Therapeutic compounds

Abstract

The present disclosure relates to compounds that are IL-17A modulators. The compounds have structural formula I, as defined herein. The disclosure also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or disorders associated with modulation of IL-17A activity. [Formula 1] TIFF2026500183000571.tif38133

Description

[Technical Field]

[0001] The present disclosure relates to therapeutic compounds. More specifically, the present disclosure relates to compounds that are modulators of IL-17A activity. The present disclosure also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or disorders associated with IL-17A activity. [Background technology]

[0002] The interleukin-17 cytokine family consists of six members (termed IL-17A through IL-17F), of which IL-17A (also known as CTLA-8) is the major effector cytokine of the T-helper-17 (Th17) cell lineage.

[0003] IL-17A is a 34-38 kDa variably glycosylated, disulfide-linked homodimeric glycoprotein that shares approximately 50% homology with its closest family member, IL-17F, and both can be secreted as either homodimers or heterodimeric IL-17AF [KF Geoghegan et al., Protein Expression and Purification 2013, 87, 27-34; JK Kolls and A. Linden / Immunity 2004, 21, 467-476].

[0004] Activation of naive CD4+ T cells in response to cytokines such as IL-6, transforming growth factor-β (TGF-β), IL-23, STAT3, and RORγt leads to their differentiation into Th17 cells and the expression of proinflammatory mediators such as IL-17A. Furthermore, various cell types from the innate and adaptive immune systems have been identified as sources of IL-17A. These include mast cells, neutrophil granulocytes, NK cells, NKT cells, CD8+ T cells, delta-γT cells, macrophages, and type 3 innate lymphoid cells [DJ Cua and CMTato, Nat Rev Immunol 2010, 10, 479-489; W. Jin and C. Dong, Emerging Microbes & Infections 2013, 2, e60].

[0005] The cytokines IL-17A, IL-17F, and IL-17AF bind to a common heteromeric receptor complex, IL-17RA and IL-17RC, albeit with different affinities. Although various cell types have been reported to express IL-17RA subunits, the highest response to IL-17A comes from epithelial cells, endothelial cells, keratinocytes, and fibroblasts [TA Moseley et al., Cytokine Growth Factor Reviews. 2003, 14, 155-174; S.L. Gaffen, Nature Rev Immunol 2009, 9, 556-567; R.M. Onishi and S.L. Gaffen, Immunology 2010, 129, 311-321].

[0006] Binding of IL-17A to its receptor activates various signaling pathways, such as nuclear factor (NF)-κB, phosphoinositide 3-kinase (PI3K), activator protein (AP1), CCAAT / enhancer-binding protein (C / EBP), and mitogen-activated protein kinase (MAPK), resulting in pro-inflammatory gene expression and the secretion of various pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, TNFα, G-CSF, PGE2, and IFN-γ, as well as numerous chemokines and other effectors [SL Gaffen, Arthritis Research & Therapy 2004, 6, 240-247; SLGaffen, Nature Rev Immunol 2009, 9, 556-567; R.M. Onishi and SLGaffen, Immunology 2010, 129, 311-321]. The attraction and activation of cells of the innate immune system to the site of inflammation completes the induction of an inflammatory loop that may be cooperatively mediated by other cytokines such as TNFα, IFN-γ and IL-1β [SL Gaffen, Arthritis Research & Therapy 2004, 6, 240-247].

[0007] These IL-17-mediated biological processes are involved in a variety of conditions, including psoriasis, ankylosing spondylitis, axial spondyloarthritis, psoriatic arthritis, eczema, enthesitis-related arthritis, asthma (including severe asthma), chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, ulcerative colitis, Crohn's disease, atopic dermatitis, contact dermatitis, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, pilonidal disease, peritonitis, multiple sclerosis, Guillain-Barré syndrome, and others. The pathogenesis of many human diseases with immune components or autoimmune pathologies, such as irritable bowel syndrome, inflammatory bowel disease, Castleman's disease, pelvic inflammatory disease, systemic juvenile idiopathic arthritis (JIA), rheumatoid arthritis, giant cell arteritis, graft-versus-host disease, discoid lupus erythematosus, systemic lupus erythematosus, lupus nephritis, vasculitis, insulin-dependent diabetes mellitus type 1, autoimmune diabetes, diabetic necrobiosis lipoidica, pyoderma gangrenosum, hidradenitis suppurativa, papulopustular rosacea, and lichen planus (Solimani). et al (2019) Front Immunol. 10:1808) and cancer (Bartlett, HS; Million, RP (2015) Nat. Rev. Drug Discovery 14:11-12; Santibanez, JF; Bjelica, S (2018) Recent Pat Anticancer Drug Discov. 13(2):133-144). In addition, due to the emerging role of neuroinflammation in neurodegeneration, IL-17 has also been implicated in the progression of neurodegenerative disorders such as Alzheimer's disease (Cristiano et al (2019) Br J Pharmacol. 176(18):3544-3557) and Parkinson's disease (Storelli et al, (2019) Front Neurol. 24;10:13). An association between serum levels of IL-17 at admission to the intensive care unit and the development of sepsis has also been observed, suggesting that increased IL-17 may increase susceptibility to septic complications and infection-related endotoxic shock [Ahmed et al., Eur J Trauma Emerg Surg 2018,44(4):621-626].Its role in sepsis has also been suggested to extend to patients with sepsis-induced acute respiratory distress syndrome (ARDS) and acute lung injury [Ding et al., Oncotarget 2017, 8(55):93704-93711]. Recently, inhibition of IL-17 has also been proposed to be used to prevent acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) [Pacha, Sallman & Evans., Nat Rev Immunol 2020, 1:1-2].

[0008] Preclinical studies have demonstrated that IL-17A (as well as IL-17F and IL-17C) are elevated in psoriatic skin [NJ Wilson et al., Nat Immunol 2007, 8, 950-957; L.C. Zaba et al., J Exp Med 2007, 204, 3183-3194; C. Ortega et al., J Leukocyte Biol 2009, 86, 435-443; C. Johansen et al., Br J Dermatol 2009, 160, 319-324]. Th17 cells in the peripheral circulation and lesional skin of patients with psoriasis have also been shown to positively correlate with disease severity as measured by the Psoriasis Area and Severity Index (PASI) score [L. Zhang et al., Clin Immunol 2010, 135, 108-117]. Serum IL-17A levels are also significantly correlated with PASI scores [H. Takahashi et al., Clin Exp Dermatol 2010, 35, 645-649; SBYilmaz et al. Arch Dermatol Res 2012, 304, 465-469; M. Caproni et al., J Clin Immunol 2009, 29, 210-214].

[0009] Animal model studies support the hypothesis that targeting the IL-17A pathway is an effective treatment for psoriasis [L. van der Fits et al., J Immunol 2009, 182, 5836-5845; K. El Malki et al., J Investig Dermatol 2013, 133, 441-451; J. Skepner et al., J Immunol 2014, 192, 2564-2575], and clinical results with antibodies against IL-17A or IL-17RA have provided final validation, with excellent efficacy observed [R. G. Langley et al., N Engl J Med 2014, 371, 326-338; K. B. Gordon et al., N Engl J Med 2016, 375, 345-356; A. S. Lonnberg et al., Clin Cosmet Investig Dermatol 2014,7,251-259;S.Coimbra et al.,Core Evid 2014,9,89-97;M.Lebwohl et al.,N Engl J Med 2015,373,1318-1328].

[0010] Elevated levels of IL-17A or IL-17F have been reported in several other diseases, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), bone erosion, intra-abdominal abscess, graft rejection, angiogenesis, atherosclerosis, and asthma [e.g., S.L. Gaffen, Arthritis Research & Therapy 2004, 6, 240-247; L.A. Tesmer et al., Immunol Rev 2008, 223, 87-113; US Publ No 20080269467].

[0011] The anti-IL-17A therapeutic antibodies secukinumab and ixekizumab have been shown to be effective in palmoplantar and nail psoriasis [A. Gottlieb et al., J Am Acad Dermatol 2016,76,70-80; A. Menter et al., J Eur Acad Dermatol Venereol 2017,31,1686-1692; C. Paul et al., J Eur Acad Dermatol Venereol 2014,28,1670-1675], PsA [P. Mease et al., Ann Rheum Dis 2018,77,890-897; P. Nash et al., Lancet 2017,389,2317-2327], and AS [K. Pavelka et al., Arthritis Res Ther 2017,19,285; A.Deodhar et al.,Arthritis Rheumatol 2018,doi:10.1002 / art.40753]. Proof-of-concept trials with secukinumab in MS have also shown promising signs of efficacy [E.Havdrova et al.,J Neurol 2016,263,1287-1295].

[0012] IL-17A expression has been shown to be increased in SLE patients and correlates with disease severity [Y. Wang et al., Clin Exp Immunol 2009, 159, 1-10; XQ Chen et al., J Clin Immunol 2010, 30, 221-225].

[0013] Additionally, IL-17A has been associated with ocular surface disorders such as DES [PCT Publications WO 2009089036, WO 2010062858, and WO 2011163452; CSDe Paiva et al., Mucosal Immunol 2009, 2, 243-253], and Th17 cells have been shown to be elevated in active uveitis and scleritis [A. Amadi-Obi et al., Nat Med 2007, 13, 711-718]. IL-17A levels in tears were associated with the clinical severity of dry eye in patients with a range of systemic autoimmune or inflammatory diseases, including Sjögren's syndrome, Stevens-Johnson syndrome (SJS), SLE, filamentous keratitis, DES, meibomian gland dysfunction (MGD), and graft-versus-host disease (GVHD) [MH Kang et al., J Korean Med Sci 2011,26,938-944].

[0014] Several studies have demonstrated that IL-17A is overexpressed in patients with various cancers, including gastric cancer, medulloblastoma, multiple myeloma, colorectal cancer, non-small cell lung cancer (NSCLC), breast cancer, hepatocellular carcinoma (HCC), and thyroid cancer [X. Meng et al., Turk J Gastroenterol 2018,29,45-51; P. Zhou et al., J Int Med Res 2010,38,611-619; D. Lemancewicz et al., Med Sci Monit 2012,18,BR 54-59; S. Le Gouvello et al., Gut 2008,57,772-779; B. Pan et al., Sci Rep 2015,5,16053; T. Welte and XH-F. Zhang, Mediators of Inflammation 2015,804347;JF.Tu et al.,Medicine(Baltimore)2016,95,e3220;DFG Carvalho et al.,Oncol Lett 2017,13,1925-1931]. Increased levels of IL-17A have been shown to correlate with poor prognosis in several cancer types, including malignant thyroid tumors, breast cancer, pancreatic cancer, gastric cancer, NSCLC, colorectal cancer, and head and neck cancer [S. Punt et al., OncoImmunol 2015,4,e984547; DFG Carvalho et al., Oncol Lett 2017,13,1925-1931; WC. Chen et al., Histopathology 2013,63,225-233; C. Xu et al., Biomarkers 2014,19,287-290; Y. Yamada et al., J Surg Res 2012,178,685-691; S. He et al., Int J Mol Sci 2011,12,7424-7437; JY. Tseng et al. al., Clin Cancer Res 2014,20,2885-2897; MH. Lee et al., Oncotarget 2018,9,9825-9837].

[0015] Taken together, modulation of the IL-17A pathway, in particular modulation of IL-17A activity by inhibiting its interaction with its receptor IL-17RA, may be considered a target for the treatment of pathologies related to the immune system and inflammation, cancer and neurodegenerative disorders.

[0016] WO 2013 / 116682, WO 2014 / 066726 and WO 2018 / 229079 describe classes of chemical compounds that are said to modulate the activity of IL-17 and are useful in the treatment of medical conditions, including inflammatory diseases. Summary of the Invention [Problem to be solved by the invention]

[0017] Nevertheless, there is a continuing need for compounds that can attenuate IL-17A activity. [Means for solving the problem]

[0018] In one aspect, the disclosure provides a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0020] In another aspect, the present disclosure relates to a compound of the present disclosure as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0021] In another aspect, the present disclosure relates to a compound of the present disclosure as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder associated with IL-17A activity.

[0022] In another aspect, the present disclosure relates to the use of a compound of the present disclosure, as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder associated with IL-17A activity.

[0023] In another aspect, the present disclosure relates to a method of treating a disease or disorder associated with IL-17A activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0024] Examples of diseases or disorders associated with IL-17A activity include diseases with an immune component or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer and neurodegenerative disorders.

[0025] In another aspect, the present disclosure provides a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of diseases with an immune component or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and neurodegenerative disorders.

[0026] In another aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt in the manufacture of a medicament for use in the treatment of diseases with an immune component or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer and neurodegenerative disorders.

[0027] In another aspect, the present disclosure provides methods of treating diseases with an immune component or autoimmune pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer and neurodegenerative disorders, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition.

[0028] The present disclosure further provides methods of synthesizing compounds as defined herein or pharmaceutically acceptable salts thereof.

[0029] In another aspect, the present disclosure provides compounds or pharmaceutically acceptable salts thereof that are obtainable, obtained, or directly obtained by a method of synthesis as defined herein.

[0030] In another aspect, the present disclosure provides novel intermediates, as defined herein, that are suitable for use in any one of the synthetic methods described herein.

[0031] Convenient, preferred and optional features of any one particular embodiment of the present disclosure are also convenient, preferred and optional features of any other embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0032] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0033] References to "treating" or "treatment" should be understood to include prevention and alleviation of established symptoms of a condition. Thus, "treating" or "treating" a condition, disorder, or condition includes (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition that occur in a person who may be afflicted with or susceptible to the condition, disorder, or condition, but who has not yet experienced or exhibited clinical or asymptomatic symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or asymptomatic symptom thereof; or (3) relieving or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or asymptomatic symptom thereof.

[0034] A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect 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 being treated.

[0035] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group and includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," are specific for the straight-chain version only, and references to individual branched-chain alkyl groups, such as "isopropyl," are specific for the branched-chain version only. For example, "C 1~6 As for "alkyl", C 1~4 Alkyl, C 1~3 alkyl, propyl, isopropyl, and t-butyl. A similar convention applies to other groups, e.g., "phenyl C 1~6 As for "alkyl", phenyl C 1~4 Examples include alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0036] The term "alkylene" includes both straight and branched chain divalent alkyl groups. For example, "C 1~4 "Alkylene" includes methylene (-CH2-), ethylene (-CH2-CH2-), methylmethylene (-CH(CH3)-), propylene, and butylene.

[0037] The term "alkoxy" includes both straight and branched chain alkyl groups single-bonded to oxygen. For example, "C 1~4 "Alkoxy" includes methoxy, ethoxy, isopropoxy and t-butoxy.

[0038] The term "C" is also used as a prefix. m~n " refers to any group having m to n carbon atoms.

[0039] "Cycloalkyl" means a hydrocarbon ring containing 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane, and bicyclo[2.2.1]heptyl.

[0040] The term "halo" refers to fluoro, chloro, bromo or iodo.

[0041] The terms "haloalkyl" or "haloalkoxy" are used herein to refer to an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms have been replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl and haloalkoxy groups include fluoroalkyl and fluoroalkoxy groups, such as -CHF, -CHCF, or perfluoroalkyl / alkoxy groups such as -CF, -CFCF, or -OCF.

[0042] The terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to a non-aromatic saturated or partially unsaturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system. Monocyclic heterocyclic rings contain about 3 to 12 (preferably 3 to 7) ring atoms, with 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocyclic rings contain 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic rings can be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Regarding sulfur-containing heterocycles, oxidized sulfur heterocycles containing SO or SO groups are also included. Examples include sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for a heterocyclyl group having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. Partially unsaturated heterocyclyl rings contain at least one double bond, such as one or two double bonds. Examples of partially unsaturated heterocyclyl rings include 1,6-dihydropyridinyl, 1,6-dihydropyridazinyl, and 2,3-dihydropyrrolyl. As will be appreciated by those skilled in the art, any heterocycle can be linked to another group via any suitable atom, such as a carbon or nitrogen atom. Suitably, the terms "heterocyclyl", "heterocyclic" or "heterocycle" refer to a 4-, 5-, 6- or 7-membered monocyclic ring as defined above.

[0043] The term "bridged ring system" refers to a ring system in which two rings share three or more atoms. See, for example, Advanced Organic Chemistry, 4th Edition, Wiley Interscience, pp. 131-133, 1992, by Jerry March. Examples of bridged heterocyclyl ring systems include, for example, azabicyclo[3.1.0]hexane, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0044] The term "spirobicyclic ring system" means that two ring systems share one common spiro carbon atom, i.e., a heterocyclic ring is linked to an additional carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spirobicyclic ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, and 2-oxa-6-azaspiro[3.3]heptane.

[0045] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, such as fused 5- and 6-membered rings or a bicyclic structure formed from two fused 6-membered rings. Each ring can typically contain up to about four heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to three heteroatoms, more typically up to two, e.g., one heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, is less than 5. Heteroaryl groups containing nitrogen atoms can exist as the corresponding N-oxides. A specific example of such a heteroaryl group is pyridine N-oxide. Preferably, the term "heteroaryl" or "heteroaromatic" refers to a 5- or 6-membered monocyclic heteroaryl ring as defined above.

[0046] Non-limiting examples of heteroaryl groups include oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, tetrazolyl, pyridyl and pyrimidinyl groups.

[0047] Non-limiting examples of 5-membered heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, pyrazolyl, and tetrazolyl groups.

[0048] Non-limiting examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl and pyrimidinyl groups.

[0049] Bicyclic heteroaryl groups include, for example: a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms, and A cyclopentyl ring fused to a 5- or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms It may be a group selected from:

[0050] Specific non-limiting examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0051] Specific non-limiting examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0052] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In one embodiment, aryl is phenyl or naphthyl. In another embodiment, aryl is phenyl.

[0053] The specification may also use multiple compound terms to describe groups containing two or more functionalities. Such terms will be understood by those skilled in the art. For example, heterocyclyl C 1~4 Alkyl is a C substituted by heterocyclyl 1~4 Contains alkyl.

[0054] The term "optionally substituted" refers to groups, structures, or molecules that are either substituted and those that are not substituted.

[0055] When optional substituents are selected from "one or more" groups, it is understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups. When there are multiple substituents, it is understood that the selected substituents can be the same or different.

[0056] Where a range of numerical values ​​is given, it is understood that the range includes the endpoints.

[0057] The phrase "compounds of the present disclosure" means compounds disclosed herein both generally and specifically.

[0058] Compounds of the Disclosure In a first aspect, the present disclosure provides a compound of formula I: [ka] (In the formula, Z is O or CR 6 R 7 and X 1 , X 2 and X 3 At least one of is N, and the others are CR 4 and Y is a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered heteroaryl fused to a 5- or 6-membered heterocyclyl, phenyl, heterocyclyl, C 3~7 Cycloalkyl and QR 8 is selected from iQ is absent, O or NR 9 and ii.R 8 is C 1~6 Alkyl, C 1~3 Alkylene-phenyl or C 1~3 alkylene-heteroaryl; iii. Y is one or more substituents Y A and optionally substituted with, in each occurrence, Y A are independently halo, oxo, C 1~4Alkyl, hydroxy, C 1~4 Alkoxy, C 1~3 Haloalkyl, cyano, C(O)R 10 and C 3~7 cycloalkyl, and iv.Y A Ha, Halo, C 1~4 Alkyl, hydroxy, C 1~4 Alkoxy, C 3~7 Cycloalkyl, C 1~3 Alkylene-NR 11 R 12 and C 1~3 optionally further substituted with one or more substituents independently selected from haloalkyl; R 1 and R 2 are independently hydrogen, C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~5 alkoxy and phenyl, 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~5 Alkoxy or phenyl is halo, C 1~4 Alkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl, with the proviso that R 1 and R 2 cannot both be hydrogen, or R 1 and R 2 together with the carbon atoms to which they are attached form a 4- to 10-membered cycloalkyl ring, and the cycloalkyl ring is 1~4 Alkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl; R 3 is hydrogen, fluoro or methyl, R in each occurrence 4 is independently selected from hydrogen, fluoro, methyl, hydroxy, and trifluoromethyl; R 5 is a 5- or 6-membered monocyclic heteroaryl, a 4- to 10-membered heterocyclyl, C(O)NR13 R 14 , OC(O)NR 15 R 16 and NR 17 C(O)C 1~6 alkyl, and R 13 , R 14 , R 15 , R 16 and R 17 are independently hydrogen and C 1~6 alkyl, and R 5 are hydroxy, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~3 Haloalkyl, C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl, cyano, and oxo; R 6 is hydrogen, fluoro, C 1~6 Alkyl or C 3~7 is cycloalkyl, and R 6 C 1~6 Alkyl or C 3~7 When cycloalkyl, the group may be selected from hydroxy, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkoxy; R 7 are hydrogen, deuterium, halo and C 1~4 alkyl; or R 6 and R 7 together with the carbon atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~3 forming a 3- to 6-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more substituents independently selected from haloalkyl; R 9 is hydrogen or C 1~4 is alkyl, R 10 is hydroxy, C 1~4 Alkyl or C1~4 is alkoxy, and R 11 and R 12 are independently hydrogen, C 1~4 Alkyl and C(O)OC 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0059] Specific compounds of the disclosure include, for example, compounds of Formula I or a pharmaceutically acceptable salt thereof, and unless otherwise specified, Z, X 1 , X 2 , X 3 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 and R 12 Each of has any of the meanings defined above or in any of paragraphs (1) to (99) below. For the avoidance of doubt, the present disclosure includes combinations of two or more substituent definitions as set out in paragraphs (1) to (99): (1) Z is O, (2) Z is CR 6 R 7 That is, (3)X 1 , X 2 and X 3 One of them is N, and the other is CR 4 That is, (4)X 1 and X 2 One of the is N, and X 3 is CR 4 That is, (5)X 1 is N and X 2 and X 3 is CR 4 That is, (6)X 1 is N and X 2 and X 3 is CH, (7)X 1 , X 2 and X 3 Two of them are N, and the other is CR. 4 That is, (8)X 1 and X 2 is N, and X 3 is CR 4 That is, (9)X 1 and X 3 is N, and X 2 is CR 4 That is, (10) Y is a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered heteroaryl fused to a 5- or 6-membered heterocyclyl, phenyl, heterocyclyl, C 3~7 Cycloalkyl and QR 8 and iQ is absent, O or NR 9 and ii.R 8 is C 1~6 Alkyl, C 1~3 Alkylene-phenyl or C 1~3 alkylene-heteroaryl; iii. Y is one or more substituents Y A and optionally substituted with, in each occurrence, Y A independently, halo, C 1~4 Alkyl, hydroxy, C 1~4 Alkoxy, C 1~3 Haloalkyl, cyano, C(O)R 10 and C 3~7 cycloalkyl, and iv.Y A Ha, Halo, C 1~4 Alkyl, hydroxy, C 1~4 Alkoxy, C 3~7 Cycloalkyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (11) Y is a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered heteroaryl fused to a 5- or 6-membered heterocyclyl, phenyl, heterocyclyl, C 3~7 Cycloalkyl and QR 8 and iQ is absent, O or NR 9 and ii.R 8 is C 1~6 Alkyl, C 1~3 Alkylene-phenyl or C 1~3 alkylene-heteroaryl; iii. Y is one or more substituents Y A and optionally substituted with, in each occurrence, Y A independently, halo, C 1~4 Alkyl, C 1~3 Haloalkyl, cyano, C(O)R 10 and C 3~7 cycloalkyl, and iv.Y A are halo, hydroxy, C 3~7 Cycloalkyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (12) Y is a 5- or 6-membered monocyclic heteroaryl, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered heteroaryl, heterocyclyl, cyclopropyl, and QR fused to a 5- or 6-membered heterocyclyl. 8 is selected from iQ is absent, O or NR 9 and ii.R 8 is C 1~6 Alkyl, C 1~3 Alkylene-phenyl or C 1~3 alkylene-heteroaryl; iii. Y is one or more substituents Y A and optionally substituted with, in each occurrence, Y A independently, halo, C 1~4Alkyl, C 1~3 Haloalkyl, cyano, C(O)R 10 and C 3~7 cycloalkyl, and iv.Y A are halo, hydroxy, C 3~7 Cycloalkyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (13) Y is a 5- or 6-membered monocyclic heteroaryl and QR 8 is selected from iQ is absent, O or NR 9 and ii.R 8 is C 1~6 Alkyl, C 1~3 Alkylene-phenyl or C 1~3 alkylene-heteroaryl; iii. Y is one or more substituents Y A and optionally substituted with, in each occurrence, Y A independently, halo, C 1~4 Alkyl, hydroxy, C 1~4 Alkoxy, C 1~3 Haloalkyl, cyano, C(O)R 10 and C 3~7 cycloalkyl, and iv.Y A Ha, Halo, C 1~4 Alkyl, hydroxy, C 1~4 Alkoxy, C 3~7 Cycloalkyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (14) Y is a 5- or 6-membered monocyclic heteroaryl and QR 8 is selected from iQ is absent or O, ii.R 8 is C 1~6 Alkyl, C 1~3 Alkylene-phenyl or C1~3 alkylene-heteroaryl; iii. Y is one or more substituents Y A and optionally substituted with, in each occurrence, Y A are independently fluoro, chloro, C 1~4 Alkyl, hydroxy, C 1~4 Alkoxy, C 1~3 Haloalkyl, cyano, C(O)R 10 and C 3~7 cycloalkyl, and iv.Y A Ha, Halo, C 1~4 Alkyl, hydroxy, C 3~7 Cycloalkyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (15) Y is QR 8 Q is absent or O, and R 8 is C 1~6 alkyl, CH2-phenyl, CH2-heteroaryl, CF2-phenyl or CF2-heteroaryl, and the phenyl and heteroaryl groups are each independently selected from the group consisting of one or more substituents Y A and optionally substituted with, in each occurrence, Y A are independently fluoro, chloro, C 1~4 Alkyl, hydroxy, C 1~4 Alkoxy, C 1~3 Haloalkyl, cyano, C(O)R 10 and cyclopropyl, and each Y A Ha, Halo, C 1~4 Alkyl, hydroxy, cyclopropyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (16) Y is QR 8 Q is absent or O, and R 8 is C 1~6alkyl, CH2-phenyl, CH2-heteroaryl, CF2-phenyl or CF2-heteroaryl, and the phenyl and heteroaryl groups are each independently selected from the group consisting of one or more substituents Y A and optionally substituted with, in each occurrence, Y A are independently fluoro, chloro, C 1~4 Alkyl, C 1~3 Haloalkyl, cyano, C(O)R 10 and cyclopropyl, and each Y A is halo, hydroxy, cyclopropyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (17) Y is OC 1~6 alkyl, OCH2-phenyl, OCH2-heteroaryl, CH2-phenyl, CH2-heteroaryl, CF2-phenyl, CF2-heteroaryl or NR 9 -CH2-phenyl, wherein the phenyl and heteroaryl groups are each independently selected from one or more substituents Y A and optionally substituted with, in each occurrence, Y A are independently fluoro, chloro, C 1~4 Alkyl, C 1~3 Haloalkyl, cyano, C(O)R 10 and cyclopropyl, and each Y A is halo, hydroxy, cyclopropyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (18) Y is O-tert-butyl, OCH2-phenyl, OCH2-heteroaryl, CH2-heteroaryl, CF2-phenyl, CF2-heteroaryl or NR 9 -CH2-phenyl, wherein the phenyl and heteroaryl groups are each independently selected from one or more substituents Y A and optionally substituted with, in each occurrence, Y A independently, C 1~4 Alkyl (e.g., methyl) and C1~3 haloalkyl, (19) Y is one or more substituents Y A and wherein, in each occurrence, Y A independently, halo, C 1~4 Alkyl, C 1~3 Haloalkyl, cyano, C(O)R 10 and C 3~7 cycloalkyl; and each Y A Ha, Halo, C 1~4 Alkyl, hydroxy, C 1~4 Alkoxy, C 3~7 Cycloalkyl, C 1~3 Alkylene-NR 11 R 12 and C 1~3 optionally further substituted with one or more substituents independently selected from haloalkyl; (20) Y is one or more substituents Y A and wherein, in each occurrence, Y A are independently fluoro, chloro, C 1~4 Alkyl, C 1~3 Haloalkyl, cyano, C(O)R 10 and cyclopropyl, and each Y A is halo, hydroxy, cyclopropyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (21) Y has the following structure: [ka] and the heteroaryl is a 5- or 6-membered monocyclic heteroaryl selected from one of the following: A and optionally substituted with, in each occurrence, Y A are independently fluoro, chloro, C 1~4 Alkyl, C 1~3 Haloalkyl, cyano, C(O)R 10and cyclopropyl, and each Y A is halo, hydroxy, cyclopropyl and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (22) Y has the following structure: [ka] and a 5-membered monocyclic heteroaryl selected from one of the following: A and optionally substituted with, in each occurrence, Y A independently, C 1~4 alkyl, cyano, and cyclopropyl; A Fluoro, hydroxy and C 1~3 Alkylene-NR 11 R 12 optionally further substituted with one or more substituents independently selected from (23)R 1 and R 2 are independently hydrogen, C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~5 alkoxy and phenyl, 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~5 Alkoxy or phenyl is fluoro, C 1~4 optionally substituted with one or more substituents independently selected from alkyl and trifluoromethyl, with the proviso that R 1 and R 2 cannot both be hydrogen, (24)R 1 and R 2 are independently hydrogen, C 1~4 Alkyl, C 3~7 Cycloalkyl and C 1~5 alkoxy, wherein C 1~4 Alkyl, C 3~7 Cycloalkyl or C 1~5 Alkoxy is halo, C1~4 Alkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl, with the proviso that R 1 and R 2 cannot both be hydrogen, (25)R 1 and R 2 independently, C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~5 alkoxy and phenyl, 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~5 Alkoxy or phenyl is halo, C 1~4 Alkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl; (26)R 1 and R 2 independently, C 1~4 Alkyl, C 3~7 Cycloalkyl and C 1~5 alkoxy, wherein C 1~4 Alkyl, C 3~7 Cycloalkyl or C 1~5 Alkoxy includes halo and C 1~4 optionally substituted with one or more substituents independently selected from alkyl; (27)R 1 and R 2 independently, C 1~4 Alkyl and C 1~5 alkoxy, each optionally substituted with one or more halo substituents; (28)R 1 and R 2 One of them is C 1~4 alkyl, and others are C 1~5 alkoxy, each optionally substituted with one or more halo substituents; (29)R 1 and R 2 One of them is C 1~2 alkyl, and others are C 2~5alkoxy, each optionally substituted with one or more halo substituents; (30)R 1 and R 2 One of the is methyl, and the other is C 1~5 alkoxy, each optionally substituted with one or more halo substituents; (31)R 1 and R 2 One of them is C 1~4 alkyl, and the other is tert-butoxy, each optionally substituted with one or more halo substituents; (32)R 1 and R 2 one of which is methyl and the other is tert-butoxy, each optionally substituted with one or more halo substituents; (33)R 1 and R 2 one of which is methyl and the other is tert-butoxy; (34)R 1 and R 2 One of the is hydrogen, and the other is C 1~5 is an alkoxy, (35)R 1 and R 2 one of which is hydrogen and the other is tert-butoxy; (36)R 1 and R 2 independently, C 3~7 cycloalkyl rings, each selected from halo and C 1~4 optionally substituted with one or more substituents independently selected from alkyl; (37)R 1 and R 2 are independently selected C 3~5 cycloalkyl rings, halo and C 1~4 optionally substituted with one or more substituents independently selected from alkyl; (38)R 1 and R 2 are both cyclopropyl rings, and each ring is independently selected from halo and C1~4 optionally substituted with one or more substituents independently selected from alkyl (such as fluoro and methyl); (39)R 1 and R 2 are both cyclopropyl, (40)R 1 and R 2 together with the carbon atoms to which they are attached form a 4- to 8-membered cycloalkyl ring, and the cycloalkyl ring is 1~4 Alkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl; (41)R 1 and R 2 taken together with the carbon atoms to which they are attached form a 4- to 8-membered cycloalkyl ring, the cycloalkyl ring being optionally substituted with one or more substituents independently selected from fluoro, methyl and trifluoromethyl; (42)R 1 and R 2 together with the carbon atoms to which they are attached form a 5- to 8-membered cycloalkyl ring, and the cycloalkyl ring is 1~4 optionally substituted with one or more substituents independently selected from alkyl; (43)R 1 and R 2 taken together with the carbon atoms to which they are attached form a 6- to 8-membered cycloalkyl ring, the cycloalkyl ring being optionally substituted with one or more substituents independently selected from fluoro, chloro, methyl and trifluoromethyl; (44)R 1 and R 2 taken together with the carbon atoms to which they are attached form a 6- to 8-membered cycloalkyl ring, the cycloalkyl ring being optionally substituted with one or more substituents independently selected from fluoro, methyl and trifluoromethyl; (45)R 1 and R 2 together with the carbon atoms to which they are attached form a cyclohexyl ring, and the cyclohexyl ring is 1~4Alkyl and C 1~3 substituted with one or more substituents independently selected from haloalkyl; (46)R 1 and R 2 together with the carbon atoms to which they are attached form a cyclohexyl ring, and the cyclohexyl ring is 1~4 substituted with one or more substituents independently selected from alkyl; (47)R 1 and R 2 together with the carbon atoms to which they are attached form a cyclohexyl ring, and the cyclohexyl ring is 1~4 substituted with one or more substituents independently selected from alkyl; (48)R 1 and R 2 taken together with the carbon atoms to which they are attached form a cyclohexyl ring, the cyclohexyl ring being substituted with one or more substituents independently selected from halo and methyl; (49)R 1 and R 2 together with the carbon atom to which they are attached form a cyclohexyl ring, the cyclohexyl ring being substituted with one or more substituents independently selected from fluoro and methyl; (50)R 1 and R 2 taken together with the carbon atoms to which they are attached form a cyclohexyl ring, the cyclohexyl ring being substituted with a methyl substituent; (51)R 1 and R 2 taken together with the carbon atoms to which they are attached form a cyclohexyl ring, the cyclohexyl ring being substituted with one or more fluoro substituents; (52)R 1 and R 2 together with the carbon atoms to which they are attached form a cyclohexyl ring, the cyclohexyl ring being substituted with two fluoro substituents; (53) Combined R 1 , R 2 and R 3 The base is [ka] is a group selected from [ka] is the point of attachment to the remainder of the compound of Formula I, and each cyclopropyl or cyclohexyl ring may be selected from halo, C 1~4 Alkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl; (54) Combined R 1 , R 2 and R 3 The base is [ka] is a group selected from [ka] is the point of attachment to the remainder of the compound of formula I, (55) Combined R 1 , R 2 and R 3 The base is [ka] is a group selected from [ka] is the point of attachment to the remainder of the compound of formula I, (56)R 3 is hydrogen or methyl; (57)R 3 is hydrogen, (58)R 3 is methyl, (59) R in each existence 4 is independently selected from hydrogen, fluoro, methyl and hydroxy; (60) R in each existence 4 is independently selected from hydrogen, fluoro and methyl; (61) R in each existence 4 is independently selected from hydrogen and fluoro; (62) R in each entity 4 is hydrogen, (63)R 4 is hydrogen and X 1 is nitrogen and X 2 and X 3 is CH, (64)R 4 is hydrogen and X 1 is nitrogen and X 2 is CH, and X 3 is CF, (65)R 5 is a 5- or 6-membered monocyclic heteroaryl, a 4- to 10-membered heterocyclyl, C(O)NR 13 R 14 , OC(O)NR 15 R 16 and NR 17 C(O)C 1~6 alkyl, and R 13 , R 14 , R 15 , R 16 and R 17 are independently hydrogen and C 1~6 alkyl, and R 5 Ha, Halo, C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl and oxo; (66)R 5 is a 5- or 6-membered monocyclic heteroaryl, a 4- to 10-membered heterocyclyl, C(O)NR 13 R 14 , OC(O)NR 15 R 16 and NR 17 C(O)C 1~6 alkyl, and R 13 , R 14 , R 15 , R 16 and R 17 are independently hydrogen and C 1~6 alkyl, and R5 is fluoro, chloro, methyl, C 1~2 optionally substituted with one or more substituents independently selected from haloalkyl and oxo; (67)R 5 is a 5- or 6-membered monocyclic heteroaryl, a 5- to 8-membered heterocyclyl, C(O)NR 13 R 14 , OC(O)NR 15 R 16 and NR 17 C(O)C 1~6 alkyl, and R 13 , R 14 , R 15 , R 16 and R 17 are independently hydrogen and C 1~6 alkyl, and R 5 is optionally substituted with one or more substituents independently selected from fluoro, methyl, trifluoromethyl and oxo; (68)R 5 represents 5-membered monocyclic heteroaryl, 5-membered heterocyclyl and NR 17 C(O)C 1~6 alkyl, and R 17 is hydrogen or methyl, and R 5 are hydroxy, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~3 Haloalkyl, C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl, cyano, and oxo; (69)R 5 represents 5-membered monocyclic heteroaryl, 5-membered heterocyclyl and NR 17 C(O)C 1~6 alkyl, and R 17 is hydrogen or methyl, and R 5 is optionally substituted with one or more substituents independently selected from fluoro, methyl, trifluoromethyl and oxo; (70)R 5 The structure: [ka] and [ka] is the point of attachment to the remainder of the compound of Formula I, and R x are hydroxy, halo, C 1~4 Alkoxy, C 1~3 Haloalkyl and C 3~7 C optionally substituted with one or more substituents independently selected from cycloalkyl 1~6 alkyl, and R y is hydrogen or C 1~6 alkyl or R x and R y together with the atoms to which they are attached, represent hydroxy, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~3 Haloalkyl, C 3~7 forming a 5- to 8-membered heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and oxo; (71)R 5 The structure: [ka] and [ka] is the point of attachment to the remainder of the compound of Formula I, and R x is optionally substituted with one or more substituents independently selected from hydroxy, fluoro, methoxy and cyclopropyl; 1~4 alkyl, and R y is hydrogen or methyl, or R x and R y together with the atoms to which they are attached, fluoro, C 1~4 forming a 5-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl, trifluoromethyl and oxo; (72)R 5 teeth, [ka] having a structure selected from [ka] is the point of attachment to the remainder of the compound of Formula I, and each structure may be fluoro, C 1~4 optionally substituted with one or more substituents independently selected from alkyl (e.g., methyl), trifluoromethyl, and oxo; (73)R 5 The structure: [ka] and [ka] is the point of attachment to the remainder of the compound of formula I, and the structure is optionally substituted with one or more substituents independently selected from fluoro, methyl, trifluoromethyl, and oxo. (74)R 5 teeth, [ka] having a structure selected from [ka] is the point of attachment to the remainder of the compound of formula I, (75)R 5 teeth, [ka] having a structure selected from [ka] is the point of attachment to the remainder of the compound of formula I, (76)R 6 is hydrogen, C 1~6 Alkyl or C 3~7 is cycloalkyl, and R 6 C1~6 Alkyl or C 3~7 When cycloalkyl, the group may be selected from hydroxy, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~3 Haloalkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkoxy; (77)R 6 is hydrogen, C 1~6 Alkyl or C 3~7 is cycloalkyl, and R 6 C 1~6 Alkyl or C 3~7 When cycloalkyl, the group may be selected from hydroxy, halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl; (78)R 6 is hydrogen, C 1~3 Alkyl or C 3~5 is cycloalkyl, and R 6 C 1~3 Alkyl or C 3~5 When cycloalkyl, the group may be hydroxy, fluoro, methyl, C 1~2 Alkoxy and C 1~2 optionally substituted with one or more substituents independently selected from haloalkyl; (79)R 6 is hydrogen, methyl or cyclopropyl, and R 6 When is methyl or cyclopropyl, said group is optionally substituted with one or more substituents independently selected from fluoro and methoxy; (80)R 6 is hydrogen, (81)R 6 is cyclopropyl, (82)R 6 is methyl optionally substituted with one or more substituents independently selected from fluoro, hydroxy and methoxy; (83)R 6is CH2OMe, (84)R 7 is selected from hydrogen, deuterium, fluoro and methyl; (85)R 7 is selected from hydrogen and deuterium, (86)R 7 is hydrogen, (87)R 6 and R 7 together with the carbon atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~3 forming a 4-6 membered cycloalkyl or heterocyclyl ring optionally substituted with one or more substituents independently selected from haloalkyl; (88)R 6 and R 7 taken together with the carbon atoms to which they are attached form a 5- or 6-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more substituents independently selected from fluoro, methyl, methoxy and trifluoromethyl; (89)R 6 and R 7 together with the carbon atom to which they are attached, form halo, C 1~4 Alkyl, C 1~4 Alkoxy and C 1~3 forming a 4- to 6-membered cycloalkyl ring optionally substituted with one or more substituents independently selected from haloalkyl; (90)R 6 and R 7 taken together with the carbon atoms to which they are attached form a 5- or 6-membered cycloalkyl ring optionally substituted with one or more substituents independently selected from fluoro, methyl, methoxy, and trifluoromethyl; (91)R 10 is hydroxy or C 1~4 is an alkoxy, (92)R 10 is hydroxy or C 3~4 is an alkoxy, (93)R 10 is C 1~4Alkoxy is (94)R 10 is tert-butoxy, (95)R 11 and R 12 are independently hydrogen, methyl and C(O)OC 1~4 selected from alkyl, (96)R 11 and R 12 are independently hydrogen and C(O)C 1~4 selected from alkyl, (97)R 11 and R 12 are both hydrogen, (98)R 11 is hydrogen, and R 12 is C(O)OC 1~4 is alkyl, (99)R 11 is hydrogen, and R 12 is C(O)O tert-butyl.

[0060] In one embodiment, Z is as defined in any one of paragraphs (1)-(2) above. In a further embodiment, Z is as defined in paragraph (2) above.

[0061] In one embodiment, X 1 ~X 3 is as defined in any one of paragraphs (3) to (9) above. In a further embodiment, X 1 ~X 3 is as defined in section (5) above. In a further embodiment, X 1 ~X 3 is as defined in paragraph (6) above.

[0062] In one embodiment, Y is as defined in any one of paragraphs (10) to (22) above. In a further embodiment, Y is as defined in paragraphs (13) to (22) above. In a further embodiment, Y is as defined in paragraph (18) above. In a further embodiment, Y is as defined in paragraph (22) above.

[0063] In one embodiment, R 1 and R 2 is as defined in any one of paragraphs (23) to (55) above. In a further embodiment, R 1 and R 2 is as defined in paragraphs (53) to (55) above. In a further embodiment, R 1 and R 2 is as defined above in item (54). In a further embodiment, R 1 and R 2 is as defined in item (55) above.

[0064] In one embodiment, R 3 is as defined in any one of paragraphs (56) to (58) above. In a further embodiment, R 3 is as defined in item (57) above.

[0065] In one embodiment, R 4 is as defined in any one of paragraphs (59) to (64) above. In a further embodiment, R 4 is as defined in paragraph (61) or (62) above.

[0066] In one embodiment, R 5 is as defined in any one of paragraphs (65) to (75) above. In a further embodiment, R 5 is as defined in paragraph (74) or (75) above.

[0067] In one embodiment, R 6 is as defined in any one of paragraphs (76) to (83) above. In a further embodiment, R 6 is as defined in any one of the above items (80) to (83).

[0068] In one embodiment, R 7is as defined in any one of paragraphs (84) to (86) above. In a further embodiment, R 7 is as defined in item (86) above.

[0069] In one embodiment, R 6 and R 7 is as defined in any one of paragraphs (87) to (90) above. In a further embodiment, R 6 and R 7 is as defined in item (90) above.

[0070] In one embodiment, R 10 is as defined in any one of paragraphs (91) to (94) above. In a further embodiment, R 10 is as defined in item (94) above.

[0071] In one embodiment, R 11 and R 12 is as defined in any one of paragraphs (95) to (99) above. In a further embodiment, R 11 and R 12 is as defined in paragraph (97) or (99) above.

[0072] In some embodiments, formulas IA-IF (subformulas of Formula I): [ka] (In the formula, Z, 1 , X 2 , X 3 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as described above, and R x are hydroxy, halo, C 1~4 Alkoxy, C 1~3 Haloalkyl and C 3~7C optionally substituted with one or more substituents independently selected from cycloalkyl 1~6 alkyl, and R y is hydrogen or C 1~6 alkyl or R x and R y together with the atoms to which they are attached, represent hydroxy, halo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~3 Haloalkyl, C 3~7 forming a 5- to 8-membered heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and oxo or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, a compound according to any one of formulas IA-IF or a pharmaceutically acceptable salt thereof is provided, wherein Z is as defined in section (2) above; and X 1 ~X 3 is as defined in paragraph (5) or (6) above, Y is as defined in paragraph (18) or (22) above, and R 1 and R 2 is as defined in (53) to (55) above, and R 3 is as defined in (57) above, and R 4 is as defined in paragraph (61) or (62) above, and R 5 is as defined in paragraph (74) or (75) above, and R 6 is as defined in any one of the above paragraphs (80) to (83), and / or R 7 is as defined in item (86) above, and R x is optionally substituted with one or more substituents independently selected from hydroxy, fluoro, methoxy and cyclopropyl; 1~4 alkyl, and R y is hydrogen or methyl, or R x and R y together with the atoms to which they are attached, fluoro, C1~4 Forming a 5-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl, trifluoromethyl and oxo.

[0074] Particular compounds of the present disclosure include any one of the following compounds or a pharmaceutically acceptable salt thereof: tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, benzyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate, tert-butyl ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate, tert-butyl 6-(((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamoyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, benzyl ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate, tert-butyl 6-(((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamoyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-3-ethylisoxazole-4-carboxamide, 1-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, tert-butyl ((1-(4-(((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamoyl)isoxazol-3-yl)cyclopropyl)methyl)carbamate, 3-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)isoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-3-isopropylisoxazole-4-carboxamide, 3-(1-(aminomethyl)cyclopropyl)-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)isoxazole-4-carboxamide, tert-butyl ((S)-2-((4-((5-methyl-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, 4-cyclopropyl-N-((S)-2-((4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((((2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)pyridin-2-yl)amino)ethyl)carbamate, (S)-(1-(4,4-difluorocyclohexyl)-2-((4-((4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-2-((4-((2,5-dioxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate tert-butyl tert-butyl ((S)-2-((4-(((R)-5-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-(((R)-4-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, (S)—N-(1,1-dicyclopropyl-3-oxo-3-((4-(2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)pyridin-2-yl)amino)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, (S)—N-(1,1-dicyclopropyl-3-oxo-3-((4-((4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-((4-(((R)-4-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 1-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((4-(((R)-4-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1,2,5-oxadiazole-3-carboxamide, N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-3-ethylisoxazole-4-carboxamide, tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((((2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)pyridin-2-yl)amino)ethyl)carbamate, 4-cyclopropyl-N-(2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-(2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-(2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, tert-butyl ((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, (1R,2S,5S)—N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-3,6,6-trimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate (5-methylisoxazol-3-yl)methyl, 4-cyclopropyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate (1,5-dimethyl-1H-pyrazol-3-yl)methyl, 4-cyclopropyl-N-((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, tert-butyl ((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, 1-fluoro-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)cyclopropane-1-carboxamide, N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1-(4,4,4-trifluoro-3-hydroxybutyl)-1H-pyrazole-5-carboxamide, (4-methyl-1,2,5-oxadiazol-3-yl)methyl((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl), tert-butyl ((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, 3-isopropyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide, 1-isopropyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide, tert-butyl ((S)-2-((4-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)carbamate, tert-butyl ((R)-1-((1r,4R)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)carbamate, benzyl ((rac)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)carbamate, N-(3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide, N-(3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((R)-1-((1r,4R)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 4-ethyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((RS)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)pyrimidine-5-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-5-methylthiazole-4-carboxamide, 5-cyano-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)thiazole-4-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-tetrazole-5-carboxamide, 6-bromo-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylpicolinamide, 2-chloro-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-5-methylpyrimidine-4-carboxamide, 4-cyclopropyl-N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, (S)-2-(3-benzylureido)-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)acetamide, (S)-2-(3-benzylureido)-2-(4,4-difluorocyclohexyl)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)acetamide, benzyl ((2R,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)carbamate, benzyl ((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)carbamate, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, tert-butyl ((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)carbamate, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)oxazole-2-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)oxazole-4-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-imidazole-2-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-imidazole-2-carboxamide, (2S)-2-(2-(3,5-dimethylisoxazol-4-yl)acetamide)-N-(4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide, (2S)—N-(4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-(2-(5-methyl-1H-pyrazol-3-yl)acetamide)-2-((1r,4S)-4-methylcyclohexyl)acetamide, 1-isopropyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-imidazole-2-carboxamide, N-((2S,3S)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-imidazole-2-carboxamide, 1-methyl-N-((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methylisoxazole-3-carboxamide, 4-cyclopropyl-N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-3-carboxamide, N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyloxazole-5-carboxamide, (S)—N-(4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)-2-(2-(3-methylisoxazol-5-yl)acetamido)acetamide, 1-ethyl-N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 3-ethyl-N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide, 3-cyclopropyl-N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-3-isopropylisoxazole-4-carboxamide, tert-butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate, 4-cyclopropyl-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, 1-cyclopropyl-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-imidazole-2-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-imidazole-2-carboxamide, 1-(cyclopropylmethyl)-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-(p-tolyl)acetamide, 2,2-difluoro-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-phenylacetamide, tert-butyl ((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl-d)pyridin-2-yl)amino)ethyl)carbamate, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(3,3,3-trifluoro-1-(4,4,4-trifluorobutanamido)propyl)pyridin-2-yl)amino)ethyl)-4-ethylisoxazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)butyl)pyridin-2-yl)amino)ethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((R)-2-methyl-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((1S)-2-((4-(cyclopropyl(3,3,3-trifluoropropanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, 4-cyclopropyl-N-((S)-2-((4-(cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-((cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((R)-1-(4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(2-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propan-2-yl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(2-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propan-2-yl)pyridin-2-yl)amino)ethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(2-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propan-2-yl)pyridin-2-yl)amino)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(2-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propan-2-yl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-5-ethylisoxazole-4-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-isopropylisoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-3-carboxamide, 4-cyclobutyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-(2,2-difluoroethoxy)isoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-isopropyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methylisoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-isopropylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, (S)-2-(4,4-difluorocyclohexyl)-N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-(2-(6-methoxypyridin-3-yl)acetamide)acetamide, 2-(3-cyanophenyl)-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)propanamide, (S)-2-(2-(3-cyanophenyl)acetamido)-2-(4,4-difluorocyclohexyl)-N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)acetamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-(4,4,4-trifluorobutanamido)propyl)pyridin-2-yl)amino)ethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((2-oxo-5-(trifluoromethyl)-2,5-dihydro-1H-pyrrol-3-yl)methyl)pyridin-2-yl)amino)ethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-4-ethyloxazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-5-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-5-isopropylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl-d)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-methyl-N-((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl-d)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((1S)-2-((4-(2-hydroxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, 4-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 2-(3-cyanophenyl)-2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)acetamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-(1-methyl-1H-pyrazol-5-yl)acetamide, 2-(3-chlorophenyl)-2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)acetamide, 2-(3,5-difluorophenyl)-2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)acetamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-(pyrazin-2-yl)acetamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-(6-methoxypyridin-3-yl)acetamide, (S)—N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)-2-(2-(5-methylisoxazol-3-yl)acetamido)acetamide, 2-fluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-phenylacetamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylbutanamide, 4-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1-(3,3-difluorocyclobutyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-1-(3,3-difluorocyclobutyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((S)-1-((1s,4R)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-methyl-N-((S)-1-((1s,4R)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-4-methylisoxazole-3-carboxamide, 4-ethyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, 3-ethyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)isoxazole-4-carboxamide, N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1H-pyrazole-5-carboxamide, N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1H-pyrazole-5-carboxamide, 4-methyl-N-((S)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, 1-methyl-N-((S)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 4-(2,2-difluoroethoxy)-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-3-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methylisoxazole-3-carboxamide, 4-ethyl-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 3-ethyl-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-4-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, 4-ethyl-N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-(1-(4-fluoro-4-methylcyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-(1-(4-fluoro-4-methylcyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-(1-(4-fluoro-4-methylcyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 3-ethyl-N-((1S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxo-1-(4-(trifluoromethyl)cyclohexyl)ethyl)isoxazole-4-carboxamide, 1-ethyl-N-((1S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxo-1-(4-(trifluoromethyl)cyclohexyl)ethyl)-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxo-1-(4-(trifluoromethyl)cyclohexyl)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((1S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxo-1-(4-(trifluoromethyl)cyclohexyl)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1-((S)-3,3-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-1-((S)-3,3-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-((S)-3,3-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-((S)-3,3-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-5-ethylisoxazole-4-carboxamide, N-((S)-1-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-5-isopropylisoxazole-4-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 3-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)isoxazole-4-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, or 1-Isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide.

[0075] The various functional groups and substituents that make up the compounds of the present disclosure are typically selected so that the molecular weight of the compound does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, e.g., less than 700, or less than 650, or less than 600.

[0076] Suitable pharmaceutically acceptable salts of compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid. In addition, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0077] 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 called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by Cahn and Prelog's R and S sequencing rules (Cahn, Ingold & Prelog, Angewandte Chemie Intl. Edtn (1966) 5(4), 385-415) or by the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0078] The compounds of the present disclosure may have one or more asymmetric centers. Apart from the stereochemistry as specified in Formula I, the description or naming of a particular compound in this specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise, at any other asymmetric centers that may be present. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemic forms (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley & Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomeric centers (E- and Z-isomers). It is understood that the present disclosure encompasses all optical, diastereomeric and geometric isomers, and mixtures thereof.

[0079] The present disclosure also encompasses compounds of the present disclosure as defined herein that contain one or more isotopic substitutions. For example, H is: 1 H, 2 H(D) and 3 It can exist in any isotopic form, including H(T), and C is 12 C. 13 C and 14 It can exist in any isotopic form, including C, and O is 16 O and 18 It may exist in any isotopic form, including O.

[0080] It is also understood that certain compounds of the present disclosure can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, and it is understood that the present disclosure encompasses all such solvated forms.

[0081] It is also to be understood that certain compounds of the present disclosure may exhibit polymorphism, and that the present disclosure encompasses all such forms.

[0082] The compounds of the present disclosure can exist in several different tautomeric forms, and a reference to a compound of the present disclosure includes all such forms. For the avoidance of doubt, if a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by the compounds of the present disclosure. Examples of tautomeric forms include keto-, enol-, and enolate forms, as in the case of the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka]

[0083] Compounds of the present disclosure containing an amine functional group may also form N-oxides. Reference herein to a compound of Formula I containing an amine functional group also includes the N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid); see, for example, Advanced Organic Chemistry, 4th Edition, by Jerry March, Wiley Interscience. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0084] The compounds of the present disclosure may be administered in the form of prodrugs that are broken down in the human or animal body to release the compounds of the present disclosure. Prodrugs may be used to modify the physical or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs may be formed when the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at a carboxy or hydroxy group in the compounds of the present disclosure and in vivo cleavable amide derivatives that can be formed at a carboxy or amino group in the compounds of the present disclosure.

[0085] Thus, the present disclosure includes those compounds of formula I as defined above when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure includes compounds of formula I produced by organic synthetic means, and also includes such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., compounds of formula I can be synthetically produced compounds or metabolically produced compounds.

[0086] synthesis In the description of synthetic methods below, and in the referenced synthetic methods used to prepare starting materials, it is understood that all suggested reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and work-up procedure, can be selected by one skilled in the art.

[0087] 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 employed.

[0088] Necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variations in the accompanying Examples. Alternatively, necessary starting materials can be obtained by analogous procedures to those shown which are within the ordinary skill of an organic chemist.

[0089] It will be understood that during the synthesis of the compounds of the present disclosure, or of particular starting materials in the processes defined below, it may be desirable to protect certain substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is required and how such protecting groups may be put in place and subsequently removed.

[0090] For examples of protecting groups, see one of the many general textbooks on the subject, such as "Protecting groups in Organic Synthesis (3rd Ed), 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, with such method being chosen to effect removal of the protecting group with minimal interference with groups elsewhere in the molecule.

[0091] Thus, if reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0092] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, e.g., alkanoyl groups such as acetyl; alkoxycarbonyl groups, e.g., methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl; arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl; or aroyl groups, e.g., benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, aryl groups, e.g., alkanoyl or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, e.g., tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl groups, can be removed by hydrogenation over a catalyst such as palladium on carbon or treatment with a Lewis acid, e.g., BF3·OEt2. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

[0093] Those skilled in the art will recognize that the compounds of the present disclosure can be prepared in a variety of known ways. Compounds of Formula I can be prepared by the methods provided below, the experimental methods, or similar methods. The routes described are merely illustrative of some of the methods that can be used to synthesize compounds of Formula I, and those skilled in the art will understand that the order of reaction steps is not limited to those described. It will also be understood that the assignment of nucleophiles and electrophiles is not limited to those described herein, and that in some cases, it may be appropriate to reverse the assignment. Different approaches to synthetic chemistry strategies are described in "Organic Synthesis: The Disconnection Approach", 2nd edition, S. Warren and P. Wyatt (2008).

[0094] A compound of formula I or a pharmaceutically acceptable salt thereof (wherein Z, X 1 , X 2 , X 3 , Y, R 1 , R 2 , R 3 , R 4 and R 5 (wherein is as previously defined) can be prepared by coupling activated acid (II) to amine (III) using standard acid activation methods such as acid chlorides, HOBt, HATU, HBTU, TOTU, EDCI, PyBOP, 1-chloro-N,N,2-trimethyl-1-propenylamine, or 1-propanephosphonic anhydride under basic conditions, e.g., diisopropylethylamine, triethylamine, etc., in aprotic solvents such as DMF, DMSO, DCM, acetonitrile, etc., or under neutral conditions, as shown in Scheme A. Compounds of general formula (III) derived from compounds of general formula (IV) can be obtained by cleaving the protecting group P, which can be an amino protecting group that is cleaved under specific conditions, such as BOC with HCl in dioxane or other suitable solvent, TFA without solvent or in DCM or other suitable solvent, CBZ with catalytic hydrogenation in methanol or ethanol, or FMOC with secondary amines such as morpholine in suitable solvents such as DMF, dioxane, methanol, or ethanol. Using standard amide formation methods as described above, compounds of general formula (IV) can be obtained from compounds of general formula (VI) and amino acids of general formula (V). Scheme A [ka]

[0095] A compound of formula (I) (wherein Z, X 1 , X 2 , X 3 , Y, R 1 , R 2 , R 3 , R 4 and R 5(wherein is as previously defined) can also be prepared using standard acid activation methods such as acid chlorides, HOBt, HATU, HBTU, TOTU, EDCI, PyBOP, 1-chloro-N,N,2-trimethyl-1-propenylamine or 1-propanephosphonic anhydride under basic conditions, e.g., diisopropylethylamine, triethylamine, etc., or under neutral conditions, in aprotic solvents such as DMF, DMSO, DCM, acetonitrile, etc., by coupling activated acid (VII) to amine (VI), as shown in Scheme B. Compounds of general formula (VII) can be obtained from esters of general formula (VIII), in which the alkyl group (Alk) is preferably methyl or ethyl, and preferably tert-butyl, which is cleaved with lithium hydroxide, sodium hydroxide or potassium hydroxide, or preferably cleaved with HCl in dioxane, TFA or TFA / DCM. Amides of general formula (VIII) can be obtained by coupling amino acid esters of general formula (IX) with acids of general formula (II) using the methods described above. Scheme B [ka]

[0096] The preparation of compounds of general formula (VI) is exemplified by the preparation of compounds of general formula (VIa) in Scheme C. Compounds of general formula (VIa) can be obtained by cleavage of the respective protecting groups P of compounds of general formula (Xa) under the conditions as described in Scheme A. Compounds of general formula (Xa) can be obtained by cyclization of compounds of general formula (XIa) in the presence of a carbonyl donating reagent such as CDI, phosgene, triphosgene, etc., in an aprotic solvent such as THF, dioxane, or DMF, preferably in the presence of a base such as TEA or DIPEA, at a temperature ranging from room temperature to 80°C, preferably 60 to 70°C. Scheme C [ka]

[0097] Compounds of general formula (XIa) can be synthesized from compounds of general formula (XIIa) and (2S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride by reductive amination in a two-step, one-pot procedure. In the first step, an imine is formed in a protic or aprotic solvent such as isopropanol or DCM in the presence of a base such as TEA or DIPEA at temperatures ranging from room temperature to 40°C (DCM) or 80°C (isopropanol), especially when the amine is used as a salt such as its hydrochloride. After imine formation, the solvent is removed, and the residue is dissolved in a protic solvent such as methanol or ethanol, and an acid such as acetic acid is added to adjust the pH to around 5. A borohydride, preferably sodium cyanoborohydride or sodium triacetoxyborohydride, can be used as the reducing agent. Compounds of general formula (XIIa) are commercially available or can be obtained from compounds of general formula (XIIIa) by oxidation using standard oxidation means such as chromic acid and TEMPO or as described by Swern or Dess-Martin. Compounds of general formula (XIIIa) can be obtained by oxidizing compounds of general formula (XIVa), which are commercially available or available by known methods, with organometallic compounds (e.g., R 6 MX) (for example, a Grignard reagent or a lithium organic compound such as nBuLi).

[0098] Pharmaceutical Composition The compounds of the present disclosure are usually, but not necessarily, formulated into pharmaceutical compositions before being administered to a patient.Accordingly, according to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0099] The pharmaceutical compositions of the present disclosure may be prepared and packaged in bulk form, where a safe and effective amount of a compound of the present disclosure may be extracted and subsequently administered to a patient, such as with a powder or syrup. Alternatively, the pharmaceutical compositions of the present disclosure may be prepared and packaged in unit dosage form, where each physically discrete unit contains a safe and effective amount of a compound of the present disclosure. When prepared in unit dosage form, the pharmaceutical compositions of the present disclosure typically contain 1 mg to 1000 mg.

[0100] Compositions of the present disclosure may be in a form suitable for oral use (e.g., as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets), topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams and gels), transdermal administration (e.g., via a transdermal patch), administration by inhalation (e.g., as dry powders, aerosols, suspensions and solutions), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

[0101] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or solvent that is involved in providing form or consistency to a pharmaceutical composition. Each excipient should be compatible with the other components of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the effectiveness of the compound of the present disclosure when administered to a patient and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. In addition, each excipient should, of course, be of sufficiently high purity to render it pharmaceutically acceptable.

[0102] The pharmaceutical compositions of the present disclosure are prepared using techniques and methods known to those skilled in the art, some of which are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0103] An effective amount of a compound of the present disclosure for use in therapy of a proliferative disease is an amount sufficient to symptomatically alleviate the symptoms of the proliferative disease in a warm-blooded animal, particularly a human, or to slow the progression of the proliferative disease, or to reduce the risk of deterioration in a patient with symptoms of the proliferative disease.

[0104] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active agent (more specifically, 0.5 to 100 mg, e.g., 1 to 30 mg), compounded with an appropriate and convenient amount of excipient, which may vary from about 5 to about 98 percent by weight of the total composition.

[0105] The size of a therapeutic or prophylactic dose of a compound of formula I will necessarily vary according to well-known principles of medicine, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0106] When using a compound of the present disclosure for therapeutic or prophylactic purposes, it is generally administered to receive a daily dose ranging, for example, from 0.1 mg / kg to 75 mg / kg of body weight, given in divided doses as needed. Generally, when parenteral routes are used, lower doses are administered. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging, for example, from 0.1 mg / kg to 30 mg / kg of body weight is generally used. Similarly, for administration by inhalation, a dose ranging, for example, from 0.05 mg / kg to 25 mg / kg of body weight is used. Oral administration may also be suitable, particularly in tablet form. Typically, a unit dosage form contains about 0.5 mg to 0.5 g of a compound of the present disclosure.

[0107] Administration route The compounds or pharmaceutical compositions of the present disclosure containing the active compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0108] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by gum, film, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., used through the mouth or nose, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal);

[0109] Therapeutic Uses and Applications Compounds of the present disclosure have been demonstrated to inhibit the binding of human IL-17A to its receptor, IL-17RA (in an AlphaLISA competition assay as described herein), with binding affinities typically less than 30 μM. Thus, compounds of Formula I, which are potent modulators of human IL-17A activity, are potentially useful as therapeutic compounds in the treatment or prevention of human diseases that arise as a result of IL-17A activity.

[0110] The compounds of the present disclosure, which are high-affinity binders to human IL-17A and potent modulators of human IL-17A activity, may be useful as pharmacological standards for use in the development of new biological tests and in the discovery of new pharmacological agents. Accordingly, the compounds of the present disclosure may be useful as radioligands in assays for detecting pharmacologically active compounds.

[0111] Thus, in one aspect, the present disclosure relates to a compound of the present disclosure as defined herein or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0112] In another aspect, the present disclosure relates to a compound of the present disclosure, as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition, as defined herein, for use in the treatment of a disease or disorder mediated by IL-17A activity.

[0113] In another aspect, the present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for use in the treatment of a disease or disorder mediated by IL-17A activity.

[0114] In another aspect, the present disclosure relates to a method of treating a disease or disorder associated with IL-17A activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0115] Examples of specific diseases or disorders that the compounds of formula I and their pharmaceutically acceptable salts can be used to treat include, but are not limited to, any one of the following: acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthropathies, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes, other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid tumors (e.g., melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, and ovarian cancer) and hematological malignancies, particularly acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer, and colon cancer), Castleman's disease, contact dermatitis, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, arthritis associated with enthesitis, endotoxic shock associated with infection, Exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, hepatoblastoma, hypochlorhydria, immune-mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barré syndrome, hidradenitis suppurativa, inflammatory bowel disease, insulin-dependent diabetes mellitus type 1, intravascular coagulation, irritable bowel syndrome, lichen planus, hepatic fibrosis, lupus nephritis, Lyme arthritis, meningoencephalitis, myocarditis, meningoencephalitis, diabetic lipoid stenosis Mortality, osteoporosis, pancreatitis, papulopustular rosacea, Parkinson's disease, pelvic inflammatory disease, periodontitis, peritonitis, Peyronie's disease, pilonidal disease, psoriasis, psoriatic arthritis (PsA), pyoderma gangrenosum, renal fibrosis, rheumatoid arthritis, scleroderma or systemic sclerosis, stroke, surgical adhesions, systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (JIA), trauma (surgery), graft rejection, type 1 diabetes, ulcerative colitis, uveitis and vasculitis.

[0116] Modulators of IL-17 activity can be administered to inhibit or reduce the severity of ocular inflammatory disorders (WO 2009 / 089036), such as ocular surface inflammatory disorders, including dry eye syndrome (DES). Accordingly, compounds according to the present disclosure are useful for treating or preventing IL-17-mediated ocular inflammatory disorders, such as IL-17-mediated ocular surface inflammatory disorders, including dry eye syndrome. Ocular surface inflammatory disorders include dry eye syndrome, penetrating keratoplasty, corneal transplantation, full- or partial-thickness keratoplasty, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal and ocular surface inflammatory disorders, conjunctival scarring disorders, ocular autoimmune disorders, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye disease, conjunctivitis, and bacterial keratitis. Specific classifications of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjogren's syndrome, Sjogren's syndrome-associated keratoconjunctivitis sicca, non-Sjogren's syndrome-associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorders, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction, and evaporative loss.

[0117] Combination therapy The compounds of the present disclosure can be administered alone as monotherapy, or they can be administered in combination with one or more additional therapeutic agents, the choice of which will, of course, vary depending on the disease or condition being treated and its severity.

[0118] The use of combination therapies to treat certain medical conditions is common.

[0119] According to certain aspects of the present disclosure, there is provided a combination suitable for use in the treatment of a disease or condition in which IL-17 activation is implicated, comprising a compound of the present disclosure as defined above or a pharmaceutically acceptable salt thereof and another therapeutic agent.

[0120] In a further aspect of the present disclosure, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0121] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, in association with a pharmaceutically acceptable diluent or carrier.

[0122] The one or more additional therapeutic agents can include additional compounds of the present disclosure. Thus, in certain embodiments, a pharmaceutical composition is provided comprising two compounds of the present disclosure, or pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0123] The above-referenced combinations may conveniently be presented for use in the form of pharmaceutical formulations and therefore pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier form a further aspect of the present disclosure.

[0124] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment, hi one embodiment, the individual compounds are administered simultaneously in a combined pharmaceutical formulation.

[0125] Such combination therapy utilizes the compounds of the present disclosure within the dosage ranges described herein and other pharmaceutically active agents within their approved dosage ranges or dosages as described in the relevant publication references. [Example]

[0126] General steps: Methods for preparing compounds of the present disclosure are illustrated in the following examples. Starting materials are either known in the art or made according to procedures as illustrated herein, or are commercially available. Commercially available reagents were used without further purification. If no reaction temperature is included, the reactions were carried out at ambient temperature, typically 17-27°C.

[0127] Those skilled in the art will understand that reaction temperatures, reaction times, and amounts of reagents may vary from those described herein.

[0128] The compounds described in the present disclosure are 1 When characterized by H NMR spectroscopy, spectra were recorded on a Bruker AVANCE II 400 (400 MHz), Bruker AVANCE III HD (400 MHz), Bruker AVANCE NEO (400 MHz), or Bruker AVANCE III (600 MHz) instrument. The instrument was equipped with a 5 mm BBI room temperature probehead. If temperature is not included, the spectra were recorded at ambient temperature. Chemical shift values ​​are expressed in parts per million (ppm). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, and br = broad.

[0129] When the compounds described in this disclosure are characterized by LCMS data, retention times and molecular weights are determined using the conditions listed below. Method A: For retention time and mass detection, a Waters LC / MS-system (UPLC / SQD; ionization: electrospray in positive and / or negative mode [ES+ / -]) was used. Detected masses are given as mass per charge [m / z]. Waters ACQUITY UPLC BEH C18, 1.7 μm; 2.1 mm x 50 mm; HO + 0.05% FA:ACN + 0.035% FA; 98:2 (0 min) to 98:2 (0.2 min) to 2:98 (3.8 min) to 2:98 (4.3 min) to 98:2 (4.5 min), 1 ml / min, 55 °C; RT in minutes at 220 nm and the observed m / z mass for each UV peak are given. Method B: For retention time and mass detection, an Agilent LC / MS system (LC1200 Series / MS6120 Quadrupole LC / MS, LC1260 Infinity / MS6120 Quadrupole LC / MS, or LC1260 Infinity II / MSD Infinity Lab) was used. Ionization: Electrospray (ES) in positive mode. +). Detected masses are given as mass per charge [m / z]. Luna C18, 3 μm; 2.0 mm x 10 mm; HO + 0.05% TFA:ACN; 93:7 (0 min) to 5:95 (1.0 min) to 5:95 (1.45 min), 1.1 ml / min; 30°C; RT in minutes at 220 nm and the observed m / z mass for each UV peak are given. Method C: For retention time and mass detection, a Shimadzu LC / MS system (LCMS-2020; software: LabSolution version 5.97SP1) was used. Ionization: electrospray (ES) in positive mode. + ) The detected mass is given as mass per charge [m / z]. Kinetex® EVO C18, 5 μm; 2.1 mm x 30 mm; 5% ACN (0.01875% TFA) in water (0.0375% TFA) at 0.60 min to 95% ACN in water followed by a 0.18 min hold at 95% ACN; 2.0 ml / min; T 50° C.; RT in minutes at 220 nm and observed m / z mass for each UV peak are given. Method D: For retention time and mass detection, a Shimadzu LC / MS system (LCMS-2020; software: LabSolution version 5.97SP1) was used. Ionization: electrospray (ES) in positive mode. + ) The detected mass is given as mass per charge [m / z]. Kinetex® EVO C18, 5 μm; 2.1 mm x 30 mm; 5% ACN in water (NH4HCO3 - 10 mmol / l) to 95% ACN in water at 1.5 ml / min for 0.8 min; followed by a hold at 95% ACN for 0.15 min at 2.0 ml / min; T 40°C; RT in minutes at 220 nm and the observed m / z mass for each UV peak are given. Method E: For retention time and mass detection, a Shimadzu LC / MS-system (LCMS-2020; software: LabSolution version 5.97SP1) was used. Ionization: electrospray (ES) in positive mode. +) The detected mass is given as mass per charge [m / z]. Kinetex® EVO C18, 5 μm; 2.1 mm x 30 mm; 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in water (flow rate 1.5 ml / min) in 0.80 min, followed by a 0.15 min hold at 95% ACN (2.0 ml / min), to 5% ACN in 0.01 min, followed by a 0.04 min hold; T 50° C.; RT in minutes at 220 nm and the observed m / z mass for each UV peak are given.

[0130] Silica gel chromatography was performed using a CombiFlash® Rf (Teledyne ISCO), a Büchi Reveleris® X2 or a Biotage Dalton 2000 instrument equipped with prepacked cartridges.

[0131] Preparative reversed-phase liquid chromatography was performed on a Biotage instrument using a C18 column and a water (0.1% FA) / ACN gradient.

[0132] For preparative reversed-phase HPLC, an Agilent 1200 preparative HPLC instrument, a Gilson apparatus (GX-271 liquid handler, 331 / 332 pumps, UV / VIS-155) or a Waters autopurification LC preparative system was used.

[0133] For preparative SFC, Waters SFC150 mgm and Waters SFC350 instruments were used.

[0134] For analytical SFC, a SHIMADZU LC-30AD instrument was used.

[0135] For compounds described as HCl-, TFA-, or other salts, the exact amount of each salt is generally not determined unless otherwise specified. Thus, the amount of salt can range from as low as 0.01 equivalents to as high as 5.0 equivalents, depending on the chemical structure (e.g., number of basic centers).

[0136] Compound names were generated using Perkin Elmer's ChemDraw®, version 20.1.0.110.

[0137] [Table 1]

[0138] [Table 2]

[0139] [Table 3]

[0140] Intermediate 1: tert-butyl ((S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)-methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] Step A1: 4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-amine [ka] To a mixture of (2-amino-4-pyridyl)methanol (20 g) and imidazole (10.97 g) in DMF (150 ml) was added TBDMSCl (24.28 g) in one portion at 0°C under N2. The mixture was stirred at 20°C for 12 hours, and then water (150 ml) was added. The mixture was extracted with EA (200 ml x 3), and the combined organic phase was washed with brine (100 ml x 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE / EA = 0 / 1 to 1 / 1) to give 27 g of the title compound. LC / MS: m / z = 239.1 [M+H]+ ;rt:0.36 min (LC / MS-Method C).

[0141] Step A2: tert-butyl ((S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] To a mixture of (2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (4.55 g) in DCM (40 ml), DMAP (4.10 g) and EDCI (6.43 g) were added at 20° C. After 5 minutes, 4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-amine (4 g) was added at 20° C. After 12 hours, water and DCM (40 ml×3) were added. The organic phases were separated, combined, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE / EA=0 / 1 to 1 / 1) to give 8.2 g of the title compound. 1 H NMR (400MHz, CDCl3, typical signal) δ=8.84-8.69(m,1H),8.26(dd,J=3.0,5.0Hz,1H),8.15(s,1H),7.13(d,J=5.1Hz,1H),5.18(br d,J=7.3Hz,1H),4.76(s,2H),4.13(m,1H),1.84(br m,1H),1.45(s,9H),0.96(s,9H),0.12(s,6H).

[0142] Step A3: tert-butyl ((S)-2-((4-(hydroxymethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] To a mixture of tert-butyl ((S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (8.20 g) in THF (82 ml) was added TBAF (1 M, 17.51 ​​ml) in one portion at 0° C. under N. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was then concentrated, and the residue was purified by column chromatography (silica gel, PE / EA = 0 / 1 to 1 / 0) to give 6.29 g of the racemic title compound, which was purified by SFC (conditions: Daicel chiralpak AD (30 mm * 250 mm, 10 μm); mobile phase A / B: CO2 / 0.1% NH3-H2O, MeOH; B%: 30% to 30%, 8.5 min; 100 ml / min) to give 2.6 g of the title compound. LC / MS: m / z = 378.3 [M+H] + ;rt:0.39 min (LC / MS-Method C). 1 H NMR (400MHz, CDCl3, typical signal): δ ppm=8.79(br s,1H),8.16(d,J=5.1Hz,1H),8.12(s,1H),7.00(d,J=5.0Hz,1H),5.34(br d. 5-40%; flow rate: 3 ml / min; T: 35°C; back pressure: 100 bar): rt: 0.57 min [for comparison: (R) enantiomer: rt: 0.70 min].

[0143] Step A4: tert-butyl ((S)-2-((4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] To a mixture of tert-butyl ((S)-2-((4-(hydroxymethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (2.6 g) in DCM (26 ml) was added DMP (4.38 g) in one portion under N at 0° C. The mixture was stirred at 20° C. for 12 h. The reaction mixture was then concentrated in vacuo, and DCM (50 ml) and water were added. The organic phase was separated, and the aqueous phase was extracted once more with DCM (50 ml). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=0 / 1 to 1 / 1) to give 2.4 g of the title compound. LC / MS: m / z=376.3 / 394.3 [M+H] + / [M+18+H] + ;rt:0.64 min (LC / MS-Method D).

[0144] Step B1: (R,E)-2,2,2-trifluoro-N-(1-phenylethyl)ethan-1-imine [ka] To a solution of (1R)-1-phenylethanamine (68 g) in toluene (600 ml) was added TsOH (580 mg) and 2,2,2-trifluoroethane-1,1-diol (78.14 g). The mixture was stirred at 120° C. for 12 hours. The reaction mixture was diluted with water (500 ml), extracted with EA (300 ml×2), washed with brine (500 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (110 g) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ ppm=7.70-7.61(m,1H),7.43-7.28(m,5H),4.62(q,J=6.6Hz,1H),1.60(d,J=6.7Hz,3H).

[0145] Step B2: (S)-1,1,1-trifluoro-3-nitro-N-((R)-1-phenylethyl)propan-2-amine [ka] A mixture of (R,E)-2,2,2-trifluoro-N-(1-phenylethyl)ethan-1-imine (110 g), nitromethane (166.87 g), and ZrCl (63.71 g) was stirred for 3 h at 25° C. The reaction mixture was diluted with water (500 ml), extracted with EA (300 ml × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified multiple times by flash silica gel chromatography (PE:EA = 1:0 to 20:1) to give 56.5 g of the title compound. 1 H NMR(400MHz,CDCl3):δ ppm=7.40-7.28(m,5H),4.66(dd,J=4.5,12.8Hz,1H),4.45(dd,J=7.9,12.7Hz,1H),4.09-4.01(m,1H),4.01-3.91(m,1H),1.78(br d,J=9.7Hz,1H),1.36(d,J=6.4Hz,3H).

[0146] Step B3: (3,3,3-trifluoropropane-1,2-diyl)(S)-dicarbamate di-tert-butyl [ka] To a solution of (S)-1,1,1-trifluoro-3-nitro-N-((R)-1-phenylethyl)propan-2-amine (46 g) in MeOH (500 ml) was added Pd / C (9 g, 10% purity) and BocO (84.23 g) under a N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (50 psi) at 50 °C for 48 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product, which was then triturated with PE (100 ml) at 25 °C for 30 min to give 40.8 g of the title compound. 1 H NMR (400MHz, CDCl3): δ ppm=5.16(br d,J=6.4Hz,1H),4.79(br s,1H),4.32(br s,1H),3.56-3.36(m,2H),1.45(s,18H).

[0147] Step B4: (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride [ka] A solution of HCl / dioxane (230 ml) and di-tert-butyl (3,3,3-trifluoropropane-1,2-diyl)(S)-dicarbamate (46 g) in dioxane (230 ml) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to give 28 g of the crude title compound along with (2R)-3,3,3-trifluoropropane-1,2-diamine hydrochloride as an impurity.

[0148] Step B5: (S)-N1,N2-dibenzyl-3,3,3-trifluoropropane-1,2-diamine [ka] To a solution of (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (8 g) in ACN (80 ml) was added K2CO3 (13.75 g) and benzyl bromide (13.61 g) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 0-8% EA / PE gradient at 60 ml / min) to give 8.6 g of residue, which was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm * 50 mm, 10 μm); mobile phase: [0.1% NH3.HO in EtOH]; B%: 30%-30%, 8 min) to give 6 g of the title compound. Analytical chiral analysis (Chiralpak IG-3, 4.6x50mm, 3μm; CO2 / EtOH (0.05% DEA); Gradient: 5-40% B in A; Flow rate: 3ml / min; T: 35°C; Back pressure: 100bar) RT: 1.06 min. 1H NMR(400MHz,CDCl3):δ ppm=7.37-7.27(m,10H),3.76(d,J=13.6Hz,2H),3.53(d,J=13.6Hz,2H),3.35(tquin,J=3.7,7.1Hz,1H),2.76-2.68(m,1H),2.66-2.57(m,1H).

[0149] Step B6: (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride [ka] To a solution of (S)-N1,N2-dibenzyl-3,3,3-trifluoropropane-1,2-diamine (7.47 g) and HCl (12 M, 2.22 ml) in EtOH (75 ml) was added Pd / C (10%, 2.2 g) under N2. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give 4.88 g of the title compound. 1 H NMR (400MHz, MeOH-d4): δ ppm=4.62-4.48(m,1H),3.63-3.56(m,1H),3.52-3.44(m,1H).

[0150] Step C1: tert-butyl ((S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)-methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((S)-2-((4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Step A4; 208 mg) and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (Step B6; 134 mg) were dissolved in DCM (8 ml) under Ar. TEA (0.339 ml) was added and the mixture was stirred at 40° C. for 1.5 h. After cooling to room temperature, sodium cyanoborohydride (122 mg), methanol (1.2 ml), and acetic acid (0.165 ml) were added and stirring was continued for 20 min. After standing overnight, the mixture was concentrated, and DCM and saturated NaHCO3 solution were added. The organic layer was separated and the aqueous phase was extracted three times with DCM. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 45 min from 95% HO+0.05% TFA / 5% ACN to 5% HO+0.05% TFA / 95% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing the pure product were combined, ACN was partially removed, and TFA was neutralized with concentrated NaHCO3 solution. After the product was extracted with DCM (3x), the combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ACN / HO and lyophilized to give 177 mg of the title compound (Intermediate 1). LC / MS: m / z = 488.2 [M+H]+; rt: 1.71 min (LC / MS-Method A).

[0151] Intermediate 2: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)acetamide HCl salt [ka] tert-Butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoro-methyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate (Example 1; 127 mg) was dissolved in dioxane (3 ml) and HCl in dioxane (4 M, 3 ml) was added. After stirring for 1 hour, the mixture was concentrated in vacuo. The residue was dissolved in a mixture of ACN / water and lyophilized to give 133 mg of crude title compound. LC / MS: m / z=414.1 [M+H] + ;rt: 1.25 min (LC / MS-Method A).

[0152] Intermediate 3: ((S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)-amino)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamic acid tert-butyl TFA salt [ka] Step 1: tert-butyl (2-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate [ka] To a solution of 2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (10.00 g) in DCM (100 ml) was added DMAP (8.33 g) and EDCI (13.07 g) over 5 min with stirring at 20 °C, followed by 4-[[tert-butyl(dimethyl)silyl]oxymethyl]pyridin-2-amine (Intermediate 1 - Step A1; 8.13 g), and stirring was continued for 12 h at 20 °C. The reaction mixture was then diluted with HO (300 ml) and extracted with DCM (200 ml × 2). The combined organic layers were washed with brine (200 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, PE / EA = 1 / 0 to 3 / 1) to give 17 g of the title compound. 1 H NMR(400MHz,DMSO-d6):δ ppm=10.42(s,1H),8.25(d,J=5.0Hz,1H),8.10(s,1H),7.11(br d,J=8.5Hz,1H),7.02(d,J=5.1Hz,1H),4.74(s,2H),4.18(br t,J=7.9Hz,1H),2.00(br s,1H),1.84-1.56(m,6H),1.38(s,9H),1.29(br s,2H),0.91(s,9H),0.09(s,6H).

[0153] Step 2: (S)-(1-(4,4-difluorocyclohexyl)-2-((4-(hydroxymethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate tert-butyl [ka] To a mixture of tert-butyl (2-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (17 g) in THF (173 ml) was added TBAF (1 M, 34.75 ml) in one portion at 0° C. under N. The mixture was stirred at 20° C. for 1 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, PE / EA=1 / 0 to 2 / 1) to give 11.6 g of the title compound as a racemate. The racemate was separated by SFC (Column: Daicel Chiralpak AD (250 mm x 50 mm, 10 μm); Mobile phase: [0.1% NH3 / H2O in IPA]; B%: 50%-50%, 4 min; 180 ml / min) to give 5.6 g of the title compound. 1 H NMR(400MHz,CDCl3):δ ppm=9.14-8.92(m,1H),8.26(d,J=5.1Hz,1H),8.20(s,1H),7.12(d,J=5.0Hz,1H),5.55(br Analytical chiral analysis (column: Chiralpak AD-3, 4.6mmx50mm, 3μm; Eluent: CO2 / IPA (0.05% DEA); Gradient: B in A 5-40%; flow rate: 3 ml / min; temp: 35°C; back pressure: 100 bar): rt: 1.64 min [for comparison: (R) enantiomer: rt: 2.70 min].

[0154] Step 3: (S)-(1-(4,4-difluorocyclohexyl)-2-((4-formylpyridin-2-yl)amino)-2-oxoethyl)carbamate tert-butyl [ka] To a solution of tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-2-((4-(hydroxymethyl)-pyridin-2-yl)amino)-2-oxoethyl)carbamate (5.6 g) in DCM (56 ml) was added DMP (8.92 g) under N at 0 °C. The mixture was stirred at 25 °C for 2 h. Then, the reaction mixture was diluted with HO (200 ml) and extracted with DCM (100 ml × 2). The combined organic layers were washed with brine (100 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, PE / EA = 1 / 0 to 3 / 1) to give 5.3 g of the title compound. 1 H NMR(400MHz,DMSO-d6):δ ppm=10.82(s,1H),10.06(s,1H),8.60(d,J=4.9Hz,1H),8.51(s,1H),7.54(dd,J=1.3,4.9Hz,1H),7.16(br d,J=8.1Hz,1H),4.22(br t,J=7.8Hz,1H),2.07-2.00(m,2H),1.85-1.59(m,6H),1.38(s,9H),1.30(br s,1H).

[0155] Step 4: ((S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)-amino)methyl)-pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamic acid tert-butyl TFA salt [ka] (S)-tert-Butyl (1-(4,4-difluorocyclohexyl)-2-((4-formylpyridin-2-yl)amino)-2-oxo-ethyl)carbamate (Step 3; 500 mg) and (2S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (303 mg) were dissolved in DCM (30 ml) under Ar. TEA (0.772 ml) was added and the mixture was stirred at 40 °C for 2 h. After cooling to room temperature, sodium cyanoborohydride (277 mg), methanol (0.127 ml) and acetic acid (0.2 ml) were added and stirring was continued for 15 min. The mixture was concentrated, and saturated NaHCO3 solution and DCM were added. The organic layer was separated and the aqueous phase was extracted three times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 45 min from 95% HO+0.05% TFA / 5% ACN to 5% HO+0.05% TFA / 95% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing pure product were combined, the ACN was partially removed, and the residue was lyophilized to give 553 mg of the title compound (Intermediate 3). LC / MS: m / z=510.2 [M+H] + ;rt: 1.47 min (LC / MS-Method A).

[0156] Intermediate 4: (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)acetamide HCl salt [ka] Tert-butyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[4-[[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]methyl]-2-pyridyl]amino]ethyl]carbamate (Example 6; 280 mg) was mixed with HCl in dioxane (4 M, 6.5 ml). After stirring for 2 hours, the mixture was concentrated in vacuo. The residue was dissolved in a mixture of ACN / water and lyophilized to give 283 mg of the crude title compound. LC / MS: m / z=436.2 [M+H] + ;rt:1.06 min (LC / MS-Method A).

[0157] Intermediate 5: ((S)-1-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)-methyl)pyridin-2-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamic acid tert-butyl TFA salt [ka] Step 1: tert-butyl (1-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate [ka] To a solution of 2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid (10.00 g) in DCM (100 ml) was added DMAP (9.07 g) and EDCI (14.24 g). 4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-amine (Intermediate 1-Step A1; 8.85 g) was then added, and stirring was continued at 20 °C for 12 h. The reaction mixture was then diluted with HO (400 ml) and extracted with DCM (400 ml x 2). The combined organic layers were washed with brine (200 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, PE / EA = 1 / 0 to 73 / 23) to give 13.17 g of the title compound. LC / MS: m / z = 490.5 [M+H] + ;rt:0.55 min (LC / MS-Method C).

[0158] Step 2: (S)-(1,1-dicyclopropyl-3-((4-(hydroxymethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)carbamate tert-butyl [ka] To a mixture of tert-butyl (1-((4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (13 g) in THF (130 ml) was added TBAF (1 M, 27.87 ml) at 0° C. under N2 with stirring. The mixture was stirred at 20° C. for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, DCM / MeOH=50 / 1 to 10 / 1) to give 9.2 g of the title compound as a racemate. The racemate was separated by SFC (column: Phenomenex-cellulose-2 (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH3 / H2O in MeOH]; B%: 20% to 20%, 2.3 min; 60 ml / min) to give 3.0 g of the title compound. 1H NMR (400 MHz, DMSO-d6, representative signals shown): δ ppm = 10.25 (s, 1H), 8.21 (d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.02 (dd, J = 0.6, 5.0 Hz, 1H), 6.91 (br d, J = 8.6 Hz, 1H), 5.41 (t, J = 5.8 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H), 4.41-4.35 (m, 1H), 1.40 (s, 9H). Analytical chiral analysis (column: Chiralcel OZ-3, 4.6 x 50 mm, 3 μm; eluent: CO2 / MeOH (0.05% DEA); gradient: B in A). 5-40%; flow rate: 3 ml / min; T: 35°C; back pressure: 100 bar): rt: 0.817 min [for comparison: (R) enantiomer: rt: 0.988 min].

[0159] Step 3: (S)-(1,1-dicyclopropyl-3-((4-formylpyridin-2-yl)amino)-3-oxopropan-2-yl)carbamate tert-butyl [ka] To a solution of tert-butyl (S)-(1,1-dicyclopropyl-3-((4-(hydroxymethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)carbamate (2.9 g) in DCM (30 ml) was added DMP (4.91 g) with stirring at 0 °C. The mixture was stirred at 20 °C for 2 h. Then, the mixture was filtered, and the filtrate was diluted with HO (100 ml) and extracted with EA (100 ml × 3). The combined organic layers were washed with brine (100 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, PE / EA = 1 / 0 to 3 / 1) to give 2.79 g of the title compound. 1H NMR (400 MHz, DMSO-d6, representative signals shown): δ ppm = 10.53 (s, 1H), 9.87 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 8.29 (s, 1H), 7.34 (dd, J = 0.9, 5.0 Hz, 1H), 6.79 (br d, J = 8.6 Hz, 1H), 4.31-4.14 (m, 1H), 1.26-1.12 (m, 10H).

[0160] Step 4: ((S)-1-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)-methyl)pyridin-2-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamic acid tert-butyl TFA salt [ka] (S)-tert-Butyl (1,1-dicyclopropyl-3-((4-formylpyridin-2-yl)amino)-3-oxopropan-2-yl)carbamate (500 mg) and (2S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (323 mg) were dissolved in DCM (30 ml) under Ar. After the addition of TEA (0.821 ml), the mixture was stirred at room temperature for 10 minutes and then at 40° C. for 1.5 hours. After cooling to room temperature, sodium cyanoborohydride (294 mg), methanol (7 ml), and acetic acid (0.399 ml) were added, and stirring was continued for 1 hour. The mixture was concentrated, and saturated NaHCO3 solution and DCM were added. The organic layer was separated, and the aqueous phase was extracted with DCM (3×). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 45 min from 95% HO+0.05% TFA / 5% ACN to 5% HO+0.05% TFA / 95% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing pure product were combined, the ACN was partially removed, and the residue was lyophilized to give 603 mg of the title compound (Intermediate 5). LC / MS: m / z=486.2 [M+H] + ;rt:1.57 min (LC / MS-Method A).

[0161] Intermediate 6: (S)-2-amino-3,3-dicyclopropyl-N-(4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)propanamide HCl salt [ka] Similar to Intermediate 4, 323 mg of crude title compound was obtained. LC / MS: m / z=412.2 [M+H] + ;rt:1.13 min (LC / MS-Method A).

[0162] Intermediate 7: tert-butyl ((S)-2-((4-((((1-(methylamino)cyclobutyl)methyl)amino)-methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((S)-2-((4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [Intermediate 1 - Step A4] (30 mg) and 1-(aminomethyl)-N-methyl-cyclobutanamine dihydrochloride (37 mg) were dissolved in DCM (2 ml) under Ar. After the addition of TEA (0.105 ml), the mixture was stirred at room temperature for 10 min and then at 40 °C for 1 h. After cooling to room temperature, sodium cyanoborohydride (18 mg), methanol (2.5 ml) and acetic acid (57 μl) were added and stirring was continued for 1 h. After standing overnight, the mixture was concentrated, and saturated NaHCO3 solution and DCM were added. The organic layer was separated and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 45 min from 95% HO+0.05% TFA / 5% ACN to 5% HO+0.05% TFA / 95% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing pure product were combined, ACN was removed, saturated NaHCO3 solution was added (pH approx. 7), and the aqueous mixture was extracted with DCM (2x). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give 22 mg of the title compound. LC / MS: m / z = 474.3 [M+H] + ;rt:0.73 min (LC / MS-Method B).

[0163] Intermediate 8: tert-butyl ((S)-2-((4-(((2-amino-2-methylpropyl)amino)methyl)-pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] Step 1: tert-butyl ((S)-2-((4-(((2-(((benzyloxy)carbonyl)amino)-2-methylpropyl)amino)-methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((S)-2-((4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [Intermediate 1 - Step A4] (100 mg) and benzyl N-(2-amino-1,1-dimethyl-ethyl)carbamate hydrochloride (181 mg) were dissolved in DCM (2 ml) under Ar. After the addition of TEA (0.163 ml), the mixture was stirred at room temperature for 10 min and then at 40 °C for 1 h. After cooling to room temperature, sodium cyanoborohydride (59 mg), methanol (4.5 ml), and acetic acid (79 μl) were added and stirring was continued for 1 h. The mixture was then concentrated, and DCM and saturated NaHCO solution were added. The organic layer was separated, and the aqueous phase was extracted with DCM (2x). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further purified by preparative RP HPLC (Agilent Prep C18, 30 mm x 250 mm, 10 μm; 50 ml / min, 12.5 min, 90% HO / 10% ACN to 10% HO / 90% ACN). Fractions containing pure product were combined, the ACN was partially removed, and the residue was lyophilized to give 63 mg of compound. LC / MS: m / z = 582.2 [M+H] + ;rt: 1.97 min (LC / MS-Method A).

[0164] Step 2: tert-butyl ((S)-2-((4-(((2-amino-2-methylpropyl)amino)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((S)-2-((4-(((2-(((benzyloxy)carbonyl)amino)-2-methylpropyl)amino)-methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (62 mg) was dissolved in MeOH (2.5 ml) and Pd / C (10%, 6 mg) was added. After flushing with hydrogen, the mixture was stirred under a hydrogen atmosphere (balloon) for 20 hours. To complete the reaction, the mixture was filtered and washed with MeOH. The volume of the filtrate was reduced in vacuo, Pd / C (6 mg) was added, and hydrogen was bubbled through the mixture for 1 hour. The mixture was then filtered, washed with MeOH, and the filtrate was concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 45 min from 95% HO+0.05% TFA / 5% ACN to 5% HO+0.05% TFA / 95% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing the pure product were combined, the ACN removed, saturated NaHCO3 solution added (pH approx. 7), and the aqueous mixture extracted with DCM (2x). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give 20 mg of the title compound (Intermediate 8). LC / MS: m / z = 448.3 [M+H] + ;rt:0.711 min (LC / MS-Method B).

[0165] Intermediate 9: (S)-2-amino-N-(4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide HCl salt [ka] Similar to Intermediate 2, 13 mg of crude title compound was obtained. LC / MS: m / z=374.2 [M+H] + ;rt: 1.27 min (LC / MS-Method A).

[0166] Intermediate 10: (2-aminopyridin-4-yl)methyl (2,2,2-trifluoroethyl)carbamate [ka] Step 1: tert-Butyl (4-(hydroxymethyl)pyridin-2-yl)carbamate [ka] tert-Butyl N-(4-formyl-2-pyridyl)carbamate (100 mg) was dissolved in MeOH (5 ml) under Ar. Sodium borohydride (19 mg) was added with stirring. After stirring for 1 h and standing overnight, the MeOH was reduced and the residue was treated with EA. The mixture was poured into water, and the aqueous mixture was extracted with EA (2x). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / EtOH: 100:0 for 5 min, 100:0 to 95:5 for 30 min, 95:5 for 10 min). Fractions containing the pure compound were combined and concentrated in vacuo to give 82 mg of the title compound. LC / MS: m / z=225.1 [M+H] + ;rt:0.380 min (LC / MS-Method B).

[0167] Step 2: tert-butyl (4-((((2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)pyridin-2-yl)carbamate [ka] tert-Butyl (4-(hydroxymethyl)pyridin-2-yl)carbamate (97 mg) was dissolved in THF (4 ml) and NaH (60% in mineral oil, 52 mg) was added. After stirring for 1 h, 1,1,1-trifluoro-2-isocyanato-ethane (136 mg) was added. After 6 h, an additional equivalent of 1,1,1-trifluoro-2-isocyanato-ethane was added. After stirring overnight, the mixture was poured into water, and the aqueous mixture was extracted with EA (2x). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative RP HPLC (Agilent Prep C18, 30 mm x 250 mm, 10 μm; 40 ml / min, 15 min 90% HO / 10% ACN to 10% HO / 90% ACN). The fractions containing the pure product were combined, the ACN was partially removed, and the residue was lyophilized to give 85 mg of the title compound. LC / MS: m / z=350.1 [M+H] + ;rt:0.716 min (LC / MS-Method B).

[0168] Step 3: (2-aminopyridin-4-yl)methyl (2,2,2-trifluoroethyl)carbamate [ka] tert-Butyl (4-((((2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)pyridin-2-yl)carbamate (72 mg) was dissolved in dioxane (2.5 ml) and HCl in dioxane (4 M, 2.5 ml) was added. After stirring at 50 °C for 2.5 h, the mixture was cooled and concentrated in vacuo. The residue was treated with EA and water. Saturated NaHCO3 solution was added (pH approx. 7) and the aqueous phase was extracted with EA (2x). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / EtOH: 100:0 for 5 min, 100:0 to 80:20 for 40 min, 80:20 for 10 min). The fractions containing the pure compound were combined and concentrated in vacuo to give 32 mg of the title compound (Intermediate 10). LC / MS: m / z=250.0[M+H] +;rt:0.65 min (LC / MS-Method A).

[0169] Intermediate 11: (S)-(2-((4-(bromomethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate tert-butyl [ka] Step 1: (S)-(1-(4,4-difluorocyclohexyl)-2-((4-(hydroxymethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate tert-butyl [ka] (S)-tert-Butyl (1-(4,4-difluorocyclohexyl)-2-((4-formylpyridin-2-yl)amino)-2-oxoethyl)carbamate [Intermediate 3 - Step 3] (215 mg) was dissolved in MeOH (5 ml). Sodium borohydride (23 mg) was added with stirring. After stirring for 5 h and standing overnight, HO was added to the mixture and the aqueous phase was extracted with EA (3x). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 12 g; nHep / EA: 100:0 in 5 min, 100:0 to 40:60 in 30 min). The fractions containing the pure compound were combined and concentrated in vacuo to give 207 mg of the title compound. LC / MS: m / z=400.2 [M+H] + ;rt:1.73 min (LC / MS-Method A).

[0170] Step 2: (S)-(2-((4-(bromomethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate tert-butyl [ka] (S)-tert-Butyl (1-(4,4-difluorocyclohexyl)-2-((4-(hydroxymethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate (50 mg) was dissolved in dry THF (2 ml) under Ar. Triphenylphosphine (66 mg) and carbon tetrabromide (62 mg) were added with stirring. After stirring for 2 h, the mixture was placed in a deep freezer over the weekend. After warming, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (nHep / EA: 100:0 for 5 min, 100:0 to 90:10 in 40 min). Fractions containing the pure compound were combined and concentrated in vacuo to give 19 mg of the title compound (Intermediate 11). LC / MS: m / z=462.0 [M+H] + ;rt:2.53 min (LC / MS-Method A).

[0171] Intermediate 12: tert-butyl ((S)-2-((4-((((R)-2-aminopropyl)amino)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate and tert-butyl ((S)-2-((4-((((R)-1-aminopropan-2-yl)amino)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] Following the procedure in Intermediate 1 using tert-butyl ((S)-2-((4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [Intermediate 1 - Step A4] (30 mg) and (2R)-propane-1,2-diamine dihydrochloride (29 mg) as starting materials, 15 mg of the title compound was obtained as a mixture. LC / MS: m / z=434.3 [M+H] + ;rt:0.704 min (LC / MS-Method B).

[0172] Intermediate 13: (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetate methyl [ka] Under Ar, (2S)-2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (1 g) was dissolved in DMF (15 ml). Cs2CO3 (555 mg) was added, followed by methyl iodide (0.23 ml). After stirring for 1 h, water (30 ml) was added, and the aqueous phase was extracted with MTB ether. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (24 g silica gel; 32 ml / min; nHep / EA 85:15 to 60:40 in 23 min). Fractions containing the pure compound were combined and concentrated in vacuo to give 1 g of the title compound. LC / MS: m / z = 252.1 [M+H-isobutene] + ;rt:2.16 min (LC / MS-Method A).

[0173] Intermediate 14: tert-butyl ((S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)-methyl)-5-fluoropyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] Step 1: 2-((tert-butoxycarbonyl)amino)-5-fluoroisonicotinic acid methyl ester [ka] To a mixture of methyl 2-bromo-5-fluoropyridine-4-carboxylate (20.5 g) in dioxane (310 ml) was added tert-butyl carbamate (25.65 g), Pd(dba) (1.60 g), CsCO (39.96 g), and Xantphos (2.03 g) in one portion under N at 20 °C. The mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled, filtered through a pad of Celite, washed with EA (10 ml), and the filtrate was dissolved in EA (200 ml), washed subsequently with water (100 ml) and brine (100 ml), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was triturated with EA (100 ml) to give 19.06 g of the title compound. 1 H NMR (400MHz, CDCl3): δ ppm=8.41(br d,J=5.1Hz,1H),8.26(s,1H),8.15(br s,1H),3.96(s,3H),1.56(s,9H).

[0174] Step 2: tert-Butyl (5-fluoro-4-(hydroxymethyl)pyridin-2-yl)carbamate [ka] To a mixture of methyl 2-((tert-butoxycarbonyl)amino)-5-fluoroisonicotinate (10 g) in THF (130 ml) was added LiBH (2.02 g) in one portion at 20 °C under N. The mixture was stirred at 40 °C for 4 h. Aqueous NaHCO was added to the mixture at 0 °C, diluted with water (100 ml) and EA (150 ml), and the combined organic phase was washed with brine (100 ml), dried over anhydrous NaSO, and concentrated to give a residue, which was purified by column chromatography (silica gel, PE / EA = 0 / 1 to 3 / 1) to give 6.5 g of the title compound. 1 H NMR (400MHz, CDCl3): δ ppm=8.10(d,J=5.4Hz,1H),8.06(d,J=1.1Hz,1H),7.80(br s,1H),4.80(s,2H),1.54(s,9H).

[0175] Step 3: (2-amino-5-fluoropyridin-4-yl)methanol [ka] A mixture of tert-butyl (5-fluoro-4-(hydroxymethyl)pyridin-2-yl)carbamate (6.5 g) in HCl / MeOH (65 ml) was stirred under N at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give 4.79 g of the title compound.

[0176] Step 4: 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluoropyridin-2-amine [ka] To a mixture of (2-amino-5-fluoropyridin-4-yl)methanol (4.79 g) and imidazole (5.48 g) in DCM (38 ml) was added TBDMSCl (6.06 g) in one portion under N at 0° C. The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, PE / EA=0 / 1 to 3 / 1) to give 4.4 g of the title compound. 1 H NMR (400MHz, CDCl3): δ ppm=7.80(d,J=1.8Hz,1H),6.65(d,J=4.8Hz,1H),4.72(s,2H),0.97-0.92(m,9H),0.13(s,6H).

[0177] Step 5: tert-butyl ((S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluoropyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] To a mixture of (2S)-2-(tert-butoxycarbonylamino)-2-(trans-4-methylcyclohexyl)acetic acid (5.29 g) in DCM (50 ml), DMAP (4.76 g) and EDC (7.48 g) were added at 20 °C for 5 min, followed by 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluoropyridin-2-amine (5 g) and stirred at 20 °C for 12 h. DCM (100 ml) and water (50 ml) were added to the mixture. The aqueous phase was extracted with DCM (2x). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE / EA = 0 / 1 to 3 / 1) to give 9.12 g of the title compound.

[0178] Step 6: tert-butyl ((S)-2-((5-fluoro-4-(hydroxymethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] To a mixture of tert-butyl ((S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluoropyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (9.12 g) in THF (91 ml) was added TBAF (1 M, 18.79 ml) in one portion at 0° C. under N. The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, PE / EA=0 / 1 to 3 / 1). Further SFC purification (Daicel chiralcel OJ (250 mm x 30 mm, 10 μm); [0.1% NH3 / HO in MeOH]; B%: 10% to 10%, 2 min; 200 ml / min) afforded 3.4 g of the title compound (Peak 1). Analytical SFC data (Daicel chiralcel OJ-3 (50 mm x 4.6 mm, 3 μm); MeOH (0.05% DEA)]; B%: 5% to 40%, flow rate 3 ml / min, T: 35 °C): Peak 1: RT = 0.54 min; Peak 2: RT = 0.69 min.

[0179] Step 7: tert-butyl ((S)-2-((5-fluoro-4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] To a mixture of tert-butyl ((S)-2-((5-fluoro-4-(hydroxymethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (3.7 g) in DCM (37 ml) was added DMP (5.95 g) in one portion at 0° C. under N. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, PE / EA=0 / 1 to 1 / 1) to give 3.1 g of the title compound. 1H NMR (400MHz, CDCl3): δ ppm=10.33(s,1H),8.71(br s,1H),8.59(d,J=5.0Hz,1H),8.34(s,1H),5.11(br d,J=8.3Hz,1H),4.13(br d,J=6.9Hz,1H),1.85-1.72(m,5H),1.46(s,9H),1.36-1.26(m,1H),1.23-1.04(m,2H),1.02-0.91(m,2H),0.88(d,J=6.5Hz,3H).

[0180] Step 8: tert-butyl ((S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)methyl)-5-fluoropyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((S)-2-((5-fluoro-4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-carbamate (500 mg) and (2S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride [Intermediate 1 - Step B6] (307 mg) were dissolved in DCM (30 ml) under Ar. TEA (0.779 ml) was added and the mixture was stirred at 40 °C for 40 min. After cooling to room temperature, sodium cyanoborohydride (280 mg), dry methanol (0.129 ml) and acetic acid (0.4 ml) were added and stirring was continued for 20 min. The mixture was concentrated, and DCM and saturated NaHCO3 solution were added. The organic layer was separated and the aqueous phase was extracted three times with DCM. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 45 min from 95% HO+0.05% TFA / 5% ACN to 5% HO+0.05% TFA / 95% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing the pure product were combined, ACN was partially removed, and TFA was neutralized with concentrated NaHCO3 solution. After extracting the product with DCM (3x), the combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ACN / HO and lyophilized to give 412 mg of the title compound (Intermediate 14). LC / MS: m / z = 506.3 [M+H] + ;rt: 1.79 min (LC / MS-Method A).

[0181] Intermediate 15: (S)-1-((2-aminopyridin-4-yl)methyl)-4-(trifluoromethyl)-imidazolidin-2-one [ka] Step 1: tert-butyl (S)-(4-(((2-amino-3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)carbamate [ka] Following the procedure of Intermediate 14 and using tert-butyl (4-formylpyridin-2-yl)carbamate (750 mg) gave 794 mg of the title compound. LC / MS: m / z=335.2 [M+H] + ;rt:1.08 min (LC / MS-Method A).

[0182] Step 2: (S)-(4-((2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)carbamate tert-butyl [ka] (S)-tert-Butyl (4-(((2-amino-3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)carbamate (435 mg) was dissolved in THF (12 ml). After the addition of DIPEA (0.906 ml), the mixture was heated to 65° C. for 5 min. CDI (633 mg) was then added and stirring was continued at 65° C. overnight. At room temperature, a portion of the THF was distilled off, and MeOH (5 ml) and aqueous NaOH (2N, 1 ml) were added. After 15 min, the mixture was poured into saturated NaHCO solution and DCM was added. The organic layer was separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (12 g silica gel; gradient: 5 min DCM / EtOH:100% DCM, 60 min 100% to 95% DCM; 10 min 95% DCM) and the combined product-containing fractions were concentrated in vacuo to give 410 mg of the title compound. LC / MS: m / z=361.2 [M+H] + ;rt:1.56 min (LC / MS-Method A).

[0183] Step 3: (S)-1-((2-aminopyridin-4-yl)methyl)-4-(trifluoromethyl)imidazolidin-2-one [ka] The procedure for Intermediate 10 was followed to give 398 mg of the crude title compound (Intermediate 15), which was used without further purification. LC / MS: m / z=261.0 [M+H]; rt: 0.4 min (LC / MS-Method A).

[0184] Intermediate 16: (S)-2-(4,4-difluorocyclohexyl)-2-((((5-methylisoxazol-3-yl)methoxy)carbonyl)amino)acetic acid [ka] Step 1: (S)-2-amino-2-(4,4-difluorocyclohexyl)acetate methyl [ka] Methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetate (Intermediate 13, 100 mg) was dissolved in dioxane (1.5 ml) and HCl in dioxane (4 M, 1.5 ml) was added. After stirring at room temperature for 5 hours, the mixture was left to stand overnight. The mixture was concentrated in vacuo, and DCM and saturated NaHCO3 solution were added (pH approx. 7). The aqueous phase was extracted with DCM (2x). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 63 mg of the crude title compound, which was used directly in the next step. LC / MS: m / z = 208.1 [M+H] + ;rt:0.31 min (LC / MS-Method B).

[0185] Step 2: (S)-2-(4,4-difluorocyclohexyl)-2-((((5-methylisoxazol-3-yl)methoxy)-carbonyl)amino)-methyl acetate [ka] 4-Nitrophenylcarbonylchloridate (80 mg) was dissolved in dry THF (2 ml) under Ar. After cooling to -78 °C, (S)-2-amino-2-(4,4-difluorocyclohexyl)methyl acetate (79 mg, dissolved in dry THF (2 ml)) and DIPEA (99 μl) were added with stirring. After 2 h, NaH (40 mg, 60% in mineral oil) was mixed with dry THF (3 ml) under Ar. Next, (5-methylisoxazol-3-yl)methanol dissolved in dry THF (0.5 ml) was added with stirring. After 30 min, this mixture was added dropwise to the above mixture at -78 °C. After 5 min, the cooling bath was removed, and after 1 h, the mixture was poured into saturated Na2CO3 solution. DCM was added, and the organic phase was washed with saturated Na2CO3 (4x) and finally saturated NaHCO3 solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative RP HPLC (Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm; 30 ml / min, 95% HO / 5% ACN to 10% HO / 90% ACN in 42 min; followed by 10% HO / 90% ACN for 8 min and 100% ACN for 3 min). Fractions containing pure product were combined, the ACN was partially removed, and the residue was lyophilized to give 64 mg of the title compound. LC / MS: m / z=347.2 [M+H] + ;rt: 1.88 min (LC / MS-Method A).

[0186] Step 3: (S)-2-(4,4-difluorocyclohexyl)-2-((((5-methylisoxazol-3-yl)methoxy)carbonyl)amino)acetic acid [ka] Methyl (S)-2-(4,4-difluorocyclohexyl)-2-((((5-methylisoxazol-3-yl)methoxy)-carbonyl)amino)acetate (63 mg) was dissolved in THF / water (1.6 / 0.4 ml) and LiOH (9 mg) was added with stirring. After 2 h, aqueous HCl was added (1 M) to adjust the pH to 2-3. The aqueous phase was then extracted with EA (2x). The combined organic phases were dried (Chem Elut cartridge) and concentrated in vacuo. The residue was purified by preparative RP HPLC (flow rate: 25 ml / min; 20 min 100% HO + 0.05%; 100% HO to 55% HO + 0.05% TFA / 45% ACN; Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). The fractions containing the pure product were combined, the ACN was partially removed and the residue was lyophilized to give 55 mg of the title compound (Intermediate 16). LC / MS: m / z=333.2 [M+H] + ;rt:1.62 min (LC / MS-Method A).

[0187] Intermediate 17: tert-butyl ((1S)-2-((4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] Step 1: tert-butyl ((1S)-2-((4-(1-hydroxy-2-methoxyethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] A suspension of HgCl2 (0.29 g) and Mg (3.05 g) in THF (1.95 ml) was purged with N2. To the mixture was added a solution of 1,2-dibromoethane (301.41 μl) in THF (1.95 ml) at 25 °C. The mixture was allowed to warm to 40 °C over 25 min. After the mixture was cooled to 25 °C, MOMCl (approximately 6 ml) in THF (18 ml) was added dropwise at 25 °C over 5 min. The mixture was cooled to -25 °C, followed by the dropwise addition of additional MOMCl (12 ml) in THF (18 ml) at -10 to -15 °C. The mixture was stirred at -20 °C for 2 h. A solution of tert-butyl ((S)-2-((4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Intermediate 1 - Step A4, 3.00 g) in THF (13.5 ml) was added to the mixture at -20 °C and stirred at -20 °C for 1 h. The reaction mixture was quenched with saturated NH Cl solution (50 ml), followed by extraction with EA (30 ml x 2). The organic phases were combined, washed with brine (30 ml x 2), dried over anhydrous Na SO , filtered, and concentrated in vacuo to give a residue which was purified by column chromatography (silica gel, PE / EA=1 / 1) to give 2.94 g of the title compound. 1 H NMR (400 MHz, CDCl3, representative signals shown): δ ppm = 8.79-8.68 (m, 1H), 8.30-8.21 (m, 2H), 7.18 (d, J = 5.1 Hz, 1H), 5.13 (br d, J = 7.3 Hz, 1H), 4.91 (br d, J = 6.5 Hz, 2H), 4.18-4.06 (m, 1H), 3.66-3.61 (m, 1H), 3.43 (s, 3H), 1.45 (s, 9H), 0.87 (d, J = 6.5 Hz, 3H).

[0188] Step 2: tert-butyl ((S)-2-((4-(2-methoxyacetyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] At 0° C., DMP (4.44 g) was slowly added to a solution of tert-butyl ((1S)-2-((4-(1-hydroxy-2-methoxyethyl)-pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (2.94 g) in DCM (30 ml), and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was filtered, and the filtrate was washed with saturated sodium bicarbonate solution (20 ml×3) and brine (10 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give 2.76 g of the title compound. 1 H NMR (400 MHz, CDCl3, representative signals shown): δ ppm = 8.81 (br s, 1H), 8.64 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.51 (d, J = 4.9 Hz, 1H), 5.12 (br d, J = 7.3 Hz, 1H), 4.72 (s, 2H), 4.16 (br s, 1H), 3.52 (s, 3H), 1.46 (s, 9H), 0.87 (d, J = 6.5 Hz, 3H).

[0189] Step 3: tert-butyl ((1S)-2-((4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((S)-2-((4-(2-methoxyacetyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (2.78 g) and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride [Intermediate 1 - Step B6] (1.33 g) were suspended in i-PrOH (28 ml). TEA (2.40 ml) was added and the reaction mixture was stirred at 75°C for 2 hours, followed by stirring at 25°C for 12 hours. The reaction mixture was concentrated in vacuo, dissolved in MeOH (28 ml), and then NaBHCN (2.34 g) was added portionwise. The resulting suspension was stirred for 5 minutes, followed by the addition of acetic acid (2.73 ml). The reaction mixture was heated with stirring at 40°C for 25 minutes, then cooled and concentrated in vacuo. The residue was diluted with EA (40 ml) and neutralized with saturated aqueous NaHCO (50 ml) with vigorous stirring for 0.5 h. The layers were separated, and the aqueous layer was extracted with EA (50 ml × 2). The combined organic layers were washed with saturated aqueous NaHCO (50 ml) and brine (50 ml), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 3.61 g of the title compound (Intermediate 17; mixture of diastereomers).

[0190] Intermediate 18: (2S)-2-amino-N-(4-((R or S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride (DS2) [ka] Following the procedure in Intermediate 4 and using tert-butyl ((S)-2-((4-((R or S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (DS2; Example 66; 420 mg), 383 mg of the title compound was obtained. LC / MS: m / z=458.3 [M+H] +;rt: 1.34 min (LC / MS-Method A).

[0191] Intermediate 19: (2S)-2-amino-N-(4-((R or S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride (DS1) [ka] Following the procedure in Intermediate 4 and using tert-butyl ((S)-2-((4-((S or R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (DS1; Example 65; 420 mg), 389 mg of the title compound was obtained. LC / MS: m / z=458.3 [M+H] + ;rt:1.41 min (LC / MS-Method A).

[0192] Intermediate 20: (S)-2-(4,4-difluorocyclohexyl)-2-((((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)carbonyl)amino)acetic acid [ka] Step 1: (S)-2-(4,4-difluorocyclohexyl)-2-((((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)carbonyl)-amino)acetate methyl [ka] 4-Nitrophenylcarbonochloridate (50 mg) was dissolved in dry THF (2 ml) under Ar. After cooling to -78 °C, (S)-2-amino-2-(4,4-difluorocyclohexyl)methyl acetate (Intermediate 16, Step 1; 50 mg, dissolved in dry THF (1 ml)) and DIPEA (63 μl) were added with stirring. After 2.5 h, NaH (25 mg, 60% in mineral oil) was mixed with dry THF (2 ml) under Ar. Next, (1,5-dimethylpyrazol-3-yl)methanol (76 mg) dissolved in dry THF (1 ml) was added with stirring. After 25 min, this mixture was added dropwise to the above mixture at -78 °C. After 5 min, the cooling bath was removed, and after 1 h, the mixture was poured into saturated Na2CO3 solution. DCM was added and the organic phase was washed with saturated Na2CO3 (4x) and finally saturated NaHCO3 solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative RP HPLC (Agilent Prep C18, 30mm x 250mm, 10µm; 50ml / min, 12.5min 90% HO / 10% ACN to 10% HO / 90% ACN). Fractions containing pure product were combined, ACN was partially removed and the residue was lyophilized to give 25mg of the title compound. LC / MS: m / z = 360.2 [M+H] + ;rt: 1.82 min (LC / MS-Method A).

[0193] Step 2: (S)-2-(4,4-difluorocyclohexyl)-2-((((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)carbonyl)amino)acetic acid [ka] (S)-2-(4,4-Difluorocyclohexyl)-2-((((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)carbonyl)amino)-methyl acetate (12 mg) was dissolved in THF / water (0.8 / 0.2 ml) and LiOH (2 mg) was added with stirring. After 1 h, aqueous HCl was added (1 M) to adjust the pH to 2-3. The aqueous phase was then extracted with EA (2x). The combined organic phases were dried (Chem Elut cartridge) and concentrated in vacuo to give 10 mg of the title compound (Intermediate 20). LC / MS: m / z=346.2 [M+H] + ;rt:1.56 min (LC / MS-Method A).

[0194] Intermediate 21: (S)-2-amino-N-(5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride [ka] Following the procedure in Intermediate 4 and using tert-butyl ((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Example 50; 342 mg), 312 mg of the title compound was obtained. LC / MS: m / z=432.2 [M+H] + ;rt: 1.38 min (LC / MS-Method A).

[0195] Intermediate 22: (S)-2-(4,4-difluorocyclohexyl)-2-((((4-methyl-1,2,5-oxadiazol-3-yl)methoxy)carbonyl)amino)acetic acid [ka] Following the sequence described for Intermediate 20 and using (4-methyl-1,2,5-oxadiazol-3-yl)methanol (71 mg) gave 34 mg of the title compound. LC / MS: m / z=334.1 [M+H] + ;rt: 1.68 min (LC / MS-Method A).

[0196] Intermediate 23: tert-butyl ((S)-2-((4-(bromomethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] Following the procedure of Intermediate 11, using tert-butyl ((S)-2-((4-(hydroxymethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Intermediate 1 - Step A3; 41 mg), 12 mg of the title compound was obtained. LC / MS: m / z=440.2 [M+H] + ;rt:2.71 min (LC / MS-Method A).

[0197] Intermediate 24: (S)-1-((5-aminopyridin-3-yl)methyl)-4-(trifluoromethyl)-imidazolidin-2-one [ka] Following the sequence of Intermediate 15 and using tert-butyl N-(5-formyl-3-pyridyl)carbamate (500 mg) as starting material, 283 mg of the title compound was obtained. LC / MS: m / z=261.1 [M+H] + ;rt:0.37 min (LC / MS-Method A).

[0198] Intermediate 25: Rac-2-amino-3-(tert-butoxy)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)propanamide [ka] Benzyl ((rac)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imid-azolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)carbamate (Example 81, 30 mg) was dissolved in MeOH (2 ml) under Ar. Pd / C (10%, 3 mg) was added and the flask was purged with H from a balloon. After stirring under an H atmosphere for 2 h, the mixture was filtered, the filter was washed with MeOH, and the filtrate was concentrated in vacuo to give 23 mg of the title compound. LC / MS: m / z=404.2 [M+H] + ;rt:1.12 min (LC / MS-Method A).

[0199] Intermediate 26: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)acetamide and (R)-2-amino-2-((1r,4R)-4-methylcyclohexyl)-N-(5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)acetamide [ka] Following the procedure of Intermediate 2 and using tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)carbamate and tert-butyl ((R)-1-((1r,4R)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)carbamate (Example 80; 99 mg), 87 mg of the crude title compound was obtained (ratio ca. 3:1). LC / MS: m / z=414.2 [M+H] + ;rt: 1.18 min (LC / MS-Method A).

[0200] Intermediate 27: (2S,3R)-2-amino-3-(tert-butoxy)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)butanamide [ka] Following the procedure of Intermediate 25 and using benzyl ((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)carbamate (Example 101; 30 mg), 23 mg of the crude title compound was obtained. LC / MS: m / z=418.1 [M+H] + ;rt:0.62 min (LC / MS-Method B).

[0201] Intermediate 28: tert-butyl ((S)-1-((4-((((S)-2-amino-3,3,3-trifluoropropyl)-amino)methyl)pyridin-2-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate [ka] ((S)-1-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)methyl)pyridin-2-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamic acid tert-butyl TFA salt (Intermediate 5) was dissolved in a mixture of ACN / water (0.05% TFA). TFA was neutralized with saturated NaHCO3 solution. After the product was extracted with DCM (3x), the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ACN / HO and lyophilized to give 183 mg of the title compound. LC / MS: m / z=486.4 [M+H] + ;rt: 1.59 min (LC / MS-Method A).

[0202] Intermediate 29: (2S,3S)-2-amino-3-(tert-butoxy)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)butanamide [ka] Step 1: ((2S,3S)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)carbamate benzyl [ka] To N-((benzyloxy)carbonyl)-O-(tert-butyl)-L-allothreonine (400 mg) was added DCM (6 ml), DMAP (221 mg), and EDCI (347 mg) with stirring. After 5 min, (4S)-1-[(2-amino-4-pyridyl)methyl]-4-(trifluoromethyl)imidazolidin-2-one (Intermediate 15; 235 mg) was added, and stirring was continued for 1 h. The mixture was then poured into saturated NaHCO3 solution. The aqueous phase was extracted with DCM (2x). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (24 g silica gel, DCM / EtOH: 100:0 for 5 min, 100:0 to 95:5 for 30 min, 95:5 for 10 min). The product-containing fractions were combined and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 15 ml / min; gradient 45 min from 95% HO + 0.05% TFA / 5% ACN to 5% HO + 0.05% TFA / 95% ACN; column: Xbridge, BEH130, Prep. C18, OBD; 19 mm x 250 mm, 10 μm). The product-containing fractions were combined, the ACN removed, saturated NaHCO solution added (pH approx. 7), and the aqueous mixture extracted with DCM (2x). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ACN / water and lyophilized to give 56 mg of the title compound. LC / MS: m / z = 552.3 [M+H]+ ;rt:2.18 min (LC / MS-Method A).

[0203] Step 2: (2S,3S)-2-amino-3-(tert-butoxy)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)butanamide [ka] Following the procedure of Intermediate 25 using benzyl ((2S,3S)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)carbamate (60 mg) gave 43 mg of crude title compound (Intermediate 29) which was used without further purification. LC / MS: m / z=418.2 [M+H] + ;rt:1.16 min (LC / MS-Method A).

[0204] Intermediate 30: (S)-(1,1-dicyclopropyl-3-oxo-3-((4-(2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)pyridin-2-yl)amino)propan-2-yl)carbamate tert-butyl [ka] Step 1: tert-butyl (4-(2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)pyridin-2-yl)carbamate [ka] 2-[2-(tert-butoxycarbonylamino)-4-pyridyl]acetic acid (505 mg) was dissolved in 8 ml of dry DMF, and 1.15 g of EDC and ethyl cyanohydroxyiminoacetate (Oxyma; 853 mg) were added along with 1.01 g of NaHCO3, followed by stirring at ambient temperature for 30 minutes. Next, 300 mg of 3,3,3-trifluoropropan-1-amine HCl was dissolved in 2 ml of dry DMF and added dropwise. The mixture was stirred at ambient temperature for 16 hours, and the solvent was removed by rotary evaporation. The crude reaction mixture was stirred with 50 ml of water, the pH was adjusted to pH 11 with 1 N NaOH, and the product was filtered off, washed with water, and dried to give 660 mg. LC / MS: m / z = 348.1 [M+H] + ;rt:0.92 min (LC / MS-Method B).

[0205] Step 2: (S)-(1,1-dicyclopropyl-3-oxo-3-((4-(2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)pyridin-2-yl)amino)propan-2-yl)carbamate tert-butyl [ka] tert-Butyl (4-(2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)pyridin-2-yl)carbamate (225 mg) was dissolved in 10 ml of dry dioxane, 1.62 ml of 4 M HCl in dioxane was added, and the mixture was stirred at ambient temperature for 20 hours, after which an additional 0.81 ml of 4 M HCl in dioxane was added. The mixture was then stirred at ambient temperature for a further 8 hours. The liquid was decanted and the residue was stirred in 10 ml of acetonitrile, after which the solid was filtered off and the liquid phase was evaporated to dryness by rotary evaporation. 120 mg of the crude product was dissolved in 1 ml of dry DMF and added dropwise to a solution of 110 mg of (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid in 4 ml of dry DMF together with 233 mg of HATU and 0.36 ml of DIPEA, and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was evaporated to dryness and redissolved in 20 ml of EA. The organic phase was washed with 10 ml of water, 10 ml of saturated NaHCO3 (aq), and 10 ml of brine, dried over MgSO4, and then evaporated to dryness. The crude product (Intermediate 30) was used directly without further purification. LC / MS: m / z = 499.3 [M+H] + ;rt:1.33 min (LC / MS-Method B).

[0206] Intermediate 31: (S)-(1,1-dicyclopropyl-3-oxo-3-((4-((4,4,4-trifluoro-butanamido)methyl)pyridin-2-yl)amino)propan-2-yl)carbamate tert-butyl [ka] Step 1: tert-Butyl (4-((4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)carbamate [ka] 4,4,4-Trifluorobutanoic acid (286 mg) was dissolved in 5 ml of dry DMF, 1.15 g of HATU and 1.05 ml of DIPEA were added, and the mixture was stirred at ambient temperature for 30 minutes. Next, tert-butyl N-[4-(aminomethyl)-2-pyridyl]carbamate (450 mg) in 5 ml of dry DMF was added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness, dissolved in 50 ml of EA, washed with 30 ml of water, 30 ml of saturated NaHCO3 (aq), and 30 ml of brine, dried over MgSO4, and evaporated to dryness. LC / MS: m / z = 348.1 [M+H] + ;rt: 1.54 min (LC / MS-Method A).

[0207] Step 2: (S)-(1,1-dicyclopropyl-3-oxo-3-((4-((4,4,4-trifluorobutan-amido)methyl)pyridin-2-yl)amino)propan-2-yl)carbamate tert-butyl [ka] tert-Butyl (4-((4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)carbamate (630 mg) was dissolved in 120 ml of dry DMF together with 1.86 g of TsOH, and the mixture was stirred at ambient temperature for 16 hours and then evaporated to dryness. The residue was dissolved in 18.2 ml of 0.5 M NaOH(aq) and extracted six times with 20 ml of DCM, and the combined organic phases were dried over MgSO4, filtered, and evaporated to dryness. 115 mg of the crude product was dissolved in 1 ml of dry DMF and added dropwise to a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid (125 mg) in 4 ml of dry DMF together with 265 mg of HATU and 0.24 ml of DIPEA, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness and redissolved in 20 ml of EA, and the organic phase was washed with 10 ml of water, 10 ml of saturated NaHCO3(aq) and 10 ml of brine, dried over MgSO4 and evaporated to dryness. The crude product (Intermediate 31) was used directly without further purification. LC / MS: m / z=499.3 [M+H] + ;rt:1.33 min (LC / MS-Method B).

[0208] Intermediate 32: (S)-2-amino-3,3-dicyclopropyl-N-(4-(((R)-4-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)propenamide HCl salt [ka] 100 mg of the title compound was prepared similarly to Intermediate 4. LC / MS: m / z=358.2 [M+H] + ;rt:0.79 min (LC / MS-Method B).

[0209] Intermediate 33: 2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)acetamide HCl salt [ka] Step 1: 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one [ka] To a solution of 6-bromo-1-methylpyridin-2(1H)-one (8 g, 42.55 mmol, 1 equiv.) in dioxane (200 mL) was added BPD (32.41 g, 127.64 mmol, 3 equiv.), KOAc (12.53 g, 127.68 mmol, 3.00 equiv.), and Pd(dppf)Cl (3.74 g, 5.11 mmol, 0.12 equiv.) under nitrogen at 25° C. The reaction mixture was stirred at 110° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filter cake was washed with warm toluene (40° C., five times 100 mL). The combined organic phases were concentrated under reduced pressure to give 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (15 g, crude) as a black oil, which was used directly in the next step.

[0210] Step 2: tert-Butyl (4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)carbamate [ka] To a mixture of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (14 g, 59.55 mmol, 1 equiv.) and tert-butyl (4-(bromomethyl)pyridin-2-yl)carbamate (4 g, 13.93 mmol, 0.23 equiv.) in dioxane (182 mL) was added KCO (2 M, 74.44 mL, 2.5 equiv.) and Pd(dppf)Cl (4.36 g, 5.96 mmol, 0.1 equiv.) in one portion under N at 25 °C. The mixture was stirred at 110 °C for 2 h. The reaction mixture was poured into HO (100 mL) and extracted with EA (3 × 150 mL). The combined organic phases were washed with brine (50 ml), dried over anhydrous NaSO, filtered and evaporated to dryness. The residue was purified by FC on silica gel using PE:DCM to give 2.2 g of the title compound as a yellow solid. 1 H NMR(400MHz,CDCl3)δ=8.16(d,J=5.2Hz,1H),7.85(s,1H),7.62(br s,1H),7.27-7.24(m,1H),6.65(d,J=5.2Hz,1H),6.52(d,J=8.4Hz,1H),6.00(d,J=6.4Hz,1H),3.93(s,2H),3.38(s,3H),1.50(s,9H).

[0211] Step 3: tert-butyl (1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate [ka] tert-Butyl (4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)-carbamate (1.0 g) was dissolved in 10 ml of dry dioxane, 7.9 ml of 4 N HCl in dioxane was added dropwise, the mixture was stirred at ambient temperature overnight, and the precipitate was then filtered off. The solid was dissolved in NaHCO3 (aq. sat.) and extracted three times with 10 ml of EA. The combined organic phases were dried over Na2SO4, filtered and evaporated to dryness to give 6-[(2-amino-4-pyridyl)methyl]-1-methyl-pyridin-2-one (256 mg). This residue was dissolved in 2 ml of DMF and added to a mixture of 2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (349 mg), 498 mg of HATU, and 308 mg of DIPEA in 10 ml of DMF. The reaction mixture was stirred for 16 h, then evaporated to dryness, redissolved in 30 ml of EA, and washed with 10 ml of water, 10 ml of NaHCO (aq. sat.), and 10 ml of brine. The organic phase was dried over anhydrous NaSO, filtered, and evaporated to dryness. The residue was purified by FC on silica gel using MeOH:DCM to give 236 mg of the title product. LC / MS: m / z=491.2 [M+H] + ;rt:1.92 min (LC / MS-Method A).

[0212] Step 4: 2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)acetamide [ka] tert-Butyl (1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate (230 mg) was dissolved in 5 ml of dry dioxane, 1.17 ml of 4 N HCl in dioxane was added dropwise and the mixture was stirred at ambient temperature overnight. The reaction mixture was dissolved in 20 ml of DCM and washed three times with Na2CO3 (aq. sat.), after which the organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness to give 138 mg of the title product (Intermediate 33), which was used without further purification.

[0213] Intermediate 34 Diastereomer 1: N-((2-((S)-2-amino-3,3-dicyclopropylpropanamido)pyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (DS1) [ka] Step 1: (R,E)-(4-(((tert-butylsulfinyl)imino)methyl)pyridin-2-yl)carbamate tert-butyl [ka] 255 mg of (R)-2-methylpropane-2-sulfinamide was dissolved in 10 ml of dry THF, 450 mg of tert-butyl N-(4-formyl-2-pyridyl)carbamate, 1.02 g of CuSO4, and 50 mg of pyridinium p-toluenesulfonate were added, and the reaction mixture was stirred at 55° C. for 16 hours. The reaction mixture was cooled, diluted with 20 ml of DCM, stirred over MgSO4, filtered, and evaporated to dryness. The crude product (570 mg) was used directly in the next step. LC / MS: m / z=326.2 [M+H] + ;rt:2.19 min (LC / MS-Method A).

[0214] Step 2: tert-Butyl (4-((((R)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)pyridin-2-yl)carbamate [ka] 570 mg of tert-butyl (R,E)-(4-(((tert-butylsulfinyl)imino)methyl)pyridin-2-yl)carbamate was dissolved in 20 ml of dry DCM under an argon atmosphere, the mixture was cooled to 0° C., and 8.0 ml of bromo(cyclopropyl)magnesium (0.5 M) was added dropwise, maintaining the temperature below 5° C. The reaction mixture was stirred at ambient temperature for 4 hours, after which a further 8.0 ml of bromo(cyclopropyl)magnesium (0.5 M) was added and the mixture was stirred for 16 hours, after which the mixture was quenched with saturated ammonium chloride solution (aq) and further diluted with 20 ml of water. The phases were separated and the aqueous phase was extracted twice with DCM, after which the combined organic phases were dried over MgSO4, filtered, and evaporated to dryness, after which the crude product (680 mg) was used directly in the next step. LC / MS: m / z=368.2 [M+H] + ;rt: 1.85 min (LC / MS-Method A).

[0215] Step 3: (R)-(4-(amino(cyclopropyl)methyl)pyridin-2-yl)carbamate tert-butyl [ka] 680 mg of tert-butyl (4-((((R)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)pyridin-2-yl)carbamate were dissolved in 20 ml of THF and 4 ml of water, then 223 mg of iodine were added and the mixture was heated to 60 °C for 2 h. After cooling, the mixture was diluted with 50 ml of EA and washed twice with 25 ml of 5% NaHCO3 (aq) and 10% Na2S2O3 (aq) and once with 20 ml of brine. The organic phase was dried over MgSO4, filtered and evaporated to dryness, after which the crude product (380 mg) was used directly in the next step. LC / MS: m / z = 264.2 [M+H] +;rt:1.07 min (LC / MS-Method A).

[0216] Step 4: tert-Butyl (4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)carbamate [ka] 205 mg of 4,4,4-trifluorobutanoic acid was diluted in 10 ml of dry DMF and 820 mg of HATU, 0.75 ml of DIPEA and 380 mg of tert-butyl (R)-(4-(amino(cyclopropyl)methyl)pyridin-2-yl)carbamate dissolved in 2 ml of dry DMF were added, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness, and the residue was dissolved in 50 ml of EA and washed with 30 ml of water, NaHCO3 (aq. sat.), and brine, then dried over MgSO4, filtered, and evaporated to dryness. The crude product (540 mg) was used directly in the next step. LC / MS: m / z = 388.1 [M+H] + ;rt: 1.87 min (LC / MS-Method A).

[0217] Step 5: N-((2-aminopyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide [ka] 540 mg of tert-butyl (4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)carbamate was dissolved in 15 ml of dry dioxane, 3.5 ml of 4N HCl in dioxane was added, and the mixture was stirred at ambient temperature for 16 hours. Then, another 3.5 ml of 4N HCl in dioxane was added, and the mixture was stirred at ambient temperature for another 6 hours, after which another 1.8 ml of 4N HCl in dioxane was added. The mixture was stirred at ambient temperature for another 6 hours, after which 30 ml of MTBE was added to precipitate the product. The solvent was decanted, and 20 ml of DCM was added. The mixture was stirred for 30 minutes, after which the solvent was decanted, and the solid was dried under vacuum. The crude product was dissolved in 50 ml of EA, washed with NaHCO3 (aq.sat), dried over MgSO4, filtered, and evaporated to dryness, after which the crude product (250 mg) was used directly in the next step. LC / MS: m / z=288.1 [M+H] + ;rt:0.75 min (LC / MS-Method B).

[0218] Step 6: tert-butyl ((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)-methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)carbamate [ka] 95 mg of (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid was dissolved in 6 ml of dry DCM, 255 mg of TBTU and 0.31 ml of DIPEA were added, and the mixture was stirred at ambient temperature for 30 minutes. Next, 100 mg of N-((2-aminopyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide dissolved in 2 ml of dry DMF was added, and the mixture was stirred at ambient temperature for 16 hours, then diluted with 20 ml of DCM. The mixture was washed with 20 ml of water, 20 ml of NaHCO (aq. sat.), and 20 ml of brine, then dried over MgSO, filtered, stirred twice with 5 ml of cyclohexane, decanted, and the solid was dried under vacuum. The crude product (200 mg) was used directly in the next step. LC / MS: m / z=539.3[M+H] + ;rt:1.49 min (LC / MS-Method B).

[0219] Step 7: N-((2-((S)-2-amino-3,3-dicyclopropylpropanamido)-pyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (DS1) [ka] 200 mg of tert-butyl ((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutan-amido)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)carbamate were dissolved in 30 ml of dry DCM, 360 mg of TsOH were added, and the mixture was stirred at ambient temperature for 16 h before being evaporated to dryness. The residue was dissolved in 3.6 ml of 0.5 M aqueous NaOH solution and extracted six times with 5 ml of DCM. The combined organic phases were dried over MgSO4, filtered, and evaporated, after which the crude product (intermediate 34 diastereomer 1) was used directly without further purification. LC / MS: m / z=439.2 [M+H] + ;rt:1.00 min (LC / MS-Method B).

[0220] Intermediate 34 Diastereomer 2: N-((2-((S)-2-amino-3,3-dicyclopropylpropanamido)-pyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide Diastereomer 2 was prepared similarly to diastereomer 1 using (S)-2-methylpropane-2-sulfinamide in step 1. LC / MS: m / z=439.2 [M+H] + ;RT: 1.24 min (LC / MS-Method B).

[0221] Intermediate 35 Diastereomer 1: N-((2-(2-amino-2-(4,4-difluorocyclohexyl)-acetamido)pyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide [ka] The title compound was prepared according to the procedure for the preparation of Intermediate 34 Diastereomer 1 using 2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid and N-((2-aminopyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 34 DS1-Step 5) to give 300 mg of product, which was used directly in the next step. LC / MS: m / z=463.2 [M+H] + ;RT: 0.98 min (LC / MS-Method B).

[0222] Intermediate 36: 4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-amine [ka] Step 1: tert-butyl (4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)carbamate [ka] 1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (232 mg) was dissolved in 22.5 ml of dioxane and 2.5 ml of water, 567 g of CsCO was added along with 51 mg of Pd(dppf)Cl and 200 mg of tert-butyl N-[4-(bromomethyl)-2-pyridyl]carbamate, and the mixture was heated to 110 °C for 3 h. After cooling, the reaction mixture was diluted with 50 ml of EA, washed three times with 20 ml of NaHCO (aq. sat), dried over NaSO, filtered, and evaporated to dryness. The crude product was purified by FC on silica gel using a gradient of heptane and EA, and the fractions containing the pure product were combined and evaporated to give 183 mg of the title compound. LC / MS: m / z = 303.2 [M+H] + ;RT: 1.68 min (LC / MS-Method A).

[0223] Step 2: 4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-amine [ka] 182 mg of tert-butyl (4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)carbamate were dissolved in 5 ml of dioxane, 1.50 ml of 4N HCl in dioxane were added, and the mixture was stirred at ambient temperature for 16 hours. Then, another 1.50 ml of 4N HCl in dioxane was added, and the mixture was stirred at ambient temperature for another 6 hours, after which the reaction mixture was diluted with 20 ml of DCM, washed three times with Na2CO3 solution (aq. sat), dried over Na2SO4, filtered, and evaporated to dryness. The crude product (Intermediate 36) was used without further purification. LC / MS: m / z=203.1 [M+H] + ;RT: 0.66 min (LC / MS-Method A).

[0224] Intermediate 37: 2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyridin-2-yl)acetamide [ka] The title compound was prepared by the same procedure as that used for 2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)acetamide [Intermediate 33]. LC / MS: m / z=391.1 [M+H] + ;RT: 0.81 min (LC / MS-Method A).

[0225] Intermediate 38: 2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)acetamide [ka] Step 1: tert-butyl (1-(4,4-difluorocyclohexyl)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate [ka] The title compound was prepared using the procedure described for the preparation of tert-butyl ((S)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [Example 053] to yield 72 mg of product. LC / MS: m / z=491.1 [M+H] + ;RT: 1.86 min (LC / MS-Method A).

[0226] Step 2: 2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)acetamide HCl salt [ka] Using the procedure described for Intermediate 33, 48 mg of the title compound (Intermediate 38) was obtained and used without further purification. LC / MS: m / z=378.3 [M+H] + ;RT: 0.94 min (LC / MS-Method B).

[0227] Intermediate 39: 2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyridin-2-yl)acetamide [ka] Step 1: N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide [ka] The title compound was prepared using the procedure described for tert-butyl ((S)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Example 53) to give 76 mg of product. LC / MS: m / z=491.3 [M+H] + ;RT: 1.87 min (LC / MS-Method A).

[0228] Step 2: 2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyridin-2-yl)acetamide [ka] Using the procedure described for Intermediate 33 with 73 mg of N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide gave 55 mg of the title compound (Intermediate 39), which was used without further purification. LC / MS: m / z=378.3 [M+H] + ;RT: 0.94 min (LC / MS-Method B).

[0229] Intermediate 40: (S)-2-amino-N-(4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide HCl salt [ka] Using the procedure described for Intermediate 33, 59 mg of tert-butyl ((S)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Example 53) was used to provide 46 mg of the title compound, which was used without further purification. LC / MS: m / z=356.3 [M+H] + ;RT: 1.40 min (LC / MS-Method A).

[0230] Intermediate 41: N-((2-((S)-2-amino-2-(4,4-difluorocyclohexyl)acetamido)pyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide [ka] The title compound was prepared according to the procedure described for N-((2-(2-amino-2-(4,4-difluorocyclohexyl)acetamido)pyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 35 Diastereomer 1) using 375 mg of ((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate tert-butyl diastereomer 1 (Example 72) to yield 275 mg of the title compound, which was used without further purification. LC / MS: m / z=461.3 [M+H] + ;RT: 1.33 min (LC / MS-Method A).

[0231] Intermediate 42: N-((2-((S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)acetamido)-pyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide [ka] The title compound was prepared according to the procedure described for N-((2-(2-amino-2-(4,4-difluorocyclohexyl)acetamido)pyridin-4-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide (Intermediate 35 Diastereomer 1) using 130 mg of ((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate tert-butyl diastereomer 1 (Example 71) to yield 100 mg of the title compound, which was used without further purification. LC / MS: m / z=441.2 [M+H] + ;RT: 1.00 min (LC / MS-Method B).

[0232] Intermediate 43: (2S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide [ka] Step 1: tert-butyl (4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)carbamate [ka] 3-Bromopyrrolidin-2-one (491 mg) was dissolved in 8 ml of dry DMF, 420 mg of tert-butyl N-(4-hydroxy-2-pyridyl)carbamate and 828 mg of potassium carbonate were added, and the mixture was heated to 80° C. under stirring for 6 hours. After cooling, the mixture was spun to dryness, 20 ml of water was added, and the mixture was stirred for 30 minutes. The product was then filtered off, washed with water, and dried under vacuum. This gave 250 mg of the title product, which was used directly in the next step. LC / MS: m / z=294.1 [M+H] + ;RT: 1.62 min (LC / MS-Method A).

[0233] Step 2: 3-((2-aminopyridin-4-yl)oxy)pyrrolidin-2-one HCl salt [ka] tert-Butyl (4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)carbamate (300 mg) was dissolved in 10 ml of dry dioxane, 2.6 ml of 4N HCl in dioxane was added, and the mixture was stirred at ambient temperature for 16 hours. Then, an additional 1.3 ml of 4N HCl in dioxane was added, and the mixture was stirred at ambient temperature for another 6 hours, after which 15 ml of MTBE was added to precipitate the product. The product was filtered off and dried under vacuum to give 215 mg of the title product, which was used directly in the next step. LC / MS: m / z=194.1 [M+H] + ;rt:0.18 min (LC / MS-Method B).

[0234] Step 3: tert-butyl ((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)carbamate [ka] The procedure described for Intermediate 34-Step 6 was followed using 220 mg of (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid and 186 mg of 3-((2-aminopyridin-4-yl)oxy)pyrrolidin-2-one HCl salt to give 400 mg of the title compound, which was used directly in the next step. LC / MS: m / z=447.2 [M+H] + ;rt:1.11 min (LC / MS-Method B).

[0235] Step 4: (2S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide [ka] Following the procedure described for Intermediate 34 - Step 7, ((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)amino)-ethyl) tert-butyl carbamate (360 mg) gave 105 mg of the title compound (Intermediate 43), which was used without further purification. LC / MS: m / z=347.3 [M+H] + ;rt:0.81 min (LC / MS-Method B).

[0236] Intermediate 44: tert-butyl ((1S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)-methyl-d)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] Following the procedure for Intermediate 1 and using NaBD3CN as the reducing agent, 96 mg (61%) of the title compound was obtained. LC / MS: m / z=489.3 [M+H] + ;rt: 1.70 min (LC / MS-Method A).

[0237] Intermediate 45, DS1: N-(1-(2-((S)-2-amino-2-(4,4-difluorocyclohexyl)acetamido)-pyridin-4-yl)-2-methoxyethyl)-4,4,4-trifluorobutanamide diastereomer 1 [ka] Using the procedure described for Intermediate 33 and 340 mg of ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)-pyridin-2-yl)amino)-2-oxoethyl)carbamate tert-butyl diastereomer 1 (Example 131), 265 mg of the title compound was obtained and used without further purification. LC / MS: m / z=467.2 [M+H]; RT: 0.88 min (LC / MS-Method B).

[0238] Intermediate 45, DS2: N-(1-(2-((S)-2-amino-2-(4,4-difluorocyclohexyl)acetamido)-pyridin-4-yl)-2-methoxyethyl)-4,4,4-trifluorobutanamide diastereomer 2 [ka] Prepared analogously to Intermediate 45 DS1 using Example 132 as starting material. LC / MS: m / z=467.2 [M+H]+; RT: 0.88 min (LC / MS-Method B).

[0239] Intermediate 46: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)acetamide [ka] Step 1: (R,E)-2-(2-((tert-butylsulfinyl)imino)ethyl)dimethyl malonate [ka] To a solution of dimethyl 2-(2-oxoethyl)malonate (33 g, 189.49 mmol, 1 equiv.) and (R)-2-methylpropane-2-sulfinamide (29.86 g, 246.34 mmol, 1.3 equiv.) in DCM (350 ml) was added pyrrolidine (1.35 g, 18.95 mmol, 1.58 mL, 0.1 equiv.). The mixture was stirred at 25° C. for 12 h, after which the solvent was removed under reduced pressure to give the crude product, which was purified by FC on silica gel using PE / EA. This gave 27.73 g of the title compound. 1 H NMR(400MHz,CDCl3)δ ppm:8.12(t,J=2.7Hz,1H),3.98(dd,J=6.1,8.1Hz,1H),3.76(d,J=4.0Hz,6H),3.25-3.10(m,2H),1.16(s,9H).

[0240] Step 2: 2-((S)-2-(((R)-tert-butylsulfinyl)amino)-3,3,3-trifluoropropyl)malonate dimethyl [ka] To a solution of (R,E)-dimethyl 2-(2-((tert-butylsulfinyl)imino)ethyl)malonate (27.7 g, 99.88 mmol, 1 equiv.) and tetrabutylammonium acetate (36.14 g, 119.85 mmol, 36.50 ml, 1.2 equiv.) in THF (554 ml) was added TMS-CF (35.51 g, 249.70 mmol, 2.5 equiv.) at −55° C. After stirring at −55° C. for 1 h, the cooling was removed and the mixture was allowed to warm to ambient temperature. After 3 h, the reaction mixture was quenched with aqueous ammonium chloride (100 ml). The mixture was diluted with water (1200 ml) and extracted with EA (3×500 ml). The organic layer was washed with brine (3×500 ml), then dried over anhydrous NaSO and subsequently concentrated under reduced pressure to give the crude product. Purification by FC on silica gel using PE / EA gave 12 g of the title compound as a yellow solid, after which the solvent was removed by rotary evaporation. LC / MS: m / z=348.1 [M+H] + ;rt:0.35 minutes. 1 H NMR(400MHz,CDCl3)δ ppm:3.84(dd,J=7.1,13.4Hz,2H),3.79(d,J=6.5Hz,6H),2.43(ddd,J=3.1,7.7,14.8Hz,1H),2.17(ddd,J=6.1,11.3,14.8Hz,1H),1.24(s,9H).

[0241] Step 3: 2-((2-((tert-butoxycarbonyl)amino)pyridin-4-yl)methyl)-2-((S)-2-(((R)-tert-butylsulfinyl)amino)-3,3,3-trifluoropropyl)malonate dimethyl [ka] To a solution of dimethyl 2-((S)-2-(((R)-tert-butylsulfinyl)amino)-3,3,3-trifluoropropyl)malonate (12 g, 34.55 mmol, 1 equiv.) in DMF (180 mL) was added CsCO (11.26 g, 34.55 mmol, 1 equiv.), KI (1.15 g, 6.91 mmol, 0.2 equiv.), and tert-butyl (4-(bromomethyl)pyridin-2-yl)carbamate (9.92 g, 34.55 mmol, 1 equiv.). The mixture was stirred at 25 °C for 11 h. The reaction mixture was diluted with water (600 mL) at 0° C. and extracted with EA (3×150 ml), and the combined organic layers were washed with brine (2×150 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by FC on silica gel using PE / EA to give 16.53 g of the title compound as a colorless solid. LC / MS: m / z=554.2 [M+H] + ;rt:0.76 minutes. 1 H NMR(400MHz,CDCl3)δ ppm:8.16(d,J=5.1Hz,1H),8.14-8.11(m,1H),7.81(s,1H),6.75(dd,J=1.1,5.1Hz,1H),4.37(d,J=5.1Hz,1H),4.03-3.92(m,1H) ,3.86(d,J=6.8Hz,6H),3.63-3.18(m,2H),2.34(dd,J=10.8,15.3Hz,1H),2.19(dd,J=2.3,15.3Hz,1H),1.52(s,9H),1.21(s,9H).

[0242] Step 4: (5S)-3-((2-((tert-butoxycarbonyl)amino)pyridin-4-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate [ka] To a solution of dimethyl 2-((2-((tert-butoxycarbonyl)amino)pyridin-4-yl)methyl)-2-((S)-2-(((R)-tert-butylsulfinyl)amino)-3,3,3-trifluoropropyl)malonate (27.8 g, 50.22 mmol, 1 equiv.) in MeOH (280 ml) was added HCl / dioxane (4 M, 25.11 ml, 2 equiv.). The reaction mixture was stirred at 20° C. for 2 h, then at 40° C. for 2 h, and then evaporated under reduced pressure to remove volatiles. The crude product was then diluted with DCM (200 ml) and NaCO solution was added at 0° C. until pH 7. The mixture was extracted with DCM (3x200ml) and the combined organic layers were washed with brine (2x200ml) before being dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 22.28g of the title compound as a yellow oil which was used directly in the next step without further purification. LC / MS: m / z=418.1 [M+H] + ;rt:0.62 minutes.

[0243] Step 5: (5S)-3-((2-((tert-butoxycarbonyl)amino)pyridin-4-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid [ka] To a solution of methyl (5S)-3-((2-((tert-butoxycarbonyl)amino)pyridin-4-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (22.2 g, 53.19 mmol, 1 equiv.) in EtOH (440 ml) and HO (440 ml) was added LiOH.HO (5.58 g, 132.97 mmol, 2.5 equiv.). The reaction mixture was stirred at 25 °C for 6 h, diluted with water (500 ml) and extracted with PE:EA 9:1 (2 x 300 ml). The aqueous phase was adjusted to pH 7 and extracted with DCM (3x400ml), the combined organic layers were washed with brine (2x200ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue to give 18.2g of the title compound as a colorless solid, which was used directly in the next step without further purification. LC / MS: m / z=404.1 [M+H] + ;rt: 0.44 and 0.46 min.

[0244] Step 6: tert-butyl (4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)carbamate and tert-butyl (4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)carbamate [ka] To a solution of (5S)-3-((2-((tert-butoxycarbonyl)amino)pyridin-4-yl)methyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylic acid (18.2 g, 45.12 mmol, 1 equiv) in DMSO (180 ml) was added LiCl (3.83 g, 90.24 mmol, 1.85 mL, 2 equiv) and HO (3.25 g, 180.49 mmol, 3.25 ml, 4 equiv). The mixture was stirred at 100° C. for 1.5 h. After cooling, the reaction mixture was diluted with water (600 ml) and extracted with EA (3×300 ml). The combined organic layers were washed with brine (3×500 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. Purification by FC using PE / EA gave 781 mg of tert-butyl (4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl-)pyridin-2-yl)carbamate as a colorless solid. LC / MS: m / z=360.1 [M+H] + ;rt:0.61 minutes. 1 H NMR(400MHz,CDCl3)δ ppm:8.19(d,J=5.3Hz,1H),8.09(s,1H),7.84(s,1H),6.85(d,J=5.1Hz,1H),6.31(br s, 1H), 3.95 (quin, J = 7.6 Hz, 1H), 3.24 (dd, J = 4.2, 13.8 Hz, 1H), 2.92 (dq, J = 4.4, 9.4 Hz, 1H), 2.66 (dd, J = 9.6, 13.8 Hz, 1H), 2.31 (dd, J = 9.1, 14.0 Hz, 1H), 2.11 (td, J = 9.6, 14.1 Hz, 1H), 1.54 (s, 9H); and 3.93 g of tert-butyl (4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)-pyridin-2-yl)carbamate as a colorless solid. LC / MS: m / z = 360.1 [M+H] + ;rt:0.61 minutes. 1H NMR(400MHz,CDCl3)δ ppm:8.51(s,1H),8.20(d,J=5.3Hz,1H),7.87(s,1H),6.83(dd,J=1.1,5.1Hz,1H),6.62(s,1H),4.13-4.03(m,1H),3.31(dd,J=4.1, 14.3Hz,1H),2.94-2.83(m,1H),2.66(dd,J=10.6,14.2Hz,1H),2.49-2.38(m,1H),1.86(ddd,J=6.9,8.3,13.9Hz,1H),1.55(s,9H).

[0245] Step 7: (3R,5S)-3-((2-aminopyridin-4-yl)methyl)-5-(trifluoromethyl)pyrrolidin-2-one HCl salt [ka] The procedure for Boc deprotection described for 3-((2-aminopyridin-4-yl)oxy)pyrrolidin-2-one (Intermediate 43, Step 2) was followed using 360 mg of tert-butyl (4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)carbamate to give 255 mg of the title compound, which was used directly in the next step. LC / MS: m / z=260.1 [M+H] + ;rt:0.56 min (LC / MS-Method A).

[0246] Step 8: tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate [ka] 230 mg of (2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid was dissolved in 20 ml of DCM, 612 mg of TBTU was added along with 0.89 ml of DIPEA, and the mixture was stirred at ambient temperature for 30 minutes, followed by the addition of 250 mg of (3R,5S)-3-((2-aminopyridin-4-yl)methyl)-5-(trifluoromethyl)pyrrolidin-2-one HCl salt. After stirring at ambient temperature for 16 hours, 50 ml of DCM was added, and the mixture was washed with 30 ml of water and 30 ml of NaCl solution, dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by FC on silica using MeOH:DCM as eluent to give 210 mg of the title compound. LC / MS: m / z=513.4 [M+H] + ;rt:2.37 min (LC / MS-Method A).

[0247] Step 9: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)acetamide [ka] 210 mg of tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate were dissolved in 30 ml of DCM, 420 mg of TsOH were added and the mixture was stirred at ambient temperature for 16 h. The solvent was removed by rotary evaporation and the residue was dissolved in 4.1 ml of 0.5 M NaOH solution and extracted with DCM (4 x 10 ml). The combined organic phases were dried over Na2SO4, filtered and evaporated to dryness to give 110 mg of the title compound (Intermediate 46), which was used without further purification. LC / MS: m / z = 413.2 [M+H] + ;rt:0.92 min (LC / MS-Method B).

[0248] Intermediate 47: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)acetamide [ka] The title compound was prepared analogously to (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)acetamide (Intermediate 46) using tert-butyl (4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)carbamate from step 7 onwards. LC / MS: m / z=413.2 [M+H] + ;rt:0.95 min (LC / MS-Method B).

[0249] Intermediate 48-DS1: (2S)-2-amino-N-(4-((R or S)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)-2-(4,4-difluorocyclohexyl)-acetamide hydrochloride - diastereomer 1 [ka] Step 1: tert-butyl ((1S)-2-((4-(cyclopropyl(hydroxy)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate [ka] To a solution of tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-2-((4-formylpyridin-2-yl)amino)-2-oxoethyl)carbamate (Int. 3, step 3; 2 g) in THF (30 ml) was added bromo(cyclopropyl)magnesium (1 M, 22.7 ml) at 0° C. The mixture was stirred at 20° C. for 20 min. The reaction mixture was then quenched by the addition of NH4Cl solution at 0° C., subsequently diluted with water (100 ml) and extracted with EA (50 ml, 3×). The combined organic layers were washed with brine (100 ml, 2x), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-30-50-80% EA (10% DCM) / PE gradient; flow rate: 80 ml / min) to give 1.64 g of the title compound. LC / MS: m / z=440.3 [M+H] + ;rt:0.36 min (LC / MS-Method C).

[0250] Step 2: (S)-(2-((4-(cyclopropanecarbonyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate tert-butyl [ka] To a solution of tert-butyl ((1S)-2-((4-(cyclopropyl(hydroxy)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (1.64 g) in DCM (20 ml) was added DMP (1.90 g) at 0° C. The mixture was stirred at 20° C. for 1.5 h. The reaction mixture was then quenched by the addition of NH4Cl solution at 0° C., diluted with water (100 ml) and extracted with EA (50 ml, 3×). The combined organic layers were washed with brine (100 ml, 2x), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-30-50-80% EA (10% DCM) / PE gradient; flow rate: 80 ml / min) to give 1.42 g of the title compound. LC / MS: m / z=438.2 [M+H] + ;rt:0.47 min (LC / MS-Method C).

[0251] Step 3: tert-butyl ((1S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)(cyclopropyl)-methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate [ka] To a solution of tert-butyl (S)-(2-((4-(cyclopropanecarbonyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (1.27 g) in IPA (15 ml) was added TEA (1.21 ml) and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (I-001-B6, 875 mg). The mixture was stirred at 80 °C for 16 h. Next, the mixture was dissolved in MeOH (15 ml), NaBHCN (547 mg) was added, and the mixture was stirred at 25 °C for 10 min, followed by the dropwise addition of AcOH (1.66 ml) and stirring at 30 °C for 30 min. The reaction mixture was dissolved in DCM (50 ml) and water (150 ml), and the pH was adjusted to 7-8 with NaHCO. The organic layer was separated and the aqueous phase was extracted with DCM (50 ml, 2x). The combined organic layers were washed with brine (50 ml, 3x), dried over anhydrous Na2SO4, filtered and concentrated to give 1.6 g of crude title compound. LC / MS: m / z = 550.3 [M+H] + ;rt:0.35 min (LC / MS-Method C).

[0252] Step 4-P1 and -P2: tert-butyl ((1S)-2-((4-((R or S)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate [ka] To a solution of tert-butyl ((1S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)(cyclopropyl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (1.6 g) in THF (50 ml) was added CDI (1.42 g) at 65 °C. The mixture was stirred at 65 °C for 1 h. Next, additional CDI (1.42 g) was added at 65 °C, and stirring was continued at 65 °C for 0.5 h. Next, NaOH solution (2 M, 20 ml) was added at 25 °C, and the mixture was stirred at 25 °C for 10 min, followed by heating to 65 °C and stirring at 65 °C for 5-10 min. After cooling, the mixture was concentrated under reduced pressure to remove THF, diluted with EA:DCM (200 mL, 10:1), and washed with brine (100 mL, 4x). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-50-100% EA / PE gradient; flow rate: 80 mL / min) to give 1.2 g of the title compound as a mixture of diastereomers. The mixture was separated by preparative SFC (column: Daicel ChiralPak IG (250 mm x 30 mm, 10 μm); mobile phase: A: CO2, B: IPA (0.1% NH3 in HO); B: 30%, isocratic elution mode) to give 470 mg of peak 1 and 430 mg of peak 2. Analytical SFC data (Chiralpak IG-3 (50mmx4.6mm, 3μm); A: CO2, B: IPA (0.05% DEA)]; B: 5%~40%, flow rate 3 ml / min, T: 35 °C): P1: RT = 1.76 min; P2: RT = 1.95 min.

[0253] Step 5: (2S)-2-amino-N-(4-((R or S)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)-2-(4,4-difluorocyclohexyl)acetamide hydrochloride - diastereomer 1 [ka] tert-Butyl ((1S)-2-((4-((R or S)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (Step 4-P1, 230 mg) was dissolved in dioxane (2.5 ml) and HCl in dioxane solution (4 M, 2.5 ml) was added with stirring. After 5 hours, the mixture was concentrated in vacuo and the residue was lyophilized from ACN / water to give 205 mg of crude title compound. LC / MS: m / z=476.2 [M+H] + ;rt:1.33 min (LC / MS-Method A).

[0254] Step 5: (2S)-2-amino-N-(4-((R or S)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)-2-(4,4-difluorocyclohexyl)acetamide hydrochloride - diastereomer 2 tert-Butyl ((1S)-2-((4-((R or S)-cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (Step 4-P2, 215 mg) was dissolved in dioxane (2.5 ml) and HCl in dioxane solution (4 M, 2.5 ml) was added with stirring. After 5 hours, the mixture was concentrated in vacuo and the residue was lyophilized from ACN / water to give 210 mg of crude title compound. LC / MS: m / z=476.2 [M+H] + ;rt:1.23 min (LC / MS-Method A).

[0255] Intermediate 49: (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((R)-1-(4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)ethyl)pyridin-2-yl)acetamide [ka] Step 1: tert-butyl (4-(1-((tert-butylsulfinyl)amino)ethyl)pyridin-2-yl)carbamate [ka] To a solution of tert-butyl (Z)-(4-(((tert-butylsulfinyl)imino)methyl)pyridin-2-yl)carbamate (18 g) in THF (360 ml) at −78° C. under N was added MeMgBr (3 M in diethyl ether, 79.28 ml) dropwise. The mixture was warmed to 0° C. and stirred at 0° C. for 2 h. The residue was then poured into saturated aqueous NH4Cl (250 ml) at 0° C. The aqueous phase was extracted with EA (300 ml, 2×). The combined organic phases were washed with brine (80 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 19.88 g of crude title compound.

[0256] Step 2: 4-(1-aminoethyl)pyridin-2-amine hydrochloride [ka] A mixture of tert-butyl (4-(1-((tert-butylsulfinyl)amino)ethyl)pyridin-2-yl)carbamate (18.31 g) in HCl / dioxane (4 M, 367 ml) was stirred at 25° C. for 12 hours. The reaction mixture was then concentrated under reduced pressure to give 12.45 g of crude title compound.

[0257] Steps 3A and 3B: (S)-tert-butyl (1-(2-aminopyridin-4-yl)ethyl)carbamate (A) and (R)-tert-butyl (1-(2-aminopyridin-4-yl)ethyl)carbamate (B) [ka] To a solution of 4-(1-aminoethyl)pyridin-2-amine hydrochloride (9.45 g) in MeOH (200 ml) was added dropwise a solution of BocO (4.95 g) and TEA (12.34 ml) in MeOH (85 ml). The mixture was stirred at -20 °C for 5 h. The reaction mixture was then quenched by the addition of HCl (1 M) at 25 °C to adjust the pH to 5-6 and concentrated under reduced pressure to give a residue which was purified by reverse-phase HPLC (column: Phenomenex luna C18, 250 x 80 mm; 10 μm; mobile phase: [A: water (FA 10%), B: ACN]; gradient: 5% to 35% B over 20 min) to give 5 g of the racemic mixture of the title compounds. The enantiomers were separated by SFC (Column: REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 μm); Mobile phase: [A: CO, B: MeOH (0.1% NH in HO)]; B%: 30%, isocratic elution mode) to give 1.66 g of the title compound A and 1.58 g of the title compound B.

[0258] Step 4-BA and 4-BB: ((S)-2-((4-((R)-1-((tert-butoxycarbonyl)amino)ethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)benzyl ((S)-2-((4-((R)-1-((tert-butoxycarbonyl)amino)ethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (BA) and ((R)-2-((4-((R)-1-((tert-butoxycarbonyl)amino)ethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (BB) [ka] To a solution of 2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (5.62 g) in DCM (17 ml) was added DIEA (3.59 ml), EDCI (5.53 g), DMAP (5.04 g), and tert-butyl (R)-(1-(2-aminopyridin-4-yl)ethyl)carbamate (Int. 49-3B, 1.63 g). The mixture was stirred at 20 °C for 12 h. Then, HO (30 ml) was added at 25 °C, and the aqueous mixture was extracted with EA (30 ml, 3 × ). The combined organic layers were washed with 1N HCl (50 ml, 2x), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, PE / EA = 1 / 0 to 1 / 1) to give 3.88 g of a diastereomeric mixture of the title compound.

[0259] The diastereomeric mixture was separated by SFC (column: Daicel Chiralpak-AD (250 mm x 30 mm, 10 μm); mobile phase: [A: CO2; B: IPA / ACN = 4 / 1]; B%: 65%, isocratic elution mode) to give 1.26 g of the title compound BA and 1.24 g of the title compound BB. Analytical SFC data (Chiralpak IG-3 (50 mm x 4.6 mm, 3 μm); A: CO2, B: IPA (0.05% DEA)]; B%: 5% to 40%, flow rate 3 ml / min, T: 35 °C). Step 4-BA: rt = 0.64 min; Step 4-BB: rt = 1.18 min.

[0260] Step 5: ((S)-2-((4-((R)-1-aminoethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate benzyl [ka] Benzyl ((S)-2-((4-((R)-1-((tert-butoxycarbonyl)amino)ethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (Step 4-BA, 200 mg) was dissolved in dioxane (1.8 ml) and HCl in dioxane solution (4 M, 1.8 ml) was added with stirring. After stirring for 2.5 h, the mixture was left to stand overnight and then concentrated in vacuo. DCM and water were added to the residue and a neutral pH was established with saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with DCM (2x). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 177 mg of crude title compound. LC / MS: m / z=447.2 [M+H] + ;rt:1.50 min (LC / MS-Method A).

[0261] Step A1: 2,5-dioxopyrrolidin-1-yl (1,1-dimethoxypropan-2-yl)carbamate [ka] Pyridine (190 μl) and 2,5-dioxopyrrolidin-1-yl carbonate (1.178 g) were mixed in ACN (5.5 ml). 1,1-Dimethoxypropan-2-amine (240 mg) dissolved in ACN (2 ml) was added with stirring. After 30 min, saturated NaHCO3 solution and brine were added, and the aqueous mixture was extracted with EE (2x). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (12 g silica gel, nHep / EE = 1 / 0 to 0 / 1) to give 548 mg of the title compound, which contained 1-hydroxypyrrolidine-2,5-dione as an impurity.

[0262] Step 6: benzyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((1R)-1-(3-(1,1-dimethoxypropan-2-yl)ureido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate [ka] Benzyl ((S)-2-((4-((R)-1-aminoethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (Step 5, 175 mg) was dissolved in dry ACN. 2,5-Dioxopyrrolidin-1-yl (1,1-dimethoxypropan-2-yl)carbamate (Step A1, 247 mg) dissolved in ACN (3 ml) and TEA (273 μl) was added with stirring. After 1 h, EE was added and the organic phase was washed with water (2×) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (12 g silica gel, nHep / EE = 1 / 0 to 0 / 1; 20 min) to give 210 mg of the title compound. LC / MS: m / z = 592.3 [M+H] + ;rt:2.05 min (LC / MS-Method A).

[0263] Step 7: ((S)-1-(4,4-difluorocyclohexyl)-2-((4-((R)-1-(4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate benzyl [ka] Benzyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((1R)-1-(3-(1,1-dimethoxypropan-2-yl)ureido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate (209 mg) was dissolved in a solution of ACN / HO / TFA (4 ml; 5 / 1 / 1.5 ml) and stirred for 2 min at 60 °C in a microwave oven. Saturated NaHCO solution was then added and the aqueous phase was extracted with EE (2x). The residue was purified by preparative RP HPLC (flow rate: 50 ml / min; gradient: 90% HO / 10% ACN to 10% HO / 90% ACN in 12.5 min; column: Agilent Prep C18 (10 μm, 30×250 mm). Fractions containing pure product were combined, the ACN was partially removed, and the remaining solution was lyophilized overnight to give 119 mg of the title compound. LC / MS: m / z=528.2 [M+H] + ;rt:2.01 min (LC / MS-Method A).

[0264] Step 8: (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((R)-1-(4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)ethyl)pyridin-2-yl)acetamide [ka] Benzyl ((S)-1-(4,4-difluorocyclohexyl)-2-((4-((R)-1-(4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate (49 mg) was dissolved in MeOH (3 ml) under Ar atmosphere. Pd / C (5 mg, 10%) was added and the flask was purged with H2 from a balloon. After stirring under H2 atmosphere for 1 h, the catalyst was filtered off and washed with MeOH. The filtrate was concentrated and lyophilized from ACN / water overnight to give 37 mg of crude title compound. LC / MS: m / z = 394.2 [M+H] + ;rt:1.09 min (LC / MS-Method A).

[0265] Intermediate 50: (2S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)acetamide hydrochloride [ka] Step 1: (S)-(2-((4-bromopyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate tert-butyl [ka] To a solution of 2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (3.5 g) and 4-bromopyridin-2-amine (3.10 g) in pyridine (35 ml) was added T3P (10.7 ml) at −20° C. The mixture was stirred at 25° C. for 12 h. Then, the solvent was removed in vacuo, and HO (250 ml) and EA (150 ml) were added. After separation of the organic phase, the aqueous phase was extracted with EA (150 ml). The combined organic layers were washed with NH4Cl (100 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 4 / 1) to give 2.53 g of the racemic title compound.

[0266] The racemate (5.6 g) was separated by SFC (Column: Daicel Chiralcel OJ (250 mm * 50 mm, 10 μm); Mobile phase: B: [0.1% NH / HO in MeOH]; B%: 20% - 20%; 20 min) to give 2.5 g of the title compound (Peak 1). Analytical SFC data (Chiralcel OJ-3 (50 mm x 4.6 mm, 3 μm); A: CO, B: MeOH (0.05% DEA)]; B%: 5% - 40%, flow rate 3 ml / min, T: 35 °C): Peak 1: RT = 0.58 min; Peak 2: RT = 0.76 min.

[0267] Step 2: (S)-(1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(prop-1-en-2-yl)pyridin-2-yl)amino)ethyl)carbamate tert-butyl [ka] (S)-tert-Butyl (2-((4-bromopyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (400 mg), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (225 mg), KPO (568 mg), and Pd(dtbpf)Cl (116 mg) were added to dioxane (14 ml) and water (3.5 ml) under Ar. After flushing with Ar for 10 min, the mixture was stirred at 100 °C for 45 min. The cooled mixture was poured into brine, and the aqueous phase was extracted with EA (2x). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (24 g silica gel, nHep / EA; 5 min 100% nHep, 40 min 100% nHep to 50% nHep, 10 min 50% nHep) to give 345 mg of the title compound. LC / MS: m / z=410.1 [M+H] + ;rt:2.42 min (LC / MS-Method A).

[0268] Step 3: (S)-(2-((4-acetylpyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate tert-butyl [ka] tert-Butyl (S)-(1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(prop-1-en-2-yl)pyridin-2-yl)amino)ethyl)carbamate (344 mg) was dissolved in dioxane (21 ml) and sodium periodate (898 mg) dissolved in water (21 ml) was added. After adding potassium osmate(IV) hydrate (56 mg), the mixture was stirred for 3 h. The mixture was then poured into water and the aqueous phase was extracted with EA (2x). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (12 g silica gel, nHep / EA; 5 min 100% nHep, 30 min 100% nHep to 50% nHep, 10 min 50% nHep) to give 318 mg of the title compound. LC / MS: m / z=412.2 [M+H] + ;rt:2.14 min (LC / MS-Method A).

[0269] Step 4: tert-butyl ((1S)-2-((4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)ethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate [ka] (S)-tert-Butyl (2-((4-acetylpyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (220 mg) and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (Int. 1, Step B6; 129 mg) were dissolved in DCM (10 ml) under Ar. TEA (328 μl) was added and stirred at room temperature for 10 min. The mixture was then stirred at 40° C. for 1 h. After cooling to room temperature, sodium cyanoborohydride (118 mg), dry methanol (6 ml), and acetic acid (0.159 ml) were added and stirring was continued for approximately 70 h. The mixture was poured into saturated NaHCO solution and DCM was added. The organic layer was separated and the aqueous phase was extracted with DCM (2×). The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 100% HO+0.05% TFA for 20 min, 100% HO+0.05% TFA in 30 min to 55% HO+0.05% TFA / 45% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing the pure product were combined, the ACN was partially removed, and the TFA was neutralized with saturated NaHCO3 solution. After extraction of the product with DCM (3x), the combined organic phases were dried on a ChemElut cartridge and concentrated in vacuo to give 192 mg of the title compound. LC / MS: m / z=524.2 [M+H] + ;rt:1.52 min (LC / MS-Method A).

[0270] Step 5-P1 and -P2: tert-butyl ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R or S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)carbamate [ka] tert-Butyl ((1S)-2-((4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)ethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (191 mg) was dissolved in dry THF (5.5 ml) and the mixture was heated to 65 °C for 5 min. CDI (177 mg) was then added and stirring was continued for 6 h. The mixture was then poured into saturated NaHCO solution and the aqueous phase was extracted with DCM (2x). The combined organic phases were dried over NaSO, filtered and concentrated in vacuo. The residue was purified by preparative RP HPLC (flow rate: 15 ml / min; gradient: 95% HO + 0.05% TFA / 5% ACN to 10% HO + 0.05% TFA / 90% ACN in 45 min; column: XBridge BEH130, Prep C18, 10 μM, OBD (19 × 250 mm)). Pure fractions of peak 2 were combined, the ACN was removed, the pH was adjusted to about 7, and the aqueous phase was extracted with DCM (2 ×). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo. The residue was lyophilized from ACN / HO to give 74 mg of P2. Peak 1 fractions were combined, the ACN was reduced in vacuo, and the residue was lyophilized. RP HPLC was repeated under the above conditions. Pure fractions of P1 were treated as described for P2 to give 41 mg of P1 after lyophilization. DS1: LC / MS: m / z = 550.2 [M+H] + ;rt:2.08 min (LC / MS-Method A). DS2:LC / MS:m / z=550.2[M+H] + ;rt:2.17 min (LC / MS-Method A).

[0271] Step 6: (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((R or S)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)acetamide hydrochloride DS1 [ka] tert-Butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)carbamate (Step 5-P1, 41 mg) was dissolved in dry dioxane (1.5 ml) and HCl solution (1.5 ml; 4 M in dioxane) was added dropwise with stirring. After 2 hours, the mixture was concentrated in vacuo and the residue was lyophilized from ACN / HO to give 42 mg of crude title compound. LC / MS: m / z=450.3 [M+H] + ;rt:1.13 min (LC / MS-Method A).

[0272] Intermediate 51-1-DS1: tert-butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate Intermediate 51-2-DS1: tert-butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate Intermediate 51-2-DS2: tert-butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate Step A1: 2-(3-methoxyprop-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 3-methoxyprop-1-yne (3.6 g, 4.24 ml), CuCl (508 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (13.04 g), tri-tert-butylphosphonium tetrafluoroborate (1.79 g), and t-BuONa (740 mg) in toluene (70 ml) was added MeOH (4.16 ml) dropwise over 30 minutes at 0°C under N2. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with MeOH (20 ml) at 0°C and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO2, PE:EA = 100:1 to 80:1) to give 5.8 g of the title compound. 1 H NMR(400MHz,CDCl3)δ ppm:5.93(br,1H),5.90(br,1H),4.03(s,2H),3.36(s,3H),1.27(s,12H).

[0273] Step A2: 2-chloro-4-(3-methoxyprop-1-en-2-yl)pyridine [ka] A mixture of 4-bromo-2-chloropyridine (38 g), 2-(3-methoxyprop-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (43 g), Ruphos Pd G3 (1.65 g), and K3PO4 (126 g) in dioxane (400 ml) and water (50 ml) was stirred at 100 °C under N2 for 2 h. Then, brine (200 ml) was added, and the aqueous phase was extracted with EA (200 ml). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO2, PE / EA = 3 / 1) to give 21 g of the title compound. LC / MS: m / z = 184.2 [M+H] + ;rt:0.36 min (LC / MS-Method C).

[0274] Step A3: 1-(2-chloropyridin-4-yl)-2-methoxyethan-1-one [ka] A mixture of 2-chloro-4-(3-methoxyprop-1-en-2-yl)pyridine (21 g), NaIO (2.45 g), and KOsO (126.4 g) in dioxane (200 ml) and water (40 ml) was stirred at 25 °C under N for 2 h. Saturated NaHCO solution (100 ml) was then added, and the aqueous phase was extracted with EA (100 ml). The organic layer was washed with brine (30 ml), dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, PE / EA = 5 / 1 to 3 / 1) to give 10 g of the title compound. LC / MS: m / z = 186.2 [M+H] + ;rt:0.27 min (LC / MS-Method C).

[0275] Step A4: 1-(2-chloropyridin-4-yl)-2-methoxyethan-1-ol [ka] To a solution of 1-(2-chloropyridin-4-yl)-2-methoxyethan-1-one (1 g) in THF (10 ml) was added NaBH (204 mg) with stirring at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was quenched with saturated aqueous NH Cl (40 ml) and the aqueous phase was extracted with EA (40 ml, 2x). The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo to give a residue which was purified by column chromatography (SiO, PE / EA = 5 / 1 to 2 / 1) to give 0.7 g of the title compound. LC / MS: m / z = 188.3 [M+H] + ;rt:0.22 min (LC / MS-Method C).

[0276] Step A5: 4-(1-bromo-2-methoxyethyl)-2-chloropyridine [ka] To a mixture of 1-(2-chloropyridin-4-yl)-2-methoxyethan-1-ol (7.15 g) and PPh3 (19.99 g) in DCM (60 ml), TEA (6.37 ml) was added, followed by CBr4 (25.28 g) with stirring at 0 °C. After stirring at 20 °C for 16 h, the mixture was concentrated, and the residue was purified by column chromatography (SiO2, PE = 5 / 1 to 3 / 1) to give 4.9 g of the title compound. LC / MS: m / z = 250.1 [M+H] + ;rt:0.38 min (LC / MS-Method C).

[0277] Step B1: dimethyl 2-(2,2-dimethoxyethyl)malonate [ka] To a solution of dimethyl malonate (50 g) in DMF (600 ml) was added NaH (15.3 g, 60%) at 0 °C, and the mixture was stirred for 30 min. Next, KI (11.3 g) and 2-bromo-1,1-dimethoxyethane (64.17 g) were added with stirring. The mixture was warmed to 25 °C, then heated to 100 °C, and maintained at this temperature for 12 h. The mixture was then diluted with water (1.5 L) at 0 °C, and the aqueous phase was extracted with EA (800 ml, 3x). The combined organic layers were washed with brine (1 L, 2x), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, PE / EA = 1 / 0 to 4 / 1) to give 41.62 g of the title compound. 1 H NMR(400MHz,CDCl3)δ ppm:4.42(t,J=5.4Hz,1H),3.75(s,6H),3.54(t,J=7.2Hz,1H),3.33(s,6H),2.24(dd,J=5.6,7.2Hz,2H).

[0278] Step B2: 2-(2-oxoethyl) dimethyl malonate [ka] To a solution of dimethyl 2-(2,2-dimethoxyethyl)malonate (41.6 g) in DCM (250 ml) and HO (250 ml) was added TFA (140 ml) at 0 °C. The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was then quenched with saturated KCO solution to adjust the pH to 6-8 at 0 °C, and the aqueous phase was extracted with DCM (350 ml, 3x). The combined organic layers were washed with brine (600 ml, 2x), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 33 g of the crude title compound.

[0279] Step B3: (R,E)-2-(2-((tert-butylsulfinyl)imino)ethyl)dimethyl malonate [ka] To a solution of dimethyl 2-(2-oxoethyl)malonate (33 g) and (R)-2-methylpropane-2-sulfinamide (29.86 g) in DCM (350 ml), pyrrolidine (1.58 ml) was added, and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , PE / EA=1 / 0 to 3 / 2) to give 27.73 g of the title compound. LC / MS: m / z=278.2 [M+H] + ;rt:0.29 min (LC / MS-Method C).

[0280] Step B4: 2-((S)-2-(((R)-tert-butylsulfinyl)amino)-3,3,3-trifluoropropyl)malonate dimethyl [ka] To a solution of (R,E)-dimethyl 2-(2-((tert-butylsulfinyl)imino)ethyl)malonate (27.7 g) and tetrabutylammonium acetate (36.14 g) in THF (554 ml) was added TMS-CF (35.51 g) with stirring at −55° C. After stirring at −55° C. for 1 h, the mixture was stirred at 0° C. for 3 h. The mixture was then quenched with aqueous ammonium chloride solution (100 ml). The mixture was diluted with water (1.2 l) and extracted with EA (500 ml, 3×). The combined organic layers were washed with brine (500 ml, 3×), dried over anhydrous NaSO, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, PE=1 / 0 to 3 / 2) to give 12 g of the title compound. LC / MS: m / z=348.1 [M+H] + ;rt:0.35 min (LC / MS-Method C).

[0281] Step 1: (5S)-3-(1-(2-chloropyridin-4-yl)-2-methoxyethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate methyl [ka] A mixture of 4-(1-bromo-2-methoxyethyl)-2-chloropyridine (Step A5; 4.4 g), 2-((S)-2-(((R)-tert-butylsulfinyl)amino)-3,3,3-trifluoropropyl)dimethylmalonate (Step B4; 6.10 g), and K2CO3 (4.85 g) in DMF (80 ml) was stirred at 25 °C for 1 h, followed by 60 °C for 1 h. Brine (50 ml) was then added, and the aqueous phase was extracted with EA (50 ml). The organic layer was washed with brine (20 ml, 2x), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO2, PE / EA = 5 / 1 to 1 / 1) to give 402 mg of the title compound. LC / MS: m / z = 381.0 [M+H] + ;rt:0.58 min (LC / MS-Method C).

[0282] Step 2-P1 and -P2: (5S)-3-(1-(2-chloropyridin-4-yl)-2-methoxyethyl)-5-(trifluoromethyl)pyrrolidin-2-one [ka] To a solution of methyl (5S)-3-(1-(2-chloropyridin-4-yl)-2-methoxyethyl)-2-oxo-5-(trifluoromethyl)pyrrolidine-3-carboxylate (402 mg) in THF (10 ml) and water (1 ml) was added LiOH.HO (89 mg). After stirring at 25 °C for 1 h, the pH was adjusted to 6 with HCl (3 M) and the aqueous phase was extracted with EA (5 ml, 2x). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was diluted with toluene (3 ml) and stirred at 80 °C for 1 h. The solution was then concentrated in vacuo to give a residue which was purified by column chromatography (SiO, PE / EA = 3 / 1 to 1 / 1) to give 70 mg of the title compounds P1 and 288 mg of P2. P1: LC / MS: m / z = 323.0 [M+H] + ;rt:0.35 min (LC / MS-Method C). P2:LC / MS:m / z=323.0[M+H] + ;rt:0.35 min (LC / MS-Method C).

[0283] Step 3-P1: tert-butyl (4-(2-methoxy-1-((5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)carbamate (diastereomer A) [ka] To a solution of (5S)-3-(1-(2-chloropyridin-4-yl)-2-methoxyethyl)-5-(trifluoromethyl)pyrrolidin-2-one (step 2-P1, 70 mg) and tert-butyl carbamate (38.12 mg) in dioxane (2 ml) was added Pd(OAc) (9.7 mg), CsCO (141 mg), and XPhos (31 mg). After stirring at 100 °C under N for 1 h, the reaction mixture was filtered. Brine (2 ml) was added to the filtrate, and the aqueous phase was extracted with EA (2 ml, 2x). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, PE / EA = 2 / 1 to 1 / 1) to give 44 mg of the title compound. LC / MS: m / z = 404.0 [M+H] + ;rt:0.32 min (LC / MS-Method C). Analytical SFC data (Chiralpak AD-3 (50mmx4.6mm, 3μm); A:CO2, B:MeOH(0.05% DEA)]; B%: 5%~40%, flow rate 3ml / min, T: 35°C): rt=0.68 min.

[0284] Step 4-P1: (5S)-3-(1-(2-aminopyridin-4-yl)-2-methoxyethyl)-5-(trifluoromethyl)pyrrolidin-2-one [ka] To a solution of tert-butyl (4-(2-methoxy-1-((5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)carbamate (step 3-P1, 42 mg) in DCM (0.5 ml) was added TFA (0.25 ml). After stirring at 25 °C for 12 h, the reaction mixture was concentrated in vacuo to give a residue which was adjusted to pH = 8 with saturated NaHCO3 solution. The aqueous mixture was extracted with EA (2 ml, 3x) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 28 mg of the title compound. LC / MS: m / z = 304.1 [M+H] + ;rt:0.21 min (LC / MS-Method C).

[0285] Step 5-P1: tert-butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate [ka] A mixture of (5S)-3-(1-(2-aminopyridin-4-yl)-2-methoxyethyl)-5-(trifluoromethyl)pyrrolidin-2-one (27 mg), (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (28 mg), and EDCI (35.4 mg) in pyridine (0.5 ml) was stirred at 25° C. for 12 h. Brine (5 ml) was then added, and the aqueous phase was extracted with EA (5 ml). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (SiO, PE / EA = 3 / 1 to 1 / 1) to give 15 mg of the title compound. The stereochemistry was tentatively assigned. LC / MS: m / z = 579.2 [M+H] + ;rt:0.44 min (LC / MS-Method C). Analytical SFC data (Chiralcel OD-3 (50mmx4.6mm, 3μm); A:CO2, B:MeOH(0.05% DEA)]; B%: 5%~40%, flow rate 3ml / min, T: 35°C): rt=0.89 min.

[0286] Step 3-P2A and -P2B: tert-butyl (4-(2-methoxy-1-((5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)carbamate [ka] Following the procedure described in Step 3-P1 using (5S)-3-(1-(2-chloropyridin-4-yl)-2-methoxyethyl)-5-(trifluoromethyl)pyrrolidin-2-one (Step 2-P2, 250 mg), 130 mg of a mixture of diastereomers was obtained in a ratio of approximately 2:1 as identified by analytical SFC. LC / MS: m / z=404.1 [M+H] + ;rt:0.32 min (LC / MS-Method C). Analytical SFC data (Chiralpak AD-3 (50mmx4.6mm, 3μm); A:CO2, B:MeOH(0.05% DEA)]; B%: 5%~40%, flow rate 3ml / min, T: 35°C): B: rt = 0.80 min (67%), C: 1.00 min (33%).

[0287] Step 5-P2A and -P2B: tert-butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate (P2A) and tert-butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate (P2B) [ka] tert-Butyl (4-(2-methoxy-1-((5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)carbamate (Step 3-P2A and -P2B, 130 mg) was treated as described for Step 4-P1 and Step 5-P1 to give 120 mg of a diastereomeric mixture of the title compound.

[0288] This mixture (120 mg) was purified by SFC (column: Daicel Chiralpak AS (250 mm × 30 mm, 10 μm); A: CO₂, B: EtOH (0.1% NH₃ in HO), B 20% isocratic mode, flow rate 100 ml / min) to give 50 mg of I-051-5-P₂A and 30 mg of I-051-5-P₂B. The stereochemistry was tentatively assigned. Analytical SFC data (Chiralpak AS-3 (50 mm × 4.6 mm, 3 μm); A: CO₂, B: EtOH (0.05% DEA); B%: 5%–40%, flow rate 3 ml / min, T: 35 °C): P₂A: rt = 1.09 min; P₂B: 1.28 min.

[0289] Step 6: Intermediate 51-1-DS1: (2S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((R or S)-2-methoxy-1-((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)acetamide DS1 [ka] tert-Butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate (step 5-P1, 8 mg) was dissolved in dry dioxane (0.5 ml) and HCl solution (0.5 ml; 4 M in dioxane) was added dropwise with stirring. After stirring for 2.5 h, the mixture was left to stand overnight. Then, DCM and water were added and the pH was adjusted to neutral with saturated NaHCO3 solution. The organic phase was separated and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was lyophilized from ACN / H2O to give 7 mg of the crude title compound. LC / MS: m / z=479.2 [M+H] + ;rt:1.22 min (LC / MS-Method A).

[0290] Step 6: Intermediate 51-2-DS1 (2S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((R or S)-2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)acetamide DS1 The procedure for DS1 ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl) tert-butyl carbamate (Step 5-P2A, 30 mg) was followed to give 25 mg of crude title compound. LC / MS: m / z=479.2 [M+H] + ;rt:1.21 min (LC / MS-Method A).

[0291] Step 6: Intermediate 51-2-DS2: (2S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((R or S)-2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)acetamide DS2 Followed the procedure for intermediate 51-1-DS1, ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-((R or S)-2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)tert-butylcarbamate (Step 5-P2B, 15 mg) to afford 13 mg of crude title compound. LC / MS: m / z=479.2 [M+H] + ;rt:1.16 min (LC / MS-Method A).

[0292] Intermediate 52: (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)acetamide hydrochloride [ka] Step 1: tert-butyl ((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate [ka] To a solution of (S)-1-((S)-1-(2-aminopyridin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one hydrochloride (Int. 54-B-P1, 6 g) in pyridine (60 ml) was added (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (5.78 g) and EDCI (11.34 g). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Phenomenex luna C18 (250x70mm, 10µm); mobile phase: A: water (FA 10%), B ACN; gradient: 30% to 60% over 15 min) followed by SFC (column: Daicel Chiralpak-AD (250mmx30mm, 10µm); mobile phase: [A: CO2, B: IPA (0.1% NH3 in H2O)]; B%: 50%, isocratic elution mode) to give 2.93g of the title compound. LC / MS: m / z=580.2 [M+H] + ;rt:0.44 min (LC / MS-Method C). Analytical SFC data: (Chiralpak AD-3 (50 × 4.6 mm, 3 μm); A: CO2, B: IPA (0.05% DEA)]; B%: 5%~40%, flow rate 3 ml / min, T: 35 °C): RT = 1.57 min.

[0293] Step 2: (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)acetamide hydrochloride [ka] tert-Butyl ((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate (251 mg) was dissolved in dry dioxane (3.0 ml) and HCl solution (3.0 ml; 4 M in dioxane) was added dropwise with stirring. After 2 hours, the mixture was concentrated in vacuo and the residue was lyophilized from ACN / HO to give 240 mg of crude title compound. LC / MS: m / z=480.3 [M+H] + ;rt:1.14 min (LC / MS-Method A).

[0294] Intermediates 53-P1 and P2: 1-(ethyl-d5)-1H-pyrazole-5-carboxylic acid and 1-(ethyl-d5)-1H-pyrazole-3-carboxylic acid [ka] Step 1-P1 and P2: Ethyl 1-(ethyl-d5)-1H-pyrazole-5-carboxylate (P1) and Ethyl 1-(ethyl-d5)-1H-pyrazole-3-carboxylate (P2) [ka] DMF (3.1 ml) was added to ethyl 1H-pyrazole-5-carboxylate (510 mg) and potassium carbonate (754 mg). While stirring, 1-bromoethane-1,1,2,2,2-d5 (415 mg) was added, and stirring was continued overnight. The mixture was then poured into water, and the aqueous phase was extracted with EA (2x). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (nHep / EA: 90:10 to 40:60 in 30 min). The fractions containing the pure respective compounds were combined and concentrated in vacuo to give 193 mg of P1 and 267 mg of P2. P1: LC / MS: m / z = 174.0 [M+H] +;rt: 1.65 min (LC / MS-Method A). P2:LC / MS:m / z=174.0[M+H] + ;rt: 1.29 min (LC / MS-Method A).

[0295] Step 2: 1-(ethyl-d5)-1H-pyrazole-5-carboxylic acid (P1) [ka] Ethyl 1-(ethyl-d5)-1H-pyrazole-5-carboxylate (Step 1-P1, 186 mg) was dissolved in THF / water (4 ml / 1 ml) and LiOH (51 mg) was added with stirring. After 5.5 h, the mixture was poured into brine and the pH was adjusted to 2-3 with HCl. EA was added and the aqueous phase was extracted with EA (3x). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in water / ACN and lyophilized overnight to give 118 mg of the title compound. LC / MS: m / z=146.0 [M+H] + ;rt:0.83 min (LC / MS-Method A).

[0296] Step 2: 1-(ethyl-d5)-1H-pyrazole-3-carboxylic acid (P2) [ka] Ethyl 1-(ethyl-d5)-1H-pyrazole-3-carboxylate (Step 1-P2, 259 mg) was treated in the same manner as P1 to give 191 mg of the title compound. LC / MS: m / z=146.0 [M+H] + ;rt:0.74 min (LC / MS-Method A).

[0297] Intermediate 54: (S)-2-amino-3,3-dicyclopropyl-N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)propanamide hydrochloride [ka] Step A-1: ​​(2-methoxyethene-1,1-diyl)dicyclopropane [ka] To a solution of (methoxymethyl)triphenylphosphonium chloride (202.3 g) in THF (1 L) was added n-BuLi (2.5 M, 236 ml) dropwise with stirring at 5 °C for 0.5 h. Next, a solution of dicyclopropylmethanone (50 g) in THF (250 ml) was added to the mixture. The mixture was stirred at 5 °C for 0.5 h, followed by stirring at 60 °C for 16 h. The reaction solution was quenched with saturated aqueous NH Cl (500 ml) and then extracted with EA (300 ml, 2x). The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, PE / EA = 1 / 0 to 20 / 1) to give 59 g of the title compound.

[0298] Step A-2: 2,2-Dicyclopropylacetaldehyde [ka] To a solution of (2-methoxyethene-1,1-diyl)dicyclopropane (57 g) in THF (300 ml) was added HCl (3 M, 302 ml). The mixture was stirred at 55° C. for 4 h. The reaction mixture was then diluted with water (200 ml) and extracted with EA (150 ml, 3×). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 43 g of the crude title compound.

[0299] Step A-3: 5-(dicyclopropylmethyl)imidazolidine-2,4-dione [ka] To a solution of 2,2-dicyclopropylacetaldehyde (43 g) in a mixture of EtOH (430 mL) and HO (430 mL) was added KCN (32.4 g) and (NH)CO (99.8 g). The mixture was stirred at 75 °C for 8 h. Next, EtOH was removed under reduced pressure, and the residue was then diluted with EA (200 mL) and extracted with EA (200 mL, 3x). The combined organic layers were washed with brine (400 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was triturated with a mixture of PE and EA (PE:EA = 5:1; 50 mL) at 25 °C for 20 min to give 45 g of the title compound. 1 H NMR(400MHz,CDCl3)δ ppm:8.78(br s,1H),6.71(br s,1H),4.26(d,J=1.6Hz,1H),0.88-0.69(m,3H),0.68-0.59(m,1H),0.56-0.44(m,2H),0.44-0.30(m,2H),0.28-0.17(m,3H).

[0300] Step A-4: 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid [ka] To a mixture of 5-(dicyclopropylmethyl)imidazolidine-2,4-dione (20 g) in HO (400 ml) was added NaOH (2.5 M, 412 ml), followed by stirring at 110 °C for 12 h. Then, THF (400 ml) and BocO (33.70 g) were added. The mixture was stirred at 25 °C for 12 h. Then, HO (190 ml) was added, and the aqueous phase was extracted with EA / PE (1:1, 200 ml, 2x). The aqueous layer was acidified to pH 4-5 with 1N HCl and extracted with EA (200 ml, 3x). The combined organic phases were washed with brine (100 ml), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 15.22 g of the crude title compound.

[0301] Step A-5: (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate 4-methoxybenzyl [ka] To a solution of 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid (15.22 g), (4-methoxyphenyl)methanol, and DMAP (6.90 g) in DCM (230 ml) was added EDCI (16.25 g). The mixture was stirred at 25 °C for 16 h. The reaction mixture was then washed with brine (200 ml). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, PE / EA = 1:0 to 10:1) to give 15 g of the racemic title compound. 1 H NMR(400MHz,CDCl3)δ ppm:7.30(br d,J=8.5Hz,2H),6.89(d,J=8.8Hz,2H),5.25(br d,J=9.0Hz,1H),5.09(s,2H),4.62-4.48(m,1H),3.82(s,3H),1.45(s,9H),0.78-0.59(m, 3H),0.54-0.39(m,3H),0.36-0.28(m,1H),0.24-0.12(m,3H),0.02(qd,J=4.9,9.4Hz,1H).

[0302] The enantiomers (15 g) were separated by preparative SFC (Column: Daicel Chiralpak AY (250 mm × 50 mm, 10 μm); Mobile phase: A: CO, B: [0.1% NH H O in IPA]; B: 50%, isocratic mode) to give 6.7 g of the title compound. 1H NMR(400MHz,CDCl3)δ ppm:7.30(br d,J=8.5Hz,2H),6.89(d,J=8.6Hz,2H),5.26(br d,J=8.6Hz,1H),5.09(s,2H),4.54(br dd,J=2.4,9.1Hz,1H),3.82(s,3H),1.45(s,9H),0.79-0.58(m,3H),0.55-0.38(m,3H),0 .37-0.28(m,1H),0.24-0.12(m,3H),0.01(qd,J=4.8,9.5Hz,1H).Analytical SFC data (Chiralpak AY-3, 50x4.6mm ID, 3 μm); A: CO2, B: IPA (0.05% DEA)]; B%: 5%~40%, flow rate 3 ml / min, T: 35°C): Peak 1 (R): RT = 0.94 min; Peak 2 (S): RT = 1.22 min.

[0303] Step A-5: (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid [ka] To a solution of (S)-4-methoxybenzyl 2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate (10 g) in MeOH (50 ml) was added Pd / C (0.4 g, 10%) under N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred at 30 °C under H (15 psi) for 16 h. Then, the mixture was filtered. After evaporation of the solvent in vacuo, the residue was purified by column chromatography (SiO, PE:EA = 1 / 0 to 5 / 1) to give 6.5 g of the title compound. 1 H NMR(400MHz,CDCl3)δ ppm:12.72-12.11(m,1H),6.84(br d,J=9.0Hz,1H),4.12(dd,J=4.4,8.9Hz,1H),1.39(s,9H),1.00-0.88(m,1H) ,0.83-0.72(m,1H),0.55-0.41(m,2H),0.40-0.20(m,4H),0.18-0.00(m,3H).

[0304] Step B-1: N,2-Dimethoxy-N-methylacetamide [ka] To a solution of N,O-dimethylhydroxylamine (100 g) and 2-methoxyacetyl chloride (37.09 g) in DCM (1 L) was added TEA (190 ml) at 0° C. The mixture was stirred at 25° C. for 1 h. The solution was then treated with HCl (1 M) to pH=2-3. The organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 82.1 g of the title compound. 1 H NMR(400MHz,CDCl3)δ ppm:4.20(s,2H),3.67(s,3H),3.45(s,3H),3.17(s,3H).

[0305] Step B-2: 1-(2-chloropyridin-4-yl)-2-methoxyethan-1-one [ka] To a solution of 2-chloro-4-iodopyridine (80.93 g) in THF (1 L) was added n-BuLi (2.5 M, 203 ml) at −78°C, and the mixture was stirred for 10 min. Next, N,2-dimethoxy-N-methylacetamide (45 g) was added over 1 h at −78°C. After stirring, the mixture was stirred at −78°C for 2 h. The reaction mixture was quenched by the addition of saturated NHCl solution (200 ml) at 0°C, diluted with water (200 ml), and extracted with EA (150 ml, 3×). The combined organic layers were washed with brine (100 ml, 2×), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, PE / EA = 1 / 0 to 3 / 1) to give 20 g of the title compound. LC / MS: m / z = 186.2 [M+H] + ;rt:0.23 min (LC / MS-Method C).

[0306] Step B-3: tert-butyl (4-(2-methoxyacetyl)pyridin-2-yl)carbamate [ka] To a solution of 1-(2-chloropyridin-4-yl)-2-methoxyethan-1-one (20 g) and NHBoc (18.93 g) in dioxane (400 ml) was added Pd(OAc) (1.21 g), XPhos (2.57 g), and CsCO (52.66 g). The mixture was stirred at 90 °C for 12 h. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, PE / EA = 1 / 0 to 3 / 1) to give 8.1 g of the title compound.

[0307] Step B-4: tert-butyl (4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)pyridin-2-yl)carbamate [ka] To a solution of tert-butyl (4-(2-methoxyacetyl)pyridin-2-yl)carbamate (6 g) and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (Int. 1, Step B6, 3.17 g) in IPA (140 ml) was added TEA (11.29 ml) in one portion at 85°C, and the mixture was stirred at 85°C for 2 h. After stirring at 25°C for 12 h, the mixture was concentrated in vacuo, and the residue was dissolved in MeOH (140 ml). NaBHCN (7.93 g) was added in small portions, resulting in gas evolution. The suspension was stirred for 5 min, followed by the addition of AcOH (9.29 ml). The reaction mixture was heated at 40°C with stirring for 25 min. The reaction mixture was then concentrated, diluted with DCM (100 ml), and rapidly stirred with saturated aqueous NaHCO (200 ml) at 25°C for 1 h. After separating the layers, the aqueous phase was extracted with DCM (200 ml, 3x). The combined organic layers were washed with brine (300 ml), dried over anhydrous Na2SO4, filtered and concentrated to give 10 g of the crude title compound. LC / MS: m / z = 379.3 [M+H] + ;rt:0.24 min (LC / MS-Method C).

[0308] Step B-5-P1 and -P2: tert-butyl (4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)carbamate and tert-butyl (4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)carbamate [ka] To a solution of tert-butyl (4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-methoxyethyl)pyridin-2-yl)carbamate (10 g) in THF (240 ml) was added CDI (12.86 g). The mixture was stirred at 60° C. for 1 h. Then, the mixture was diluted with water (150 ml) and extracted with EA (150 ml, 3×). The combined organic layers were washed with citric acid (100 ml, 2×), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, PE / EA=1 / 0 to 0 / 1) to give 2.5 g of a diastereoisomeric mixture of the title compound.

[0309] The diastereomers (5.5 g) were separated by preparative SFC (Column: Regis (S,S) Whelk-O1 (250 mm x 50 mm, 10 μm); Mobile phase: A: CO2, B: [0.1% NH3·H2O in MeOH]; B: 25% isocratic) to give 2.8 g of B-5-P1 and 2 g of B-5-P2. P1: LC / MS: m / z = 405.3 [M+H] + ;rt:0.31 min (LC / MS-Method C). P2:LC / MS:m / z=405.3[M+H] + ;rt:0.32 min (LC / MS-Method C). Analytical SFC data: (Regis, Whelk (50 × 4.6 mm, 3.5 μm); A: CO2, B: MeOH (0.05% DEA)]; B%: 5%~40%, flow rate 3 ml / min, T: 35 °C): P1: RT = 1.16 min; P2: RT = 1.27 min.

[0310] Step B-6-P1: (S)-1-((S)-1-(2-aminopyridin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one hydrochloride [ka] To a solution of tert-butyl (4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)carbamate (2.8 g) was added HCl / dioxane (4 M, 10.39 ml). The mixture was stirred at 25 °C for 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 1.9 g of the title compound. Analytical SFC data: (Chiralpak IC-3 (50 × 4.6 mm, 3 μm); A: CO2, B: MeOH (0.05% DEA)]; B%: 5%-40%, flow rate 3 ml / min, T: 35 °C): P1: RT = 1.56 min.

[0311] Step B-6-P2: (S)-1-((R)-1-(2-aminopyridin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one hydrochloride [ka] The procedure described for B-6-P1 (tert-butyl 4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)carbamate (2 g) was followed to give 1.4 g of the title compound. Analytical SFC data: (Chiralpak IC-3 (50 × 4.6 mm, 3 μm); A: CO, B: MeOH (0.05% DEA)]; B%: 5%-40%, flow rate 3 ml / min, T: 35 °C): P1: RT = 1.76 min.

[0312] Step 1: tert-butyl ((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)carbamate (DS2) [ka] To (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid (Step A-5, 100 mg) in DCM (2.8 ml) were added DMAP (91 mg) and EDCI (142 mg). After stirring for 5 minutes, (S)-1-((S)-1-(2-aminopyridin-4-yl)-2-methoxyethyl)-4-(trifluoromethyl)imidazolidin-2-one hydrochloride (Step B-6-P1, 113 mg) was added. After stirring for 1 hour, the mixture was left overnight. It was poured into saturated NaHCO3 solution, and the aqueous phase was extracted with DCM (2x). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (12 g silica gel; DCM / EtOH:100:0 in 5 min, 100:0 to 92:8 in 30 min, 92:8 in 10 min). Fractions containing pure compounds were combined and concentrated in vacuo to give 125 mg of the diastereomeric mixture.

[0313] The diastereomeric mixture (120 mg) was separated by preparative SFC column chromatography (Chiralpak IE / 67 (30x250 mm, 5 μM); A CO2B:MeOH (35%); flow rate: 120 ml / min; T: 40 °C) to give 24 mg DS1 and 69 mg DS2 of the title compound. Analytical chiral analysis (HPLC; Chiralpak IE / 179, 4.6x250 mm, 5 μM; MeOH / EtOH 1:1, flow rate: 1.0 ml / min; T: 30 °C): DS1: rt: 4.19 min. DS2: 4.80 min.

[0314] Step 2: (S)-2-amino-3,3-dicyclopropyl-N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)propanamide hydrochloride [ka] tert-Butyl ((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)carbamate (Step 1, 60 mg) was dissolved in dry dioxane (2.0 ml) and HCl solution (2.0 ml; 4 M in dioxane) was added dropwise with stirring. After 2 hours, the mixture was concentrated in vacuo and the residue was lyophilized from ACN / HO to give 58 mg of crude title compound. LC / MS: m / z=456.2 [M+H] + ;rt:1.19 min (LC / MS-Method A).

[0315] Intermediate 55: (2S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl-d)pyridin-2-yl)acetamide hydrochloride [ka] Step 1: tert-butyl ((1S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)methyl-d)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((S)-2-((4-formylpyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Int. 1, Step A4, 120 mg) and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (Int. 1, Step B6, 77 mg) were dissolved in DCM (8 ml) under Ar. After the addition of TEA (196 μl), the mixture was stirred for 10 min. The mixture was then heated to 40° C. for 3.5 h. NaBD3CN (74 mg), dry MeOH (33 μl), and AcOH (95 μl) were then added at room temperature, and the mixture was stirred for 20 min. After standing overnight, DCM and saturated NaHCO3 solution were added. After separation of the organic phase, the aqueous phase was extracted with DCM (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 45 min from 95% HO+0.05% TFA / 5% ACN to 10% HO+0.05% TFA / 90% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing the pure product were combined, the ACN was partially removed, and the TFA was neutralized with concentrated NaHCO3 solution. After the product was extracted with DCM (3x), the combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ACN / HO and lyophilized to give 96 mg of the title compound. LC / MS: m / z = 489.3 [M+H] + ;rt: 1.70 min (LC / MS-Method A).

[0316] Step 2: tert-butyl ((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl-d)pyridin-2-yl)amino)ethyl)carbamate [ka] tert-Butyl ((1S)-2-((4-((((S)-2-amino-3,3,3-trifluoropropyl)amino)methyl-d)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Step 1, 95 mg) was dissolved in THF (5 ml) and heated to 65 °C for 5 min. CDI (95 mg) was then added and the mixture was heated with stirring for 5.5 h. After standing at room temperature overnight, heating was continued at 65 °C for 2 h. After cooling, DCM was added and the mixture was washed with saturated NaHCO solution. The aqueous phase was extracted with DCM (2x). The combined organic phases were dried over NaSO, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 12 g, DCM / EtOH gradient). The pure fractions containing the product were combined and concentrated in vacuo to give 86 mg of the title compound. LC / MS: m / z=515.3 [M+H] + ;rt:2.33 min (LC / MS-Method A).

[0317] Step 3: (2S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl-d)pyridin-2-yl)acetamide hydrochloride [ka] tert-Butyl ((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl-d)pyridin-2-yl)amino)ethyl)carbamate (Step 2, 81 mg) was dissolved in HCl (4N in dioxane, 2 ml). After 1.75 h, the solvent was removed in vacuo and the residue was lyophilized from ACN / water to give 78 mg of the title compound. LC / MS: m / z=415.2 [M+H] + ;rt: 1.27 min (LC / MS-Method A).

[0318] Intermediate 56-DS1 and DS2: (2S)-2-amino-N-(4-((R or S)-2-hydroxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride [ka] Step 1: tert-butyl ((S)-2-((4-bromopyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (6 g) and 4-bromopyridin-2-amine (5.74 g) in pyridine (60 ml) at −20° C. under N was added T3P (19.73 ml) in one portion. The mixture was stirred at 20° C. for 12 h. The reaction mixture was then partitioned between water (120 ml) and EA (120 ml). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, PE / DCM / EA=16 / 4 / 1) to give 4.1 g of the title compound. LC / MS: m / z=426.2 [M+H] + ;rt:0.50 min (LC / MS-Method C).

[0319] Step 2: tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-vinylpyridin-2-yl)amino)ethyl)carbamate [ka] To tert-butyl ((S)-2-((4-bromopyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (750 mg), potassium vinyltrifluoroborate (353 mg), KPO (1.12 g), and Pd(dtpbf)Cl (229 mg) were added dioxane (16 ml) and water (3.5 ml). The mixture was purged with Ar for 15 min and then stirred at 100 °C for 30 min. The mixture was poured into brine, and the aqueous phase was extracted with EA (2x). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 24 g, Hep / EA: 100% Hep (5 min), 100% EA in 45 min, 100% EA in 10 min). The pure fractions containing the product were combined and concentrated in vacuo to give 517 mg of the title compound. LC / MS: m / z=374.2 [M+H] + ;rt:2.62 min (LC / MS-Method A).

[0320] Step 3: tert-butyl ((1S)-2-((4-(1,2-dihydroxyethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] To tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-vinylpyridin-2-yl)amino)ethyl)carbamate (510 mg) was added dioxane (6 ml) and water (3 ml). Then, 4-methylmorpholine N-oxide (420 mg) and potassium osmate(VI) dihydrate (14 mg) were added with stirring. After stirring at 40 °C for 2 h, saturated NaHCO3 solution (5 ml) was added and the mixture was stirred for 15 min. Then, water and EA were added and the mixture was filtered. The residue was washed with EA and water. Brine was added to the filtrate and the aqueous phase was extracted with EA (3x). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (12 g silica gel, 100% DCM (5 min), 85% DCM / 15% EtOH in 45 min, 15% EtOH in 5 min). Pure fractions containing the product were combined and concentrated in vacuo to give 421 mg of the title compound. LC / MS: m / z=408.2 [M+H] + ;rt:1.91 min (LC / MS-Method A).

[0321] Step 4: tert-butyl ((1S)-2-((4-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((1S)-2-((4-(1,2-dihydroxyethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (420 mg) was dissolved in DCM and DMAP (13 mg), and TEA (180 μL) and tert-butylchlorodiphenylsilane (320 μL) were added with stirring at room temperature. After stirring for 2 h, the mixture was allowed to stand overnight, after which additional silane (53 μL) was added. After standing for 4 days, further silane (266 μL) was added, and the mixture was stirred at 35 °C for 4 h. After standing overnight, the mixture was poured into brine, and the aqueous phase was extracted with DCM (2×). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (24 g silica gel, nHep / EA: 100% Hep (5 min), 50 / 50 in 30 min, 0 / 100 in 20 min). The pure fractions containing the product were combined and concentrated in vacuo to give 382 mg of the title compound. LC / MS: m / z=644.4 [M+H] + ;rt:3.56 min (LC / MS-Method A).

[0322] Step 5: tert-butyl ((S)-2-((4-(2-((tert-butyldiphenylsilyl)oxy)acetyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((1S)-2-((4-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (380 mg) was dissolved in dry DCM, and DMP (15% in DCM, 1.47 ml) was added with stirring at room temperature. After stirring for 2 hours and standing overnight, further DMP (0.244 ml) was added. After standing overnight, the mixture was poured into water and brine was added. The aqueous phase was extracted with DCM (3x), and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 12 g, nHep / EA: 100% nHep (5 min), 60 / 40 for 30 min, 60 / 40 for 10 min). The pure fractions containing the product were combined and concentrated in vacuo to give 321 mg of the title compound. LC / MS: m / z=644.4 [M+H] + ;rt:3.56 min (LC / MS-Method A).

[0323] Step 6: tert-butyl ((1S)-2-((4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-((tert-butyldiphenylsilyl)oxy)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((S)-2-((4-(2-((tert-butyldiphenylsilyl)oxy)acetyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Step 5, 320 mg) and (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (Int. 1, Step B6, 119 mg) were dissolved in DCM (8 ml) under Ar. After the addition of TEA (0.3 ml), the mixture was stirred for 10 min. The mixture was then heated to 40 °C for 1 h. NaBDCN (109 mg), dry MeOH (5 ml), and AcOH (150 μl) were then added at room temperature, and the mixture was stirred over the weekend. The mixture was then poured into saturated NaHCO solution, and the aqueous phase was extracted with DCM (3x). The combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 20 min 100% HO + 0.05% TFA; followed by 30 min approximately 55% HO + 0.05% TFA / 45% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing pure product were combined, ACN was partially removed, and TFA was neutralized with concentrated NaHCO3 solution. After extracting the product with DCM (2x), the combined organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ACN / HO and lyophilized to give 124 mg of the title compound. LC / MS: m / z = 756.2 [M + H] + ;rt:3.06 min (LC / MS-Method A).

[0324] Step 7: tert-butyl ((1S)-2-((4-(2-((tert-butyldiphenylsilyl)oxy)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate [ka] tert-Butyl ((1S)-2-((4-(1-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-2-((tert-butyldiphenylsilyl)oxy)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate (Step 6, 123 mg) was dissolved in THF (5 ml) and heated to 65 °C with stirring. After 5 min, CDI (79 mg) was added and stirring at 65 °C was continued for 23 h. After cooling, the mixture was poured into saturated NaHCO solution and the aqueous phase was extracted with DCM (2x). The combined organic phases were dried over NaSO, filtered and concentrated in vacuo. The residue was further purified by preparative RP HPLC (flow rate: 25 ml / min; gradient 45 min from 95% HO+0.05% TFA / 5% ACN to 10% HO+0.05% TFA / 90% ACN; column: Purosphere® STAR-RP18, 25 mm x 250 mm, 10 μm). Fractions containing the pure product were combined, the ACN was partially removed, and the TFA was neutralized with saturat...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Z is O or CR ６ R ７ and X １ , X ２ and X ３ At least one of is N and the others are CR ４ and Y is a 5- or 6-membered monocyclic heteroaryl, a 9- or 10-membered bicyclic heteroaryl, a 5- or 6-membered cycloalkyl or a 5- or 6-membered heteroaryl fused to a 5- or 6-membered heterocyclyl, phenyl, heterocyclyl, C ３～７ Cycloalkyl and QR ８ is selected from i. Q is absent, O or NR ９ and ii. R ８ is C １～６ Alkyl, C １～３ Alkylene-phenyl or C １～３ alkylene-heteroaryl; iii. Y is one or more substituents Y Ａ and optionally substituted with, in each occurrence, Y Ａ are independently halo, oxo, C １～４ Alkyl, hydroxy, C １～４ Alkoxy, C １～３ Haloalkyl, cyano, C(O)R １０ and C ３～７ cycloalkyl, and iv. Y Ａ Ha, Halo, C １～４ Alkyl, hydroxy, C １～４ Alkoxy, C ３～７ Cycloalkyl, C １～３ Alkylene -NR １１ R １２ and C １～３ optionally further substituted with one or more substituents independently selected from haloalkyl; R １ and R ２ are independently hydrogen, C １～４ Alkyl, C ３～７ Cycloalkyl, C １～５ alkoxy and phenyl, １～４ Alkyl, C ３～７ Cycloalkyl, C １～５ Alkoxy or phenyl is halo, C １～４ Alkyl and C １～３ optionally substituted with one or more substituents independently selected from haloalkyl, with the proviso that R １ and R ２ cannot both be hydrogen, or R １ and R ２ together with the carbon atoms to which they are attached form a 4- to 10-membered cycloalkyl ring, said cycloalkyl ring being free of halo, C １～４ Alkyl and C １～３ optionally substituted with one or more substituents independently selected from haloalkyl; R ３ is hydrogen, fluoro or methyl, R in each occurrence ４ is independently selected from hydrogen, fluoro, methyl, hydroxy, and trifluoromethyl; R ５ is a 5- or 6-membered monocyclic heteroaryl, a 4- to 10-membered heterocyclyl, C(O)NR １３ R １４ , OC(O)NR １５ R １６ and NR １７ C(O)C １～６ alkyl, and R １３ , R １４ , R １５ , R １６ and R １７ are independently hydrogen and C １～６ alkyl, and R ５ is hydroxy, halo, C １～４ Alkyl, C １～４ Alkoxy, C １～３ Haloalkyl, C ３～７ optionally substituted with one or more substituents independently selected from cycloalkyl, cyano, and oxo; R ６ is hydrogen, fluoro, C １～６ Alkyl or C ３～７ is cycloalkyl, and R ６ is C １～６ Alkyl or C ３～７ When cycloalkyl, the group may be selected from hydroxy, halo, C １～４ Alkyl, C １～４ Alkoxy, C １～３ Haloalkyl and C １～３ optionally substituted with one or more substituents independently selected from haloalkoxy; R ７ is hydrogen, deuterium, halo and C １～４ alkyl; or R ６ and R ７ together with the carbon atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Alkoxy and C １～３ forming a 3- to 6-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more substituents independently selected from haloalkyl; R ９ is hydrogen or C １～４ is alkyl, R １０ is hydroxy, C １～４ Alkyl or C １～４ is alkoxy, and R １１ and R １２ are independently hydrogen, C １～４ Alkyl and C(O)OC １～４ alkyl) or a pharmaceutically acceptable salt thereof.

2. Formula IA: 【Chemistry 2】 (In the formula, Z, １ , X ２ , X ３ , Y., R. １ , R ２ , R ３ , R ４ and R ５ is as defined in claim 1) 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

3. Z is CR ６ R ７ 3. The compound according to claim 1 or 2, wherein

4. X １ , X ２ and X ３ One of the is N and the other is CR ４ The compound according to any one of claims 1 to 3,

5. X １ is N and X ２ and X ３ is CR ４ 5. The compound of claim 4, wherein:

6. Y is a 5- or 6-membered monocyclic heteroaryl, a 5- or 6-membered cycloalkyl, or a 5- or 6-membered heteroaryl, heterocyclyl, cyclopropyl, and QR fused to a 5- or 6-membered heterocyclyl. ８ is selected from i. Q is absent, O or NR ９ and ii. R ８ is C １～６ Alkyl, C １～３ Alkylene-phenyl or C １～３ alkylene-heteroaryl; iii. Y is one or more substituents Y Ａ and optionally substituted with, in each occurrence, Y Ａ are independently halo, C １～４ Alkyl, C １～３ Haloalkyl, cyano, C(O)R １０ and C ３～７ cycloalkyl, and iv. Y Ａ is halo, hydroxy, C ３～７ Cycloalkyl and C １～３ Alkylene -NR １１ R １２ 6. The compound of any one of claims 1 to 5, optionally further substituted with one or more substituents independently selected from:

7. Y is QR ８ Q is absent or O, and R ８ is C １～６ Alkyl, CH ２ -phenyl, CH ２ -heteroaryl, CF ２ -phenyl or CF ２ -heteroaryl, and the phenyl and heteroaryl groups are each independently substituted with one or more substituents Y Ａ and optionally substituted with, in each occurrence, Y Ａ are independently fluoro, chloro, C １～４ Alkyl, C １～３ Haloalkyl, cyano, C(O)R １０ and cyclopropyl, and each Y Ａ is halo, hydroxy, cyclopropyl and C １～３ Alkylene -NR １１ R １２ 7. The compound of claim 6, optionally further substituted with one or more substituents independently selected from:

8. Y is one or more substituents Y Ａ and wherein, in each occurrence, Y Ａ are independently fluoro, chloro, C １～４ Alkyl, C １～３ Haloalkyl, cyano, C(O)R １０ and cyclopropyl, and each Y Ａ is halo, hydroxy, cyclopropyl and C １～３ Alkylene -NR １１ R １２ 7. The compound of claim 6, optionally further substituted with one or more substituents independently selected from:

9. Y has the following structure: 【Transformation 3】 and a 5- or 6-membered monocyclic heteroaryl selected from one of the following: Ａ and optionally substituted with, in each occurrence, Y Ａ are independently fluoro, chloro, C １～４ Alkyl, C １～３ Haloalkyl, cyano, C(O)R １０ and cyclopropyl, and each Y Ａ is halo, hydroxy, cyclopropyl and C １～３ Alkylene -NR １１ R １２ 9. The compound of claim 8, optionally further substituted with one or more substituents independently selected from:

10. R １ and R ２ are independently hydrogen, C １～４ Alkyl, C ３～７ Cycloalkyl and C １～５ alkoxy, wherein C １～４ Alkyl, C ３～７ Cycloalkyl or C １～５ Alkoxy is halo, C １～４ Alkyl and C １～３ optionally substituted with one or more substituents independently selected from haloalkyl, with the proviso that R １ and R ２ and (iii) cannot both be hydrogen.

11. R １ and R ２ together with the carbon atoms to which they are attached form a cyclohexyl ring, said cyclohexyl ring being free of halo, C １～４ Alkyl and C １～３ The compound of any one of claims 1 to 9, substituted with one or more substituents independently selected from haloalkyl.

12. The combined R １ , R ２ and R ３ The base is 【Chemistry 4】 is a group selected from 【Transformation 5】 is the point of attachment to the remainder of the compound of Formula I, and each cyclopropyl or cyclohexyl ring may be selected from halo, C １～４ Alkyl and C １～３ The compound of any one of claims 1 to 9, optionally substituted with one or more substituents independently selected from haloalkyl.

13. R ３ The compound according to any one of claims 1 to 12, wherein is hydrogen.

14. R in each occurrence ４ The compound of any one of claims 1 to 13, wherein is independently selected from hydrogen, fluoro and methyl.

15. R in each occurrence ４ is independently selected from hydrogen and fluoro.

16. R ５ is a 5- or 6-membered monocyclic heteroaryl, a 4- to 10-membered heterocyclyl, C(O)NR １３ R １４ , OC(O)NR １５ R １６ and NR １７ C(O)C １～６ alkyl, and R １３ , R １４ , R １５ , R １６ and R １７ are independently hydrogen and C １～６ alkyl, and R ５ Ha, Halo, C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ The compound of any one of claims 1 to 15, optionally substituted with one or more substituents independently selected from cycloalkyl and oxo.

17. R ５ is a 5-membered monocyclic heteroaryl, a 5-membered heterocyclyl, and NR １７ C(O)C １～６ alkyl, and R １７ is hydrogen or methyl, and R ５ is hydroxy, halo, C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ 17. The compound of claim 16, optionally substituted with one or more substituents independently selected from cycloalkyl and oxo.

18. R ５ Here is the structure: 【Transformation 6】 and 【Transformation 7】 is the point of attachment to the remainder of the compound of formula I, and R ｘ is hydroxy, halo, C １～４ Alkoxy, C １～３ Haloalkyl and C ３～７ C optionally substituted with one or more substituents independently selected from cycloalkyl １～６ alkyl, and R ｙ is hydrogen or C １～６ alkyl or R ｘ and R ｙ together with the atom to which they are attached, represent hydroxy, halo, C １～４ Alkyl, C １～４ Alkoxy, C １～３ Haloalkyl, C ３～７ 16. The compound of any one of claims 1 to 15, which forms a 5-8 membered heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and oxo.

19. R ｘ is C optionally substituted with one or more substituents independently selected from hydroxy, fluoro, methoxy and cyclopropyl １～４ alkyl, and R ｙ is hydrogen or methyl, or R ｘ and R ｙ together with the atoms to which they are attached, represent fluoro, C １～４ 20. The compound of claim 18, which forms a 5-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl, trifluoromethyl, and oxo.

20. R ５ Here is the structure: 【Transformation 8】 and 【Chemistry 9】 is the point of attachment to the remainder of the compound of formula I, and the structure is optionally substituted with one or more substituents independently selected from fluoro, methyl, trifluoromethyl, and oxo.

21. R ５ teeth, 【Chemistry 10】 having a structure selected from 【Chemistry 11】 The compound of any one of claims 1 to 15, wherein is the point of attachment to the remainder of the compound of formula I.

22. R ６ is hydrogen, C １～６ Alkyl or C ３～７ is cycloalkyl, and R ６ is C １～６ Alkyl or C ３～７ When cycloalkyl, the group may be selected from hydroxy, halo, C １～４ Alkyl, C １～４ Alkoxy and C １～３ 22. The compound of any one of claims 1 to 21, optionally substituted with one or more substituents independently selected from haloalkyl.

23. R ６ is hydrogen, methyl or cyclopropyl, and R ６ 23. The compound of claim 22, wherein when is methyl or cyclopropyl, the group is optionally substituted with one or more substituents independently selected from fluoro and methoxy.

24. R ７ The compound of any one of claims 1 to 23, wherein is selected from hydrogen, deuterium, fluoro and methyl.

25. R ７ 25. The compound of claim 24, wherein is hydrogen.

26. R ６ and R ７ together with the carbon atom to which they are attached, form halo, C １～４ Alkyl, C １～４ Alkoxy and C １～３ 26. The compound of any one of claims 1 to 25, which forms a 4- to 6-membered cycloalkyl ring optionally substituted with one or more substituents independently selected from haloalkyl.

27. Formulas IB-IE: 【Chemistry 12】 (In the formula, Z, １ , X ２ , X ３ , Y., R. １ , R ２ , R ３ , R ４ , R ５ , R ６ and R ７ is as defined in any one of claims 1 to 26) 10. The compound of claim 1 having a structure according to any one of:

28. Formula IF: 【Chemistry 13】 (In the formula, Y, R １ , R ２ , R ３ , R ４ , R ６ and R ７ is as defined in any one of claims 1 to 26, and R ｘ is hydroxy, halo, C １～４ Alkoxy, C １～３ Haloalkyl and C ３～７ C optionally substituted with one or more substituents independently selected from cycloalkyl １～６ alkyl, and R ｙ is hydrogen or C １～６ alkyl or R ｘ and R ｙ together with the atom to which they are attached, represent hydroxy, halo, C １～４ Alkyl, C １～４ Alkoxy, C １～３ Haloalkyl, C ３～７ forming a 5- to 8-membered heterocyclic ring optionally substituted with one or more substituents independently selected from cycloalkyl and oxo.

2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

29. The following compounds: tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, benzyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate, tert-butyl ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate, tert-butyl 6-(((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamoyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, benzyl ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate, tert-butyl 6-(((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamoyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-3-ethylisoxazole-4-carboxamide, 1-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, tert-butyl ((1-(4-(((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamoyl)isoxazol-3-yl)cyclopropyl)methyl)carbamate, 3-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)isoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-3-isopropylisoxazole-4-carboxamide, 3-(1-(aminomethyl)cyclopropyl)-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)isoxazole-4-carboxamide, tert-butyl ((S)-2-((4-((5-methyl-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, 4-cyclopropyl-N-((S)-2-((4-((4,4-dimethyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((((2,2,2-trifluoroethyl)carbamoyl)oxy)methyl)pyridin-2-yl)amino)ethyl)carbamate, (S)-(1-(4,4-difluorocyclohexyl)-2-((4-((4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate tert-butyl tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-2-((4-((2,5-dioxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-(((R)-5-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-(((R)-4-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, (S)—N-(1,1-dicyclopropyl-3-oxo-3-((4-(2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)-pyridin-2-yl)amino)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, (S)—N-(1,1-dicyclopropyl-3-oxo-3-((4-((4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-((4-(((R)-4-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 1-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((4-(((R)-4-methyl-2-oxoimidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1,2,5-oxadiazole-3-carboxamide, N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)-methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)-methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-3-ethylisoxazole-4-carboxamide, tert-butyl (S)-(1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((((2,2,2-trifluoroethyl)-carbamoyl)oxy)methyl)pyridin-2-yl)amino)ethyl)carbamate, 4-cyclopropyl-N-(2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-(2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-(2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, tert-butyl ((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(1-(4,4-difluorocyclohexyl)-2-((4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((1,4-dimethyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, (1R,2S,5S)-N-((2S)-1,1-dicyclopropyl-3-((4-(cyclopropyl(4,4,4-trifluorobutanamido)-methyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-3,6,6-trimethyl-3-azabicyclo[3.1.0]-hexane-2-carboxamide, ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate (5-methylisoxazol-3-yl)methyl 4-cyclopropyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, ((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)carbamate (1,5-dimethyl-1H-pyrazol-3-yl)methyl, 4-cyclopropyl-N-((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-2-((5-fluoro-4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, tert-butyl ((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-2-((4-((R)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, 1-fluoro-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)cyclopropane-1-carboxamide, N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1-(4,4,4-trifluoro-3-hydroxybutyl)-1H-pyrazole-5-carboxamide, (4-methyl-1,2,5-oxadiazol-3-yl)methyl((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl), tert-butyl ((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, 3-isopropyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide, 1-isopropyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide, tert-butyl ((S)-2-((4-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate, tert-butyl ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)carbamate, tert-butyl ((R)-1-((1r,4R)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)carbamate, benzyl ((rac)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)carbamate, N-(3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide, N-(3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((R)-1-((1r,4R)-4-methylcyclohexyl)-2-oxo-2-((5-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-3-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 4-ethyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((RS)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-methyl-4-(trifluoromethyl)pyrimidine-5-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-5-methylthiazole-4-carboxamide, 5-cyano-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)thiazole-4-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-tetrazole-5-carboxamide, 6-bromo-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylpicolinamide, 2-chloro-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-5-methylpyrimidine-4-carboxamide, 4-cyclopropyl-N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, (S)-2-(3-benzylureido)-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)acetamide, (S)-2-(3-benzylureido)-2-(4,4-difluorocyclohexyl)-N-(4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)acetamide, benzyl ((2R,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)carbamate, benzyl ((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)carbamate, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, tert-butyl ((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl)pyridin-2-yl)amino)propan-2-yl)carbamate, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)oxazole-2-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)oxazole-4-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-imidazole-2-carboxamide, N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-imidazole-2-carboxamide, (2S)-2-(2-(3,5-dimethylisoxazol-4-yl)acetamide)-N-(4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide, (2S)—N-(4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-(2-(5-methyl-1H-pyrazol-3-yl)acetamide)-2-((1r,4S)-4-methylcyclohexyl)-acetamide, 1-isopropyl-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-imidazole-2-carboxamide, N-((2S,3S)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-4-cyclopropyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-imidazole-2-carboxamide, 1-methyl-N-((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((2-oxopyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methylisoxazole-3-carboxamide, 4-cyclopropyl-N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-3-carboxamide, N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyloxazole-5-carboxamide, (S)—N-(4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)-2-(2-(3-methylisoxazol-5-yl)acetamido)acetamide, 1-ethyl-N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 3-ethyl-N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide, 3-cyclopropyl-N-((S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((2S,3R)-3-(tert-butoxy)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)butan-2-yl)-3-isopropylisoxazole-4-carboxamide, tert-butyl ((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)carbamate, 4-cyclopropyl-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, 1-cyclopropyl-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-imidazole-2-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-imidazole-2-carboxamide, 1-(cyclopropylmethyl)-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-(p-tolyl)acetamide, 2,2-difluoro-N-((1S)-2-((4-(2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-phenylacetamide, tert-butyl ((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl)methyl-d)pyridin-2-yl)amino)ethyl)carbamate, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(3,3,3-trifluoro-1-(4,4,4-trifluorobutanamido)propyl)pyridin-2-yl)amino)ethyl)-4-ethylisoxazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)butyl)pyridin-2-yl)amino)ethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((R)-2-methyl-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((1S)-2-((4-(cyclopropyl(3,3,3-trifluoropropanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, 4-cyclopropyl-N-((S)-2-((4-(cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-((cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(cyclopropyl((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((R)-1-(4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(2-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propan-2-yl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(2-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propan-2-yl)pyridin-2-yl)amino)ethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(2-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propan-2-yl)pyridin-2-yl)amino)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(2-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propan-2-yl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-5-ethylisoxazole-4-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-2-((4-((S)-1-(5,5-difluoro-2-oxotetrahydropyrimidin-1(2H)-yl)-2-methoxyethyl)pyridin-2-yl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((1S)-1-(4,4-difluorocyclohexyl)-2-((4-(2-methoxy-1-((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-isopropylisoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-(ethyl-d5)-1H-pyrazole-3-carboxamide, 4-cyclobutyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-(2,2-difluoroethoxy)isoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-isopropyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methylisoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-isopropylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole, N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, (S)-2-(4,4-difluorocyclohexyl)-N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-(2-(6-methoxypyridin-3-yl)acetamido)acetamide, 2-(3-cyanophenyl)-N-((S)-1-(4,4-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)propanamide, (S)-2-(2-(3-cyanophenyl)acetamido)-2-(4,4-difluorocyclohexyl)-N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)acetamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(1-(4,4,4-trifluorobutanamido)propyl)pyridin-2-yl)amino)ethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-((2-oxo-5-(trifluoromethyl)-2,5-dihydro-1H-pyrrol-3-yl)methyl)pyridin-2-yl)amino)ethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-4-ethyloxazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-5-ethylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-5-isopropylisoxazole-4-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)ethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((S)-1,1-dicyclopropyl-3-oxo-3-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)methyl)pyridin-2-yl)amino)propan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl-d)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-methyl-N-((1S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl-d)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((1S)-2-((4-(2-hydroxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-((1S)-2-((4-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, 4-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((1S)-2-((4-(2-methoxy-1-(4,4,4-trifluorobutanamido)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 2-(3-cyanophenyl)-2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)acetamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-(1-methyl-1H-pyrazol-5-yl)acetamide, 2-(3-chlorophenyl)-2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)acetamide, 2-(3,5-difluorophenyl)-2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)acetamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-(pyrazin-2-yl)acetamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-(6-methoxypyridin-3-yl)acetamide, (S)—N-(4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)-2-(2-(5-methylisoxazol-3-yl)acetamido)acetamide, 2-fluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-2-phenylacetamide, 2,2-difluoro-N-((S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylbutanamide, 4-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-((R)-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)propyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1-(3,3-difluorocyclobutyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-1-(3,3-difluorocyclobutyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-((S)-1-((1s,4R)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-methyl-N-((S)-1-((1s,4R)-4-methylcyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-4-methylisoxazole-3-carboxamide, 4-ethyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, 3-ethyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)isoxazole-4-carboxamide, N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1H-pyrazole-5-carboxamide, N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((S)-1-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-1-oxo-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1H-pyrazole-5-carboxamide, 4-methyl-N-((S)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1,2,5-oxadiazole-3-carboxamide, 1-methyl-N-((S)-1-oxo-1-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)-3-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)propan-2-yl)-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 4-(2,2-difluoroethoxy)-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-3-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-(2,2,2-trifluoroethoxy)-1,2,5-oxadiazole-3-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methylisoxazole-3-carboxamide, 4-ethyl-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, 3-ethyl-N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-4-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(1-(4-fluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, 4-ethyl-N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1-((1r,4S)-4-fluorocyclohexyl)-2-oxo-2-((4-(((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)methyl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, 4-cyclopropyl-N-(1-(4-fluoro-4-methylcyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,5-oxadiazole-3-carboxamide, N-(1-(4-fluoro-4-methylcyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, 1-ethyl-N-(1-(4-fluoro-4-methylcyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1H-pyrazole-5-carboxamide, 3-ethyl-N-((1S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxo-1-(4-(trifluoromethyl)cyclohexyl)ethyl)isoxazole-4-carboxamide, 1-ethyl-N-((1S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxo-1-(4-(trifluoromethyl)cyclohexyl)ethyl)-1H-pyrazole-5-carboxamide, N-((1S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxo-1-(4-(trifluoromethyl)cyclohexyl)ethyl)-1-methyl-1H-pyrazole-5-carboxamide, 1-isopropyl-N-((1S)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxo-1-(4-(trifluoromethyl)cyclohexyl)ethyl)-1H-pyrazole-5-carboxamide, N-((S)-1-((S)-3,3-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((S)-1-((S)-3,3-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-((S)-3,3-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((S)-1-((S)-3,3-difluorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethylisoxazole-3-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-((1S)-1-(4-chlorocyclohexyl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide, N-((S)-1-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-5-ethylisoxazole-4-carboxamide, N-((S)-1-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)-2-((4-((S)-2-methoxy-1-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)ethyl)pyridin-2-yl)amino)-2-oxoethyl)-5-isopropylisoxazole-4-carboxamide, 1-isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, 3-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)isoxazole-4-carboxamide, 1-ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3S,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide, and 1-Isopropyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(((3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)amino)ethyl)-1H-pyrazole-5-carboxamide 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from one of:

30. 30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

31. A compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 30 for use in therapy.

32. acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthropathies, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes, other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid tumors (e.g., melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma and ovarian cancer) and hematological malignancies, in particular acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), Castleman's disease, contact dermatitis, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, arthritis associated with enthesitis, endotoxic shock associated with infection, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, hepatoblastoma, hypochlorhydria, immune-mediated inflammatory disorders of the central and peripheral nervous system, e.g., Multiple sclerosis and Guillain-Barré syndrome, hidradenitis suppurativa, inflammatory bowel disease, insulin-dependent diabetes mellitus type 1, intravascular coagulation, irritable bowel syndrome, lichen planus, hepatic fibrosis, lupus nephritis, Lyme arthritis, meningoencephalitis, myocarditis, meningoencephalitis, diabetic necrobiosis lipoidica, osteoporosis, pancreatitis, papulopustular rosacea, Parkinson's disease, pelvic inflammatory disease, periodontitis, peritonitis, Peyronie's disease, pilonidal disease, psoriasis, psoriatic arthritis (PsA), 31. The compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 30, for use in the treatment of pyoderma gangrenosum, renal fibrosis, rheumatoid arthritis, scleroderma or systemic sclerosis, stroke, surgical adhesions, systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (JIA), trauma (surgery), graft rejection, type 1 diabetes, ulcerative colitis, uveitis or vasculitis.

33. Acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthropathies, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes, other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid tumors (e.g., melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, and ovarian cancer) and hematological malignancies, especially acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer, and colon cancer), Castleman's disease, contact skin inflammation, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, arthritis associated with enthesitis, endotoxic shock associated with infection, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, hepatoblastoma, hypochlorhydria, immune-mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barré syndrome, suppuration Hidradenitis urinaria, inflammatory bowel disease, insulin-dependent diabetes mellitus type 1, intravascular coagulation, irritable bowel syndrome, lichen planus, hepatic fibrosis, lupus nephritis, Lyme arthritis, meningoencephalitis, myocarditis, meningoencephalitis, diabetic necrobiosis lipoidica, osteoporosis, pancreatitis, papulopustular rosacea, Parkinson's disease, pelvic inflammatory disease, periodontitis, peritonitis, Peyronie's disease, pilonidal disease, psoriasis, psoriatic arthritis (PsA), pyoderma gangrenosum, renal fibrosis, rheumatoid arthritis, scleroderma or systemic sclerosis, cerebral A method for treating a disease or disorder selected from stroke, surgical adhesions, systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (JIA), trauma (surgery), transplant rejection, type 1 diabetes, ulcerative colitis, uveitis and vasculitis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30.

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