dioxane (2.4 mL) was added 4 M HCI in 1 ,4-dioxane (0.88 mL) and stirred at RT for 6 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.18 g). LCMS (Method N): 457.2 [M+H]+.Intermediate 102: tert-Butyl ( )-3-((3-(((benzyloxy)carbonyl)amino)- propyl)amino)pyrrolidine-1 -carboxylate

[0252] Prepared in an analogous manner to Intermediate 31 using 3- [(benzyloxycarbonyl)amino]propionaldehyde (8.35 g, 40.3 mmol, CAS 65564-05-8), ( )- (+)-1-Boc-3-aminopyrrolidine (5.0 g, 26.8 mmol, CAS 147081-49-0) and AcOH (1.7 mL, 26.8 mmol) in MeOH (0.15 L) at RT for 1 h, then sodium cyanoborohydride (5.06 g, 80.5mmol) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 1-3% MeOH in DCM) to provide the title compound (10.0 g). LCMS (Method B): 378.4 [M+H]+.Intermediate 103: tert-Butyl ( ?)-3-((3-aminopropyl)amino)pyrrolidine-1 -carboxylate

[0253] To a stirred solution of Intermediate 102 (10.0 g, 19.1 mmol) in MeOH (0.20 L), was added palladium on carbon (10%, 4.14 g) and the mixture stirred under a hydrogen atmosphere for 5 h. The mixture was filtered through Celite®, washed with MeOH and the filtrate was concentrated under reduced pressure, to provide the title compound (2.20 g). LCMS (Method B): 244.3 [M+H]+.Intermediate 104: tert-Butyl (3F?)-3-((3-((1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)- amino)propyl)amino)pyrrolidine-1 -carboxylate

[0254] The title compound (2.60 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (6.29 g, 15.6 mmol, CAS 1374038-21-7) and Intermediate 103 (2.71 g, 10.4 mmol) in THF (60 mL) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 70-80% EtOAc in isohexane). LCMS (Method N): 483.4 [M+H]+.Intermediate 105: tert-Butyl (3F?)-3-(3-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2- oxotetrahvdropyrimidin-1(2 / 7)-yl)pyrrolidine-1 -carboxylate

[0255] Prepared in an analogous manner to Intermediate 17 using Intermediate 104 (0.50 g, 0.97 mmol), triethylamine (0.27 mL, 1.93 mmol) and triphosgene (0.20 g, 0.68 mmol) in DCM (40 mL) at 0 °C then RT for 1 h. Purified by flash chromatography (silica gel, eluting 40-50% EtOAc in hexane), to provide the title compound (1.20 g). LCMS (Method B): 509.3 [M+H]+.Intermediate 106: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-(( )-pyrrolidin-3- yl)tetrahvdropyrimidin-2(1 / 7)-one

[0256] A solution of Intermediate 105 (1.04 g, 1.54 mmol) in TFA (0.24 mL) and DCM (5.0 mL) was stirred at RT for 1 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.90 g). LCMS (Method B): 409.3 [M+H]+.Intermediate 107: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-(( )-1- (cvclopropylmethyl)pyrrolidin-3-yl)tetrahvdropyrimidin-2(1 / 7)-one

[0257] Prepared in an analogous manner to Intermediate 31 using cyclopropanecarbaldehyde (0.15 g, 2.09 mmol, CAS 1489-69-6), Intermediate 106 (0.90 g, 1.39 mmol) and AcOH (87 pL, 1.39 mmol) in MeOH (20 mL) at RT for 1 h, then sodium cyanoborohydride (0.26 g, 4.18 mmol) at RT for 16 h. Purified by flash chromatography(silica gel, eluting 1-3% MeOH in DCM) and then by preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 85% CO2 with 15% 1 :1 MeCN 1 1 PA modifier) and then again (GreenSep™-ethyl pyridine, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 85% CO2 with 15% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) - to provide the title compound (0.16 g) as Peak 2. LCMS (Method A): 463.4 [M+H]+.Intermediate 108: tert-Butyl 6-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,6- diazaspirof3.41octane-2-carboxylate

[0258] The title compound (1.90 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (2.00 g, 4.12 mmol, CAS 1374038-21-7) and terf-butyl 2,7- diazaspiro[3.4]octane-2-carboxylate (1.05 g, 4.95 mmol, CAS 885270-84-8) in MeCN (21 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-40% EtOAc in cyclohexane).1H NMR (300 MHz; DMSO-d6) 5: 8.77 (dd, 1 H), 8.16 (dd, 1 H), 7.49 (d, 1 H), 4.61 (q, 1 H), 3.64 (dd, 4H), 2.85 - 2.70 (m, 3H), 2.68 - 2.59 (m, 1 H), 1.92 (t, 2H), 1.36 (s, 9H).Intermediate 109: tert-Butyl 6-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-5-oxo-2,6- diazaspirof3.41octane-2-carboxylate

[0259] Prepared in an analogous manner to Intermediate 28 using Intermediate 108 (1.95 g, 4.33 mmol) in 1 ,4-dioxane (15.6 mL) and sodium chlorite (0.78 g, 8.66 mmol) in water (3.9 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h. Purified by flash chromatography (120 g silica gel, 0-50% EtOAc in cyclohexane) to provide the title compound (1.09 g).1H NMR (300 MHz; DMSO-d6) 5: 8.79 (dd, 1 H), 8.17 (dd, 1 H), 7.57 (d, 1 H), 6.10 (q, 1 H), 3.95 - 3.72 (m, 4H), 3.50 - 3.36 (m, 2H), 2.40 - 2.21 (m, 2H), 1.38 (s, 9H).Intermediate 110: tert-Butyl 6-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-5-oxo-2,6-diazaspirof3.41octane-2-carboxylate

[0260] The title compound (0.25 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 109 (0.30 g, 0.65 mmol), 5-chloro-4-fluoro-2,3- dihydro-1 / 7-inden-2-amine (0.12 g, 0.65 mmol, CAS 1934610-84-0), CS2CO3 (0.63 g, 1.94 mmol) and BrettPhosPdG3 (88 mg, 0.10 mmol) in toluene (3.2 mL) at 90 °C for2 h. Purified by flash chromatography (25 g silica gel, eluting 0-40% EtOAc in cyclohexane). LCMS (Method E): 569.3 [M+H]+.Intermediate 111 : 6-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,6-diazaspirof3.41octan-5-one

[0261] A solution of Intermediate 110 (0.21 g, 0.37 mmol) in TFA (0.20 mL) and DCM (1.8 mL) was stirred at RT for 16 h. The mixture was poured into saturated aqueous NaHCCh and extracted with DCM. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.17 g). LCMS (Method E): 468.9 [M+H]+.Intermediate 112: terf-Butyl 6-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,6- diazaspiro[3.51nonane-2-carboxylate

[0262] The title compound (4.50 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (8.67 g, 19.9 mmol, CAS 1374038-21-7) and terf-butyl 2,8- diazaspiro[3.5]nonane-2-carboxylate (3.0 g, 13.3 mmol, CAS 1086394-57-1) in THF (0.10 L) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method B): 466.3 [M+H]+.Intermediate 113: terf-Butyl 6-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-5-oxo-2,6->-2-i

[0263] Prepared in an analogous manner to Intermediate 28 using Intermediate 112 (4.50 g, 8.614 mmol) in MeCN (36 mL) and sodium chlorite (3.68 g, 40.7 mmol) in water (3.6 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 8 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane). Chiral purification by preparative SFC (LUX i-Amylose, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% I PA modifier) to provide the title compound (0.90 g) as Peak 2. LCMS (Method I): 478.2 [M-H]’.Intermediate 114: terf-Butyl 6-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-5-oxo-2,6-diazaspiro[3.51nonane-2-carboxylate

[0264] The title compound (0.17 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 113 (0.40 g, 0.82 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.18 g, 0.98 mmol, CAS 2740843-37-0), CS2CO3 (0.80 g, 2.46 mmol) and RuPhosPdG3 (69 mg, 0.08 mmol) in toluene (4.4 mL) at 95 °C for 16 h. Purified by flash chromatography (silica gel, eluting 60-70% EtOAc in hexane). LCMS (Method B): 583.5 [M+H]+.Intermediate 115: 6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,6-diazaspiro[3.51nonan-5-one

[0265] A solution of Intermediate 114 (0.17 g, 0.14 mmol) in TFA (0.11 mL) and DCM (18 mL) was stirred at RT for 2 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The combined organics were washed with water, brine, driedover Na2SC>4, filtered and concentrated under reduced pressure to provide the title compound (0.14 g). LCMS (Method E): 483.5 [M+H]+.Intermediate 116: A / 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-A / 3-(oxetan-3- yl)propane-1 ,3-diamine

[0266] The title compound (1.70 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (5.98 g, 13.5 mmol, CAS 1374038-21-7) and A / 1-(oxetan-3- yl)propane-1 ,3-diamine (1.53 g, 11.3 mmol, CAS 1343978-28-8) in THF (10 mL) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-10% MeOH in DCM). LCMS (Method B): 370.2 [M+H]+.Intermediate 117: 1-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3-(oxetan-3- yl)tetrahydropyrimidin-2(1H)-one

[0267] Prepared in an analogous manner to Intermediate 17 using Intermediate 116 (0.70 g, 1.72 mmol), triethylamine (0.68 mL, 4.85 mmol) and triphosgene (0.44 g, 1.49 mmol) in DCM (20 mL) at 0 °C then -78 °C for 1 h. Purified by flash chromatography (silica gel, eluting 25-40% EtOAc in hexane), to provide the title compound (80 mg). LCMS (Method B): 396.3 [M+H]+.Intermediate 118: terf-Butyl 2-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-

[0268] The title compound (0.49 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 7 (1.0 g, 2.03 mmol), 5-chloro-4-fluoro-2,3-dihydro- 1 / 7-inden-2-amine (0.38 g, 2.03 mmol, CAS 1934610-84-0), CS2CO3 (1.99 g, 6.09 mmol) and BrettPhosPdG3 (0.39 g, 0.41 mmol) in toluene (5.1 mL) at 90 °C for 1.5 h. Purified by flash chromatography (80 g silica gel, eluting 0-40% EtOAc in cyclohexane). LCMS (Method E): 597.3 [M+H]+.Intermediate 119: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5ldecan-1-one

[0269] A solution of Intermediate 118 (0.49 g, 0.81 mmol) in TFA (0.63 mL) and DCM (4.3 mL) was stirred at RT for 4 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.40 g). LCMS (Method E): 497.1 [M+H]+.>-2,7-

[0270] The title compound (2.80 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (6.40 g, 14.7 mmol, CAS 1374038-21-7) and 2,9- diazaspiro[4.5]decan-1-one hydrochloride (1.53 g, 11.3 mmol, CAS 1187173-43-8) with triethylamine (4.39 mL, 31.5 mmol) in THF (50 mL) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in hexane). LCMS (Method B): 392.3 [M+H]+.Intermediate 121 : terf-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1-oxo-2,7->-2-i

[0271] Prepared in an analogous manner to Intermediate 12a / 12b using Intermediate 120 (6.90 g, 15.8 mmol), Boc anhydride (6.91 g, 31.7 mmol), and triethylamine (6.62 mL, 47.5 mmol) in DCM (0.14 L) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 10-20% EtOAc in hexane) to provide the title compound (8.0 g). LCMS (Method I): 494.3 [M+H]+. idin-2-yl)-2,2,2-tri-1 ,6-dioxo-idin-2-yl)-2,2,2-trii-1,6-dioxo-

[0272] Prepared in an analogous manner to Intermediate 28 using Intermediate 121(8.0 g, 15.9 mmol) in MeCN (80 mL) and sodium chlorite (4.32 g, 47.8 mmol) in water (4 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane). Chiral purification by preparativeSFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% MeOH modifier) to provide Intermediate 122a (0.57 g) as Peak 2 and Intermediate 122b (0.36 g) as Peak 3. Intermediate 122a LCMS(Method B): 508.2 [M+H]+; Intermediate 122b LCMS (Method B): 508.5 [M+H]+.Intermediate 123: tert-i-chloro-4-fluoro-2,3-dii-1 / 7-inden-2->-2-

[0273] The title compound (69 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 122a (0.10 g, 0.19 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (52 mg, 0.23 mmol, CAS 2740843-37-0), CS2CO3 (0.19 g, 0.58 mmol) and BrettPhosPdG3 (24 mg, 29 pmol) in toluene (10 mL) at 90 °C for 16 h. Purified by flash chromatography (25 g silica gel, eluting 40-60% EtOAc in hexane). LCMS (Method B): 611.7 [M+H]+.Intermediate 124: terf-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- lin-2-yl)-2,2,2- i-1 ,6-dioxo-2,7-di >-2-

[0274] The title compound (69 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 122b (0.10 g, 0.19 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (52 mg, 0.23 mmol, CAS 2740843-37-0), CS2CO3 (0.19 g, 0.58 mmol) and BrettPhosPdG3 (24 mg, 29 pmol) in toluene (10 mL) at 90 °C for 16 h. Purified by flash chromatography (25 g silica gel, eluting 40-60% EtOAc in hexane). LCMS (Method B): 611.7 [M+H]+.Intermediate 125: 7-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,7- i-1 -one

[0275] The title compound (4.0 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (11.8 g, 27.0 mmol, CAS 1374038-21-7) and 2,7-diazaspiro[4.4]nonan-1-one (2.50 g, 17.9 mmol, CAS 1203796-97-7) with triethylamine (7.0 mL, 53.0 mmol) in THF (0.10 L) at 70 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-20% MeOH in DCM). LCMS (Method L): 380.4 [M+H]+.Intermediate 126: 2-(1-(5-in-2-yl)-2,2,2-trifluoroethyl)-2,7- diazaspiro[4.4]nonane-1 ,6-dione

[0276] Prepared in an analogous manner to Intermediate 28 using Intermediate 125 (4.0 g, 7.30 mmol) in 1 ,4-dioxane (6.7 mL) and sodium chlorite (1 .98 g, 21 .9 mmol) in water (0.7 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h, to provide the title compound (1.23 g). LCMS (Method B): 394.3 [M+H]+.Intermediate 127a: terf-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1 ,6-dioxo- 2,7-diazaspiro[4.41nonane-2-carboxylateIntermediate 127b: terf-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1 ,6-dioxo- 2,7-diazaspiro[4.41nonane-2-carboxylate

[0277] Prepared in an analogous manner to Intermediate 12a / 12b using Intermediate 126 (1.59 g, 3.07 mmol), Boc anhydride (1.01 g, 4.61 mmol), triethylamine (1.29 mL, 9.22 mmol) and DMAP (75 mg, 0.62 mmol) in DCM (56 mL) at RT for 2 h. Purified by flash chromatography (silica gel, eluting 0-30% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 85% CO2 with 15% MeOH modifier) to provide Intermediate 127b (0.31 g) as Peak 3. Peak 1 and 2 were further purified by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% IPA modifier) to provide Intermediate 127a (0.31 g) as Peak 2.Intermediate 127a LCMS (Method B): 492.4 [M+H]+; Intermediate 127b LCMS (Method B): 494.4 [M+H]+.Intermediate 128: terf-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- idin-2-yl)-2,2,2-tri i-1 ,6-dioxo-2,7-di s-2-

[0278] The title compound (0.20 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 127a (0.30 g, 0.59 mmol), 5-chloro-4-fluoro-2,3- dihydro-1 / 7-inden-2-amine (0.15 g, 0.77 mmol, CAS 1934610-84-0), CS2CO3 (0.58 g, 1.77 mmol) and BrettPhosPdG3 (80 mg, 89 pmol) in toluene (58 mL) at 95 °C for 16 h. Purified by flash chromatography (12 g silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method A): 599.4 [M+H]+.Intermediate 129: terf-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- idin-2-yl)-2,2,2-tri i-1 ,6-dioxo-2,7-di s-2-

[0279] The title compound (90 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 127b (0.20 g, 0.59 mmol), 5-chloro-4-fluoro-2,3- dihydro-1 / 7-inden-2-amine (0.10 g, 0.51 mmol, CAS 1934610-84-0), CS2CO3 (0.38 g, 1.18 mmol) and RuPhosPdG3 (49 mg, 59 pmol) in toluene (39 mL) at 95 °C for 16 h. Purified by flash chromatography (12 g silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method A): 599.4 [M+H]+. idin-2-yl)-2,2,2-trii-1 ,7-

[0280] The title compound (5.5 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (13.9 g, 31.8 mmol, CAS 1374038-21-7) and 1 ,9-diazaspiro[4.5]decan-2-one (3.50 g, 22.7 mmol, CAS 1158749-84-8) with triethylamine (9.49 mL, 68.1 mmol) in THF (0.20 L) at 60 °C for 36 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method B): 394.3 [M+H]+. i-1 ,7-

[0281] Prepared in an analogous manner to Intermediate 28 using Intermediate 130 (5.6 g, 13.4 mmol) in MeCN (0.15 L) and sodium chlorite (6.07 g, 67.1 mmol) in water (15 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 8 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in hexane), to provide the title compound (1.37 g). LCMS (Method B): 408.3 [M+H]+.Intermediate 132a: tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,6-dioxo-1 ,7-diazaspiro[4.51decane-1 -carboxylateIntermediate 132b: tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,6-dioxo-1.7-diazaspiro[4.51decane-1 -carboxylateIntermediate 132c: tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,6-dioxo-1.7-diazaspiro|4.51decane-1 -carboxylate

[0282] Prepared in an analogous manner to Intermediate 12a / 12b using Intermediate 131 (1.37 g, 2.93 mmol), Boc anhydride (0.77 g, 3.52 mmol), triethylamine (1.22 mL, 8.80 mmol) and DMAP (36 mg, 0.29 mmol) in DCM (15 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-30% EtOAc in hexane), to provide fraction 1 (0.72 g) and fraction 2 (0.80 g). Chiral purification of fraction 1 was carried out by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 77% CO2 with 23% MeOH modifier) to provide Intermediate 132a (0.30 g) as Peak 1 and Intermediate 132b (0.30 g) as Peak 2. Chiral purification of fraction 2 was carried out by preparative SFC (LUX Cellulose-2, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% I PA modifier) to provide Intermediate 132c (0.35 g) as Peak 2. Intermediate 132a LCMS (Method B): 508.5 [M+H]+; Intermediate 132b LCMS (Method B): 508.5 [M+H]+; Intermediate 132c LCMS (Method B): 506.5 [M+H]+.Intermediate 133: tert-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,6-dioxo-1 ,7-diazaspirof4.51decane-1- carboxylate

[0283] The title compound (0.19 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 132a (0.28 g, 0.55 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.16 g, 0.71 mmol, CAS 2740843-37-0), CS2CO3 (0.54 g, 1.64 mmol) and BrettPhosPdG3 (99 mg, 0.11 mmol) in toluene (9 mL) at 95 °C for 16 h. Purified by flash chromatography (25 g silica gel, eluting 80-90% EtOAc in hexane). LCMS (Method A): 611.8 [M+H]+.Intermediate 134: tert-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,6-dioxo-1 ,7-diazaspirof4.51decane-1- carboxylate

[0284] The title compound (0.15 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 132b (0.27 g, 0.50 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.14 g, 0.65 mmol, CAS 2740843-37-0), CS2CO3 (0.49 g, 1.50 mmol) and BrettPhosPdG3 (91 mg, 0.10 mmol) in toluene (9 mL) at 95 °C for 16 h. Purified by flash chromatography (25 g silica gel, eluting 80-90% EtOAc in hexane). LCMS (Method A): 611.5 [M+H]+.Intermediate 135: tert-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,6-dioxo-1 ,7-diazaspirof4.51decane-1- carboxylate

[0285] The title compound (0.17 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 132c (0.30 g, 0.58 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.17 g, 0.76 mmol, CAS 2740843-37-0), CS2CO3 (0.57 g, 1.74 mmol) and BrettPhosPdG3 (0.11 g, 0.12 mmol) in toluene (10 mL) at 95 °C for 16 h. Purified by flash chromatography (25 g silica gel, eluting 80-90% EtOAc in hexane). LCMS (Method A): 611.8 [M+H]+.Intermediate 136: tert-Butyl ((3S)-1-((1 S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden- 2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)carbamate

[0286] The title compound (77 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 3 (82 mg, 0.19 mmol), 5-chloro-4-fluoro-2,3-dihydro- 1 / 7-inden-2-amine (45 mg, 0.24 mmol, CAS 1934610-84-0), CS2CO3 (0.18 g, 0.57 mmol) and BrettPhosPdG3 (33 mg, 36 pmol) in toluene (2 mL) at 90 °C for 4 h. Purified by flash chromatography (40 g silica gel, eluting 0-100% EtOAc in cyclohexane). LCMS (Method G): 543.5 [M+H]+.Intermediate 137: (3S)-3-Amino-1-((1 S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)pyrrolidin-2-one

[0287] To a stirred solution of Intermediate 136 (0.10 g, 0.17 mmol) in 1 ,4-dioxane (1.3 mL) was added 4 M HCI in 1 ,4-dioxane (0.42 mL) and stirred at RT for 6 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (90 mg). LCMS (Method E): 442.9 [M+H]+.Intermediate 138: 4-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1-oxa-9-thia-4- azaspirof5.51undecane 9,9-dioxide

[0288] The title compound (2.5 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (5.49 g, 31.5 mmol, CAS 1374038-21-7) and 1-oxa-9-thia-4-azaspiro[5.5]undecane 9,9-dioxide(2.30 g, 11.2 mmol, CAS 1480461-85-5) with triethylamine (7.81 mL, 56.0 mmol) in THF (60 mL) at 70 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-40% EtOAc in hexane). LCMS (Method A): 445.4 [M+H]+.Intermediate 139: 4-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1-oxa-9-thia-4- azaspiro[5.5]undecan-5-one 9,9-dioxide

[0289] Prepared in an analogous manner to Intermediate 28 using Intermediate 138 (1.9 g, 4.20 mmol) in MeCN (50 mL) and sodium chlorite (1.14 g, 12.6 mmol) in water (2.6 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in petroleum ether). Chiral purification by preparative SFC (Chiralpak®-IA, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide the title compound (0.22 g). LCMS (Method A): 459.5 [M+H]+.Intermediate 140: terf-Butyl ((3S)-1-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)- piperidin-3-yl)carbamate

[0290] The title compound (2.25 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1,1,1- trifluoromethanesulfonate (2.0 g, 4.64 mmol, CAS 1374038-21-7) and (S)-3-Boc- aminopiperidine (1.12 g, 5.57 mmol, CAS 216854-23-8) with DIPEA (1.62 mL, 9.30 mmol) in THF (21 mL) at RT for 16 h. Purified by flash chromatography (silica gel, eluting 0-20% EtOAc in cyclohexane).1H NMR (300 MHz; DMSO-d6) 5: 8.76 (d, 1 H), 8.19 - 8.08 (m, 1 H), 7.47 (d, 1 H), 6.65 (dd, 1 H), 4.89 - 4.72 (m, 1 H), 3.44 - 3.32 (m, 2H), 3.10 - 2.75 (m, 2H), 2.38 - 2.05 (m, 1 H), 1.95 - 1.52 (m, 3H), 1 .40 (s, 9H), 1.30 - 0.95 (m, 1 H).Intermediate 141 : terf-Butyl ((3S)-1-(1-(5-in-2-yl)-2,2,2-trifluoroethyl)-2- oxopiperidin-3-yl)carbamate

[0291] Prepared in an analogous manner to Intermediate 28 using Intermediate 140 (3.19 g, 7.14 mmol) in MeCN (20 mL) and 1 ,4-dioxane (20 mL) and sodium chlorite (1.94 g, 21.4 mmol) in water (10 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-50% EtOAc in cyclohexane), to provide the title compound (0.57 g) as the 2ndfraction.1H NMR (300 MHz; DMSO-d6) 5: 8.79 (d, 1 H), 8.16 (dd, 1 H), 7.49 (dd, 1 H), 7.12 (d, 1 H), 6.54 (q, 1 H), 4.14 - 4.02 (m, 1 H), 3.44 - 3.32 (m, 2H), 2.00 - 1.95 (m, 1 H), 1.83 - 1.71 (m, 3H), 1.39 (s, 9H).Intermediate 142: terf-Butyl ((3S)-1-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- idin-2-yl)-2,2,2-tri i-2-oxopiperidin-3-

[0292] The title compound (0.34 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 141 (0.57 g, 1.25 mmol), 5-chloro-4-fluoro-2,3-dihydro-1 H-inden-2-amine hydrochloride (0.29 g, 1.31 mmol, CAS 2740843-37-0), CS2CO3 (1.63 g, 5.01 mmol) and BrettPhosPdG3 (0.23 g, 0.25 mmol) in toluene (6.3 mL) at 90 °C for 3 h. Purified by flash chromatography (40 g silica gel, eluting 0-100% EtOAc in isohexane).1H NMR (300 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.38 (t, 1 H), 7.23 - 6.99 (m, 4H), 6.55 (d, 1 H), 6.31 (q, 1 H), 4.41 - 4.27 (m, 1 H), 4.11 - 4.04 (m, 1 H), 3.47 - 3.38 (m, 4H), 2.86 (dd, 2H), 1.99 - 1 .90 (m, 1 H), 1.80 - 1.59 (m, 3H), 1.40 (s, 9H).Intermediate 143: (3S)-3-Amino-1-(1-(5-((5-chloro-4-fluoro-2,3-dihydro- inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperidin-2-one

[0293] To a stirred solution of Intermediate 142 (0.44 g, 0.78 mmol) in 1 ,4-dioxane (4 mL) was added 4 M HCI in 1 ,4-dioxane (1.96 mL) and stirred at RT for 1 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.35 g). LCMS (Method E): 457.0 [M+H]+.Intermediate 144: 7-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1 ,7- diazaspirof4.41nonan-2-one

[0294] The title compound (3.0 g) was prepared in an analogous manner to Intermediate 9 using 1-(5-bromo-2-pyridinyl)-2,2,2-trifluoroethyl 1 ,1 ,1 -trifluoromethanesulfonate (15.5 g, 40.0 mmol, CAS 1374038-21-7) and 1 ,7-diazaspiro[4.4]nonan-2-one (4.0 g, 28.5 mmol, CAS 1400797-52-5) with triethylamine (11.9 mL, 85.6 mmol) in THF (60 mL) at 60 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-100% EtOAc in petroleum ether). LCMS (Method A): 378.2 [M+H]+.Intermediate 145: 7-(1-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethyl)-1 ,7- diazaspirof4.41nonane-2, 6-dione

[0295] Prepared in an analogous manner to Intermediate 28 using Intermediate 144 (3.0 g, 7.54 mmol) in MeCN (40 mL) and sodium chlorite (3.41 g, 37.7 mmol) in water (8 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 8 h. Purified by flash chromatography (silica gel, 0-10% EtOAc in petroleum ether), to provide the title compound (1.90 g). LCMS (Method A): 394.4 [M+H]+.Intermediate 146: tert-Butyl 7-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-2,6-dioxo-1 ,7- diazaspirof4.41nonane-1-carboxylate

[0296] Prepared in an analogous manner to Intermediate 12a / 12b using Intermediate 145 (1.90 g, 4.60 mmol), Boc anhydride (1.51 g, 6.90 mmol), triethylamine (1.92 mL, 13.8 mmol) and DMAP (0.11 g, 0.92 mmol) in DCM (20 mL) at RT for 1 h. Purified by flash chromatography (silica gel, eluting 30-40% EtOAc in hexane). Chiral purification by preparative SFC (LUX-Amylose-IA3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100bar, flow rate: 100 g / min, 75% CO2 with 25% MeOH modifier) and peak 2 was further purified by preparative SFC (Chiralpak®-IE, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% 10 mM NH4HCO3 in MeOH modifier) to provide the title compound (0.28 g) as Peak 2. LCMS (Method A): 494.3 [M+H]+.Intermediate 147: tert-Butyl 7-(1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,6-dioxo-1 ,7-diazaspirof4.41nonane-1- carboxylate

[0297] The title compound (0.12 g) was prepared in an analogous manner to Intermediate 4 using Intermediate 146 (0.28 g, 0.56 mmol), 5-chloro-4-fluoro-2,3- dihydro-1 / 7-inden-2-amine hydrochloride (0.16 g, 0.73 mmol, CAS 2740843-37-0), CS2CO3 (0.54 g, 1.67 mmol) and BrettPhosPdG3 (0.10 g, 0.11 mmol) in toluene (10 mL) at 95 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 60-80% EtOAc in hexane). LCMS (Method A): 597.2 [M+H]+.Intermediate 148: 2-(1-(6-Bromopyridin-3-yl)-2,2,2-trifluoroethyl)-9-thia-2- azaspirof5.51undecane

[0298] The title compound (3.2 g) was prepared in an analogous manner to Intermediate 9 using 9-thia-2-azaspiro[5.5]undecane (0.75 g, 4.38 mmol, CAS 86697-02-1) and [1-(6- bromo-3-pyridyl)-2,2,2-trifluoro-ethyl] trifluoromethanesulfonate (2.97 g, 6.13 mmol, CAS 2565622-62-8), with triethylamine (1.83 mL, 13.1 mmol) in THF (43 mL) at 60 °C for 36 h. LCMS (Method A): 411.3 [M+H]+.Intermediate 149: 2-(1-(6-Bromopyridin-3-yl)-2,2,2-trifluoroethyl)-9-thia-2- azaspirof5.51undecane 9,9-dioxide

[0299] To a stirred solution of Intermediate 148 (3.2 g, 3.91 mmol) in DCM (78 mL) at 0 °C was added MCPBA (2.41 g, 9.77 mmol) and stirred at RT for 16 h. The mixture was poured into saturated aqueous NaHCOs 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, 0-100% EtOAc in hexane) to provide the title compound (1.6 g). LCMS (Method B): 443.4 [M+H]+.Intermediate 150: 2-(1-(6-Bromopyridin-3-yl)-2,2,2-trifluoroethyl)-9-thia-2- azaspirof5.51undecan-1-one 9,9-dioxide

[0300] Prepared in an analogous manner to Intermediate 28 using Intermediate 149 (1.6 g, 3.05 mmol) in MeCN (82 mL) and sodium chlorite (1.38 g, 15.2 mmol) in water (8.3 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h. Purified by flashchromatography (silica gel, 0-45% EtOAc in petroleum ether), to provide the title compound (0.36 g). LCMS (Method A): 457.2 [M+H]+. in-3-yl)-2,2,2-trifluoroethyl)-2,9-

[0301] Prepared in an analogous manner to Intermediate 9 using terf-butyl 2,9- diazaspiro[5.5]undecane-9-carboxylate (4.0 g, 15.7 mmol, CAS 1023595-19-8) and [1-(6- bromo-3-pyridyl)-2,2,2-trifluoro-ethyl] trifluoromethanesulfonate (10.8 g, 23.6 mmol, CAS 2565622-62-8), with triethylamine (6.58 mL, 47.2 mmol) in THF (0.15 L) at 70 °C for 36 h. Purified by flash chromatography (silica gel, 0-30% EtOAc in petroleum ether), to provide the title compound (6.19 g). LCMS (Method K): 494.4 [M+H]+.Intermediate 152: terf-Butyl 2-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-1-oxo-2,9->-9-i

[0302] Prepared in an analogous manner to Intermediate 28 using Intermediate 151 (6.19 g, 9.43 mmol) in MeCN (75 mL) and sodium chlorite (3.41 g, 37.7 mmol) in water (7.5 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-20% MeOH in DCM), to provide the title compound (1.80 g). LCMS (Method K): 506.6 [M-H]’.Intermediate 153: terf-Butyl 2-(1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-‘-9-

[0303] The title compound (75 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 152 (0.48 g, 0.68 mmol), 5-chloro-4-fluoro-2,3- dihydro-1 / 7-inden-2-amine (0.21 g, 0.95 mmol, CAS 1934610-84-0), CS2CO3 (0.66 g, 2.03 mmol) and RuPhosPdG3 (0.11 g, 0.14 mmol) in toluene (50 mL) at 100 °C for 16 h. Purified by flash chromatography (12 g silica gel, eluting 0-50% EtOAc in petroleum ether). LCMS (Method A): 612.3 [M+H]+.Intermediate 154: 2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-2,9-diazaspiro[5.5lundecan-1-one

[0304] A solution of Intermediate 153 (0.15 g, 0.16 mmol) in TFA (37 pL) and DCM (4.1 mL) was stirred at RT for 2 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.11 g). LCMS (Method A): 511.5 [M+H]+.Intermediate 155: tert-Butyl 4-(1-(6- in-3-yl)-2,2,2-trifluoroethyl)-1-oxa-4,9->-9-i

[0305] Prepared in an analogous manner to Intermediate 9 using terf-butyl 1-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate (2.0 g, 7.80 mmol, CAS 930785-40-3) and [1-(6- bromo-3-pyridyl)-2,2,2-trifluoro-ethyl] trifluoromethanesulfonate (4.04 g, 9.36 mmol, CAS 2565622-62-8), with triethylamine (3.26 mL, 23.4 mmol) in THF (50 mL) at 70 °C for 16 h. Purified by flash chromatography (silica gel, 0-20% EtOAc in petroleum ether), to provide the title compound (2.0 g). LCMS (Method A): 440.4 [M-tBu+H]+.Intermediate 156: tert-Butyl 4-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-5-oxo-1-oxa- 4,9-diazaspirof5.51undecane-9-carboxylate

[0306] Prepared in an analogous manner to Intermediate 28 using Intermediate 155 (6.2 g, 10.3 mmol) in MeCN (80 mL) and sodium chlorite (2.79 g, 30.9 mmol) in water (2.0 mL) dropwise at 60 °C and stirred at 60 °C under CO2 for 16 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in petroleum ether), to provide the title compound (1.10 g). LCMS (Method A): 408.3 [M-Boc+H]+.Intermediate 157: tert-Butyl 4-(1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-5-oxo-1-oxa-4,9-diazaspirof5.51undecane-9- carboxylate

[0307] The title compound (92 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 156 (0.25 g, 0.38 mmol), 5-chloro-4-fluoroindan-2- amine hydrochloride (0.10 g, 0.45 mmol, CAS 2740843-37-0), CS2CO3 (0.37 g, 1.14 mmol), Pd2(dba)s (35 mg, 38 pmol) and rac-BINAP (47 mg, 76 pmol) in toluene (1 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-20% EtOAc in petroleum ether). LCMS (Method A): 613.5 [M+H]+.Intermediate 158: 4-(1-(6-((5-Chloro-4-fluoro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspirof5.51undecan-5-one

[0308] A solution of Intermediate 157 (0.14 g, 0.19 mmol) in TFA (0.45 mL) and DCM (3.0 mL) was stirred at RT for 2 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.11 g). LCMS (Method A): 513.6 [M+H]+.Intermediate 159: tert-Butyl ((3S)-1-(1-(6-bromopyridin-3-yl)-2,2,2- trifluoroethyl)piperidin-3-yl)carbamate

[0309] Prepared in an analogous manner to Intermediate 9 using terf-butyl A / -[(3S)-3- piperidyl]carbamate (1.92 g, 9.59 mmol, CAS 216854-23-8) and [1-(6-bromo-3-pyridyl)- 2,2,2-trifluoro-ethyl] trifluoromethanesulfonate (3.10 g, 7.99 mmol, CAS 2565622-62-8), with DIPEA (2.79 mL, 16.0 mmol) in MeCN (31 mL) at RT for 16 h. Purified by flashchromatography (silica gel, 0-20% EtOAc in cyclohexane), to provide the title compound (3.16 g).1H NMR (300 MHz; DMSO-d6) 5: 8.42 (s, 1 H), 7.76 (s, 2H), 6.68 (dd, 1 H), 4.93 - 4.79 (m, 1 H), 2.95 - 2.65 (m, 2H), 2.26 - 2.07 (m, 1 H), 2.02 - 1.52 (m, 5H), 1 .37 (s, 9H), 1.12 - 0.95 (m, 1 H).Intermediate 160: tert-Butyl ((3S)-1-(1-(6-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2- oxopiperidin-3-yl)carbamate

[0310] Prepared in an analogous manner to Intermediate 28 using Intermediate 159 (3.16 g, 7.21 mmol) in MeCN (37 mL) and sodium chlorite (1.30 g, 14.4 mmol) at 60 °C under CO2 for 17 h. Additional sodium chlorite (1.30 g, 14.4 mmol) was added and stirred at 60 °C under CO2 for 22 h. Purified by flash chromatography (silica gel, 9-175% EtOAc in cyclohexane), to provide the title compound (1.05 g). 1 H NMR (400 MHz; DMSO-d6) 5: 8.43 (s, 1 H), 7.85 - 7.72 (m, 2H), 7.14 (d, 1 H), 6.72 - 6.53 (m, 1 H), 4.21 - 4.02 (m, 1 H), 3.30 - 3.08 (m, 1 H), 3.00 - 2.88 (m, 1 H), 2.02 - 1.88 (m, 1 H), 1.86 - 1.58 (m, 3H), 1.45 - 1.34 (m, 9H).Intermediate 161 : tert-Butyl ((3S)-1-(1-(6-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)-2-oxopiperidin-3-yl)carbamate

[0311] The title compound (87 mg) was prepared in an analogous manner to Intermediate 4 using Intermediate 160 (0.96 g, 2.12 mmol), 5-chloro-4-fluoro-2,3- dihydro-1 / 7-inden-2-amine hydrochloride (0.47 g, 2.12 mmol, CAS 2740843-37-0), CS2CO3 (2.07 g, 6.35 mmol) and BrettPhosPdG3 (0.38 g, 0.42 mmol) in toluene (15 mL) at 90 °C for 4 h. Purified by reverse phase chromatography (80 g C18, eluting 20-95% MeCN in water). LCMS (Method F): 557.2 [M+H]+.Intermediate 162: (3S)-3-Amino-1-(1-(6-((5-chloro-4-fluoro-2,3-dihydro- inden-2-yl)amino)pyridin-3-yl)-2,2,2-trifluoroethyl)piperidin-2-one hydrochloride

[0312] To a stirred solution of Intermediate 161 (63 mg, 0.11 mmol) in 1 ,4-dioxane (0.7 mL) was added 4 M HCI in 1 ,4-dioxane (0.27 mL) and stirred at RT for 6 h. The mixture was concentrated under reduced pressure to provide the title compound (63 mg). LCMS (Method N): 457.3 [M+H]+.Synthesis of ExamplesExample 1 : A / -((S)-1-((S)-1-(5-(((S)-1 ,1-Dimethyl-2.3-dihvdro-1H-inden-2- yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-2-oxopyrrolidin-3- vDmethanesulfonamide

[0313] To a solution of Intermediate 5 (70 mg, 0.14 mmol) and triethylamine (58 pL, 0.42 mmol) in DCM (4.3 mL) at 0 °C was added methanesulfonyl chloride (1 M in DCM, 0.18 mL, 0.18 mmol) and stirred at 0 °C for 30 min. The mixture was poured into water and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1% aqueous formic acid with MeCN 50% to 57% over 6 min, held at 57% for 6 min, then ramped to 95% over 0.2 min and held for 1.8 min) to provide the title compound (24 mg).1H NMR (400 MHz; DMSO-d6) 5: 8.15 (d, 1 H), 7.74 (d, 1 H), 7.25 - 7.06 (m, 6H), 6.26 (d, 1 H), 5.74 (q, 1 H), 4.17 - 3.96 (m, 2H), 3.54 (t, 1 H), 3.26 - 3.12 (m, 2H), 3.07 (s, 3H), 2.75 (dd, 1 H), 2.41 - 2.26 (m, 1 H), 1.89 - 1.75 (m, 1 H), 1.33 (s, 3H), 1.10 (s, 3H). LCMS (Method H): 497.0 [M+H]+.Example 2: 2-(( / ?)-1-(5-(((S)-1,1-Dimethyl-2,3-dihvdro-1H-inden-2-yl)amino)pyridin- 2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5ldecan-1-oneExample 3: 2-((S)-1-(5-(((S)-1,1-Dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5ldecan-1-one

[0314] To a stirred solution of Intermediate 8 (0.50 g, 0.87 mmol) in 1 ,4-dioxane (4.4 mL) was added 4 M HCI in 1 ,4-dioxane (2.18 mL) and stirred at RT for 18 h. The mixture was poured into saturated aqueous NaHCOs 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 preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 63% CO2 with 37% (0.2% diethylamine in MeOH) modifier) to provide Example 2 (72 mg) as Peak 1 andExample 3 (0.18 g) as Peak 2. Example 2:1H NMR (400 MHz; DMSO-d6) 6: 8.13 (d, 1 H), 7.20 - 7.11 (m, 6H), 6.23 (d, 1 H), 5.74 (q, 1 H), 4.04 (q, 1 H), 3.48 - 3.40 (m, 2H), 3.22 - 3.11 (m, 3H), 2.86 - 2.67 (m, 3H), 2.07 - 1.91 (m, 2H), 1.82 - 1.66 (m, 2H), 1.51 - 1.31 (m, 2H), 1.27 (s, 3H), 1.10 (s, 3H) - one H not observed. LCMS (Method A): 473.5 [M+H]+. Example 3:1H NMR (400 MHz; DMSO-d6) 5: 8.13 (d, 1 H), 7.20 - 7.11 (m, 6H), 6.22 (d, 1 H), 5.73 (dd, 1 H), 4.03 (dd, 1 H), 3.44 - 3.32 (m, 2H), 3.19 (dd, 1 H), 2.89 - 2.83 (m, 2H), 2.74 (dd, 1 H), 2.59 - 2.54 (m, 2H), 1.99 - 1.85 (m, 2H), 1.61 - 1.54 (m, 2H), 1.32 (s, 3H), 1.28 - 1.12 (m, 2H), 1.10 (s, 3H) - one H not observed. LCMS (Method A): 473.5 [M+H]+.Example 4: 2-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-8-(methylsulfonyl)-2,8-diazaspiro[4.5ldecan-1-one

[0315] The title compound (17 mg) was prepared in an analogous manner to Example 1 using Example 3 (30 mg, 0.06 mmol), methanesulfonyl chloride (2 M in DCM, 35 pL, 70 pmol), triethylamine (27 pL, 0.19 mmol) in DCM (0.3 mL) at 0 °C then RT for 1 h. Purified by Prep-TLC (eluting 10% MeOH in DCM).1H NMR (400 MHz; DMSO-d6) 5: 8.14 (d, 1 H), 7.27 - 7.06 (m, 5H), 6.25 (d, 1 H), 5.76 (dd, 1 H), 4.05 (dd, 1 H), 3.51 - 3.45 (m, 4H), 3.19 (dd, 1 H), 2.92 - 2.87 (m, 5H), 2.75 (dd, 1 H), 2.02 - 1.80 (m, 2H), 1.77 - 1.60 (m, 2H), 1.59 - 1.52 (m, 1 H), 1.49 - 1.44 (m, 1 H), 1.32 (s, 3H), 1.10 (s, 3H) - NH not observed. LCMS (Method H): 551.3 [M+H]+.Example 5: 2-((S)-1-(5-(((S)-1,1-Dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-A / ,A / -dimethyl-1-oxo-2,8-diazaspiro[4.5]decane-8- carboxamide

[0316] To a solution of Example 3 (30 mg, 63 pmol) and triethylamine (27 pL, 0.19 mmol) in DCM (0.6 mL) at 0 °C was added dimethylcarbamoyl chloride (7.0 pL, 76 pmol) and stirred at RT for 3 h. The mixture was poured into water and extracted with DCM. The combined organics were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1 % aqueous formic acid with MeCN 50% isocratic for11 min) to provide the title compound (19 mg).1H NMR (300 MHz; DMSO-de) 5: 8.13 (d, 1 H), 7.30 - 7.05 (m, 6H), 6.23 (d, 1 H), 5.75 (dd, 1 H), 4.04 (dd, 1 H), 3.50 - 3.38 (m, 4H), 3.19 (dd, 1 H), 2.92 - 2.74 (m, 3H), 2.72 (s, 6H), 2.03 - 1.72 (m, 2H), 1.74 - 1.55 (m, 2H), 1.40 (d, 1 H), 1.32 (s, 3H), 1.25 (s, 1 H), 1.10 (s, 3H). LCMS (Method H): 544.3 [M+H]+.Example 6: 1-(1-(5-((1,1-Dimethyl-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one - Diastereomer 1Example 7: 1-(1-(5-((1,1-Dimethyl-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one - Diastereomer 2

[0317] To a stirred solution of Intermediate 13 (0.24 g, 0.39 mmol) in 1 ,4-dioxane (3.0 mL) was added 4 M HCI in 1 ,4-dioxane (5.0 mL) and stirred at RT for 2 h. The mixture was concentrated under reduced pressure then diluted with saturated aqueous NaHCOs and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% 1 :1 MeCN I MeOH modifier) to provide Example 6 (56 mg) as Peak 1 and Example 7 (70 mg) as Peak 2. Example 6:1H NMR (400 MHz; DMSO-d6) 5: 8.14 (s, 1 H), 7.20 - 7.13 (m, 6H), 6.46 - 6.39 (q, 1 H), 6.22 (d, 1 H), 4.07 - 4.01 (q, 1 H), 3.44 - 3.36 (m, 3H), 3.21 - 3.16 (m, 2H), 2.90 - 2.85 (m, 1 H), 2.77 - 2.67 (m, 2H), 1.32 (s, 3H), 1.09 (s, 3H) - one H not visible. LCMS (Method O):419.2 [M+H]+. Example 7:1H NMR (400 MHz; DMSO-d6) 5: 8.14 (s, 1 H), 7.21 - 7.13 (m,6H), 6.43 (d, 1 H), 6.22 (d, 1 H), 4.07 - 4.01 (q, 1 H), 3.44 - 3.36 (m, 3H), 3.22 - 3.16 (m,2H), 2.89 - 2.86 (m, 1 H), 2.77 - 2.71 (m, 2H), 1.31 (s, 3H), 1.09 (s, 3H) - one H not observed. LCMS (Method O): 419.2 [M+H]+.Example 8: 1-(1-(5-((1,1-Dimethyl-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one - Diastereomer 3

[0318] To a stirred solution of Intermediate 14 (0.30 g, 0.49 mmol) in 1 ,4-dioxane (2.0 mL) was added 4 M HCI in 1 ,4-dioxane (2.0 mL) and stirred at RT for 3 h. The mixture was concentrated under reduced pressure. The crude product was purified preparative HPLC (X Bridge C8, 19 x 150 mm x 5 pm, flow rate: 17 mL / min, 10 mM aqueous NH4OAC with MeCN 25% to 50% over 9 min, held at 50% for 4.5 min then ramped to 100% over 0.1 min and held for 3.4 min). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) to provide Example 8 (20 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.14 (s, 1 H), 7.20 - 7.13 (m, 6H), 6.46 - 6.39 (q, 1 H), 6.22 (d, 1 H), 4.07 - 4.01 (q, 1 H), 3.44 - 3.36 (m, 3H), 3.21 - 3.16 (m, 2H), 2.89 - 2.86 (m, 1 H), 2.77 - 2.71 (m, 2H), 1.32 (s, 3H), 1.09 (s, 3H) - one H not observed. LCMS (Method O): 419.2 [M+H]+.Example 9: 8-(Cvclopropanecarbonyl)-2-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H- inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one

[0319] To a solution of Example 3 (25 mg, 53 pmol) and triethylamine (22 pL, 0.16 mmol) in DCM (0.4 mL) at 0 °C was added cyclopropanecarbonyl chloride (5.0 pL, 58 pmol) and stirred at 0 °C for 1 h. The mixture was poured into water and extracted with DCM. The combined organics were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 50-62% over 6 min, held at 62% for 5 min, ramped to 95% over 0.2 min, held at 95% for 1.8 min) to provide the title compound (14 mg).1H NMR (400 MHz; CDCI3) 6: 8.11 (d, 1 H), 7.28 - 7.16 (m, 6H), 6.97 (dd, 1 H), 5.85 (q, 1 H), 4.26 - 4.09 (m, 3H), 4.06 - 3.96 (m, 2H), 3.70 - 3.53 (m, 2H), 3.51 - 3.40 (m, 1 H), 3.37 (dd, 1 H), 3.28 - 3.15 (m, 2H), 2.74 (dd, 1 H), 2.05 - 1.68 (m, 4H), 1.41 (s, 3H), 1.22 (s, 3H), 1.02 - 0.98 (m, 2H), 0.79 - 0.74 (m, 2H). LCMS (Method H): 541.5 [M+H]+.Example 10: 8-(Cyclopropylsulfonyl)-2-((S)-1-(5-(((S)-1 ,1-dimethyl-2,3-dihydro-1H- inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one

[0320] To a solution of Example 3 (25 mg, 53 pmol) and triethylamine (15 pL, 0.11 mmol) in DCM (0.3 mL) at 0 °C was added cyclopropanesulfonyl chloride (6.0 pL, 58 pmol) and stirred at RT for 3 h. The mixture was poured into water and extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 60-65% over 6 min, held at 65% for 5 min, ramped to 95% over 0.2 min, held at 95% for 1.8 min) to provide the title compound (18 mg).1H NMR (400 MHz; DMSO-d6, 353 K) 5: 8.16 (d, 1 H), 7.23 - 7.12 (m, 6H), 5.94 (d, 1 H), 5.75 (q, 1 H), 4.03 (dd, 1 H), 3.62 - 3.52 (m, 2H), 3.50 - 3.44 (m, 2H), 3.24 (dd, 1 H), 2.77 (dd, 1 H), 2.59 - 2.53 (m, 1 H), 2.03 - 1.89 (m, 3H), 1.85 - 1.70 (m, 3H), 1.57 (d, 1 H), 1.46 (d, 1 H), 1.34 (s, 3H), 1.14 (s, 3H), 1.01 - 0.94 (m, 4H). LCMS (Method H): 577.2 [M+H]+.Example 11 : 1-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)- 2,2,2-trifluoroethyl)-4-(methylsulfonyl)piperazin-2-one

[0321] The title compound (8.5 mg) was prepared in an analogous manner to Example 1 using Example 7 (20 mg, 48 pmol), methanesulfonyl chloride (1 M in DCM, 58 pL, 58 pmol), triethylamine (20 pL, 0.14 mmol) in DCM (0.2 mL) at 0 °C then RT for 30 min. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 60% isocratic over 11 min).1H NMR (300 MHz; DMSO-d6) 5: 8.15 (d, 1 H), 7.21 - 7.10 (m, 6H), 6.46 - 6.21 (m, 2H), 4.08 - 3.95 (m, 3H), 3.51 (d, 2H), 3.19 (dd, 3H), 2.97 (s, 3H), 2.74 (dd, 1 H), 1.31 (s, 3H), 1.09 (s, 3H). LCMS (Method H): 497.2 [M+H]+.Example 12: 4-(Cyclopropanecarbonyl)-1 -(1 -(5-((1 ,1 -dimethyl-2,3-dihydro-1 H-inden- 2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one

[0322] The title compound (12 mg) was prepared in an analogous manner to Example 9 using Example 6 (20 mg, 48 pmol), cyclopropanecarbonyl chloride (5.0 pL, 54 pmol), triethylamine (20 pL, 0.15 mmol) in DCM (0.3 mL) at 0 °C for 1 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 50-65% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held for 1.8 min ).1H NMR (400 MHz; DMSO-d6) 5: 8.16 (s, 1 H), 7.23 - 7.13 (m, 6H), 6.38 - 6.28 (m, 1 H), 6.27 (d, 1 H), 4.63 - 4.41 (m, 1 H), 4.29 - 3.88 (m, 3H), 3.78 - 3.42 (m, 3H), 3.20 (dd, 1 H), 2.75 (dd, 1 H), 1.98 - 1.90 (m, 1 H), 1.33 (s, 3H), 1.11 (s, 3H), 0.78 - 0.70 (m, 4H). LCMS (Method H): 487.3 [M+H]+.Example 13: 4-(Cyclopropylmethyl)-1 -(1 -(5-((1 ,1 -dimethyl-2,3-dihydro-1 H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one

[0323] Prepared in an analogous manner to Intermediate 31 using Example 7 (21 mg, 49 pmol), cyclopropanecarbaldehyde (3.6 mg, 52 pmol) and AcOH (17 pL, 0.30 mmol) in DCE (0.6 mL) and STAB (42 mg, 0.20 mmol) at RT for 16 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 60-70% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held for 1.8 min) to provide the title compound (3 mg).1H NMR (300 MHz; DMSO-de) 5: 8.15 (t, 1 H), 7.26 - 7.07 (m, 6H), 6.38 (q, 1 H), 6.24 (d, 1 H), 4.04 (q, 1 H), 3.28 - 3.11 (m, 5H), 2.82 - 2.69 (m, 2H), 2.59 (dd, 1 H), 2.23 (d, 2H), 1.32 (s, 3H), 1.10 (s, 3H), 0.92 - 0.72 (m, 1 H), 0.45 (dt, 2H), 0.11 - 0.02 (m, 2H). LCMS (Method H): 473.3 [M+H]+.Example 14: 8-(Cyclopropylmethyl)-2-((S)-1-(5-(((S)-1,1-dimethyl-2,3-dihydro-1H- inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one

[0324] Prepared in an analogous manner to Intermediate 31 using Example 3 (60 mg, 0.13 mmol), cyclopropanecarbaldehyde (9.4 mg, 0.13 mmol) and AcOH (44 pL, 0.76 mmol) in DCE (0.6 mL) and STAB (0.11 g, 0.51 mmol) at RT for 42 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1% aqueous formic acid with MeCN 30-35% over 15 min) to provide the title compound (30 mg).1H NMR (400 MHz; DMSO-d6) 5: 8.16 (s, 1 H), 7.28 - 7.09 (m, 6H), 5.92 (d, 1 H), 5.75 (q, 1 H), 4.03 (q, 1 H), 3.50 - 3.35 (m, 2H), 3.25 (dd, 1 H), 2.88 (t, 2H), 2.77 (dd, 1 H), 2.23 (d, 2H), 2.20 - 2.04 (m, 2H), 2.03 - 1 .67 (m, 4H), 1.42 (d, 1 H), 1 .35 (s, 3H), 1.30 (d, 1 H), 1.15 (s, 3H), 0.85 (s, 1 H), 0.55 - 0.40 (m, 2H), 0.11 - 0.07 (m, 2H). LCMS (Method H): 527.3 [M+H]+.Example 15: 4-(Cvclopropylsulfonyl)-1-(1-(5-((1,1-dimethyl-2,3-dihvdro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one

[0325] The title compound (14 mg) was prepared in an analogous manner to Example 1 using Example 6 (21 mg, 50 pmol), cyclopropanesulfonyl chloride (6 pL, 55 pmol), triethylamine (21 pL, 0.15 mmol) in DCM (0.3 mL) at 0 °C then RT for 30 min. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, water with MeCN 60-65% over 6 min, held 4 min, ramped to 95% over 0.2 min, held for 1.8 min).1H NMR (300 MHz; DMSO-d6) 5: 8.16 (s, 1 H), 7.25 - 7.12 (m, 6H), 6.38 (q, 1 H), 6.28 (d, 1 H), 4.10 - 3.97 (m, 3H), 3.60 - 3.37 (m, 4H), 3.20 (dd, 1 H), 2.80 - 2.67 (m, 2H), 1.33 (s, 3H), 1.11 (s, 3H), 1.03 - 0.93 (m, 4H). LCMS (Method H): 523.2 [M+H]+.Example 16: A / -Cvclopropyl-4-(1-(5-((1,1-dimethyl-2,3-dihvdro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-3-oxopiperazine-1 -carboxamide

[0326] The title compound (14 mg) was prepared in an analogous manner to Example 1 using Example 7 (20 mg, 48 pmol), cyclopropyl isocyanate (4 pL, 57 pmol), DIPEA (13 pL, 96 pmol) in DCM (0.2 mL) at 0 °C then RT for 16 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, water with MeCN 50-60%over 6 min, held 5 min, ramped to 95% over 0.2 min, held for 1.8 min).1H NMR (300 MHz; DMSO-d6) 5: 8.14 (s, 1 H), 7.18 (m, 6H), 6.64 (s, 1 H), 6.36 - 6.24 (m, 2H), 4.16 - 3.94 (m, 3H), 3.60 - 3.48 (m, 1 H), 3.48 - 3.37 (m, 3H), 3.28 (dd, 2H), 2.74 (dd, 1 H), 1.31 (s, 3H), 1.10 (s, 3H), 0.55 - 0.49 (m, 2H), 0.43 - 0.31 (m, 2H). LCMS (Method M): 502.3 [M+H]+.Example 17: 1-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-methylimidazolidin-2-one

[0327] Prepared in an analogous manner to Intermediate 4 using Intermediate 17 (0.25 g, 0.68 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.17 g, 0.75 mmol, CAS 73536-86-4), CS2CO3 (0.26 g, 0.81 mmol) and RuPhosPdG3 (57 mg, 68 pmol) in toluene (2.5 mL) at 110 °C for 16 h. Repeated and combined and purified by flash chromatography (silica gel, eluting 0-100% EtOAc in cyclohexane). Chiral purification carried out by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 78% CO2 with 22% MeCN modifier) to provide the title compound (44 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 7.99 (d, 1 H), 7.30 (s, 1 H), 7.25 (d, 1 H), 7.21 - 7.16 (m, 2H), 7.01 - 6.98 (dd, 1 H), 6.45 (d, 1 H), 5.53 (q, 1 H), 4.29 - 4.24 (m, 1 H), 3.44 - 3.36 (m, 1 H), 3.34 - 3.25 (m, 5H), 2.83 - 2.78 (m, 2H), 2.77 - 2.74 (m, 3H). LCMS (Method A): 425.3 [M+H]+.Example 18: 3-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)oxazolidin-2-one - Diastereomer 1Example 19: 3-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)oxazolidin-2-one - Diastereomer 2

[0328] Prepared in an analogous manner to Intermediate 4 using Intermediate 20 (0.26 g, 0.77 mmol), 1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.19 g, 0.92 mmol, CAS 74413-86-8), CS2CO3 (0.75 g, 2.31 mmol) and RuPhosPdG3 (64 mg, 77 pmol) in toluene (2.5 mL) at 110 °C for 16 h. Purified by preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% MeOH modifier). Chiral purification by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% 1 :1 MeOH I MeCN modifier) to provide Example 18 (13 mg) as Peak 1 and Example 19 (19 mg) as Peak 2. Example 18:1H NMR (400 MHz; DMSO-d6) 5: 8.15 (d, 1 H), 7.23 (d, 1 H), 7.20 - 7.13 (m, 5H), 6.27 (d, 1 H), 5.54 (q, 1 H), 4.38 - 4.27 (m, 2H), 4.08 - 4.02 (m, 1 H), 3.73 - 3.59 (m, 2H), 3.19 (dd, 1 H), 2.75 (dd, 1 H), 1.32 (s, 3H), 1.10 (s, 3H). LCMS (Method A): 406.4 [M+H]+; Example 19:1H NMR (400 MHz; DMSO-d6) 5: 8.16 (d, 1 H), 7.25 (d, 1 H), 7.21 - 7.13 (m, 5H), 6.27 (d, 1 H), 5.52 (q, 1 H), 4.38 - 4.27 (m, 2H), 4.05 (q, 1 H), 3.73 - 3.61 (m, 2H), 3.19 (dd, 1 H), 2.74 (dd, 1 H), 1.32 (s, 3H), 1.10 (s, 3H). LCMS (Method A): 406.4 [M+H]+.Example 20: 1-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-methyltetrahydropyrimidin-2(1H)-one - Diastereomer 1Example 21 : 1-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-methyltetrahydropyrimidin-2(1H)-one - Diastereomer 2

[0329] Prepared in an analogous manner to Intermediate 4 using Intermediate 23 (0.30 g, 0.84 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.19 g, 0.92 mmol, CAS 73536-86-4), Cs2CO3(0.82 g, 2.51 mmol) and RuPhosPdG3 (0.14 g, 0.17 mmol) in toluene (5 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in petroleum ether). Chiral purification by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% MeCN modifier) to provide Example 20 (18 mg) as Peak 1 and Example 21 (15 mg) as Peak 2. Example 20:1H NMR (400 MHz; DMSO-d6) 5: 7.99 (d, 1 H), 7.31 (s, 1 H), 7.25(d, 1 H), 7.20 (dd, 1 H), 7.11 (d, 1 H), 7.00 (dd, 1 H), 6.42 (d, 1 H), 6.27 (q, 1 H), 4.29 -4.22 (m, 1 H), 3.36 - 3.22 (m, 4H), 3.20 - 3.13 (m, 2H), 2.85 (s, 3H), 2.83 - 2.75 (m, 2H), 1.83 - 1.72 (m, 2H). LCMS (Method A): 439.3 [M + H]+; Example 21 :1H NMR (400 MHz; DMSO- d6) 5: 7.99 (d, 1 H), 7.31 (s, 1 H), 7.25 (d, 1 H), 7.20 (dd, 1 H), 7.11 (d, 1 H), 7.00 (dd, 1 H), 6.42 (d, 1 H), 6.27 (q, 1 H), 4.29 -4.22 (m, 1 H), 3.36 - 3.22 (m, 4H), 3.20 - 3.13 (m, 2H), 2.85 (s, 3H), 2.83 - 2.75 (m, 2H), 1.83 - 1.69 (m, 2H). LCMS (Method A): 439.3 [M+ H]+.Example 22: 3-(1-(5-((1 ,1-Dimethyl-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-1,3-oxazinan-2-one

[0330] Prepared in an analogous manner to Intermediate 4 using Intermediate 26 (0.31 g, 0.72 mmol), 1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.16 g, 0.80 mmol, CAS 74413-86-8), CS2CO3 (0.71 g, 2.17 mmol) and RuPhosPdG3 (60 mg, 72 pmol) in toluene (2.5 mL) at 110 °C for 16 h. Purified by preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 85% CO2 with 15% MeOH modifier). Chiral purification by preparative SFC (LUX-i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% 1 :1 MeCN I MeOH modifier) to provide the title compound (6.6 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.15 (d, 1 H), 7.23 - 7.14 (m, 6H), 6.24 (d, 1 H), 6.11 - 6.04 (q, 1 H), 4.27 - 4.21 (m, 2H), 4.03 (q, 1 H), 3.40 - 3.37 (m, 1 H), 3.24 (dd, 2H), 2.73 (dd, 1 H), 1.99 - 1.81 (m, 2H), 1.32 (s, 3H), 1.09 (s, 3H). LCMS (Method A): 420.3 [M+H]+.Example 23: 4-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)morpholin-3-one - Diastereomer 1Example 24: 4-(1-(5-((1 ,1-Dimethyl-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)morpholin-3-one - Diastereomer 2

[0331] Prepared in an analogous manner to Intermediate 4 using Intermediate 28 (0.30 g, 0.87 mmol), 1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.19 g, 0.87 mmol, CAS 74413-86-8), CS2CO3 (0.85 g, 2.60 mmol) and RuPhosPdG3 (73 mg, 87 pmol) in toluene (2.0 mL) at 90 °C for 16 h. Purified by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% 1 :1 MeCN I MeOH modifier) to provide Example 23 (47 mg) as Peak 1 and Example 24 (62 mg) as Peak 2. Example 23:1H NMR (400 MHz; DMSO-d6) 5: 8.15 (d, 1 H), 7.20 - 7.12 (m, 6H), 6.37 (q, 1 H), 6.26 (d, 1 H), 4.19 (dd, 2H), 4.05 (dd, 1 H), 3.88 - 3.84 (m, 1 H), 3.74 - 3.69 (m, 1 H), 3.45 - 3.42 (m, 1 H), 3.38 - 3.35 (m, 1 H), 3.20 (dd, 1 H), 2.74 (dd, 1 H), 1.32 (s, 3H), 1.10 (s, 3H). LCMS (Method A): 420.4 [M+H]+; Example 24:1H NMR (400 MHz; DMSO-d6) 5: 8.15 (d, 1 H), 7.22 - 7.13 (m, 6H), 6.37 (q, 1 H), 6.26 (d, 1 H), 4.19 (dd, 2H), 4.05 (dd, 1 H), 3.88 - 3.84 (m, 1 H), 3.74 - 3.69 (m, 1 H), 3.45 - 3.42 (m, 1 H), 3.38 - 3.35 (m, 1 H), 3.20 (dd, 1 H), 2.74 (dd, 1 H), 1.32 (s, 3H), 1.10 (s, 3H). LCMS (Method K): 420.4 [M+H]+.Example 25: 2-(1-(5-((5-Chloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-oxa-2-azaspiro[4.5ldecan-1-one

[0332] Prepared in an analogous manner to Intermediate 4 using Intermediate 29 (0.10 g, 0.25 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine (44 mg, 0.26 mmol, CAS 73536- 83-1), CS2CO3 (0.25 g, 0.76 mmol) and RuPhosPdG3 (32 mg, 38 pmol) in toluene (1.3 mL) at 110 °C for 24 h. Purified by preparative HPLC (Kinetex XB-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.1% aqueous formic acid with MeCN 60% over 6 min, gradient to 70 % over 5 min, ramped to 95% over 0.2 min, held for 1.8 min) to provide the title compound (24 mg).1H NMR (400 MHz; DMSO-d6) 5: 8.03 (d, 1 H), 7.32 - 7.14 (m, 4H), 7.03 (dd, 1 H), 6.23 (d, 1 H), 5.76 (q, 1 H), 4.39 - 4.25 (m, 1 H), 3.91 - 3.76 (m, 2H), 3.54 - 3.41 (m, 4H), 3.41 - 3.28 (m, 2H), 2.90 - 2.78 (m, 2H), 2.12 - 1.90 (m, 2H), 1.85 - 1.66 (m, 2H), 1.38 (d, 1 H), 1.26 (d, 1 H). LCMS (Method H): 480.1 [M+H]+.Example 26: 1-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one

[0333] Prepared in an analogous manner to Intermediate 4 using Intermediate 32 (0.18 g, 0.42 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (83 mg, 0.47 mmol, CAS 73536-86-4), CS2CO3 (0.41 g, 1.27 mmol) and RuPhosPdG3 (35 mg, 42 pmol) in toluene (2.5 mL) at 95 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0- 70% EtOAc in petroleum ether) and preparative SFC (DCPAK-P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% MeCN modifier) to provide the title compound (11 mg).1H NMR (400 MHz; DMSO-de) 5: 8.00 (d, 1 H), 7.31 (s, 1 H), 7.26 (d, 1 H), 7.22 - 7.17 (m, 2H), 7.00 (dd, 1 H), 6.46 (d, 1 H), 5.56 (q, 1 H) 4.28 - 4.26 (m, 1 H), 3.90 - 3.84 (m, 2H), 3.81 - 3.72 (m, 1 H), 3.43 - 3.26 (m, 8H), 2.79 (dt, 2H), 1.64 (dt, 2H), 1.54 - 1.47 (m, 2H). LCMS (Method A): 495.4 [M+H]+.Example 27: 1-(1-(5-((5-Chloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)pyrrolidin-2-one

[0334] Prepared in an analogous manner to Intermediate 4 using Intermediate 34 (0.40 g, 1.23 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.29 g, 1.35 mmol, CAS 73536-86-4), CS2CO3 (1.20 g, 3.68 mmol) and RuPhosPdG3 (82 mg, 98 pmol) in toluene (4 mL) at 110 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0- 70% EtOAc in hexane) and by preparative SFC (DCPAK-D4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% MeOH modifier) to provide the title compound (15 mg).1H NMR (400 MHz; DMSO-de) 5: 8.00 (d, 1 H), 7.31 (s, 1 H), 7.28 - 7.18 (m, 3H), 7.00 (dd, 1 H), 6.48 (d, 1 H), 5.76 (q, 1 H), 4.30 - 4.25 (m, 1 H), 3.54 - 3.40 (m, 2H), 3.31 - 3.26 (m, 2H), 2.79 (dt, 2H), 2.40 - 2.21 (m, 2H), 2.00 - 1.82 (m, 2H). LCMS (Method A): 410.3 [M+H]+.Example 28: 3-((3S)-1-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2-oxopyrrolidin-3-yl)-1,1 -dimethylurea

[0335] Prepared in an analogous manner to Example 5 using Intermediate 36 (53 mg, 85 pmol), triethylamine (36 pL, 0.26 mmol), dimethylcarbamoyl chloride (12 pL, 0.13 mmol) in DCM (0.9 mL) at RT for 14 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1 % aqueous formic acid with MeCN 60% isocratic for 11 min) to provide the title compound (11 mg).1H NMR (400 MHz; DMSO-de) 5: 8.01 (d, 1 H), 7.39 - 7.16 (m, 4H), 7.01 (dd, 1 H), 6.67 (d, 1 H), 6.50 (d, 1 H), 5.73 (q, 1 H), 4.40 - 4.11 (m, 2H), 3.50 (t, 1 H), 3.29 - 3.22 (m, 2H), 3.20 - 3.13 (m, 1 H), 2.89 - 2.73 (m, 8H), 2.22 - 2.07 (m, 1 H), 2.00 - 1.84 (m, 1 H). LCMS (Method H): 496.2 [M+H]+.Example 29: 1-(1-(5-((5-Chloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-4-(tetrahvdro-2H-pyran-4-yl)piperazin-2-one

[0336] Prepared in an analogous manner to Intermediate 4 using Intermediate 38 (0.30 g, 0.65 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.15 g, 0.71 mmol, CAS 73536-86-4), CS2CO3 (0.63 g, 1.94 mmol) and RuPhosPdG3 (54 mg, 65 pmol) in toluene (8 mL) at 95 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0- 70% EtOAc in petroleum ether) and by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) to provide the title compound (5.5 mg) as Peak 1.1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.31 (s, 1 H), 7.26 (d, 1 H), 7.21 - 7.16 (m, 2H), 7.02 (dd, 1 H), 6.51 (d, 1 H), 6.38 (q, 1 H), 4.29 - 4.27 (m, 1 H), 3.88 - 3.85 (m, 2H), 3.32 - 3.18 (m, 8H), 2.83 - 2.75 (m, 3H), 2.61 - 2.54 (m, 1 H), 2.50 - 2.41 (m, 1 H), 1.70 - 1.67 (m, 2H), 1.38 - 1.32 (m, 2H). LCMS (Method K): 509.4 [M+H]+.Example 30: 1-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)tetrahydropyrimidin-2(1H)-one

[0337] Prepared in an analogous manner to Intermediate 4 using Intermediate 42 (0.30 g, 0.70 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.23 g, 1.05 mmol, CAS 73536-86-4), Cs2CO3(0.69 g, 2.10 mmol) and RuPhosPdG3 (0.12 g, 0.14 mmol) in toluene (10 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0- 100% EtOAc in petroleum ether) and by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% 1 :1 MeCN I MeOH modifier) to provide the title compound (37 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.02 (d, 1 H), 7.84 (s, 1 H), 7.31 - 7.19 (m, 4H), 7.02 (dd, 1 H), 6.48 (d, 1 H), 6.34 (dd, 1 H), 4.31 - 4.24 (m, 1 H), 4.05 (s, 3H), 3.78 (t, 2H), 3.48 - 3.40 (m, 1 H), 3.46 - 3.25 (m, 3H), 2.84 - 2.73 (m, 2H), 2.01 - 1.80 (m, 2H). LCMS (Method A): 506.3 [M+H]+.Example 31 : 2-(1-(5-((5-Chloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-thia-2-azaspiro[4.5ldecan-1-one 8,8-dioxide

[0338] Prepared in an analogous manner to Intermediate 4 using Intermediate 46 (0.11 g, 0.25 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine (44 mg, 0.27 mmol, CAS 73536- 83-1), CS2CO3 (0.24 g, 0.73 mmol) and RuPhosPdG3 (31 mg, 37 pmol) in toluene (1.1 mL) at 110 °C for 20 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, 30 mL / min, 0.05% aqueous ammonia with MeCN 53% over 7.3 min, ramped to 95% over 0.2 min, held for 1.2 min) to provide the title compound (6.5 mg).1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1 H), 7.33 - 7.18 (m, 4H), 7.01 (dd, 1 H), 6.52 (d, 1 H), 5.77 (q, 1 H), 4.29 - 4.24 (m, 1 H), 3.50 - 3.45 (m, 2H), 3.30 - 3.08 (m, 6H), 2.86 - 2.75 (m, 2H), 2.13 - 1.78 (m, 6H). LCMS (Method H): 528.1 [M+H]+.Example 32: 9-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-oxa-9-azaspiro[5.5]undecan-8-one

[0339] Prepared in an analogous manner to Intermediate 4 using Intermediate 48 (0.23 g, 0.55 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.13 g, 0.60 mmol, CAS 73536-86-4), CS2CO3 (0.53 g, 1.64 mmol) and RuPhosPdG3 (46 mg, 55 pmol) in toluene (2.4 mL) at 110 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0- 100% EtOAc in petroleum ether) and by preparative SFC (LUX i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 50% CO2 with 50% MeOH modifier) to provide the title compound (14 mg) as Peak 1.1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1 H), 7.31 (s, 1 H), 7.25 (d, 1 H), 7.21 - 7.14 (m, 2H), 7.01 (dd, 1 H), 6.48 - 6.39 (m, 2H), 4.27 - 4.26 (m, 1 H), 3.57 - 3.50 (m, 4H), 3.36 - 3.27 (m, 1 H), 3.25 - 3.20 (m, 3H), 2.83 - 2.74 (m, 2H), 2.43 - 2.31 (m, 2H), 1.78 - 1.70 (m, 1 H), 1.62 - 1.54 (m, 1 H), 1.41 - 1.37 (m, 2H), 1.31 - 1.29 (m, 2H). LCMS (Method A): 494.4 [M+H]+.Example 33: 2-(1-(5-((5-Chloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-9-oxa-2-azaspiro[5.51undecan-3-one

[0340] Prepared in an analogous manner to Intermediate 4 using Intermediate 50 (0.22 g, 0.55 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.13 g, 0.60 mmol, CAS 73536-86-4), CS2CO3 (0.53 g, 1.64 mmol) and RuPhosPdG3 (46 mg, 55 pmol) in toluene (2.0 mL) at 110 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0- 100% EtOAc in petroleum ether) and by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 67% CO2 with 33% IPA modifier) to provide the title compound (11 mg) as Peak 1.1H NMR (400 MHz; DMSO-de) 5: 8.02 (d, 1 H), 7.31 (s, 1 H), 7.25 (d, 1 H), 7.22 - 7.15 (m, 2H), 7.01 (dd, 1 H), 6.52 - 6.40 (m, 2H), 4.34 - 4.26 (m, 1 H), 3.57 - 3.50 (m, 1 H), 3.43 - 3.38 (m, 1 H), 3.30 - 3.15 (m, 5H), 3.08 - 3.02 (m, 1 H), 2.83 - 2.72 (m, 2H), 2.43 - 2.31 (m, 2H), 1.75 - 1.67 (m, 1 H), 1.62 - 1.54 (m, 1 H), 1.48 - 1.30 (m, 2H), 1.31 - 1.01 (m, 2H). LCMS (Method A): 494.4 [M+H]+.Example 34: 2-(1-(5-((5-Chloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-9-oxa-2-azaspiro[5.5lundecan-1-one - Diastereomer 1Example 35: 2-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-9-oxa-2-azaspiror5.5]undecan-1-one - Diastereomer 2

[0341] Prepared in an analogous manner to Intermediate 4 using Intermediate 51 (0.25 g, 0.60 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.14 g, 0.66 mmol, CAS 73536-86-4), CS2CO3 (0.58 g, 1.79 mmol) and RuPhosPdG3 (50 mg, 60 pmol) in toluene (2.6 mL) at 110 °C for 16 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in petroleum ether). Chiral purification by preparative SFC (Chiralpak®-IG, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 67% CO2 with 33% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) to provide Example 34 (3.8 mg) as Peak 1 and Example 35 (4.7 mg) as Peak 2. Example 34:1H NMR (400 MHz; DMSO-de) 5: 8.00 (d, 1 H), 7.31 (s, 1 H), 7.24 (d, 1 H), 7.20 (dd, 1 H), 7.12 (d, 1 H), 7.01 (dd, 1 H), 6.50 - 6.43 (m, 2H), 4.30 - 4.23 (m, 1 H), 3.78 - 3.68 (m, 2H), 3.54 - 3.46 (m, 2H), 3.34 - 3.25 (m, 3H), 3.20 - 3.12 (m, 1 H), 2.84 - 2.75 (m, 2H), 2.03 - 1.98 (m, 2H), 1.84 - 1.70 (m, 3H), 1.65 - 1.55 (m, 1 H), 1.44 - 1 .30 (m, 2H). LCMS (Method A): 494.4 [M+H]+; Example 35:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1 H), 7.31 (s, 1 H), 7.25 (d, 1 H), 7.21 (dd, 1 H), 7.11 (d, 1 H), 7.01 (dd, 1 H), 6.50 - 6.43 (m, 2H), 4.30 - 4.23 (m, 1 H), 3.78 - 3.68 (m, 2H), 3.54 - 3.47 (m, 2H), 3.34 - 3.25 (m, 3H), 3.20 - 3.12 (m, 1 H), 2.84 - 2.74 (m, 2H), 2.03 - 1.98 (m, 2H), 1.84 - 1.70 (m, 3H), 1.65 - 1 .55 (m, 1 H), 1.44 - 1.30 (m, 2H). LCMS (Method A): 494.3 [M+H]+.Example 36: A / -((3S)-1-((1 S)-1-(5-((5-chloro-4-cvclopropyl-2,3-dihvdro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-

[0342] The title compound (1.7 mg) was prepared in an analogous manner to Example 1 using Intermediate 57 (30 mg, 48 pmol), methanesulfonyl chloride (1 M in DCM, 78 pL, 78 pmol), triethylamine (20 pL, 0.14 mmol) in DCM (0.6 mL) at 0 °C then RT for 3 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1% aqueous formic acid with MeCN 40-48% over 6 min, held for 5, ramped to 95 % over 0.2 min, held for 1.8 min).1H NMR (400 MHz; CDCI3) 6: 8.05 (s, 1 H), 7.22 (dd, 2H), 7.05 (d, 1 H), 6.92 (dd, 1 H), 5.78 (q, 1 H), 4.82 (d, 1 H), 4.33 (s, 1 H), 4.20 (dt, 1 H), 3.73 (t, 1 H), 3.62 - 3.42 (m, 2H), 3.34 (dd, 1 H), 3.18 (s, 3H), 3.01 (dd, 1 H), 2.85 (dd, 1 H), 2.70 - 2.48 (m, 1 H), 2.06 - 1.98 (m, 1 H), 1.87 - 1.76 (m, 1 H), 1.52 - 1.45 (m, 1 H), 1.04 (d, 2H), 0.74 - 0.53 (m, 2H). LCMS (Method H): 543.1 [M+H]+.Example 37: 1-(1-(5-((5-Chloro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)tetrahvdropyrimidin-2(1H)-one - Diastereomer 1Example 38: 1-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)tetrahydropyrimidin-2(1H)-one - Diastereomer 2

[0343] Prepared in an analogous manner to Intermediate 4 using Intermediate 61 (0.35 g, 0.82 mmol), 5-chloro-2,3-dihydro-1 / 7-inden-2-amine hydrochloride (0.23 g, 1.07 mmol, CAS 73536-86-4), CS2CO3 (0.80 g, 2.46 mmol) and RuPhosPdG3 (0.14 g, 0.16 mmol) in toluene (9 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, 60-70% EtOAc in isohexane). Chiral purification by preparative SFC (Chiralpak®-IK, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 62% CO2 with 38% MeOH modifier) to provide Example 37 (14 mg) as Peak 1 and Example 38 (16 mg) as Peak 2. Example 37:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.82 (s, 1 H), 7.51 (s, 1 H), 7.31 (s, 1 H), 7.28 - 7.15 (m, 3H), 7.02 (dd, 1 H), 6.46 (d, 1 H), 6.33 (q, 1 H), 4.32 - 4.23 (m, 1 H), 3.78 (s, 3H), 3.64 - 3.51 (m, 2H), 3.45 - 3.25 (m, 4H), 2.86 - 2.73 (m, 2H), 2.03 - 1.94 (m, 1 H), 1.89 - 1.80 (m, 1 H). LCMS (Method D): 505.3 [M+H]+; Example 38:1HNMR (400 MHz; DMSO-d6) 6: 8.01 (d, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 7.29- 7.15 (m, 3H), 7.02 (dd, 1H), 6.46 (d, 1H), 6.33 (q, 1H), 4.32-4.23 (m, 1H), 3.78 (s, 3H), 3.63-3.51 (m, 2H), 3.45-3.25 (m, 4H), 2.84-2.73 (m, 2H), 2.03- 1.94 (m, 1H), 1.89- 1.80 (m, 1H). LCMS (Method D): 505.3 [M+H]+.Example 39: 1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-3-(1,1-dioxidotetrahvdro-2H-thiopyran-4- yl)tetrahvdropyrimidin-2(1H)-one - Diastereomer 1Example 40: 1-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-3-(1,1-dioxidotetrahvdro-2H-thiopyran-4- yl)tetrahvdropyrimidin-2(1H)-one - Diastereomer 2

[0344] Prepared in an analogous manner to Intermediate 4 using Intermediate 63 (0.20 g, 0.41 mmol), 5-chloro-4-fluoroindan-2-amine hydrochloride (0.12 g, 0.53 mmol, CAS 2740843-37-0), CS2CO3 (0.40 g, 1.23 mmol) and RuPhosPdG3 (68 mg, 82 pmol) in toluene (10 mL) at 95 °C for 16 h. Purified by flash chromatography (silica gel, 60-70% EtOAc in isohexane). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% MeOH modifier) to provide Example 39 (16 mg) as Peak 1 and Example 40 (20 mg) as Peak 2. Example 37:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1H), 7.37 (t, 1H), 7.12 (d, 2H), 7.02 (dd, 1H), 6.49 (d, 1H), 6.30 (q, 1H), 4.48-4.32 (m, 2H), 3.45-3.25 (m, 5H), 3.20-3.11 (m, 3H), 3.08-3.01 (m, 2H), 2.86 (dd, 2H), 2.21 -2.11 (m, 2H), 1.94-1.76 (m, 3H), 1.70 -1.60 (m, 1H). LCMS (Method A): 575.4 [M+H]+; Example 38:1H NMR (400 MHz; DMSO- d6) 5: 8.00 (d, 1H), 7.37 (t, 1H), 7.12 (d, 2H), 7.02 (dd, 1H), 6.49 (d, 1H), 6.30 (q, 1H), 4.48 - 4.32 (m, 2H), 3.45 - 3.25 (m, 5H), 3.20 - 3.11 (m, 3H), 3.08 - 3.01 (m, 2H), 2.89 - 2.80 (m, 2H), 2.21-2.11 (m, 2H), 1.94-1.76 (m, 3H), 1.70-1.60 (m, 1H). LCMS (Method A): 575.4 [M+H]+.Example 41 : 1-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)tetrahydropyrimidin-2(1H)-one - Diastereomer 1Example 42: 1-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-3-(1,1-dioxidotetrahydro-2H-thiopyran-4- yl)tetrahydropyrimidin-2(1H)-one - Diastereomer 2

[0345] Prepared in an analogous manner to Intermediate 4 using Intermediate 65 (0.20 g, 0.42 mmol), 5-chloro-4-fluoroindan-2-amine hydrochloride (0.11 g, 0.53 mmol, CAS 2740843-37-0), Cs2CO3(0.41 g, 1.25 mmol), Pd2(dba)3(38 mg, 42 pmol) and rac-BINAP (52 mg, 83 pmol) in 1 ,4-dioxane (6 mL) at 95 °C for 16 h. Purified by preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 73% CO2with 27% MeOH modifier). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2with 40% MeOH modifier) to provide Example 41 (8 mg) as Peak 1 and Example 42 (14 mg) as Peak 2. Example 41 :1H NMR (400 MHz; DMSO-d6) 5: 7.98 (d, 1 H), 7.40 - 7.32 (m, 2H), 7.20 (d, 1 H), 7.11 (d, 1 H), 6.52 (d, 1 H), 6.30 (q, 1 H), 4.71 - 4.62 (m, 1 H), 4.49 - 4.40 (m, 1 H), 3.40 - 3.30 (m, 4H), 3.25 - 3.11 (m, 3H), 3.09 - 2.95 (m, 3H), 2.87 (dd, 2H), 2.21 - 2.11 (m, 2H), 1.94 - 1.79 (m, 3H), 1.71 - 1.62 (m, 1 H). LCMS (Method A): 575.3 [M+H]+; Example 42:1H NMR (400 MHz; DMSO-d6) 5: 7.98 (d, 1 H), 7.40 - 7.33 (m, 2H), 7.20 (d, 1H), 7.11 (d, 1 H), 6.53 (d, 1 H), 6.30 (q, 1 H), 4.71 - 4.63 (m, 1 H), 4.49 - 4.40 (m, 1 H), 3.40 - 3.30 (m, 4H), 3.23 - 3.12 (m, 3H), 3.10 - 2.95 (m, 3H), 2.87 (dt, 2H), 2.21 - 2.11 (m, 2H), 1.93 - 1.80 (m, 3H), 1.70 - 1.62 (m, 1 H). LCMS (Method A): 575.3 [M+H]+.Example 43: 2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5ldecan-1-one - Diastereomer 1Example 44: 2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiror4.5]decan-1-one - Diastereomer 2

[0346] Prepared in an analogous manner to Intermediate 31 using Intermediate 68 (0.15 g, 0.25 mmol), cyclopropanecarbaldehyde (26 mg, 0.37 mmol) and AcOH (0.29 mL, 2.04 mmol) in DCE (2.5 mL) and STAB (0.32 g, 1.49 mmol) at RT for 24 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 70-80% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 63% CO2 with 37% 10 mM NH4HCO3 in MeOH modifier) to provide Example 43 (14 mg) as Peak 1 and Example 44 (15 mg) as Peak 2. Example 43:1H NMR (400 MHz; DMSO-d6) 5: 8.05 (d, 1 H), 7.48 (dd, 1 H), 7.36 (t, 1 H), 7.25 (d, 1 H), 7.11 (d, 1 H), 6.53 (d, 1 H), 5.72 (q, 1 H), 4.70 - 4.62 (m, 1 H), 3.48 - 3.41 (m, 1 H), 3.35 - 3.27 (m, 2H), 3.24 - 3.15 (m, 2H), 2.95 (br s, 1 H), 2.90 - 2.82 (m, 3H), 2.02 - 1.70 (br m, 6H), 1.55 - 1 .30 (br m, 3H), 0.95 - 0.80 (br m, 1 H), 0.58 - 0.45 (br m, 2H), 0.20 - 0.05 (br m, 2H). LCMS (Method C): 551.5 [M+H]+; Example 44:1H NMR (400 MHz; DMSO-d6) 5: 8.06 (d, 1 H), 7.48 (dd, 1 H), 7.36 (t, 1 H), 7.26 (d, 1 H), 7.11 (d, 1 H), 6.53 (d, 1 H), 5.72 (q, 1 H), 4.70 - 4.62 (m, 1 H), 3.48 - 3.41 (m, 1 H), 3.35 - 3.27 (m, 2H), 3.24 - 3.15 (m, 2H), 3.05 (br s, 1 H), 2.88 (dt, 3H), 2.02 - 1.70 (br m, 6H), 1.55 - 1.30 (br m, 3H), 0.95 - 0.80 (br m, 1 H), 0.58 - 0.45 (br m, 2H), 0.20 - 0.05 (br m, 2H). LCMS (Method C): 551.5 [M+H]+.Example 45: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-9-(cyclopropylmethyl)-2,9-diazaspiro[5.5lundecan-1-one - Diastereomer 1Example 46: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-9-(cyclopropylmethyl)-2,9-diazaspiro[5.5lundecan-1-one - Diastereomer 2

[0347] Prepared in an analogous manner to Intermediate 4 using Intermediate 72 (90 mg, 0.19 mmol), 5-chloro-4-fluoroindan-2-amine hydrochloride (51 mg, 0.23 mmol, CAS 2740843-37-0), CS2CO3 (0.19 g, 0.57 mmol) and RuPhosPdG3 (32 mg, 38 pmol) in toluene (5.4 mL) at 95 °C for 16 h. Purified by flash chromatography (silica gel, eluting 1-5% MeOH in DCM). Chiral purification by preparative SFC (Chiralcel®-OD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% 10 mM NH4HCO3 in MeOH modifier) to provide Example 45 (4.3 mg) as Peak 1 and Example 46 (5.7 mg) as Peak 2. Example 45:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1 H), 7.37 (t, 1 H), 7.12 (d, 2H), 7.02 (dd, 1 H), 6.52 (d, 1 H), 6.47 (q, 1 H), 4.39 - 4.31 (m, 1 H), 3.47 - 3.30 (m, 3H), 3.20 - 3.11 (m, 1 H), 2.90 - 2.72 (m, 4H), 2.20 - 1.98 (m, 6H), 1.78 - 1.65 (m, 3H), 1.61 - 1.52 (m, 1 H), 1.49 - 1.38 (m, 2H), 0.88 - 0.76 (m, 1 H), 0.49 - 0.42 (m, 2H), 0.08 - 0.04 (m, 2H). LCMS (Method C): 565.5 [M+H]+; Example 46:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1 H), 7.37 (t, 1 H), 7.12 (d, 2H), 7.02 (dd, 1 H), 6.52 (d, 1 H), 6.47 (q, 1 H), 4.39 - 4.31 (m, 1 H), 3.47 - 3.30 (m, 3H), 3.20 - 3.11 (m, 1 H), 2.89 - 2.72 (m, 4H), 2.20 (d, 2H), 2.12 - 1.98 (m, 4H), 1.78 - 1.65 (m, 3H), 1.61 - 1.52 (m, 1 H), 1.49 - 1.38 (m, 2H), 0.88 - 0.76 (m, 1 H), 0.49 - 0.42 (m, 2H), 0.08 - 0.04 (m, 2H). LCMS (Method C): 565.5 [M+H]+.Example 47: 6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2-oxa-6-azaspiro[3.41octan-5-one

[0348] Prepared in an analogous manner to Intermediate 4 using Intermediate 74 (0.21 g, 0.58 mmol), 5-chloro-4-fluoroindan-2-amine (0.12 g, 0.63 mmol, CAS 1934610-84-0), CS2CO3 (0.43 g, 1.32 mmol) and RuPhosPdG3 (96 mg, 0.12 mmol) in toluene (3 mL) at 95 °C for 16 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 50-54% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held at 95% for 1.8 min) to provide the title compound (6 mg).1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1 H), 7.38 (t, 1 H), 7.26 (d, 1 H), 7.13 (d, 1 H), 7.02 (dd, 1 H), 6.57 (d, 1 H), 5.81 (q, 1 H), 4.65 (dd, 2H), 4.52 (d, 1 H), 4.43 (d, 1 H), 4.38 - 4.32 (m, 1 H), 3.47 - 3.41 (m, 3H), 2.85 (d, 2H), 2.44 - 2.30 (m, 3H). LCMS (Method H): 470.4 [M+H]+.Example 48: 6-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2-oxa-6-azaspiro[3.41octan-7-one

[0349] Prepared in an analogous manner to Intermediate 4 using Intermediate 75 (74 mg, 0.20 mmol), 5-chloro-4-fluoroindan-2-amine (45 mg, 0.24 mmol, CAS 1934610-84-0), CS2CO3 (0.15 g, 0.47 mmol) and RuPhosPdG3 (34 mg, 41 pmol) in toluene (0.7 mL) at 90 °C for 17 h. Purified preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 50-70% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held at 95% for 1.8 min) to provide the title compound (3.5 mg).1H NMR (400 MHz; DMSO-d6) 5: 8.03 (d, 1 H), 7.38 (t, 1 H), 7.26 (d, 1 H), 7.13 (d, 1 H), 7.03 (dd, 1 H), 6.57 (d, 1 H), 5.78 (q, 1 H), 4.57 (d, 1 H), 4.50 (t, 2H), 4.38 (d, 2H), 3.82 (d, 1 H), 3.76 (d, 1 H), 3.46 - 3.37 (m, 2H), 2.88 (s, 1 H), 2.84 (s, 1 H), 2.82 - 2.75 (m, 1 H), 2.74 - 2.68 (m, 1 H). LCMS (Method H): 470.1 [M+H]+.Example 49: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.4lnonane-1, 8-dione - Diastereomer 1Example 50: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.4lnonane-1, 8-dione - Diastereomer 2

[0350] To a stirred solution of Intermediate 79a (80 mg, 84 pmol) in DCM (1.0 mL) was added TFA (33 pL, 0.42 mmol) and stirred at RT for 2 h. The mixture was poured into saturated aqueous NaHCOs and extracted with DCM. The combined 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 0- 5% MeOH in DCM). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% (10 mM NH4HCO3 in 1 :1 MeCN I MeOH) modifier) to provide Example 49 (10. mg) as Peak 1 and Example 50 (9 mg) as Peak 2. Example 49:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1 H), 7.70 (s, 1 H), 7.37 (dd, 1 H), 7.26 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.56 (d, 1 H), 5.77 (q, 1 H), 4.37 - 4.31(m, 1 H), 3.48 - 3.35 (m, 4H), 3.27 (d, 1 H), 3.13 (d, 1 H), 2.87 - 2.82 (m, 2H), 2.30 (dd, 2H), 2.13 - 2.02 (m, 2H). LCMS (Method A): 497.3 [M+H]+; Example 50:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1 H), 7.71 (s, 1 H), 7.37 (dd, 1 H), 7.26 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.56 (d, 1 H), 5.77 (q, 1 H), 4.37 - 4.31 (m, 1 H), 3.48 - 3.35 (m, 4H), 3.27 (d, 1 H), 3.13 (d, 1 H), 2.87 - 2.80 (m, 2H), 2.30 (dd, 2H), 2.13 - 2.02 (m, 2H). LCMS (Method A): 497.3 [M+H]+.Example 51 : 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2,7-diazaspiro[4.4]nonane-1, 8-dione - Diastereomer 3Example 52: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2,7-diazaspiro[4.4]nonane-1, 8-dione - Diastereomer 4

[0351] Prepared in an analogous manner to Example 49 / 50 using Intermediate 79b (0.13 g, 0.21 mmol) and TFA (84 pL, 1.09 mmol) in DCM (2.0 mL) at RT for 2 h. Purified by flash chromatography (silica gel, eluting 0-5% MeOH in DCM). Chiral purification bypreparative SFC (Chiralpak®-IC, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 63% CO2 with 37% MeOH modifier) to provide Example 51 (10 mg) as Peak 1 and Example 52 (9 mg) as Peak 2. Example 51 :1H NMR (400 MHz; DMSO- d6) 5: 8.01 (d, 1 H), 7.73 (s, 1 H), 7.37 (t, 1 H), 7.25 (d, 1 H), 7.12 (d, 1 H), 7.03 (dd, 1 H), 6.57 (d, 1 H), 5.77 (q, 1 H), 4.37 - 4.31 (m, 1 H), 3.48 - 3.35 (m, 4H), 3.27 (d, 2H), 2.87 - 2.82 (m, 2H), 2.32 (d, 1 H), 2.19 - 2.10 (m, 2H), 2.06 - 1.98 (m, 1 H). LCMS (Method A): 497.3 [M+H]+; Example 52:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.73 (s, 1 H), 7.37 (t, 1 H), 7.25 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.56 (d, 1 H), 5.77 (q, 1 H), 4.37 - 4.32 (m, 1 H), 3.51 - 3.35 (m, 4H), 3.27 (d, 2H), 2.87 - 2.82 (m, 2H), 2.32 (d, 1 H), 2.19 - 2.10 (m, 2H), 2.06 - 1.99 (m, 1 H). LCMS (Method A): 497.3 [M+H]+.Example 53: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-7-(cvclopropylmethyl)-2,7-diazaspiror4.4lnonan-1-one

[0352] Prepared in an analogous manner to Intermediate 31 using Intermediate 84 (0.18 g, 0.33 mmol), cyclopropanecarbaldehyde (35 mg, 1.51 mmol) and AcOH (40 pL, 0.70 mmol) in DCE (3 mL) and STAB (0.42 g, 1.99 mmol) at RT for 18 h. Purified by preparative HPLC (Kinetex XB-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1% aqueous formic acid with MeCN 32-50% over 6 min, held for 1 min, ramped to 95% over 0.2 min, held for 1.8 min) to provide the title compound (36 mg).1H NMR (400 MHz; DMSO- d6) 5: 8.25 (s, 1 H), 8.01 (d, 1 H), 7.38 (t, 1 H), 7.24 (d, 1 H), 7.13 (d, 1H), 7.03 (dd, 1 H), 6.57 (d, 1 H), 5.77 (q, 1 H), 4.36 (d, 1 H), 3.36 - 3.30 (m, 4H), 2.86 (dd, 3H), 2.79 - 2.54 (m, 1 H), 2.44 - 2.19 (m, 3H), 2.15 - 1.83 (m, 3H), 1.82 - 1.53 (m, 1 H), 0.83 (d, 1 H), 0.49 - 0.39 (m, 2H), 0.10 - 0.07 (m, 2H). LCMS (Method Q): 537.2 [M+H]+.Example 54: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-7-(cyclopropylmethyl)-2,7-diazaspiro[4.4]nonan-3-one

[0353] Prepared in an analogous manner to Intermediate 31 using Intermediate 86 (88 mg, 0.14 mmol), cyclopropanecarbaldehyde (14 mg, 0.21 mmol) and AcOH (16 pL, 0.29mmol) in DCE (1.4 mL) and STAB (0.17 g, 0.82 mmol) at RT for 18 h. Purified by preparative HPLC (Kinetex XB-C18, 21 x 250 mm x 5 pm, flow rate: 29 mL / min, 0.1% aqueous formic acid with MeCN 30-35% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held for 1.8 min) to provide the title compound (36 mg).1H N MR (400 MHz; DMSO- d6) 5: 8.21-8.08 (m, 1H), 8.00 (d, 1H), 7.37 (t, 1H), 7.24 (dd, 1H), 7.12 (dd, 1H), 7.02 (dd, 1H), 6.56 (d, 1H), 5.78 (q, 1H), 4.39-4.28 (m, 1H), 3.56-3.30 (m, 3H), 2.90-2.64 (m, 3H), 2.55 (dd, 2H), 2.46-2.14 (m, 5H), 1.86-1.58 (m, 2H), 0.79 (d, 1H), 0.50-0.33 (m, 2H), 0.16 - 0.01 (m, 2H). LCMS (Method P): 536.8 [M+H]+.Example 55: 8-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,8-diazaspiror4.51decane-3,7-dione - Diastereomer 1Example 56: 8-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,8-diazaspiror4.51decane-3,7-dione - Diastereomer 2

[0354] Prepared in an analogous manner to Example 49 / 50 using Intermediate 90 (0.30 g, 0.26 mmol) and TFA (0.1 mL, 1.30 mmol) in DCM (5.0 mL) at RT for 1 h. Purified by preparative SFC (PrincetonSFC 2-Ethylpyridine, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% MeOH modifier). Chiral purification by preparative SFC (LUX-i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% MeOH modifier) to provide Example 55 (24 mg) as Peak 1 and Example 56 (22 mg) as Peak 2. Example 55:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.58 (s, 1H), 7.37 (t, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 7.03 (dd, 1H), 6.56 (d, 1H), 6.44 (q, 1H), 4.39 - 4.32 (m, 1H), 3.47 - 3.35 (m, 3H), 3.23-3.13 (m, 2H), 2.98 (d, 1H), 2.89-2.82 (m, 2H), 2.50-2.45 (m, 2H), 2.06 (d, 1H), 1.90 (d, 1 H), 1.89- 1.80 (m, 1 H), 1.78 - 1.70 (m, 1 H). LCMS (Method C): 511.4 [M+H]+; Example 56:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.58 (s, 1H), 7.37 (t, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 7.03 (dd, 1H), 6.56 (d, 1H), 6.44 (q, 1H), 4.39-4.32 (m, 1H), 3.47- 3.35 (m, 3H), 3.23-3.13 (m, 2H), 2.98 (d, 1H), 2.89-2.82 (m, 2H), 2.50-2.45 (m, 2H),2.06 (d, 1 H), 1.90 (d, 1 H), 1.89 - 1.80 (m, 1 H), 1.78 - 1.70 (m, 1 H). LCMS (Method C): 511.4 [M+H]+.Example 57: 8-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2,8-diazaspiro[4.51decane-3, 7-dione - Diastereomer 3Example 58: 8-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2,8-diazaspiror4.5]decane-3, 7-dione - Diastereomer 4

[0355] Prepared in an analogous manner to Example 49 / 50 using Intermediate 91 (0.16 g, 0.21 mmol) and TFA (32 pL, 1.30 mmol) in DCM (5.0 mL) at RT for 1 h. Purified by preparative SFC (PrincetonSFC 2-Ethylpyridine, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% MeOH modifier). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% MeOH modifier) to provide Example 57 (8 mg) as Peak 1 and Example 58 (11 mg) as Peak 2. Example 57:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.57 (s, 1 H), 7.37 (t, 1 H), 7.17 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.55 (d, 1 H), 6.44 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.47 - 3.35 (m, 3H), 3.30 - 3.20 (m, 1 H), 3.02 (d, 1 H), 2.94 (d, 1 H), 2.89 - 2.82 (m, 2H), 2.50 - 2.45 (m, 2H), 2.19 (d, 1 H), 1.95 (d, 1 H), 1.89 - 1.80 (m, 1 H), 1.75 - 1.67 (m, 1 H). LCMS (Method C): 511.3 [M+H]+; Example 58:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.57 (s, 1 H), 7.37 (t, 1 H), 7.17 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.55 (d, 1 H), 6.44 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.47 - 3.35 (m, 3H), 3.30 - 3.20 (m, 1 H), 3.02 (d, 1 H), 2.94 (d, 1 H), 2.89 - 2.82 (m, 2H), 2.50 - 2.45 (m, 2H), 2.20 (d, 1 H), 1.95 (d, 1 H), 1.88 - 1.80 (m, 1 H), 1.75 - 1.67 (m, 1 H). LCMS (Method C): 511.3 [M+H]+.Example 59: 2-(1-(5-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5ldecan-1-one

[0356] Prepared in an analogous manner to Intermediate 31 using Intermediate 93 (0.11 g, 0.23 mmol), cyclopropanecarbaldehyde (24 mg, 0.35 mmol) and AcOH (0.26 mL, 0.46 mmol) in DCE (1.9 mL) and STAB (0.29 g, 1.38 mmol) at RT for 18 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 29 mL / min, 0.1% aqueous formic acid with MeCN 30-40% over 6 min, held for 2 min, ramped to 95% over 0.2 min, held for 1.8 min) to provide the title compound (26 mg).1H N MR (400 MHz; DMSO- d6) 5: 8.00 (d, 1 H), 7.31 - 7.21 (m, 4H), 7.01 (dd, 1 H), 6.50 (d, 1 H), 5.76 (q, 1 H), 4.31 - 4.22 (m, 1 H), 2.93 - 2.74 (m, 5H), 2.20 (d, 2H), 2.11 - 1.89 (m, 4H), 1.88 - 1.64 (m, 4H), 1.44 - 1.37 (m, 1 H), 1.27 (dd, 2H), 0.83 (td, 1 H), 0.48 - 0.42 (m, 2H), 0.10 - 0.04 (m, 2H). LCMS (Method Q): 533.2 [M+H]+.Example 60: A / -( -1-(1-(6-((5-Chloro-4-fluoro-2,3-dihvdro-1 H-inden-2-yl)amino)pyridin-3-yl)-2.2.2-trifluoroethyl)-2-oxopyrrolidin-3- vDmethanesulfonamide

[0357] The title compound (4 mg) was prepared in an analogous manner to Example 1 using Intermediate 97 (29 mg, 65 pmol), methanesulfonyl chloride (6 pL, 83 pmol), triethylamine (37 pL, 0.26 mmol) in DCM (0.4 mL) at 0 °C then RT for 3 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1% aqueous formic acid with MeCN 50-60% over 6 min, held for 5, ramped to 95 % over 0.2 min, held for 1.8 min).1H NMR (400 MHz; DMSO-d6) 5: 8.07 (d, 1 H), 7.63 (d, 1 H), 7.48 (dd, 1 H), 7.36 (t, 1 H), 7.27 (d, 1 H), 7.12 (d, 1 H), 6.53 (d, 1 H), 5.76 (q, 1 H), 4.73 - 4.61 (m, 1 H), 4.29 - 4.19 (m, 1 H), 3.43 - 3.34 (m, 2H), 3.31 - 3.25 (m, 2H), 3.06 (s, 3H), 2.93 - 2.81 (m, 2H), 2.47 - 2.37 (m, 1 H), 1.79 - 1.64 (m, 1 H). LCMS (Method P): 521.1 [M+H]+.

[0358] The title compound (65 mg) was prepared in an analogous manner to Example 1 using Intermediate 101 (0.18 g, 0.38 mmol), methanesulfonyl chloride (44 pL, 0.56 mmol), triethylamine (0.21 mL, 1.53 mmol) in DCM (2.6 mL) at 0 °C then RT for 16 h. Purified by Prep-TLC (70% EtOAc in cyclohexane).1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.58 (d, 1 H), 7.37 (t, 1 H), 7.22 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.55 (d, 1 H), 6.35 (q, 1 H), 4.42 - 4.29 (m, 1 H), 4.14 - 4.01 (m, 1 H), 3.45 - 3.33 (m, 4H), 3.03 (s, 3H), 2.90 - 2.81 (m, 2H), 2.13 - 2.03 (m, 1 H), 1.84 - 1.63 (m, 3H). LCMS (Method P): 535.0 [M+H]+.Example 62: 1-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-3-(( / ?)-1-(cvclopropylmethyl)pyrrolidin-3- yl)tetrahvdropyrimidin-2(1H)-one - Diastereomer 1Example 63: 1-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-3-(( / ?)-1-(cvclopropylmethyl)pyrrolidin-3- yl)tetrahvdropyrimidin-2(1H)-one - Diastereomer 2

[0359] Prepared in an analogous manner to Intermediate 4 using Intermediate 107 (0.16 g, 0.34 mmol), 5-chloro-4-fluoroindan-2-amine hydrochloride (98 mg, 0.44 mmol, CAS 2740843-37-0), CS2CO3 (0.33 g, 1.02 mmol) and RuPhosPdG3 (57 mg, 68 pmol) in toluene (6.4 mL) at 95 °C for 16 h. Purified by preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% 10 mM NH4HCO3 in MeOH modifier). Chiral purification by preparative SFC (Chiralpak®- AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back pressure 100 bar, flow rate: 100 g / min, 75% CO2 with 25% (0.1% diethylamine in 1 :1 MeCN 1 1 PA) modifier) to provide Example 62 (3.1 mg) as Peak 1 and Example 63 (3.2 mg) as Peak 2. Example 62:1H NMR (400 MHz;DMSO-d6) 6: 8.00 (d, 1 H), 7.37 (t, 1 H), 7.12 (d, 2H), 7.02 (dd, 1 H), 6.49 (d, 1 H), 6.31 (q, 1H), 4.92 (brs, 1 H), 4.39-4.31 (m, 1H), 3.48-3.36 (m, 2H), 3.28-3.15 (m, 2H), 2.97- 2.70 (m, 4H), 2.49 - 2.20 (br m, 4H), 2.02 - 1.95 (br m, 1 H), 1.88- 1.62 (br m, 3H), 1.32 -1.30 (m, 2H), 0.90-0.80 (brm, 1H), 0.50-0.40 (m, 2H), 0.15-0.07 (brm, 2H). LCMS (Method A): 566.4 [M+H]+; Example 63:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1H), 7.37 (t, 1H), 7.16-7.11 (m, 2H), 7.02 (dd, 1H), 6.49 (d, 1H), 6.31 (q, 1H), 4.92 (brs, 1H), 4.39-4.31 (m, 1H), 3.48-3.36 (m, 2H), 3.28-3.15 (m, 2H), 2.97-2.70 (m, 4H), 2.49- 2.20 (br m, 4H), 2.02 - 1.95 (br m, 1H), 1.88 - 1.62 (br m, 3H), 1.32 - 1.30 (m, 2H), 0.90 - 0.80 (br m, 1H), 0.50 - 0.40 (m, 2H), 0.15 - 0.07 (br m, 2H). LCMS (Method A): 566.4 [M+H]+.Example 64: 6-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2.2.2-trifluoroethyl)-2-(methylsulfonyl)-2.6-diazaspiror3.41octan-5-one

[0360] The title compound (46 mg) was prepared in an analogous manner to Example 1 using Intermediate 111 (0.20 g, 0.38 mmol), methanesulfonyl chloride (31 pL, 0.40 mmol), triethylamine (0.16 mL, 1.15 mmol) in DCM (1.7 mL) at 0 °C then RT for 2 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 60-64% over 6 min, held for 2 min, ramped to 95 % over 0.2 min, held for 1.8 min).1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1H), 7.38 (t, 1H), 7.27 (d, 1H), 7.13 (d, 1H), 7.02 (dd, 1H), 6.58 (d, 1H), 5.79 (q, 1H), 4.40-4.31 (m, 1H), 3.99 (dd, 2H), 3.89 (d, 1 H), 3.79 (d, 1 H), 3.52 - 3.38 (m, 4H), 3.04 (s, 3H), 2.89 - 2.80 (m, 2H), 2.42-2.26 (m, 2H). LCMS (Method P): 547.1 [M+H]+.idin-2- i-2-li-2,6-diazaspiro[3.51nonan-5-one -(5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-' idin-2- i-2,2,2-trifluoroethvl)-2-i i-2,6-diazaspiro[3.51nonan-5-one -Diastereomer 2

[0361] Prepared in an analogous manner to Example 1 using Intermediate 115 (0.11 g, 0.11 mmol), methane sulfonic anhydride (24 mg, 0.14 mmol), triethylamine (48 pL, 0.34 mmol) in DCM (10 mL) at 0 °C then RT for 1 h. Purified by preparative SFC (PrincetonSFC 2-Ethylpyridine, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% MeOH modifier). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2 with 20% MeOH modifier) to provide Example 65 (4.9 mg) as Peak 1 and Example 66 (4.6 mg) as Peak 2. Example 65:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1H), 7.37 (t, 1H), 7.19 (d, 1H), 7.13 (d, 1H), 7.02 (dd, 1H), 6.55 (d, 1H), 6.44 (q, 1H), 4.39 -4.34 (m, 1H), 4.11 (dd, 2H), 3.68 (dd, 2H), 3.32-3.34 (m, 3H), 3.13-3.15 (m, 1H), 3.03 (s, 3H), 2.84 (dd, 2H), 2.06 - 2.07 (m, 2H), 1.73-1.74 (m, 1 H), 1.62 - 1.63 (m, 1 H). LCMS (Method A): 561.3 [M+H]+; Example 66:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1H), 7.37 (t, 1H), 7.19 (d, 1H), 7.13 (d, 1H), 7.02 (dd, 1H), 6.55 (d, 1H), 6.44 (q, 1H), 4.39 - 4.34 (m, 1H), 4.11 (dd, 2H), 3.68 (dd, 2H), 3.32-3.34 (m, 3H), 3.13-3.15 (m, 1H), 3.03 (s, 3H), 2.89-2.82 (m, 2H), 2.06 - 2.07 (m, 2H), 1.73-1.74 (m, 1H), 1.62-1.63 (m, 1H). LCMS (Method A): 561.3 [M+H]+.Example 67: 1-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-3-(oxetan-3-yl)tetrahvdropyrimidin-2(1H)-one

[0362] Prepared in an analogous manner to Intermediate 4 using Intermediate 117 (80 mg, 0.16 mmol), 5-chloro-4-fluoroindan-2-amine hydrochloride (44 mg, 0.20 mmol, CAS 2740843-37-0), CS2CO3 (0.16 g, 0.49 mmol) and RuPhosPdG3 (27 mg, 33 pmol) in toluene (1.2 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, eluting 70-90% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-IE, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide the title compound (3.6 mg) as Peak 3 and 4 mixture. Example 41:1H NMR (400 MHz; DMSO-d6) 5: 8.00 (d, 1H), 7.37 (t, 1H), 7.14-7.10 (m, 2H), 7.01 (dd, 1H), 6.49 (d, 1H), 6.24 (q, 1H), 5.29-5.18 (m, 1H), 4.69-4.56 (m, 4H), 4.38-4.31 (m, 1H),3.45 - 3.35 (m, 5H), 3.25 - 3.18 (m, 1 H), 2.89 - 2.81 (m, 2H), 1.94 - 1.83 (m, 1 H), 1.78 - 1.67 (m, 1 H). LCMS (Method A): 499.3 [M+H]+.Example 68: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]decan-1-one

[0363] Prepared in an analogous manner to Intermediate 31 using Intermediate 119 (0.16 g, 0.32 mmol), cyclopropanecarbaldehyde (34 mg, 0.48 mmol) and AcOH (39 mg, 0.64 mmol) in DCE (1.3 mL) and STAB (0.41 g, 1.93 mmol) at RT for 18 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.1% aqueous formic acid with MeCN 30-43% over 9 min, ramped to 95% over 0.2 min, held for 1.8 min) to provide the title compound (46 mg).1H NMR (400 MHz; DMSO-de) 5: 8.23 (s, 1 H), 8.01 (d, 1 H), 7.38 (t, 1 H), 7.23 (d, 1 H), 7.13 (d, 1 H), 7.02 (dd, 1 H), 6.56 (d, 1 H), 5.77 (q, 1 H), 4.37 - 4.31 (m, 1 H), 3.32 (d, 2H), 2.95 - 2.82 (m, 4H), 2.22 (d, 2H), 2.15 - 2.01 (m, 2H), 1.94 (ddd, 1 H), 1 .84 (ddd, 1 H), 1.77 - 1.68 (m, 2H), 1.44 - 1.38 (m, 1 H), 1.32 - 1.23 (m, 1 H), 0.83 (t, 1 H), 0.50 - 0.43 (m, 2H), 0.08 (q, 2H) - one proton not observed. LCMS (Method P): 551.2 [M+H]+.Example 69: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-1, 6-dione - Diastereomer 1Example 70: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-1, 6-dione - Diastereomer 2

[0364] Prepared in an analogous manner to Example 49 / 50 using Intermediate 123 (68 mg, 98 pmol) and TFA (8 pL, 98 pmol) in DCM (2.0 mL) at RT for 1 h. Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure100 bar, flow rate: 100 g / min, 55% CO2 with 45% 1:1 MeCN I I PA modifier) to provide Example 69 (7 mg) as Peak 1 and Example 70 (13 mg) as Peak 2. Example 69:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.85 (s, 1H), 7.37 (t, 1H), 7.14 (dd, 2H), 7.05 (dd, 1H), 6.55 (m, 1H), 6.45 (q, 1H), 4.41 -4.32 (m, 1H), 3.46-3.36 (m, 3H), 3.26-3.12 (m, 3H), 2.75 (d, 2H), 2.48 - 2.43 (m, 1H), 2.04 - 1.96 (m, 3H), 1.79 - 1.62 (m, 2H). LCMS (Method I): 511.3[M+H]+; Example 70:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.85 (s, 1H), 7.37 (t, 1H), 7.14 (dd, 2H), 7.05 (dd, 1H), 6.55 (m, 1H), 6.45 (q, 1H), 4.41 -4.32 (m, 1H), 3.46-3.36 (m, 3H), 3.26-3.12 (m, 3H), 2.75 (d, 2H), 2.48-2.43 (m, 1H), 2.04 - 1.96 (m, 3H), 1.79 - 1.62 (m, 2H). LCMS (Method I): 511.3 [M+H]+.Example 71 : 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,7-diazaspiror4.5ldecane-1, 6-dione - Diastereomer 3Example 72: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,7-diazaspiror4.5ldecane-1, 6-dione - Diastereomer 4

[0365] Prepared in an analogous manner to Example 49 / 50 using Intermediate 124 (0.14 g, 0.19 mmol) and TFA (0.63 mL, 8.16 mmol) in DCM (3.0 mL) at RT for 1 h. Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% MeOH modifier) to provide Example 71 (21 mg) as Peak 1 and Example 72 (17 mg) as Peak 2. Example 71:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.84 (s, 1H), 7.37 (t, 1H), 7.14 (t, 2H), 7.03 (dd, 1H), 6.54 (m, 1H), 6.42 (q, 1H), 4.41 -4.32 (m, 1H), 3.46-3.36 (m, 3H), 3.26-3.18 (m, 3H), 2.89-2.81 (m, 2H), 2.48-2.40 (m, 1H), 2.08- 1.88 (m, 3H), 1.75- 1.65 (m, 1H), 1.60 - 1.48 (m, 1H). LCMS (Method O): 511.3 [M+H]+; Example 72:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.84 (s, 1H), 7.37 (t, 1H), 7.14 (t, 2H), 7.03 (dd, 1H), 6.54 (m, 1H), 6.42 (q, 1H), 4.41 -4.32 (m, 1H), 3.46-3.36 (m, 3H), 3.26-3.18 (m, 3H), 2.89- 2.81 (m, 2H), 2.48-2.40 (m, 1H), 2.08- 1.88 (m, 3H), 1.75- 1.65 (m, 1H), 1.60-1.48 (m, 1H). LCMS (Method O): 511.3 [M+H]+.Example 73: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2,7-diazaspiror4.4]nonane-1, 6-dione - Diastereomer 1Example 74: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-2,7-diazaspiror4.4]nonane-1, 6-dione - Diastereomer 2

[0366] Prepared in an analogous manner to Example 49 / 50 using Intermediate 128 (0.28 g, 0.30 mmol) and TFA (0.12 mL, 1.50 mmol) in DCM (0.2 mL) at RT for2 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in petroleum ether). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% 1:1 MeCN I I PA modifier) to provide Example 73 (28 mg) as Peak 1 and Example 74 (23 mg) as Peak 2. Example 73:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.94 (s, 1H), 7.37 (t, 1H), 7.26 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1H), 6.56 (d, 1H), 5.75 (q, 1H), 4.39 - 4.31 (m, 1H), 3.63 - 3.58 (q, 1H), 3.49-3.36 (m, 3H), 3.26-3.22 (m, 1H), 3.22-3.16 (m, 1H), 2.88-2.81 (m, 2H), 2.38- 2.26 (m, 2H), 1.98-1.81 (m, 2H). LCMS (Method O): 497.3 [M+H]+; Example 74:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.94 (s, 1H), 7.37 (t, 1H), 7.26 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1 H), 6.56 (d, 1 H), 5.75 (q, 1 H), 4.39 - 4.31 (m, 1 H), 3.63 - 3.58 (q, 1 H), 3.49 - 3.36 (m, 3H), 3.26-3.22 (m, 1H), 3.22-3.16 (m, 1H), 2.88-2.81 (m, 2H), 2.38-2.26 (m, 2H), 1.98 - 1.81 (m, 2H). LCMS (Method O): 497.3 [M+H]+.Example 75: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.4lnonane-1, 6-dione - Diastereomer 3Example 76: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2,7-diazaspiro[4.4lnonane-1, 6-dione - Diastereomer 4

[0367] Prepared in an analogous manner to Example 49 / 50 using Intermediate 129 (0.13 g, 0.21 mmol) and TFA (80 pL, 1.03 mmol) in DCM (1.4 mL) at RT for 2 h. Purified by flash chromatography (silica gel, 0-100% EtOAc in petroleum ether). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 63% CO2 with 37% 1 :1 MeCN I I PA modifier) to provide Example 75 (16 mg) as Peak 1 and Example 76 (10 mg) as Peak 2. Example 75:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.94 (s, 1 H), 7.37 (t, 1 H), 7.25 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.56 (d, 1 H), 5.75 (q, 1 H), 4.41 - 4.32 (m, 1 H), 3.58 - 3.48 (m, 2H), 3.47 - 3.36 (m, 3H), 3.26 - 3.19 (m, 1 H), 2.90 - 2.82 (m, 2H), 2.40 - 2.22 (m, 2H), 2.08 - 1.92 (m, 2H). LCMS (Method A): 497.3 [M+H]+; Example 76:1H NMR (400 MHz; DMSO- d6) 5: 8.01 (d, 1 H), 7.94 (s, 1 H), 7.37 (t, 1 H), 7.25 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.56 (d, 1 H), 5.75 (q, 1 H), 4.41 - 4.32 (m, 1 H), 3.58 - 3.48 (m, 2H), 3.47 - 3.36 (m, 3H), 3.26 - 3.19 (m, 1 H), 2.90 - 2.82 (m, 2H), 2.40 - 2.22 (m, 2H), 2.08 - 1.92 (m, 2H). LCMS (Method O): 497.3 [M+H]+.Example 77: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-1 ,7-diazaspiro[4.5ldecane-2,6-dione - Diastereomer 1Example 78: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-1 ,7-diazaspiro[4.5ldecane-2,6-dione - Diastereomer 2

[0368] Prepared in an analogous manner to Example 49 / 50 using Intermediate 133 (0.19 g, 0.25 mmol) and TFA (0.12 mL, 2.54 mmol) in DCM (18 mL) at RT for 2 h. Purified by flash chromatography (silica gel, 80-100% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide Example 77 (36 mg)as Peak 1 and Example 78 (38 mg) as Peak 2. Example 77:1H NMR (400 MHz; DMSO- d6) 5: 8.01 (d, 1 H), 7.99 (s, 1 H), 7.37 (t, 1 H), 7.18 (d, 1 H), 7.12 (d, 1 H), 7.03 (dd, 1 H), 6.56 (d, 1 H), 6.42 (q, 1 H), 4.40 - 4.32 (m, 1 H), 3.56 - 3.45 (m, 3H), 3.09 - 3.01 (m, 1 H), 2.85 (dd, 2H), 2.36 - 2.25 (m, 1 H), 2.22 - 2.12 (m, 2H), 1.95 - 1.82 (m, 3H), 1.81 - 1.74 (m, 2H). LCMS (Method O): 511.3 [M+H]+; Example 78:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.99 (s, 1 H), 7.37 (t, 1 H), 7.18 (d, 1 H), 7.12 (d, 1 H), 7.03 (dd, 1 H), 6.56 (d, 1 H), 6.42 (q, 1 H), 4.40 - 4.32 (m, 1 H), 3.56 - 3.45 (m, 3H), 3.09 - 3.01 (m, 1 H), 2.85 (dd, 2H), 2.36 - 2.25 (m, 1 H), 2.22 - 2.12 (m, 2H), 1.95 - 1.82 (m, 3H), 1.81 - 1.74 (m, 2H). LCMS (Method O): 511.3 [M+H]+.Example 79: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-1 ,7-diazaspiror4.5ldecane-2,6-dione - Diastereomer 3

[0369] Prepared in an analogous manner to Example 49 / 50 using Intermediate 134 (0.15 g, 0.19 mmol) and TFA (0.15 mL, 1.89 mmol) in DCM (15 mL) at RT for 2 h. Purified by flash chromatography (silica gel, 80-100% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 55% CO2 with 45% 1 :1 MeCN 1 1 PA modifier) to provide the title compound (37 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.99 (s, 1 H), 7.37 (t, 1 H), 7.18 (d, 1 H), 7.12 (d, 1 H), 7.03 (dd, 1 H), 6.56 (d, 1 H), 6.42 (q, 1 H), 4.40 - 4.32 (m, 1 H), 3.49 - 3.43 (m, 3H), 3.09 - 3.01 (m, 1 H), 2.85 (dd, 2H), 2.36 - 2.26 (m, 1 H), 2.21 - 2.12 (m, 2H), 1.95 - 1.82 (m, 3H), 1.81 - 1.74 (m, 2H). LCMS (Method O): 511.3 [M+H]+.Example 80: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-1 ,7-diazaspiro[4.5ldecane-2, 6-dione - Diastereomer 4Example 81 : 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-1 ,7-diazaspiro[4.5ldecane-2, 6-dione - Diastereomer 5

[0370] Prepared in an analogous manner to Example 49 / 50 using Intermediate 135 (0.17 g, 0.21 mmol) and TFA (0.16 mL, 2.09 mmol) in DCM (17 mL) at RT for 2 h. Purified by flash chromatography (silica gel, 80-100% EtOAc in hexane). Chiral purification by preparative SFC (LUX-i-Amylose-3, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% 1 :1 MeCN 11 PA modifier) to provide Example 80 (25 mg) as Peak 1 and Example 81 (18 mg) as Peak 2. Example 80:1H NMR (400 MHz; DMSO-d6) 5: 8.07 (s, 1 H), 8.01 (d, 1 H), 7.37 (t, 1 H), 7.16 (d, 1 H), 7.12 (d, 1 H), 7.03 (dd, 1 H), 6.55 (d, 1 H), 6.38 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.46 - 3.35 (m, 4H), 2.89 - 2.82 (m, 2H), 2.35 - 2.27 (m, 1 H), 2.22 - 2.10 (m, 2H), 2.01 - 1.93 (m, 1 H), 1.88 - 1.79 (m, 3H), 1.79 - 1.68 (m, 1 H). LCMS (Method O): 511.3 [M+H]+; Example 81 :1H NMR (400 MHz; DMSO-d6) 5: 8.08 (s, 1 H), 8.01 (d, 1 H), 7.37 (t, 1 H), 7.16 (d, 1 H), 7.12 (d, 1 H), 7.03 (dd, 1 H), 6.55 (d, 1 H), 6.38 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.46 - 3.35 (m, 4H), 2.86 (dd, 2H), 2.35 - 2.27 (m, 1 H), 2.22 - 2.10 (m, 2H), 2.01 - 1.93 (m, 1 H), 1.88 - 1.79 (m, 3H), 1.79 - 1.68 (m, 1 H). LCMS (Method O): 511 .3 [M+H]+.Example 82: A / -((3S)-1-((1 S)-1-(5-((5-chloro-4-fluoro-2,3-dihvdro-1H-inden-2- yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-2-oxopyrrolidin-3- vDmethanesulfonamide - Diastereomer 1Example 83: A ((3S)-1-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihvdro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3- vDmethanesulfonamide - Diastereomer 2

[0371] Prepared in an analogous manner to Example 1 using Intermediate 137 (90 mg, 0.16 mmol), methanesulfonyl chloride (24 mg, 0.21 mmol), triethylamine (68 pL, 0.49 mmol) in THF (1.6 mL) at 0 °C then RT for 2 h. Purified by preparative HPLC (Kinetex XB-C18, 21 x 250 mm x 5 pm, flow rate: 29 mL / min, 0.1 % aqueous formic acid with MeCN 50- 58% over 6 min, held for 5 min, ramped to 95% over 0.2 min, held for 1.8 min). Chiral purification by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% MeOH modifier) to provide Example 82 (4.9 mg) as Peak 1 and Example 83 (5.3 mg) as Peak 2. Example 82:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.72 (br s, 1 H), 7.37 (t, 1 H), 7.26 (d, 1 H), 7.12 (d, 1 H), 7.01 (dd, 1 H), 6.57 (d, 1 H), 5.75 (q, 1 H), 4.39 - 4.33 (m, 1 H), 4.18 - 4.08 (m, 1 H), 3.52 (t, 1 H), 3.45 - 3.34 (m, 2H), 3.23 - 3.15 (m, 1 H), 3.03 (s, 3H), 2.84 (dd, 2H), 2.41 - 2.32 (m, 1 H), 1.88 - 1.77 (m, 1 H). LCMS (Method A): 521.2 [M+H]+; Example 83:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.72 (br s, 1 H), 7.37 (t, 1 H), 7.26 (d, 1 H), 7.12 (d, 1 H), 7.01 (dd, 1 H), 6.57 (d, 1 H), 5.75 (q, 1 H), 4.39 - 4.33 (m, 1 H), 4.18 - 4.08 (m, 1 H), 3.52 (t, 1 H), 3.45 - 3.34 (m, 2H), 3.23 - 3.15 (m, 1 H), 3.06 (s, 3H), 2.88 - 2.81 (m, 2H), 2.41 - 2.32 (m, 1 H), 1.88 - 1.77 (m, 1 H). LCMS (Method A): 521.2 [M+H]+.Example 84: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-8-(cyclopropylsulfonyl)-2,8-diazaspiror4.5]decan-1-one

[0372] Prepared in an analogous manner to Example 1 using Intermediate 119 (0.13 g, 0.26 mmol), cyclopropanesulfonyl chloride (28 pL, 0.28 mmol), triethylamine (0.11 mL, 0.79 mmol) in DCM (1.3 mL) at RT for 2 h. Purified by preparative HPLC (Gemini NX-C18, 21 x 250 mm x 5 pm, flow rate: 30 mL / min, 0.05% aqueous ammonia with MeCN 60-67% over 6 min, held for 4 min, ramped to 95% over 0.2 min, held for 2 min). Chiral purification by preparative SFC (Art Amylose SA, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 62% CO2 with 38% (1 :1 MeCN 1 1 PA) modifier) to provide the title compound (8.8 mg) as Peak 2.1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.37 (t, 1 H), 7.24 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.56 (d, 1 H), 5.76 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.59 - 3.35 (m, 6H), 3.06 - 2.94 (m, 2H), 2.86 (dd, 2H), 2.61 - 2.55 (m, 1 H), 2.02 - 1.87 (m, 2H), 1.79 - 1.63 (m, 2H), 1.58 - 1.52 (m, 1 H), 1.47 - 1.38 (m, 1 H), 1.00 - 0.89 (m, 4H). LCMS (Method A): 601.2 [M+H]+.Example 85: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-8-(2-methoxyethyl)-2,8-diazaspiro[4.5ldecan-1-one

[0373] To a solution of Intermediate 119 (0.13 g, 0.26 mmol) and in MeCN (1.3 mL) was added K2CO3 (72 mg, 0.52 mmol) and 1-bromo-2-methyoxyethane (25 pL, 0.26 mmol, CAS 6482-24-2) and stirred at 90 °C for 18 h. The mixture was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by Prep- TLC (silica plate, 50% EtOAc in cyclohexane) then reverse-phase chromatography (4 g C18, eluting 0-100% MeCN in pH 7 buffer) to provide the title compound (9 mg).1H NMR (300 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.38 (t, 1 H), 7.22 (d, 1 H), 7.13 (d, 1 H), 7.02 (dd, 1 H), 6.55 (d, 1 H), 5.76 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.52 - 3.35 (m, 6H), 3.23 (s, 3H), 2.88 - 2.64 (m, 4H), 2.03 - 1.56 (m, 7H), 1.40 - 1.30 (m, 1 H), 1.24 - 1.19 (m, 1 H) - one H not observed. LCMS (Method P): 555.4 [M+H]+.Example 86: 4-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-1 -oxa-9-thia-4-azaspiror5.51undecan-5-one 9,9-dioxide - Diastereomer 1Example 87: 4-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-1 -oxa-9-thia-4-azaspiror5.5]undecan-5-one 9,9-dioxide - Diastereomer 2

[0374] Prepared in an analogous manner to Intermediate 4 using Intermediate 139 (0.12 g, 0.25 mmol), 5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-amine (55 mg, 0.30 mmol, CAS 1934610-84-0), CS2CO3 (0.24 g, 0.75 mmol) and BrettPhosPdG3 (45 mg, 0.05 mmol) in toluene (0.5 mL) at 100 °C for 16 h. Purified by flash chromatography (40 g silica gel, eluting 0-50% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with40% MeOH modifier) to provide Example 86 (9.8 mg) as Peak 1 and Example 87 (11 mg) as Peak 2. Example 86:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.37 (t, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 7.03 (dd, 1H), 6.60 (d, 1H), 6.35 (q, 1H), 4.39-4.31 (m, 1H), 3.96- 3.90 (m, 1H), 3.83 - 3.75 (m, 1H), 3.54 - 3.48 (m, 1H), 3.45 - 3.34 (m, 3H), 3.20 - 3.01 (m, 4H), 2.85 (dd, 2H), 2.45 - 2.23 (m, 4H). LCMS (Method O): 562.3 [M+H]+; Example 87:1H NMR (400 MHz; DMSO-d6) 5: 8.02 (d, 1H), 7.37 (t, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 7.03 (dd, 1 H), 6.60 (d, 1 H), 6.35 (q, 1 H), 4.39 - 4.32 (m, 1 H), 3.96 - 3.89 (m, 1 H), 3.83 - 3.75 (m, 1 H), 3.54 - 3.48 (m, 1 H), 3.45 - 3.34 (m, 3H), 3.20 - 3.01 (m, 4H), 2.85 (dd, 2H), 2.45 - 2.23 (m, 4H). LCMS (Method O): 562.3 [M+H]+.Example 88: / V-((3S)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopiperidin-3- vDcyclopropanesulfonamide - Diastereomer 1Example 89: / V-((3S)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopiperidin-3- vDcyclopropanesulfonamide - Diastereomer 2

[0375] Prepared in an analogous manner to Example 1 using Intermediate 143 (0.18 g, 0.38 mmol), cyclopropanesulfonyl chloride (0.13 g, 0.96 mmol), triethylamine (0.11 mL, 0.77 mmol) in DCM (2.1 mL) at RT for 16 h. Purified by reverse phase chromatography (25 g C18, eluting with MeCN 20-95% in water). Chiral purification by preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 70% CO2 with 30% 1:1 MeCN 11 PA modifier) to provide Example 88 (33 mg) as Peak 1 and Example 89 (29 mg) as Peak 2. Example 88:1H NMR (400 MHz; DMSO- d6) 5: 8.01 (d, 1H), 7.49 (d, 1H), 7.37 (t, 1H), 7.20 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1H), 6.55 (d, 1H), 6.34 (q, 1H), 4.40-4.32 (m, 1H), 4.11 -4.03 (m, 1H), 3.46-3.36 (m, 4H), 2.84 (dd,2H), 2.79-2.72 (m, 1H), 2.15-2.07 (m, 1H), 1.82-1.66 (m, 3H), 0.91 (d, 4H). LCMS (Method O): 561.4 [M+H]+; Example 89:1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.49 (d, 1H), 7.37 (t, 1H), 7.20 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1H), 6.55 (d, 1H), 6.34 (q,1H), 4.40-4.32 (m, 1H), 4.11 -4.03 (m, 1H), 3.47-3.36 (m, 4H), 2.89-2.82 (m, 2H), 2.79-2.72 (m, 1H), 2.14-2.07 (m, 1H), 1.82-1.68 (m, 3H), 0.91 (d, 4H). LCMS (Method O): 561.4 [M+H]+.Example 90: -1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopiperidin-3-yl)methanesulfonamide

[0376] Prepared in an analogous manner to Example 1 using Intermediate 143 (0.18 g, 0.38 mmol), methanesulfonyl chloride (33 pL, 0.42 mmol), triethylamine (0.11 mL, 0.77 mmol) in DCM (2.1 mL) at RT for 16 h. Purified by reverse phase chromatography (25 g C18, eluting with MeCN 20-95% in water) to provide the title compound (0.11 g).1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1H), 7.58 (d, 1H), 7.38 (t, 1H), 7.22 (d, 1H), 7.13 (d, 1H), 7.02 (dd, 1H), 6.55 (d, 1H), 6.35 (q, 1H), 4.40-4.32 (m, 1H), 4.12-4.01 (m, 1H), 3.46- 3.36 (m, 4H), 3.09 (s, 3H), 2.90-2.82 (m, 2H), 2.13-2.05 (m, 1H), 1.82-1.66 (m, 3H). LCMS (Method P): 535.2 [M+H]+.Example 91: / V-((3S)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopiperidin-3-yl)methanesulfonamide - Diastereomer 1

[0377] Example 90 was purified by preparative SFC (LUX Cellulose-4, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 65% CO2 with 35% MeOH modifier) to provide Example 91 (34 mg) as Peak 1 and Example 92 (24 mg) as Peak 2.Example 91:1H NMR (400 MHz; DMSO-d6) 6: 8.01 (d, 1H), 7.58 (d, 1H),7.37 (t, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1H), 6.55 (d, 1H), 6.35 (q, 1H), 4.40-4.32 (m, 1H), 4.12- 4.01 (m, 1H), 3.46-3.36 (m, 4H), 3.03 (s, 3H), 2.85 (dd, 2H), 2.12 - 2.04 (m, 1H), 1.82- 1.66 (m, 3H). LCMS (Method O): 535.4 [M+H]+. Example 92:1H NMR (400 MHz; DMSO- d6) 5: 8.01 (d, 1H), 7.57 (d, 1H), 7.37 (t, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 7.02 (dd, 1H), 6.55 (d, 1H), 6.35 (q, 1H), 4.40-4.32 (m, 1H), 4.12-4.01 (m, 1H), 3.47-3.36 (m, 4H), 3.03 (s, 3H), 2.89 - 2.82 (m, 2H), 2.13 - 2.05 (m, 1H), 1.82 - 1.66 (m, 3H). LCMS (Method O): 535.4 [M+H]+.Example 93: 2-(1-(5-((5-Chloro-4-fluoro-2,3-dihvdro-1H-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-8-(methylsulfonyl)-2,8-diazaspiror4.5ldecan-1-one

[0378] Prepared in an analogous manner to Example 1 using Intermediate 119 (0.14 g, 0.28 mmol), methanesulfonyl chloride (21 pL, 0.28 mmol), triethylamine (58 pL, 0.28 mmol) in DCM (1.4 mL) at RT for 16 h. Purified by Prep-TLC (Silica plate, eluting 70% EtOAc in cyclohexane) to provide the title compound (17 mg).1H NMR (400 MHz; DMSO- d6) 5: 8.01 (d, 1H), 7.38 (t, 1H), 7.25 (d, 1H), 7.13 (d, 1H), 7.02 (dd, 1H), 6.57 (d, 1H), 5.78 (q, 1 H), 4.40 - 4.32 (m, 1 H), 3.52 - 3.36 (m, 8H), 2.92 - 2.70 (m, 5H), 2.03 - 1.80 (m, 2H), 1.78-1.65 (m, 2H), 1.56 (d, 1 H), 1.44 (d, 1 H). LCMS (Method R): 574.9 [M+H]+.Example 94: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-1,7-diazaspiro[4.4lnonane-2, 6-dione - Diastereomer 1Example 95: 7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-2- yl)-2, 2, 2-trifluoroethyl)-1,7-diazaspiro[4.4lnonane-2, 6-dione - Diastereomer 2

[0379] To a stirred solution of Intermediate 147 (0.12 g, 0.17 mmol) in DCM (4.0 mL) was added TFA (27 pL, 0.35 mmol) and stirred at RT for 1 h. The mixture was concentrated under reduced pressure then diluted with saturated aqueous NaHCOs and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative SFC (DCPAK P4VP, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 80% CO2with 20% (10 mM in NH4HCO3 in 1 :1 MeCN I MeOH) modifier). Chiral purification was carried out preparative SFC (Chiralpak®-AD-H, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2with 40% MeOH modifier) to provide Example 94 (12 mg) as Peak 1 and Example 95 (13 mg) as Peak 2. Example 94:1H NMR (400 MHz; DMSO-d6) 5: 8.11 (s, 1 H), 8.01 (d, 1 H), 7.37 (t, 1 H), 7.25 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.57 (d, 1 H), 5.72 (q, 1 H), 4.40 - 4.31 (m, 1 H), 3.58 - 3.49 (m, 1 H), 3.44 - 3.36 (m, 2H), 3.30 - 3.22 (m, 1 H), 2.90 - 2.83 (m, 2H), 2.30 - 2.05 (m, 4H), 1.93 - 1.89 (m, 2H). LCMS (Method A): 497.2 [M+H]+. Example 95:1H NMR (400 MHz; DMSO-d6) 5: 8.11 (s, 1 H), 8.01 (d, 1 H), 7.37 (t, 1 H), 7.25 (d, 1 H), 7.12 (d, 1 H), 7.02 (dd, 1 H), 6.57 (d, 1 H), 5.74 (q, 1 H), 4.40 - 4.31 (m, 1 H), 3.58 - 3.50 (m, 1 H), 3.46 - 3.36 (m, 2H), 3.29 - 3.21 (m, 1 H), 2.90 - 2.83 (m, 2H), 2.30 - 2.13 (m, 2H), 2.11 - 2.05 (m, 2H), 1.93 - 1.89 (m, 2H). LCMS (Method A): 497.2 [M+H]+.Example 96: A / -((3S)-1-((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3- vDcyclopropanesulfonamide

[0380] Prepared in an analogous manner to Example 1 using Intermediate 137 (90 mg, 0.16 mmol), cyclopropanesulfonyl chloride (47 pL, 0.46 mmol), triethylamine (0.13 mL, 0.92 mmol) in DCM (1.5 mL) at 0 °C then RT for 16 h. Purified by reverse phase chromatography (25 g C18, eluting water with MeCN 20-95%) to provide the title compound (0.10 g).1H NMR (400 MHz; DMSO-d6) 5: 8.01 (d, 1 H), 7.67 (d, 1 H), 7.37 (t, 1 H), 7.26 (d, 1 H), 7.12 (d, 1 H), 7.01 (dd, 1 H), 6.57 (d, 1 H), 5.75 (q, 1 H), 4.38 - 4.33 (m, 1 H), 4.15 - 4.05 (m, 1 H), 3.52 (t, 1 H), 3.45 - 3.34 (m, 2H), 3.23 - 3.17 (m, 1 H), 2.90 - 2.82 (m, 2H), 2.72 - 2.68 (m, 1 H), 2.41 - 2.32 (m, 1 H), 1.91 - 1.77 (m, 1 H), 0.95 - 0.90 (m, 4H). LCMS (Method Q): 547.0 [M+H]+.Example 97: 2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiror5.5]undecan-1-one 9,9-dioxide -Diastereomer 1Example 98: 2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3- yl)-2,2,2-trifluoroethyl)-9-thia-2-azaspiror5.5]undecan-1-one 9,9-dioxide -Diastereomer 2

[0381] Prepared in an analogous manner to Intermediate 4 using Intermediate 150 (0.29 g, 0.56 mmol), 5-chloro-4-fluoroindan-2-amine hydrochloride (0.15 g, 0.67 mmol, CAS 2740843-37-0), CS2CO3 (0.55 g, 1.68 mmol), Pd2(dba)s (51 mg, 56 pmol) and rac- BINAP (70 mg, 0.11 mmol) in 1 ,4-dioxane (58 mL) at 100 °C for 16 h. Purified by flash chromatography (silica gel, eluting 0-55% EtOAc in hexane). Chiral purification by preparative SFC (Chiralpak®-IH, 30 x 250 mm x 5 pm, temp 30 °C, Back Pressure 100 bar, flow rate: 100 g / min, 60% CO2 with 40% MeOH modifier) to provide Example 97 (11 mg) as Peak 1 and Example 98 (10 mg) as Peak 2. Example 97:1H NMR (400 MHz; DMSO- d6) 5: 8...

Claims

CLAIMS1. A compound according to Formula I, or a pharmaceutically acceptable salt thereof:wherein:R1and R2are independently selected from hydrogen and halo;R3and R4are independently selected from hydrogen, Ci-4alkyl, Ci.4alkoxy, Ci- 4haloalkyl, Ci.4haloalkoxy, halo, cyano, hydroxy, Cs-ecycloalkyl, S(O)2Ci-4alkyl, and 3-, 4-, or 5-membered heterocyclyl;R5a, R5b, R6a, and R6bare independently selected from hydrogen and Ci-4alkyl;X1, X2, and X3are independently selected from CH or N;Ring A is a 5- or 6-membered heterocyclic ring: i) optionally comprising one or more additional heteroatoms selected from N, O and S(O)n, wherein n is 0, 1 , or 2; ii) optionally substituted with one or more substituents independently selected from 5- or 6-membered heterocyclyl and Y1a-R7a; wherein Y1ais Ci-salkylene, C(O), NR8a, S(O)2, or NR8aS(O)2, and R7ais Ci-4alkyl, NR9aR10aor Cs-ecycloalkyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring optionally substituted with one or more substituents independently selected from oxo and Y1 b-R7b; wherein Y1 bis Ci.3alkylene, C(O), NR8b, S(O)2or NR8bS(O)2, and R7bis Ci-4alkyl, NR9bR10bor Cs-ecycloalkyl;R8a, R8b, R10a, and R10bare independently selected from hydrogen and Ci-4alkyl;R9aand R9bare independently selected from hydrogen, Ci-4alkyl, and Cs-ecycloalkyl; X4is CR11R12, NR13, O, S(O)m, or S(O)NHR14, wherein m is 0, 1 , or 2;R11and R12are independently selected from hydrogen, Y1c-R7c, and 4-, 5- or 6- membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from Ci-salkyl, oxo, and Ci-salkylene-Cs-ecycloalkyl; wherein Y1cis S(0)2, NR8cC(O), or NR8cS(O)2, and R7cis Ci-4alkyl, NR9cR10c, or Cs-ecycloalkyl; ORR11and R12, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring optionally substituted with one or more substituents independently selected from oxo and Y1d-R7d; wherein Y1dis Ci- 3alkylene, C(O), NR8d, S(O)2or NR8dS(O)2, and R7dis Ci-4alkyl, Ci-4alkoxy, NR9dR10dor Cs-ecycloalkyl; andR13is hydrogen, Ci-salkyl, 5- or 6-membered heteroaryl, or 4-, 5- or 6-membered heterocyclyl, wherein said heteroaryl or heterocyclyl group is optionally substituted with one or more substituents independently selected from Ci-salkyl, oxo, and Ci- salkylene-Cs-ecycloalkyl; andR8c, R8d, R9c, R9d, R10c, and R10dare independently selected from hydrogen and Ci- 4alkyl.

2. A compound according to claim 1 , wherein the compound is of formula IA, or a pharmaceutically acceptable salt thereof:wherein, R1, R2, R3, R4, R5a, R5b, R6a, R6b, Ring A, X1, X2, X3, and X4are as defined in claim 1.

3. A compound according to claim 1 or claim 2, wherein R1and R2are independently selected from hydrogen, fluoro and chloro.

4. A compound according to claim 3, wherein R1and R2are both hydrogen.

5. A compound according to any one of claims 1 to 4, wherein R3and R4are independently selected from hydrogen, methyl, methoxy, trifluoromethyl, fluoro, chloro, cyano, hydroxy, and cyclopropyl.

6. A compound according to claim 5, wherein R3and R4are independently selected from hydrogen, fluoro, chloro, and cyclopropyl.

7. A compound according to claim 6, wherein R3is chloro.

8. A compound according to any one of claims 1 to 7, wherein R4is fluoro.

9. A compound according to any one of claims 1 to 8, wherein R5aand R5bare independently selected from hydrogen and methyl.

10. A compound according to any one of claims 1 to 9, wherein R6aand R6bare both hydrogen.

11. A compound according to any one of claims 1 to 10, wherein X1, X2, and X3are independently selected from CH or N, provided that at least one of X1, X2, and X3is N.

12. A compound according to claim 11 , wherein one of X1, X2, and X3is N, and the other two are CH.

13. A compound according to claim 12, wherein X3is N, and X1and X2are CH.

14. A compound according to any one of claims 1 to 13, wherein X4is CR11R12.

15. A compound according to claim 14, wherein R11and R12are independently selected from hydrogen, Y1c-R7cand 4-, 5- or 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and Ci-salkylene-Cs-ecycloalkyl; wherein Y1cis S(O)2, NR8cC(O), or NR8CS(O)2, and R7cis Ci-4alkyl, NR9cR10c, or Cs-ecycloalkyl.

16. A compound according to claim 14, wherein R11and R12, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d-R7d; wherein Y1dis Ci-salkylene, C(O), or S(O)2, and R7dis Ci-4alkyl, Ci-4alkoxy, NR9dR10dor Cs-ecycloalkyl.

17. A compound according to any one of claims 1 to 13, wherein X4is NR13.

18. A compound according to claim 17, wherein R13is hydrogen, methyl, 5- or 6- membered heteroaryl, or 4-, 5- or 6-membered heterocyclyl, wherein said heteroarylor heterocyclyl group is optionally substituted with one or more substituents independently selected from methyl, oxo, and CH2cyclopropyl.

19. A compound according to any one of claims 1 to 18, wherein Ring A is a 5- or 6- membered heterocyclic ring: i) optionally comprising one additional heteroatom selected from N, O and S(O)2; ii) optionally substituted with a substituent selected from 5- or 6-membered heterocyclyl and Y1a-R7a; wherein Y1ais Ci-salkylene, C(O), NR8a, S(O)2 or NR8aS(O)2, and R7ais Ci-4alkyl, NR9aR10aor C3.6cycloalkyl; and iii) optionally spiro-attached to a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or two substituents independently selected from oxo and Y1 b-R7b; wherein Y1 bis Ci-salkylene and R7bis Cs-ecycloalkyl.

20. A compound according to any one of claims 1 to 13, wherein Ring A is selected from: whereinare independently selected from CR15R16, NR17, O, and S(O)n, wherein R11, R12and R13are as defined in claim 1 ; R15and R16are independently selected from hydrogen, S(O)2Me, and 5- or 6-membered heterocyclyl; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs-ecycloalkyl; and R17is hydrogen, 5- or 6-membered heterocyclyl ring, or Y2-R18, wherein Y2is Ci-salkylene, C(0), or S(0)2, and R18is Ci- 4alkyl, NR9aR10aor Cs-ecycloalkyl; m and n are independently 0, 1 , or 2; provided that: (i) if X4is NR13, O, S(O)n, or S(O)NHR14, then X5is CR15R16; and (ii) if X5is NR17, O, or S(O)m, then X4is CR11R12and X6is CR15R16.

21. A compound according to any one of claims 1 to 13, wherein Ring A is selected from:wherein R11and R12are independently selected from hydrogen, Y1c-R7cand and 4-,5- or 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from oxo, and Ci-salkylene- cyclopropyl, and wherein Y1cis S(O)2, NHC(O), or NHS(O)2, and R7cis methyl, NR9cR10c, or cyclopropyl; or R11and R12taken together with the carbon atom to which they are attached form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Y1d- R7d; wherein Y1dis Ci.2alkylene, C(O), or S(O)2, and R7dis methyl, methoxy, NMe2 or cyclopropyl; R13is hydrogen, Ci-salkyl, 5- or 6-membered heteroaryl, or 4-, 5- or6-membered heterocyclyl, wherein said heteroaryl or heterocyclyl is optionally substituted with one or more substituents independently selected from Ci-salkyl, oxo, and Ci-salkylene-Cs-6cycloalkyl; R15and R16are both hydrogen; or R15is S(O)2Me and R16is hydrogen; or R15and R16, taken together with the carbon atom to which they are attached, form a 4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs- ecycloalkyl; and R17is hydrogen, a 6-membered heterocyclyl ring or Y2-R18, wherein Y2is CH2, C(O), or S(O)2, and R18is methyl, NHcyclopropyl, or cyclopropyl.

22. A compound according to claim 1, wherein the compound has one of the structural formulae IB to IL shown below, or a pharmaceutically acceptable salt thereof:wherein X1, X2, X3, X4, R1, R2, R3, R4, R5a, R5b, R6a, and R6bare as defined in claim 1 ; and X5and X6are independently selected from CR15R16, NR17, O, and S(O)n; wherein R15and R16are both hydrogen; or R15is S(O)2Me and R16is hydrogen; or R15and R16, taken together with the carbon atom to which they are attached, form a4-, 5- or 6-membered heterocyclyl ring, optionally substituted with one or more substituents independently selected from oxo and Ci-salkylene-Cs-ecycloalky; and R17is hydrogen, 5- or 6-membered heterocyclyl ring, or Y2-R18, wherein Y2is Ci- salkylene, C(O), or S(O)2, and R18is Ci-4alkyl, NR9aR10aor Cs-ecycloalkyl; and n is 0, 1 , or 2; provided that: (i) if X4is NR13, O, S(O)n, or S(O)NHR14, then X5is CR15R16; and (ii) if X5is NR17, O, or S(O)m, then X4is CR11R12and X6is CR15R16.

23. A compound according to claim 1 , wherein the compound is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: A / -((S)-1-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)- 2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)methanesulfonamide;2-(( )-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one;2-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one;2-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one;2-((S)-1-(5-(((S)-1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)- / V, / V-dimethyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide;1-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)piperazin-2-one;8-(Cyclopropanecarbonyl)-2-((S)-1-(5-(((S)-1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one;8-(Cyclopropylsulfonyl)-2-((S)-1-(5-(((S)-1 ,1-dimethyl-2,3-dihydro-1 H-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one;1-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-4-(methylsulfonyl)piperazin-2-one;4-(Cyclopropanecarbonyl)-1-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one;4-(Cyclopropylmethyl)-1-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one;8-(Cyclopropylmethyl)-2-((S)-1-(5-(((S)-1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-1-one;4-(Cyclopropylsulfonyl)-1-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)piperazin-2-one;A / -Cyclopropyl-4-(1-(5-((1 ,1-dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)- 2, 2, 2-trifluoroethyl)-3-oxopiperazine-1 -carboxamide;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-methylimidazolidin-2-one;3-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)oxazolidin-2-one;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-methyltetrahydropyrimidin-2(1 / - / )-one;3-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1 ,3-oxazinan-2-one;4-(1-(5-((1 ,1-Dimethyl-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)morpholin-3-one;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-oxa-2-azaspiro[4.5]decan-1-one;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)pyrrolidin-2-one;3-((3S)-1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxopyrrolidin-3-yl)-1 ,1 -dimethylurea;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-2-one;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(2-methyl-2H-1 ,2,3-triazol-4-yl)tetrahydropyrimidin-2(1 / 7)-one;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-thia-2-azaspiro[4.5]decan-1-one 8,8-dioxide;9-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-oxa-9-azaspiro[5.5]undecan-8-one;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-9-oxa-2-azaspiro[5.5]undecan-3-one;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-9-oxa-2-azaspiro[5.5]undecan-1-one;N-((3S)-1-((1 S)-1-(5-((5-chloro-4-cyclopropyl-2,3-dihydro-1 / 7-inden-2- yl)amino)pyridin-2-yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)methanesulfonamide;1-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(1-methyl-1 / 7-pyrazol-4-yl)tetrahydropyrimidin-2(1 / 7)-one;1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(1 ,1-dioxidotetrahydro-2 / 7-thiopyran-4-yl)tetrahydropyrimidin-2(1 / 7)- one;1-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-3-(1 ,1-dioxidotetrahydro-2 / 7-thiopyran-4-yl)tetrahydropyrimidin-2(1 / 7)- one;2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]decan-1-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-9-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-1-one;6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxa-6-azaspiro[3.4]octan-5-one;6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-oxa-6-azaspiro[3.4]octan-7-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,7-diazaspiro[4.4]nonane-1 , 8-dione;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-7-(cyclopropylmethyl)-2,7-diazaspiro[4.4]nonan-1-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-7-(cyclopropylmethyl)-2,7-diazaspiro[4.4]nonan-3-one;8-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,8-diazaspiro[4.5]decane-3, 7-dione;2-(1-(5-((5-Chloro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]decan-1-one;N-((3R)-1-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2.2.2-trifluoroethyl)-2-oxopyrrolidin-3-yl)methanesulfonamide;N-((3R)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-2-oxopiperidin-3-yl)methanesulfonamide;1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-((R)-1-(cyclopropylmethyl)pyrrolidin-3-yl)tetrahydropyrimidin-2(1 / 7)- one;6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-(methylsulfonyl)-2,6-diazaspiro[3.4]octan-5-one;6-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-5-one;1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-3-(oxetan-3-yl)tetrahydropyrimidin-2(1 / 7)-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(cyclopropylmethyl)-2,8-diazaspiro[4.5]decan-1-one;7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,7-diazaspiro[4.5]decane-1, 6-dione;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-2,7-diazaspiro[4.4]nonane-1, 6-dione;7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1,7-diazaspiro[4.5]decane-2, 6-dione;N-((3S)-1-((1S)-1-(5-((5-chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)methanesulfonamide;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(cyclopropylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(2-methoxyethyl)-2,8-diazaspiro[4.5]decan-1-one;4-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1-oxa-9-thia-4-azaspiro[5.5]undecan-5-one 9,9-dioxide;A / -((3S)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-2-oxopiperidin-3-yl)cyclopropanesulfonamide;N-((3S)-1-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2.2.2-trifluoroethyl)-2-oxopiperidin-3-yl)methanesulfonamide;7-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-1 ,7-diazaspiro[4.4]nonane-2, 6-dione;N-((3S)-1-((1 S)-1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2- yl)-2,2,2-trifluoroethyl)-2-oxopyrrolidin-3-yl)cyclopropanesulfonamide;2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-9-thia-2-azaspiro[5.5]undecan-1-one 9,9-dioxide;2-(1-(5-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-2-yl)-2,2,2- trifluoroethyl)-8-(methylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one;2-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-9-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-1-one;4-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2,2,2- trifluoroethyl)-9-(cyclopropylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one; and A / -((3S)-1-(1-(6-((5-Chloro-4-fluoro-2,3-dihydro-1 / 7-inden-2-yl)amino)pyridin-3-yl)-2.2.2-trifluoroethyl)-2-oxopiperidin-3-yl)methanesulfonamide.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

25. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for use in therapy.

26. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for use in the treatment of diseases or disorders mediated by MALT1.

27. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24, for use in the treatment of non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large 13- 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 leukaemia (CLL), small lymphocytic lymphoma (SLL),Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), 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, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis.

28. A method of treating a disease or disorders mediated by MALT1 , said 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 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24.

29. A method of treating non-Hodgkin's lymphoma (IN-IL), B-cell NHL, diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukaemia, chronicmyelogenous leukaemia (CML), hairy-cell leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia, erythroleukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, oesophageal cancer, salivary gland cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumour), 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, dermatomyositis, psoriasis, Behcet's diseases, uveitis, myasthenia gravis, Grave's disease, Hashimoto thyroiditis, Sjoergen's syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, or polymyositis, said 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 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24.

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