Il-17a modulators

Abstract

The present invention relates to compounds as IL-17A modulators. The compounds have the structural formula I as defined herein. The invention also relates to processes for preparing these compounds, pharmaceutical compositions comprising these compounds and the use of these compounds in the treatment of diseases or disorders associated with the modulation of IL-17A activity.

Description

[0001] introduction

[0002] This invention relates to therapeutic compounds. More specifically, this invention relates to compounds that act as modulators of IL-17A activity. The invention also relates to methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of diseases or disorders associated with IL-17A activity. Background Technology

[0003] The interleukin-17 cytokine family consists of six members (called IL-17A to IL-17F), among which IL-17A (also known as CTLA-8) is the primary effector cytokine of the helper T cell-17 (Th17) cell lineage.

[0004] IL-17A is a 34-38 kDa variable glycosylated, disulfide-linked homodimeric glycoprotein that shares approximately 50% homology with its closest family member, IL-17F. Both IL-17A and IL-17F can be secreted as homodimers or heterodimers, IL-17AF [KFGeoghegan et al., Protein Expression and Purification 2013, 87, 27-34; JKKolls and A.Lindén / Immunity 2004, 21, 467-476].

[0005] In response to cytokines such as IL-6, transforming growth factor β (TGF-β), IL-23, STAT3, and RORγt, naive CD4+ T cells are activated, leading to their differentiation into TH17 cells and resulting in the expression of pro-inflammatory 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 cell types include mast cells, neutrophils, NK cells, NKT cells, CD8+ T cells, δγT cells, macrophages, and type 3 innate lymphoid cells [DJCua and CMTato, Nat Rev Immunol 2010, 10, 479-489; W. Jin and C. Dong, Emerging Microbes & Infections 2013, 2, e60].

[0006] Cytokines IL-17A, IL-17F, and IL-17AF bind to the common heteromeric receptor complexes IL-17RA and IL-17RC, but with different affinities. Although the expression of the IL-17RA subunit has been reported in various cell types, the highest responses to IL-17A have been observed in epithelial cells, endothelial cells, keratinocytes, and fibroblasts [TAMoseley et al. / Cytokine Growth Factor Reviews. 2003, 14, 155-174; SLGaffen / Nature Rev Immunol 2009, 9, 556-567; RMOnishi and SLGaffen / Immunology 2010, 129, 311-321].

[0007] The binding of IL-17A to its receptor activates various signal transduction pathways, such as nuclear factor (NF)-κB, phosphoinositol 3-kinase (PI3K), activator protein (AP1), CCAAT / enhancer-binding protein (C / EBP), and mitogen-activated protein kinase (MAPK). These pathways lead to the expression of pro-inflammatory genes 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 many chemokines and other effectors [SLGaffen, Arthritis Research & Therapy 2004, 6, 240-247; SLGaffe, Nature Rev Immunol 2009, 9, 556-567; RMOnishi and SLGaffen, Immunology 2010, 129, 311-321]. The induction of the inflammatory loop is completed by attracting cells of the innate immune system to inflammatory sites and activating them. This induction can also be mediated in collaboration with other cytokines (TNFα, IFN-γ and IL-1β) [SLGaffen, Arthritis Research & Therapy 2004, 6, 240-247].

[0008] These IL-17-mediated biological processes have been involved in the pathology or autoimmune pathology of many human diseases with immune components, such as psoriasis, ankylosing spondylitis, axial spondyloarthritis, psoriatic arthritis, eczema, enthesitis-associated 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, penile nodules, celiac disease, gallbladder disease, pilonidal disease, peritonitis, multiple sclerosis, Guillain-Barré syndrome, irritable bowel syndrome, inflammatory bowel disease, Kassman disease, pelvic inflammatory disease, and generalized seizures. Juvenile idiopathic arthritis (JIA), rheumatoid arthritis, giant cell arteritis, graft-versus-host disease, discoid lupus erythematosus, systemic lupus erythematosus, lupus nephritis, vasculitis, insulin-dependent type 1 diabetes mellitus, autoimmune diabetes mellitus, diabetic lipoid necrosis, gangrenous pyoderma, hidradenitis suppurativa, papulopustular rosacea, lichen planus, heart disease including ischemic diseases such as myocardial infarction and atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypoacidity, pain (especially inflammation-related pain), 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). Furthermore, due to the novel role of neuroinflammation in neurodegeneration, IL-17 is also involved 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). In addition, due to the key regulatory role of IL-17A in host defense, related pathological conditions also include viral, bacterial, fungal and parasitic infections. An association between serum IL-17 levels upon admission to the intensive care unit and the occurrence of sepsis has also been observed, suggesting that increased IL-17 may increase susceptibility to septic complications and infection-associated endotoxin shock [Ahmed et al., Eur J Trauma Emerg Surg 2018, 44(4):621-626]. It is also suggested that its role in sepsis be extended to patients with sepsis-induced acute respiratory distress syndrome (ARDS) [Ding et al., Oncotarget 2017, 8(55): 93704-93711].Recently, it has also been suggested that IL-17 inhibition 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].

[0009] Preclinical studies have demonstrated that IL-17A (as well as IL-17F and IL-17C) is elevated in psoriatic skin [NJ Wilson et al., Nat Immunol 2007, 8, 950-957; LC 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 JDermatol 2009, 160, 319-324]. Th17 cells in the peripheral circulation and affected skin of psoriatic patients, as measured by the Psoriasis Area and Severity Index (PASI) score, also showed a positive correlation with disease severity [L. Zhang et al., Clin Immunol 2010, 135, 108-117]. Serum IL-17A levels were also significantly correlated with PASI scores [H. Takahashi et al., Clin Exp Dermatol 2010, 35, 645-649; SB Yilmaz et al., Arch Dermatol Res 2012, 304, 465-469; M. Caproni et al., J Clin Immunol 2009, 29, 210-214].

[0010] Animal model studies support the hypothesis that targeting the IL-17A pathway will be effective in treating 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 using antibodies against IL-17A or IL-17RA provide final validation, with remarkable efficacy observed [R. Glangley 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.

[0011] Elevated levels of IL-17A or IL-17F have been reported in many 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, allograft rejection, angiogenesis, atherosclerosis, and asthma [e.g., SLGaffen, Arthritis Research & Therapy 2004, 6, 240-247; LATTesmer et al., Immunol Rev 2008, 223, 87-113; US Publication No. 20080269467].

[0012] Therapeutic antibodies against IL-17A, cecujinumab and ixekizumab, have shown efficacy in treating palmoplantar psoriasis 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 There is evidence of positive efficacy in Rheumatol 2018, doi:10.1002 / art.40753. Proof-of-concept studies of cesuginumab in MS have also shown signs of positive efficacy [E. Havdrova et al., J Neurol 2016, 263, 1287-1295].

[0013] IL-17A expression has been shown to be increased in SLE patients and is associated 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].

[0014] In addition, IL-17A is 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]. In patients with a range of systemic autoimmune or inflammatory diseases, IL-17A levels in tears are associated with the clinical severity of dry eye, including Sjögren's syndrome, Sjögren's syndrome (SJS), SLE, filamentous keratitis, DES, meibomian gland dysfunction (MGD), and graft-versus-host disease (GVHD) [MHKang et al., J Korean Med Sci 2011, 26, 938-944].

[0015] Several studies have demonstrated that IL-17A is overexpressed in patients with a range of 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., JInt 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 Inflammation]. 2015, 804347; JF. Tu et al., Medicine (Baltimore) 2016, 95, e3220; DFG Carvalho et al., Oncol Lett 2017, 13, 1925-1931. Increased IL-17A levels have been shown to be associated 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; DFGCarvalho 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., Clin Cancer Res]. 2014, 20, 2885-2897; MH. Lee et al., Oncotarget 2018, 9, 9825-9837.

[0016] In summary, the regulation of the IL-17A pathway, particularly the regulation of IL-17A activity, by inhibiting the interaction between IL-17A and its receptor IL-17RA can be considered a target for the treatment of conditions related to the immune system and inflammation, cancer, and neurodegenerative disorders.

[0017] WO 2013 / 116682, WO 2014 / 066726 and WO 2018 / 229079 describe a class of compounds that are believed to modulate IL-17 activity and can be used to treat medical conditions, including inflammatory diseases.

[0018] Nevertheless, there remains a persistent need for compounds that can reduce the activity of IL-17A. Summary of the Invention

[0019] In one aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof.

[0020] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention as defined herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0021] In another aspect, the present invention relates to compounds of the invention as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for therapeutic purposes.

[0022] In another respect, the present invention relates to compounds of the present invention as defined herein or pharmaceutically acceptable salts thereof or pharmaceutical compositions as defined herein for the treatment of diseases or disorders associated with IL-17A activity.

[0023] In another aspect, the present invention relates to the use of compounds of the invention as defined herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating diseases or disorders associated with IL-17A activity.

[0024] In another aspect, the present invention relates to a method for treating a disease or disorder associated with IL-17A activity, the method comprising administering to a subject requiring such treatment a therapeutically effective amount of a compound of the present invention as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0025] Examples of diseases or disorders associated with IL-17A activity include diseases with immune components or autoimmune pathologies (such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and neurodegenerative diseases.

[0026] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts or pharmaceutical compositions thereof for the treatment of diseases with immune components or autoimmune pathologies (such as psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis), cancer and neurodegenerative disorders.

[0027] In another aspect, the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating diseases having immune components or autoimmune pathologies (such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and neurodegenerative disorders.

[0028] In another aspect, the present invention provides a method for treating diseases with immune components or autoimmune pathologies (such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and neurodegenerative disorders, the method comprising administering to a subject requiring such treatment a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0029] The present invention further provides a method for synthesizing compounds as defined herein or pharmaceutically acceptable salts thereof.

[0030] In another aspect, the present invention provides compounds or pharmaceutically acceptable salts thereof that are obtainable or directly obtained by synthetic methods as defined herein.

[0031] In another aspect, the present invention provides novel intermediates as defined herein, which are suitable for use in any of the synthetic methods listed herein.

[0032] Preferred, suitable, and optional features of any particular aspect of the invention are also preferred, suitable, and optional features of any other aspect. Detailed Implementation

[0033] definition

[0034] Unless otherwise stated, the following terms used in the specification and claims have the meanings listed below.

[0035] It should be understood that references to “treating” or “treatment” include the prevention and relief of established symptoms of a condition. Therefore, “treating” or “treatment” of a state, disorder, or condition includes: (1) preventing or delaying the onset of clinical symptoms of a state, disorder, or condition in a person who may have or is susceptible to the state, disorder, or condition but has not yet experienced or exhibited clinical or subclinical symptoms of the state, disorder, or condition; (2) suppressing the state, disorder, or condition, i.e., (in the case of maintenance treatment) preventing, reducing, or delaying the development of the disease, or its recurrence, or at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing the disease, i.e., leading to the resolution of the state, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0036] "Therapeutic effective amount" refers to the amount of a compound that is sufficient to achieve therapeutic effect when administered to a mammal to treat a disease. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

[0037] The term "alkyl" refers to an aliphatic hydrocarbon group. In this specification, the term "alkyl" includes both straight-chain and branched alkyl groups. References to individual alkyl groups, such as "propyl," specifically refer to the straight-chain form only, while references to individual branched alkyl groups, such as "isopropyl," specifically refer to the branched form only. For example, "C..." 1-6 "alkyl" includes C 1-4 Alkyl, C 1-3 Alkyl, propyl, isopropyl, and tert-butyl. Similar conventions apply to other groups, such as "phenyl C". 1-6 "alkyl" includes phenyl C 1-4 Alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0038] The term "alkylene" includes both straight-chain and branched divalent alkyl groups. For example, "C 1-4 "Alkylene" includes methylene (-CH2-), ethylene (-CH2CH2-), propylene, and butene.

[0039] The term "alkoxy" includes both straight-chain and branched alkyl groups bonded separately to oxygen. For example, "C 1-4 "Alkoxy" includes methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0040] Term "C" m-n "When used as a prefix, it refers to any group having m to n carbon atoms.

[0041] “Cycloalkyl” refers to a hydrocarbon ring containing 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane and bicyclo[2.2.1]heptyl.

[0042] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0043] The terms “haloalkyl” or “haloalkoxy” are used herein to refer to alkyl or alkoxy groups, 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 -CHF2, -CH2CF3, or perfluoroalkyl / perfluoroalkoxy groups such as -CF3, -CF2CF3, or -OCF3.

[0044] The terms "heterocyclic group," "heterocyclic," or "heterocyclic" refer to one or more non-aromatic, saturated, or partially unsaturated monocyclic, fused, bridged, or spirobicyclic heterocyclic systems. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7) ring atoms, wherein 1 to 5 (suitably 1, 2, or 3) heteroatoms in the ring are selected from nitrogen, oxygen, or sulfur. Bicyclic heterocycles contain 7 to 17 member atoms, suitably 7 to 12 member atoms. One or more bicyclic heterocycles can be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxetane, oxetane, tetrahydrofuranyl, dioxane, etc., as well as substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azirone, pyrrolidinyl, piperidinyl, piperazine, tetrahydrotriazine, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiaran, and hexahydrothiophene. Other heterocycles include dihydro-oxazolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxazinyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, sulfur oxide heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. For heterocyclic groups with one or two oxygen (=O) or sulfur (=S) substituents, suitable values ​​are, for example, 2-oxopyrrolyl, 2-thiooxopyrrolyl, 2-oxopymidazolyl, 2-thiooxopymidazolyl, 2-oxopyridinyl, 2,5-dioxopyrrolyl, 2,5-dioxopymidazolyl, or 2,6-dioxopyridinyl. Specific heterocyclic groups are saturated monocyclic 3- to 7-membered heterocyclic groups containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. Partially unsaturated heterocyclic groups contain at least one double bond, such as one or two double bonds. Examples of partially unsaturated heterocyclic rings include 1,6-dihydropyridinyl, 1,6-dihydropyridazinyl, and 2,3-dihydropyrrolithyl. As those skilled in the art will understand, any heterocycle can be attached to another group via any suitable atom (e.g., via a carbon or nitrogen atom). Suitably, as defined above, the terms “heterocyclic group,” “heterocyclic,” or “heterocyclic” will refer to a 4, 5, 6, or 7-membered monocyclic ring.

[0045] "Bridged ring system" refers to a ring system in which two rings share more than two atoms, see, for example, Advanced Organic Chemistry, Jerry March, 4th ed., Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclic ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinine ring.

[0046] A “spirobicyclic system” refers to a system in which two rings share a common spirocarbon atom, meaning that a heterocycle is connected to another carbon ring or heterocycle through a single common spirocarbon atom. Examples of spirocyclic 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.

[0047] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring containing one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryls are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. The heteroaryl can be, for example, a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic, such as a bicyclic structure formed from a fused five-membered ring and a six-membered ring or two fused six-membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur, and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or inherently non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituent) will be less than five. Heteroaryl groups containing nitrogen atoms can exist as corresponding nitride oxides. A specific example of such heteroaryl groups is pyridine nitride oxide. Appropriately, as defined above, the terms "heteroaryl" or "heteroarylene" will refer to a 5- or 6-membered monocyclic heteroaryl ring.

[0048] Non-limiting examples of heteroaryl groups include furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenoyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, benzothiazolyl, indolyl, purinyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalyl The following are listed: yl, cyclolinyl, pteridinyl, naphridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furano[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazolo[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl.

[0049] Non-limiting examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, furazonyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0050] Non-limiting examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0051] The bicyclic heteroaryl group can be, for example, selected from the following groups:

[0052] A benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0053] A pyridine ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0054] A pyrimidine ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0055] Pyrrole rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0056] A pyrazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0057] A pyrazine ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0058] An imidazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0059] Oxazole rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

[0060] An isoxazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0061] A thiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0062] An isothiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0063] Thiophene rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0064] Furan rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0065] Cyclohexyl rings fused with 5- or 6-membered heteroaromatic rings containing 1, 2, or 3 cyclic heteroatoms; and

[0066] A cyclopentyl ring fused with a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 cyclic heteroatoms.

[0067] Specific non-limiting examples of bicyclic heteroaryl groups containing a six-membered ring fused with a five-membered ring include, but are not limited to, benzofuranyl, benzobenzylthio, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indazinyl, indololinyl, isoindololinyl, purine (e.g., adenine, guanine), indazole, benzodioxolyl, pyrrolopyridine, and pyrazolopyridyl.

[0068] Specific non-limiting examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromyl, thiochromyl, chromenyl, isochromenyl, chromyl, isochromyl, benzodioxane, quinazinyl, benzooxazinyl, benzodiazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, terolinyl, phthalazinyl, naphthidyl, and pteridylyl.

[0069] 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 types. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In one embodiment, the aryl group is phenyl or naphthyl, especially phenyl.

[0070] This specification also uses compound terms to describe groups containing more than one functional group. Those skilled in the art will understand such terms. For example, heterocyclic C... 1-4 Alkyl groups containing C atoms substituted with heterocyclic groups 1-4 alkyl.

[0071] The term "optionally substituted" refers to both substituted and unsubstituted groups, structures, or molecules.

[0072] In the case where the optional substituents are selected from "one or more" groups, it should be understood that this definition includes all substituents being selected from one of the specified groups or substituents being selected from two or more of the specified groups. It should be understood that in the case of multiple substituents, the selected substituents may be the same or different.

[0073] Given a numerical range, it should be understood that the range includes end values.

[0074] The phrase “compounds of the present invention” means those compounds disclosed herein, both generally and specifically.

[0075] The compounds of the present invention

[0076] In a first aspect, the present invention provides compounds of formula I.

[0077]

[0078] in:

[0079] X 1 X 2 X 3 and X 4 Each is CR independently 5 Or N;

[0080] Y is an aryl or heteroaryl group, each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-4

[0081] Alkyl, C 1-4 Alkoxy, C 1-3 Alkylene-C 1-4 Alkoxy, C 1-3 Alkylene-N(C) 1-3 Alkyl)2 and C 1-4 Halogenated alkyl groups;

[0082] And where Y is a 5- or 6-membered heteroaryl ring, the ring is optionally fused with a 5- or 6-membered cycloalkyl or heterocyclic ring, each optionally substituted by one or more substituents independently selected from: halogen, C 1-4 Alkyl, C 1-4 Alkoxy

[0083] base, C 1-3 Alkylene-C 1-4 Alkoxy, C 1-3 Alkylene-N(C) 1-3 Alkyl)2 and C 1-4 Halogenated alkyl groups;

[0084] R 1 and R 2Together with the carbon atoms to which they are attached, they form 4- to 10-membered cycloalkyl rings, wherein the cycloalkyl rings are:

[0085] a. Optionally substituted by one or more substituents independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; and

[0086] b. Optionally screwed to one or more independently selected C 3-6 cycloalkyl;

[0087] R 3 Is it hydrogen, fluorine, or C? 1-4 alkyl;

[0088] R 4 yes:

[0089] (A) 5 to 10 aryl compounds, C 3-7 Cycloalkyl or 3 to 12-membered heterocyclic rings, each optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy,

[0090] C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups, wherein the C 3-7 The cycloalkyl and heterocyclic substituents are optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy,

[0091] C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 and CO2R 10 ;

[0092] (B) Optionally replaced by hydroxyl, halogen, C 1-4 Alkoxy, cyano, NR 6 R 7 C(O)NR 8 R 9 or CO2R10 Replacement C 1-6 alkyl;

[0093] (C) A 5- or 6-membered heteroaryl ring, said ring being fused with a 5- or 6-membered cycloalkyl or heterocyclic ring, each optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0094] (D) A 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic ring fused to a phenyl or 5- to 6-membered heteroaryl ring, each of which is optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 ,

[0095] CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups; or

[0096] (E) A partially unsaturated heterocycle, optionally fused to a 5- to 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene

[0097] -R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0098] R 5 It is hydrogen, halogen, C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or cyano groups;

[0099] R 11 It is hydroxyl, halogen, C 1-4 Alkoxy, cyano, NR 12 R 13 C(O)R 14 aryl or heteroaryl;

[0100] R 14 It is hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy or NR 15 R 16 ;

[0101] R 6 R 7 R 8 R 9 R 10 R 12 and R 13 Independently selected from hydrogen and C 1-4 alkyl;

[0102] R 15 and R 16 Independently selected from hydrogen and C 1-4 Alkyl; or

[0103] R 15 and R 16 Together with the nitrogen atoms to which they are attached, they form 3- to 7-membered heterocyclic rings, which optionally contain additional selective...

[0104] Heteroatoms from O, S, and N, and optionally C 1-4 Alkyl substitution;

[0105] Or its pharmaceutically acceptable salt.

[0106] Compounds according to formula (I) can exist as mixtures of stereoisomers. Conveniently, compounds according to formula (I) have the following structures:

[0107]

[0108] Where X 1 X 2 X 3 X 4 Y, R 1 R 2 R 3 and R 4 It is as defined above or below.

[0109] Specific compounds of the present invention include, for example, compounds of formula I or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, X 1 X 2 X 3 X 4 Y, R 1 R 2 R 3 R 4 R 5 R 11 R 14 R 15 and R 16 Each of these has any meaning as defined above or in any of paragraphs (1) through (72) below. For the avoidance of doubt, the invention covers combinations of two or more substituents as defined in paragraphs (1) through (72):

[0110] (1)X 1 X 2 X 3 and X 4 Each can be CH or N independently;

[0111] (2)X 1 X 2 X 3 and X 4 The two in the middle are CR 5 And both are N;

[0112] (3)X 2 and X 4 It is N, and X 1 and X 3 It is CR 5 ;

[0113] (4)X 2 and X 4 It is N, and X 1 and X 3 It is CH;

[0114] (5)X 1 X 2 X 3 and X 4 The three are CR 5 And the other is N;

[0115] (6)X 1 It is N, and X 2 X 3 and X 4 It is CR 5 ;

[0116] (7)X 1 It is N, and X 2 X 3 and X 4 It is CH;

[0117] (8)X 2 It is N, and X 1 X 3 and X 4 It is CR 5 ;

[0118] (9)X 2 It is N, and X 1 X 3 and X 4 It is CH;

[0119] (10)X 1 X 2 X 3 and X 4 All are CR 5 ;

[0120] (11)X 1 X 2 X 3 and X 4 All of them are CH;

[0121] (12) Y is aryl or heteroaryl, each optionally substituted by one or more substituents independently selected from: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Alkylene-C 1-4 Alkoxy, C 1-3 Alkylene-N(C) 1-3 Alkyl)2 and C 1-4 Halogenated alkyl groups;

[0122] (13) Y is a phenyl group optionally substituted with one or more substituents independently selected from the following: halogen, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Alkylene-C 1-2 Alkoxy and C 1-2 Halogenated alkyl groups;

[0123] (14) Y is a heteroaryl ring optionally substituted with one or more substituents independently selected from the following: halogen, C 1-3 Alkyl, C 1-2 Alkoxy, C 1-2 Alkylene-C 1-2 Alkoxy and C 1-2 Halogenated alkyl groups;

[0124] (15) Y is a 5- to 6-membered heteroaryl ring optionally substituted with one or more substituents independently selected from chlorine, fluorine, methyl and difluoromethyl;

[0125] (16) Y is a 5- to 6-membered heteroaryl ring that is substituted at the ortho position of the NHC(O)- moiety with methyl or ethyl (such as methyl);

[0126] (17) Y is a 5- or 6-membered heteroaryl ring fused to a 5- or 6-membered cycloalkyl or heterocyclic ring, each optionally substituted by one or more substituents independently selected from: halogen, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Alkylene-C 1-2 Alkoxy, C 1-2 Alkylene-N(C) 1-3 Alkyl)2 and C 1-2 Halogenated alkyl groups;

[0127] (18) Y is a 5-membered heteroaryl ring fused to a 5- or 6-membered heterocyclic ring, each optionally substituted by one or more substituents independently selected from: halogen, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Alkylene-C 1-2 Alkoxy and C 1-2 Halogenated alkyl groups;

[0128] (19) Y is a pyrazolyl, pyrroleyl, isoxazolyl, oxadiazolyl or triazolyl group that is independently substituted by one or more substituents selected from chlorine, fluorine, methyl and difluoromethyl.

[0129] (20) Y is:

[0130]

[0131] in It is the attachment point to the rest of the compound of formula I and Y is optionally substituted by one or more substituents independently selected from: halogen, C 1-3 Alkyl, C 1-2 Alkoxy, C 1-2 Alkylene-C 1-2 Alkoxy, C 1-2 Alkylene-N(C) 1-3 Alkyl)2 and C 1-2 Halogenated alkyl groups;

[0132] (21) Y is a pyrazolyl group substituted by one or more substituents independently selected from chlorine, fluorine, methyl, ethyl, isopropyl and difluoromethyl;

[0133] (22) Y is:

[0134]

[0135] in It is the attachment point to the rest of the compound of formula I;

[0136] (23)R 1 and R 2 Together with the carbon atoms to which they are attached, they form 4- to 10-membered cycloalkyl rings, wherein the cycloalkyl rings are:

[0137] a. Optionally substituted by one or more substituents independently selected from the following: halogen, C 1-2 Alkyl, C 1-2

[0138] Alkoxy and C 1-2 Halogenated alkyl groups; and

[0139] b. Optionally screwed to one or more independently selected C 3-5 cycloalkyl;

[0140] (24)R 1 and R 2 Together with the carbon atoms to which they are attached, they form 4- to 8-membered cycloalkyl rings, wherein the cycloalkyl rings are:

[0141] c. Optionally substituted by one or more substituents independently selected from the following: halogen, C 1-2 Alkyl, C 1-2

[0142] Alkoxy and C 1-2 Halogenated alkyl groups; and

[0143] d. Optionally screwed to one or more independently selected C 3-5 cycloalkyl;

[0144] (25)R 1 and R 2 Together with the carbon atoms to which they are attached, they form 4- to 8-membered cycloalkyl rings, wherein the cycloalkyl rings are:

[0145] a. Optionally substituted by one or more substituents independently selected from the following: fluorine, methyl, trifluoromethyl, and methoxy; and

[0146] b. Optionally screwed to one or more (e.g., one or two) cyclopropyl groups;

[0147] (26)R 1 and R 2Together with the carbon atoms to which they are attached, they form a cyclohexyl ring, wherein the cyclohexyl ring is substituted by one or more substituents independently selected from: fluorine, trifluoromethyl, and methyl; and optionally screwed to C. 3-5 cycloalkyl;

[0148] (27)R 1 and R 2 Together with the carbon atoms to which they are attached, they form a cyclohexyl ring, wherein the cyclohexyl ring is substituted by one or more substituents independently selected from the group consisting of fluorine, trifluoromethyl, and methyl; and optionally threaded to a cyclopropyl group;

[0149] (28)R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups selected from the following:

[0150]

[0151] in * It is R 1 and R 2 Attached carbon atom, R 17 Each occurrence is independently selected from halogen groups and C. 1-2 Alkyl, C 1-2 Alkoxy and C 1-2 Halogenated alkyl groups and C 1-2 Haloalkoxy groups, and m is 0 to 6;

[0152] (29)R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups selected from the following:

[0153]

[0154] in * It is R 1 and R 2 Attached carbon atom, R 17 Each time it appears, it is independently selected from fluorine, methyl, trifluoromethyl and methoxy, and m is 0 to 6;

[0155] (30)R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups selected from the following:

[0156]

[0157] in * It is R 1 and R 2 The attached carbon atom, and R 17Each time it appears, it is independently selected from hydrogen, fluorine, methyl, trifluoromethyl, and methoxy;

[0158] (31)R 1 and R 2 Together with the carbon atoms to which they are attached, they form the following:

[0159]

[0160] in * It is R 1 and R 2 Attached carbon atoms, and each R 17 Independently selected from hydrogen, fluorine, trifluoromethyl, and methyl;

[0161] (32)R 3 It is hydrogen, fluorine, or methyl;

[0162] (33)R 3 It is hydrogen;

[0163] (34)R 3 It is methyl;

[0164] (35)R 4 yes:

[0165] (A) 5 to 10 aryl heteroaryl groups or C 3-7 The cycloalkyl ring is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano,

[0166] NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups, wherein the C 3-7 The cycloalkyl and heterocyclic substituents are optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano,

[0167] NR 6 R 7 C(O)NR 8 R 9 and CO2R 10 ;

[0168] (B) Optionally replaced by hydroxyl, halogen, C 1-4 Alkoxy, cyano, NR 6 R 7 or CO2R 10 Replacement C 1-6 alkyl;

[0169] (C) A 5- or 6-membered heteroaryl ring, said ring being fused with a 5- or 6-membered cycloalkyl or heterocyclic ring, each optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0170] (D) A 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic ring fused to a phenyl or 5- to 6-membered heteroaryl ring, each of which is optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 ,

[0171] CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups; or

[0172] (E) A partially unsaturated heterocycle, optionally fused to a 5- to 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene

[0173] -R11 C 3-7 cycloalkyl and heterocyclic groups;

[0174] (36)R 4 yes:

[0175] (A) A 5- to 10-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from:

[0176] Hydroxyl group, halogen group, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 ,

[0177] CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0178] (C) A 5- or 6-membered heteroaryl ring, said ring being fused with a 5- or 6-membered cycloalkyl or heterocyclic ring, each optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0179] (D) A 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic ring fused to a phenyl or 5- to 6-membered heteroaryl ring, each of which is optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 ,

[0180] C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene-R 11 C 3-7cycloalkyl and heterocyclic groups; or

[0181] (E) A partially unsaturated heterocycle, optionally fused to a 5- to 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene

[0182] -R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0183] (37)R 4 yes:

[0184] (A) A 5- to 10-membered heteroaryl group, optionally substituted by one or more substituents independently selected from the following:

[0185] Hydroxyl group, halogen group, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 ,

[0186] CO2R 10 C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl;

[0187] (C) A 5- or 6-membered heteroaryl ring, said ring being fused with a 5- or 6-membered cycloalkyl or heterocyclic ring, each optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 and C 1-3 Alkylene-R 11 ;or

[0188] (E) A partially unsaturated heterocycle, optionally fused to a 5- to 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 and C 1-3 Alkylene

[0189] -R 11 ;

[0190] (38)R 4 yes:

[0191] (A) A 5- to 10-membered heteroaryl group, optionally substituted by one or more substituents independently selected from the following:

[0192] Hydroxyl group, halogen group, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 ,

[0193] CO2R 10 C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl; or

[0194] (E) A partially unsaturated heterocycle, optionally fused to a 5- to 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-4 Alkyl, C 1-4

[0195] Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 and C 1-3 Alkylene

[0196] -R 11 ;

[0197] (39)R 4 It is a 5- to 10-membered heteroaryl group, C 3-7Cycloalkyl or 3 to 12-membered heterocyclic rings, each optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-2 Fluoroalkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 and C 1-3 Alkylene-R 11 ;

[0198] (40)R 4 It is a 6- to 10-membered heteroaryl group, C 3-7 Cycloalkyl or 3- to 7-membered heterocyclic rings, each optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-2 Fluoroalkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 and C 1-3 Alkylene-R 11 ;

[0199] (41)R 4 It is a 5- to 10-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from: halogen, C 1-4 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkyl, cyano, NR 6 R 7 C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl;

[0200] (42)R 4 It is a 5- to 6-membered monocyclic heteroaryl ring or a 9- to 10-membered bicyclic heteroaryl ring, optionally substituted by one or more substituents independently selected from: fluorine, chlorine, methyl, methoxy, trifluoromethoxy, cyano, NR. 6 R 7 CH2-R 11 and cyclopropyl;

[0201] (43)R 4 It is a 6- to 10-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from: halogen, C 1-4 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkyl, cyano, NR 6 R7 and C 1-3 Alkylene-R 11 ;

[0202] (44)R 4 It is C 3-7 A cycloalkyl ring, optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, C 1-2 Alkyl, C 1-2 Alkoxy, cyano, NR 6 R 7 C(O)NR 8 R 9 and C 1-3 Alkylene-R 11 ;

[0203] (45)R 4 It is C 3-5 A cycloalkyl ring, optionally substituted by one or more substituents independently selected from the following: hydroxyl, fluorine, methyl, methoxy, cyano, NR. 6 R 7 and C(O)NR 8 R 9 ;

[0204] (46)R 4 It is a 3- to 7-membered heterocyclic ring, optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 and C 1-3 Alkylene-R 11 ;

[0205] (47)R 4 It is a 3- to 7-membered heterocyclic ring, optionally substituted by one or more substituents independently selected from: hydroxyl, methyl, methoxy, cyano, NR. 6 R 7 and C(O)NR 8 R 9 ;

[0206] (48)R 4 It is optionally coated with hydroxyl, halogen, C 1-2 Alkoxy, cyano, NR 6 R 7 C(O)NR 8 R 9 or CO2R 10 Replacement C1-6 alkyl;

[0207] (49)R 4 It is optionally coated with hydroxyl, fluorine, NR 6 R 7 or CO2R 10 Replacement C 2-5 alkyl;

[0208] (50)R 4 It is a 5- or 6-membered heteroaryl ring, said ring being fused with a 5- or 6-membered cycloalkyl or heterocyclic ring, each optionally substituted by one or more substituents independently selected from: halogen, oxo, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkyl groups and cyano groups;

[0209] (51)R 4 It is a 5- or 6-membered heteroaryl ring, said ring being fused with a 5-membered cycloalkyl or heterocyclic ring, each optionally being substituted by one or more substituents independently selected from the following: chlorine, fluorine, methyl, methoxy and cyano;

[0210] (52)R 4 It is a 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic ring, said ring being fused with a phenyl or 5- to 6-membered heteroaryl ring, each optionally substituted by one or more substituents independently selected from: halogen, oxo, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkyl groups and cyano groups;

[0211] (53)R 4 It is a partially unsaturated heterocycle, optionally fused to a 5- to 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, oxo, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkyl groups and cyano groups;

[0212] (54)R 4 It is optionally composed of one or more groups independently selected from fluorine, oxo, and C. 1-2 The alkyl substituents replace the partially unsaturated heterocycles;

[0213] (55)R 4 It is a partially unsaturated heterocycle that is optionally substituted by one or more substituents independently selected from oxo and methyl groups;

[0214] (56)R 4 It is a partially unsaturated 6-membered nitrogen-containing heterocycle that is substituted by one or more substituents independently selected from oxo and methyl groups;

[0215] (57)R 4 It is a partially unsaturated heterocycle fused with a 5- to 6-membered heteroaryl ring and optionally surrounded by one or more independently selected from fluorine, oxo, and C groups. 1-2 Alkyl substituents;

[0216] (58)R 4 It is a partially unsaturated heterocycle that is fused with a 5- to 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from oxo and methyl groups;

[0217] (59)R 4 It is a partially unsaturated 6-membered nitrogen-containing heterocycle that is fused with a 5-membered nitrogen-containing heteroaryl ring and optionally substituted by one or more substituents independently selected from oxo and methyl groups;

[0218] (60)R 4 Selected from one of the following groups:

[0219]

[0220]

[0221] in:

[0222] It is the attachment point to the rest of the compound of formula I;

[0223] R 18 Independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 ,

[0224] C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl;

[0225] R 19 Independently selected from hydrogen and C 1-4 Alkyl, C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl; and

[0226] p is 0, 1, or 2;

[0227] Where R 4 When it is a bicyclic group and p is 1 or 2, each R 18 The substituents may be present on either ring of the bicyclic group;

[0228] (61)R 4 Selected from one of the following groups:

[0229]

[0230] in:

[0231] It is the attachment point to the rest of the compound of formula I;

[0232] R 18 Independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl;

[0233] R 19 Independently selected from hydrogen, C 1-4 Alkyl, C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl; and

[0234] p is 0, 1, or 2;

[0235] Where R 4 When it is a bicyclic group and p is 1 or 2, each R 18 The substituents may be present on either ring of the bicyclic group;

[0236] (62)R 4 Selected from one of the following groups:

[0237]

[0238] in:

[0239] It is the attachment point to the rest of the compound of formula I;

[0240] R 18 Independently selected from hydroxyl, fluorine, chlorine, methyl, methoxy, CF3, NR 6 R 7 C 1-3 Alkylene-R 11 and cyclopropyl;

[0241] R 19 Independently selected from hydrogen, methyl, and cyclopropyl; and

[0242] p is 0, 1, or 2;

[0243] Where R 4 When it is a bicyclic group and p is 1 or 2, each R 18 The substituents may be present on either ring of the bicyclic group;

[0244] (63)R 5 It is hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, or cyano;

[0245] (64)R 5 It is hydrogen, fluorine, chlorine, or methyl;

[0246] (65)R 5 It is hydrogen;

[0247] (66)R 5 It is fluorine;

[0248] (67)R 11 It is hydroxyl, halogen, methoxy, cyano, NR 12 R 13 C(O)R 14 Or aryl;

[0249] (68)R 11 It is hydroxyl, methoxy, cyano, NR 12 R 13 C(O)R 14 Or phenyl;

[0250] (69)R 14 Is it hydroxyl, methoxy, or NR? 15 R 16 ;

[0251] (70)R 14 It is NR 15 R 16 ;

[0252] (71)R 15 and R 16 Together with the nitrogen atoms to which they are attached, they form 3 to 7-membered heterocyclic rings, which optionally contain additional heteroatoms selected from O, S, or N and optionally are C-shaped. 1-4 Alkyl substitution;

[0253] (72)R 15 and R 16 Together with the nitrogen atoms to which they are attached, they form a 5- to 6-membered heterocyclic ring, which optionally contains additional heteroatoms selected from O, S or N and optionally substituted with methyl groups.

[0254] Appropriately, X 1 To X 4It is as defined in any of paragraphs (1) to (11) above. In one implementation, X 1 To X 4 It is as defined in any of paragraphs (6) to (7) and (10) to (11) above. In another embodiment, X 1 To X 4 It is as defined in paragraph (11) above. In another implementation, X 1 To X 4 It is as defined in paragraph (7) above.

[0255] Suitablely, Y is as defined in any of paragraphs (12) to (22) above. In one embodiment, Y is as defined in any of paragraphs (19) to (22) above. In another embodiment, Y is as defined in paragraph (22) above.

[0256] Appropriately, R 1 and R 2 It is as defined in any of paragraphs (23) to (31) above. In one implementation, R 1 and R 2 It is as defined in any of paragraphs (26) to (31) above. Conveniently, R 1 and R 2 It is as defined in paragraph (28) above.

[0257] Appropriately, R 3 It is as defined in any of paragraphs (32) to (34) above. Conveniently, R 3 It is as defined in paragraph (33) above.

[0258] Appropriately, R 4 It is as defined in any of paragraphs (35) to (62) above. In one implementation, R 4 It is as defined in any of paragraphs (61) to (62) above. Conveniently, R 4 It is as defined in paragraph (62) above.

[0259] Appropriately, R 5 It is as defined in any of paragraphs (63) to (66) above. Conveniently, R 5 It is as defined in paragraph (65) above.

[0260] Appropriately, R 11 It is as defined in any of paragraphs (67) to (68) above. Conveniently, R 11 It is as defined in paragraph (68) above.

[0261] Appropriately, R14 It is as defined in any of paragraphs (69) to (70) above. Conveniently, R 14 It is as defined in paragraph (70) above.

[0262] Appropriately, R 15 and R 16 It is as defined in any of paragraphs (71) to (72) above. Conveniently, R 15 and R 16 It is as defined in paragraph (72) above.

[0263] In the other groups of the compound, the compound has one of the following structural formulas: IA, IB, IC, or ID:

[0264]

[0265] Where X 1 To X 4 and R 4 As defined above; each R 17 Independently selected from halogen groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Haloalkoxy; R 20 and R 21 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy group; and n is 0 to 4.

[0266] In the other groups of the compound, the compound has one of the above structural formulas IA, IB, IC, or ID, wherein X 1 To X 4 It is as defined in any of paragraphs (1) to (11) above; R 4 It is as defined in any of paragraphs (35) to (62) above; each R 17 Independently selected from halogen groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Haloalkoxy; R 20 and R 21 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy group; and n is 0 to 4.

[0267] In the other groups of the compound, the compound has one of the above structural formulas IA, IB, IC, or ID, wherein X 1 To X 4 It is as defined in any of paragraphs (6) to (7) or (10) to (11) above; R 4 It is as defined in any of paragraphs (61) to (62) above; R 20 and R 21 Independently selected from hydrogen, fluorine, methyl, trifluoromethyl, and methoxy; and n is 0 to 4. In the other groups of the compound, the compound has one of the above structural formulas IA, IB, IC, or ID, wherein X 1 To X 4 It is as defined in paragraph (11) above; R 20 and R 21 Independently selected from hydrogen, fluorine, trifluoromethyl, and methyl; and n is 0 to 3. In further additional groups of the compound, the compound has one of the above structural formulas IA, IB, IC, or ID, wherein X 1 To X 4 It is as defined in paragraph (11) above; R 20 and R 21 All are hydrogen; and n is 0. In another group of the compound, the compound has one of the above structural formulas IA, IB, IC, or ID, wherein X 1 To X 4 It is as defined in paragraph (11) above; R 20 and R 21 All are methyl groups; and n is 0. In another group of the compound, the compound has one of the above structural formulas IA, IB, IC, or ID, wherein X 1 To X 4 It is as defined in paragraph (11) above; R 20 It is methyl and R 21 It is hydrogen; and n is 0.

[0268] In the other groups of the compound, the compound has one of the following structural formulas: IE, IF, IG, IH, IJ, IK, IL, or IM:

[0269]

[0270]

[0271] Among them, Y and R 1 R 2 R 3 R 4 and R 5As defined above; each R 17 Independently selected from halogen groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Haloalkoxy; R 20 and R 21 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy group; and n is 0 to 4.

[0272] In the other groups of the compound, the compound has one of the structural formulas IE, IF, IG, IH, IJ, IK, IL, or IM, wherein Y is as defined in any of paragraphs (12) to (22) above; R 1 and R 2 It is as defined in any of paragraphs (23) to (31) above; R 3 It is as defined in any of paragraphs (32) to (34) above; R 4 It is as defined in any of paragraphs (35) to (62) above; each R 5 Independently defined as in any of paragraphs (63) to (66) above; each R 17 Independently selected from halogen groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Haloalkoxy; R 20 and R 21 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy group; and n is 0 to 4.

[0273] In the other groups of the compound, the compound has the structural formula IE, IF, IG or IH shown above, wherein Y is as defined in any of paragraphs (19) to (22) above; R 1 and R 2 It is as defined in any of paragraphs (26) to (31) above; R 3 It is as defined in any of paragraphs (32) to (34) above; R 4 It is as defined in any of paragraphs (61) to (62) above; and each R 5Independently defined as in any of paragraphs (64) to (65) above. In other groups of the compound, the compound has the structural formula IE, IF, IG, or IH shown above, where Y is as defined in paragraph (22) above; R 1 and R 2 It is as defined in paragraph (31) above; R 3 It is as defined in paragraph (33) above; R 4 It is as defined in paragraph (62) above; and each R 5 It is as defined in paragraph (65) above.

[0274] In the other groups of the compound, the compound has the structural formula IJ, IK, IL or IM shown above, wherein Y is as defined in any of paragraphs (19) to (22) above; R 4 It is as defined in any of paragraphs (61) to (62) above; each R 5 Independently defined as in any of paragraphs (64) to (65) above; each R 17 Independently selected from fluorine, methyl, methoxy and C 1-2 Halogenated alkyl; R 20 and R 21 Independently selected from hydrogen, fluorine, methyl, ethyl, methoxy, C 1-2 Halogenated alkyl and C 1-2 Haloalkoxy group; and n is 0 to 4. In other groups of the compound, the compound has the structural formula IJ, IK, IL or IM shown above, where Y is as defined in paragraph (22) above; R 4 As defined in paragraph (62) above; each R 5 As defined in paragraph (65) above; each R 17 Independently selected from fluorine, methyl, methoxy and C 1-2 Halogenated alkyl; R 20 and R 21 Independently selected from hydrogen, fluorine, methyl, ethyl, methoxy, and C 1-2 Halogenated alkyl groups (such as trifluoromethyl); and n is 0 to 3.

[0275] Specific compounds of the present invention include any one of the following:

[0276] N-((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 1);

[0277] N-((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 2);

[0278] 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 3);

[0279] 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 4);

[0280] N-((S)-2-((4-(imidazol[1,2-a]pyridin-5-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 5);

[0281] N-((S)-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 6);

[0282] 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(3-(2-oxo-2-(pyrrolidone-1-yl)ethyl)pyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 7);

[0283] N-((S)-2-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 8);

[0284] N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridinyl]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 9);

[0285] N-((S)-2-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 10);

[0286] N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 11);

[0287] 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 12);

[0288] N-((S)-2-((4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 13);

[0289] N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 14);

[0290] N-((S)-2-((4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 15);

[0291] N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 16);

[0292] N-(1-(4,4-difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 17);

[0293] N-((S)-2-((5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 18);

[0294] N-(1-(4,4-dimethylcyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 19);

[0295] N-(1-(4,4-difluorocyclohexyl)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 20);

[0296] N-(2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-(4,4-dimethylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 21);

[0297] N-(1-Cyclooctyl-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 22);

[0298] N-(1-Cyclooctyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 23);

[0299] N-(1-Cyclooctyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 24);

[0300] N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 25);

[0301] N-(1-Cyclooctyl-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 26);

[0302] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 27);

[0303] N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 28);

[0304] N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 29);

[0305] N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 30);

[0306] N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazol-4-carboxamide (Example 31);

[0307] N-(1-Cyclooctyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 32);

[0308] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 33);

[0309] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 34);

[0310] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide (Example 35);

[0311] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide (Example 36);

[0312] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 37);

[0313] (S)-N-(1-cyclohexyl-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 38);

[0314] N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 39);

[0315] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide (Example 40);

[0316] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 41);

[0317] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 42);

[0318] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 43);

[0319] N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 44);

[0320] N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 45);

[0321] N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 46);

[0322] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 47);

[0323] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 48);

[0324] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Example 49);

[0325] N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 50);

[0326] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 51);

[0327] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide (Example 52);

[0328] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 53);

[0329] N-((S)-2-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 54);

[0330] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 55);

[0331] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-(methoxymethyl)isoxazole-4-carboxamide (Example 56);

[0332] N-((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 57);

[0333] 6-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamide)-2-((1r,4S)-4-methylcyclohexyl)acetamide)-3',5'-dimethyl-[3,4'-bipyridine]1'-oxide (Example 58);

[0334] 3-Ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-((5-(5-methylpyrimidin-4-yl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-4-carboxamide (Example 59);

[0335] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-1,2,3-triazol-5-carboxamide (Example 60);

[0336] N-((S)-2-((5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 61);

[0337] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 62);

[0338] (S)-N-(1-(4,4-difluorocyclohexyl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 63);

[0339] N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 64);

[0340] 1-Methyl-N-((S)-2-((4-methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazol-5-carboxamide (Example 65);

[0341] N-((S)-2-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 66);

[0342] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 67);

[0343] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 68);

[0344] (S)-N-(1-cycloheptyl-2-((5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 69);

[0345] N-((S)-2-((3'-methoxy-2'-methyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 70);

[0346] N-((S)-2-((2',3'-dimethyl-[3,4'-bipyridinyl]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 71);

[0347] N-((S)-2-((2',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 72);

[0348] N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 73);

[0349] N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 74);

[0350] N-((S)-2-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 75);

[0351] (S)-N-(1-cycloheptyl-2-((5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 76);

[0352] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 77);

[0353] N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 78);

[0354] N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 79);

[0355] (S)-N-(1-cycloheptyl-2-((5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 80);

[0356] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 81);

[0357] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 82);

[0358] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 83);

[0359] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 84);

[0360] (S)-N-(1-cycloheptyl-2-((5-(4-hydroxy-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 85);

[0361] N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide (Example 86);

[0362] N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-1,2,3-triazol-5-carboxamide (Example 87);

[0363] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 88);

[0364] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide (Example 89);

[0365] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 90);

[0366] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 91);

[0367] (S)-N-(1-cycloheptyl-2-((5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 92);

[0368] (S)-N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 93);

[0369] (S)-N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 94);

[0370] (S)-N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 95);

[0371] (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 96);

[0372] (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 97);

[0373] N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 98);

[0374] N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 99);

[0375] (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 100);

[0376] (S)-N-(1-cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 101);

[0377] (S)-N-(1-cyclopentyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 102);

[0378] N-(1-(bicyclo[2.2.1]heptane-2-yl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 103);

[0379] N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 104);

[0380] N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 105);

[0381] N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)-3-ethylisoxazole-4-carboxamide (Example 106);

[0382] N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 107);

[0383] N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 108);

[0384] (S)-N-(1-cycloheptyl-2-((5-(1-(2-(dimethylamino)-2-oxoethyl)-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 109);

[0385] N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-isopropylisoxazole-4-carboxamide (Example 110);

[0386] 3-(tert-butyl)-N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide (Example 111);

[0387] N-((S)-2-((5-(4-cyano-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 112);

[0388] N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-(trifluoromethyl)isoxazole-4-carboxamide (Example 113);

[0389] (S)-N-(1-cycloheptyl-2-oxo-2-((5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 114);

[0390] N-((S)-2-((5-(3,5-dimethylisothiazolyl-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 115);

[0391] N-((S)-2-((5-(3,5-dimethylisothiazolyl-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide (Example 116);

[0392] (S)-N-(1-cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 117);

[0393] N-((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 118);

[0394] N-((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide (Example 119);

[0395] N-((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 120);

[0396] (S)-N-(1-cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 121);

[0397] N-((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 122);

[0398] N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazol-5-carboxamide (Example 123);

[0399] 1-Ethyl-N-((S)-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazol-5-carboxamide (Example 124);

[0400] N-((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 125);

[0401] (S)-N-(1-cyclohexyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 126);

[0402] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 127);

[0403] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide (Example 128);

[0404] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 129);

[0405] N-((S)-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 130);

[0406] N-((S)-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide (Example 131);

[0407] N-((S)-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 132);

[0408] (S)-N-(1-cycloheptyl-2-oxo-2-((1',2',4'-trimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 133);

[0409] 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((1',2',4'-trimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)amino)ethyl)-1H-pyrazole-5-carboxamide (Example 134);

[0410] (S)-N-(1-cycloheptyl-2-oxo-2-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 135);

[0411] 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)-1H-pyrazol-5-carboxamide (Example 136);

[0412] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 137);

[0413] 1-Methyl-N-((S)-2-((5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazol-5-carboxamide (Example 138); or

[0414] N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-(dispiro[2.1.2]) 5 .2 3 Nonane-4-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 139);

[0415] Or its pharmaceutically acceptable salt.

[0416] The various functional groups and substituents constituting the compounds of the present invention are typically selected such that the molecular weight of the compounds does not exceed 1000. More generally, the molecular weight of the compounds will be less than 750, for example less than 700, or less than 650, or less than 600.

[0417] Suitable or preferred features of any compound of the present invention may also be suitable features of any other aspect.

[0418] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic acid addition salts of the compounds of the present invention, such as acid addition salts formed with inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid). Furthermore, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present invention are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts formed with organic bases that provide physiologically acceptable cations (e.g., salts formed with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine).

[0419] Compounds with the same molecular formula but differing atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." Enantiomer pairs are possible when a compound has an asymmetry center, for example, when it is bonded to four different groups. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the Kahn and Prelog's R- and S-sequence rules, or by the manner in which the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0420] The compounds of the present invention may have one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of specific compounds in the specification and claims is intended to include both individual enantiomers and mixtures thereof (racemic or otherwise). Stereochemical determinations and methods for the separation of stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley, and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution in racemic form. Some of the compounds of the present invention may have geometric isomer centers (E- and Z-isomers). It should be understood that the present invention covers all optically diastereomers and geometric isomers and mixtures thereof.

[0421] This invention also covers compounds of the invention as defined herein, said compounds comprising one or more isotopic substitutions. For example, H can be any isotopic form, including 1H, 2H(D), and 3H(T); C can be any isotopic form including 12C, 13C, and 14C; and O can be any isotopic form, including 16O and 18O; etc.

[0422] It should also be understood that some compounds of the present invention can exist in solvated and non-solvated forms (e.g., hydrated forms). It should be understood that the present invention covers all such solvated forms.

[0423] It should also be understood that some compounds of the present invention may exhibit polymorphism, and the present invention covers all such forms.

[0424] The compounds of the present invention can exist in many different tautomeric forms, and references to the compounds of the present invention include all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all other forms are also covered by the compounds of the present invention. Examples of tautomeric forms include ketone, enol, and enolate forms, such as in, for example, the following tautomeric pairs: ketone / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0425]

[0426] The compounds of the present invention containing amine functionality can also form nitrogen oxides. Reference herein to compounds of formula I containing amine functionality also includes nitrogen oxides. In the case of compounds containing some amine functionality, one or more nitrogen atoms can be oxidized to form nitrogen oxides. Specific examples of nitrogen oxides are nitrogen oxides of tertiary amines or nitrogen oxides of nitrogen atoms in nitrogen-containing heterocycles. Nitrogen oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, pp. 509-514. More particularly, nitrogen oxides can be prepared by the LWDeady process (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0427] The compounds of the present invention can be administered as prodrugs, which are broken down in humans or animals to release the compounds of the present invention. Prodrugs can be used to modify the physical or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents that can attach characteristic modifying groups. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl group in the compounds of the present invention, and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino group in the compounds of the present invention.

[0428] Accordingly, the present invention includes those compounds of Formula I as defined above, which are available through organic synthesis and in the human or animal body by cleaving their prodrugs. Accordingly, the present invention includes those compounds of Formula I produced by organic synthesis and also includes such compounds produced in the human or animal body by the metabolism of precursor compounds, i.e., the compounds of Formula I can be synthetically produced or metabolically produced compounds.

[0429] synthesis

[0430] In the description of the synthetic methods described below and in the synthetic methods cited for the preparation of the starting materials, it should be understood that all proposed reaction conditions (including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and post-treatment procedures) can be selected by those skilled in the art.

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

[0432] The necessary starting materials can be obtained through standard procedures in organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variations and in the accompanying examples. Alternatively, the necessary starting materials can be obtained through procedures similar to those demonstrated within the general technical scope of organic chemists.

[0433] It will be understood that during the synthesis of the compounds of the present invention, as defined below, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent unwanted reactions. A skilled chemist will understand when such protection is required and how to place and subsequently remove such protecting groups.

[0434] For an example of protecting groups, see one of the many general texts on this subject, such as “Protecting groups in Organic Synthesis (3rd Edition), John Wiley & Sons, NY (1999),” T. Greene & P. ​​Wuts. Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist as appropriate for removing the protecting group in question, such method being chosen to achieve the removal of the protecting group and to minimize interference from groups at other positions in the molecule.

[0435] Therefore, if the reactants include groups such as amino, carboxyl, or hydroxyl, it may be necessary to protect these groups in some of the reactions mentioned herein.

[0436] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups (e.g., alkanoyl groups (such as acetyl groups)), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aromatic acyl groups (e.g., benzoyl). The deprotection conditions for these protecting groups must vary depending on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl groups, alkoxycarbonyl groups, or aromatic acyl groups can be removed, for example, by hydrolysis with a suitable base (e.g., an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide). Alternatively, acyl groups such as tert-butoxycarbonyl groups can be removed, for example, by treatment with a suitable acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid), and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon or by treatment with a Lewis acid (e.g., BF3·OEt2). Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines (e.g., dimethylaminopropylamine) or with hydrazine.

[0437] Those skilled in the art will recognize that the compounds of the present invention can be prepared in various ways and in known manners. Compounds of Formula I can be prepared by the methods given below, the methods described in the experiments, or similar methods. The described pathways merely illustrate some methods that can be used to synthesize compounds of Formula I, and those skilled in the art will understand that the order of reaction steps is not limited to those described. It will also be understood that the partitioning of the nucleophile and electrophile is not limited to that described herein, and in some cases, an inverted partitioning may be appropriate. Different approaches to synthetic chemistry strategies are described in "Organic Synthesis: The Disconnection Approach", 2nd edition, S. Warren and P. Wyatt (2008).

[0438] Compounds of Formula I or pharmaceutically acceptable salts thereof (where R) 1 R 2 R 3 R 4 X 1 X 2 X 3 X 4 (and Y is as defined above) can be reacted by formic acid of formula III or a suitable reactive derivative of formic acid (where R) 1 R 2 R 3 Y is as defined above in Formula I) and an amine of Formula II (where R is... 4 X 1 X 2 X 3 and X 4It is prepared by the reaction as defined above in Formula I (Scheme A, Step i).

[0439] Alternatively, compounds of formula I or their pharmaceutically acceptable salts (wherein R) 1 R 2 R 3 R 4 X 1 X 2 X 3 X 4 (and Y is as defined above) can be made by amines of formula IV (where R) 1 R 2 R 3 R 4 X 1 X 2 X 3 and X 4 It is prepared by reacting (as defined above in Formula I) with formic acid or a suitable reactive derivative of formic acid of Formula V (where Y is as defined above in Formula I) (Scheme A, step ii).

[0440] Option A

[0441]

[0442] Compounds of formula III can be made by suitably protecting an amine of formula VI (where R... 1 R 2 and R 3 It is prepared by reacting (as defined above in Formula I) with formic acid or a suitable reactive derivative of formic acid of Formula V (where Y is as defined above in Formula I) (Scheme B, step i).

[0443] Compounds of formula IV can be reacted with a suitably protected formic acid or a suitably protected formic acid derivative of formula VI (where R... 1 R 2 and R 3 (as defined above in Formula I) and amines of Formula II (where R) 4 X 1 X 2 X 3 and X 4 It is prepared by the reaction as defined in Formula I above (Scheme B, step ii).

[0444] Option B

[0445]

[0446] Suitable reactive derivatives of formic acids of formulas III, V, and VI include, for example: acyl halides formed by the reaction of an acid with an inorganic acid chloride such as thionyl chloride; mixed acid anhydrides formed by the reaction of an acid with a chloroformate such as isobutyl chloroformate; esters formed by the reaction of an acid with an alcohol in the presence of an acid or base; activated esters formed by the reaction of an acid with a phenol such as pentafluorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; or products of the reaction of an acid with an amide coupling agent such as dicyclohexylcarbodiimide. In the case of the conversion of formic acids of formulas III and V to esters (e.g., by the reaction of an acyl chloride with an organic alcohol such as methanol), they can be reacted with a suitable amine in the presence of an organometallic activator (e.g., a Grignard reagent such as isopropyl magnesium bromide). Typically, formic acid of formula III and amine of formula II, or formic acid of formula V and amine of formula IV, or suitably protected formic acid of formula VI and amine of formula II, are coupled in a suitable solvent (such as DMF, ethyl acetate, or MeCN) in the presence of a non-nucleophilic base (such as triethylamine, 2,4,6-trimethylpyridine, or N,N-diisopropylethylamine) with an amide coupling agent (such as HATU or...). )deal with.

[0447] Those skilled in the art will understand that the conversion of amino acids of formula VI to compounds of formulas III and IV may require a suitable synthetic strategy involving multiple steps. Such synthetic strategies will be able to identify, and may include the selection, preparation, and removal of suitable protecting groups.

[0448] Natural and non-natural amino acids of formula VI and their derivatives (where R 1 R 2 and R 3 Amino acids (as defined in Formula I) are commercially available or can be prepared by methods known to those skilled in the art. For a review of amino acid synthesis, see (a) C. Najera and J. M. S.sano, Chem Rev, 2007, 107, 4584; (b) R. M. Williams and J. A. Hendrix, Chem Rev, 1992, 92, 889; (c) R. O. Duthaler, Tetrahedron, 1994, 50, 1539.

[0449] Formic acid of formula V or its derivatives (where Y is as defined in formula I) are commercially available or can be prepared by methods known to those skilled in the art. Compounds of formula V can be prepared by: acid- or base-catalyzed hydrolysis of esters, amides, or nitriles (e.g., hydrolysis of methyl esters with sodium hydroxide); transition metal-catalyzed oxidation of aldehydes or alcohols; treatment with organolithium or Grignard reagents with carbon dioxide; or transition metal-catalyzed carbonylation of aryl halides in the presence of water. Transition metal-catalyzed carbonylation of aryl halides in the presence of amines of formula VI or IV can directly form compounds of formula III or I.

[0450] Option C

[0451]

[0452] Amines of formula II (where R) 4 X 1 X 2 X 3 and X 4 (As defined above in Formula I) is commercially available or can be prepared by methods known to those skilled in the art.

[0453] Compounds of formula II can be derived from formula VII (where R 4 (as defined in Equation I) and Equation VIII (where X) 1 X 2 X 3 and X 4 It is as defined in equation I, and Z 1 and Z 2 These are functional groups that promote R 4 Preparation of compounds (scheme C, step i) involving the formation of bonds between the phenyl / heteroaryl ring and the substitution / removal of bonds during the bond-forming reaction. Such bond-forming reactions, conditions, and suitable Z... 1 and Z 2 Functional groups are known to those skilled in the art. For example, in R 4 In the case of heteroaryl groups, a suitable bond-forming reaction could be the Suzuki reaction, and Z... 1 or Z 2 One is boric acid or borate ester, and the other is a halide. Typically, Z is... 1 or Z 2 One of them is boric acid or borate ester and the other is a combination of compounds of formula VII and VIII, which react together in a solvent or solvent mixture (such as 1,4-dioxane / water, ethanol / water) or toluene in the presence of a base (such as potassium carbonate, sodium carbonate or potassium phosphate) and a catalyst (such as Pd(dppf)Cl2 or XPhos Pd G2).

[0454] Amines of formula II can also be derived from compounds of formula IX (where R... 4 X 1 X 2 X 3 and X 4 It is as defined in Equation I above and Z 3 It can be prepared by converting the functional group of an amine using known methods (Scheme C, step ii). Examples of known methods include: reduction (where Z... 3 For example, azides or nitro groups); rearrangements (where Z... 3Examples include primary amides (Hoffmann rearrangement), carboxylic acids (Schmidt rearrangement), and acyl azides (Curtius rearrangement); or CN bond formation (where Z... 3 (It is H or a halide), for example, nitration, followed by reduction or amination (e.g., the Buchwald-Hartwig reaction).

[0455] Compounds of formula IX (where R 4 X 1 X 2 X 3 and X 4 It is commercially available or can be prepared by methods known to those skilled in the art, as defined above in Formula I as described herein.

[0456] Pharmaceutical Composition

[0457] Before administration to a patient, the compounds of the present invention are normally (but not necessarily) formulated into a pharmaceutical composition. Therefore, according to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers.

[0458] The pharmaceutical compositions of the present invention can be prepared and packaged in bulk form, wherein a safe and effective amount of the compound of the present invention can be extracted and then administered to the patient, for example, as a powder or syrup. Alternatively, the pharmaceutical compositions of the present invention can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of the compound of the present invention. When prepared in unit dosage forms, the pharmaceutical compositions of the present invention typically contain 1 mg to 1000 mg.

[0459] The pharmaceutical compositions of the present invention can be in forms suitable for oral administration (e.g., as tablets, capsules, pouches, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and capsules), for external use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels), for transdermal administration (e.g., via transdermal patches), for administration by inhalation (e.g., as dry powders, aerosols, suspensions, and solutions), for administration by blowing (e.g., as fine powders), or for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration).

[0460] As used herein, "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or carrier relating to a form of administration or consistency with a pharmaceutical composition. Each excipient must be compatible with the other components of the pharmaceutical composition to avoid interactions that would significantly reduce the efficacy of the compounds of the present invention when administered to a patient, and to avoid interactions that would create pharmaceutically unacceptable pharmaceutical compositions. Furthermore, each excipient must have sufficiently high purity to be pharmaceutically acceptable.

[0461] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods common in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0462] The effective amount of the compounds of the present invention for treating proliferative diseases is sufficient to alleviate the symptoms of proliferative diseases in warm-blooded animals, particularly humans, slow the progression of proliferative diseases, or reduce the risk of disease deterioration in patients with symptoms of proliferative diseases.

[0463] The amount of active ingredient combined with one or more excipients to produce a single dosage form will need to vary depending on the host being treated and the specific 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 the active ingredient (more suitably 0.5 mg to 100 mg, e.g., 1 mg to 30 mg), compounded with an appropriate and convenient amount (varying between about 5% and about 98% by weight of the total composition) of excipients.

[0464] According to well-known medical principles, the dosage of a compound of Formula I for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0465] When using the compounds of the present invention for therapeutic or preventative purposes, taking into account the need for divided administration, they are generally administered in a daily dose ranging from, for example, 0.1 mg / kg to 75 mg / kg body weight. Generally, smaller doses are administered when using a parenteral route. Therefore, for example, for intravenous or intraperitoneal administration, doses ranging from, for example, 0.1 mg / kg to 30 mg / kg body weight will be used. Similarly, for inhalation administration, doses ranging from, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration, particularly in tablet form, is also suitable. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention.

[0466] Application route

[0467] The compounds of the present invention or pharmaceutical compositions containing the active compounds may be administered to subjects via any convenient route of administration (systemic / peripheral or topical) (i.e., at the site of desired action).

[0468] Routes of administration include, but are not limited to, oral (e.g., by swallowing); buccal; sublingual; transdermal (e.g., by patches, plasters, etc.); transmucosal (e.g., by gels, films, etc.); intranasal (e.g., by nasal sprays); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); extragastric, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and by implantation of a reservoir or storage device (e.g., subcutaneous or intramuscular).

[0469] Therapeutic uses and applications

[0470] As a high-affinity conjugate of human IL-17A and a potent modulator of human IL-17A activity, the compounds of the present invention are therefore beneficial as therapeutic compounds for the treatment or prevention of human diseases caused by IL-17A activity.

[0471] As high-affinity conjugates of human IL-17A and potent modulators of human IL-17A activity, the compounds of this invention can serve as pharmacological standards beneficial for developing new biological assays and identifying new drugs. Therefore, the compounds of this invention can be used as radioligands in assays for the detection of pharmacologically active compounds.

[0472] Therefore, in one aspect, the present invention relates to compounds of the invention as defined herein or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions as defined herein, for therapeutic purposes.

[0473] In another respect, the present invention relates to compounds of the invention as defined herein or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions as defined herein, for the treatment of diseases or disorders mediated by IL-17A activity.

[0474] In another aspect, the present invention relates to the use of compounds of the present invention as defined herein, or pharmaceutically acceptable salts or solvates thereof, in the manufacture of medicaments for treating diseases or disorders mediated by IL-17A activity.

[0475] In another aspect, the present invention relates to a method for treating a disease or disorder in which IL-17A activity is involved, the method comprising administering to a subject requiring such treatment a therapeutically effective amount of a compound of the present invention as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

[0476] Examples of specific diseases or disorders that can be treated with compounds of formula (I) or their pharmaceutically acceptable salts include, but are not limited to, any one of the following: acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthritis, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes and other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (solid tumors such as melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, and hematologic malignancies, and especially acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer, and colon cancer), Kassman disease, contact dermatitis, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, enthesitis-associated arthritis, infection-associated endotoxic shock, exophthalmos, fibrosis including pulmonary fibrosis, gallbladder disease, megaloblastic leukemia, and other conditions. Cellular arteritis, graft-versus-host disease, heart diseases including ischemic diseases such as myocardial infarction and atherosclerosis, hepatoblastoma, hypoacidity, immune-mediated inflammatory disorders in the central and peripheral nervous systems such as multiple sclerosis and Guillain-Barré syndrome, infections (viral, bacterial, fungal, and parasitic infections), inflammatory bowel disease, intravascular coagulation, irritable bowel syndrome, liver fibrosis, Lyme arthritis, meningoencephalitis, myocarditis, osteoporosis, pancreatitis Inflammation, Parkinson's disease, pelvic inflammatory disease, pain (especially inflammation-related pain), periodontitis, peritonitis, penile nodules, pilonidal disease, psoriasis, psoriatic arthritis (PsA), renal fibrosis, rheumatoid arthritis, scleroderma or systemic sclerosis, stroke, surgical adhesions, systemic lupus erythematosus (SLE), generalized juvenile idiopathic arthritis (JIA), trauma (surgery), transplant rejection, type I diabetes, ulcerative colitis, uveitis, and vasculitis.

[0477] Modifiers of IL-17 activity can be administered to inhibit or reduce the severity of ocular inflammatory disorders, such as ocular surface inflammatory disorders including dry eye syndrome (DES) (WO 2009 / 089036). Therefore, compounds according to the invention can be used to treat or prevent 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, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, artificial cornea surgery, corneal and ocular surface inflammatory disorders, conjunctival scarring disorders, ocular autoimmune disorders, pemphigoid syndrome, Schwarz-Jones syndrome, ocular allergies, severe allergic (atopic) eye disease, conjunctivitis, and microbial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjögren's syndrome, keratoconjunctivitis sicca associated with Sjögren's syndrome, keratoconjunctivitis sicca not associated with Sjögren's syndrome, keratoconjunctivitis sicca, Sjögren's syndrome, dry eye syndrome, tear film disorder, decreased tear production, aqueous-deficient dry eye (ATD), meibomian gland dysfunction, and evaporative dry eye.

[0478] Combination therapy

[0479] The compounds of this invention can be administered alone as a monotherapy or in combination with one or more other therapeutic agents. The selection of such one or more other therapeutic agents will necessarily vary depending on the disease or condition to be treated and its severity.

[0480] Combination therapy is commonly used to treat certain medical conditions.

[0481] According to a particular aspect of the invention, a combination suitable for treating a disease or condition in which IL-17 activity is involved is provided, the combination comprising a compound of the invention as defined above or a pharmaceutically acceptable salt thereof and another therapeutic agent.

[0482] According to this aspect of the invention, suitable combinations for the prevention or treatment of the following are provided: acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthritis, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes and other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (solid tumors such as melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, and hematologic malignancies, and particularly acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer, and colon cancer), Kassman disease, and exposure. Atopic dermatitis, Crohn's disease, chronic myeloid leukemia, chronic obstructive pulmonary disease (COPD), celiac disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema, enthesitis-associated arthritis, infection-associated endotoxin shock, exophthalmos, fibrotic diseases including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, heart diseases including ischemic diseases such as myocardial infarction and atherosclerosis, hepatoblastoma, hypoacidity, and immune-mediated inflammatory disorders in the central and peripheral nervous systems such as multiple sclerosis and Guillain-Barré syndrome, as well as infections (pathogens). Infectious diseases include: toxic, bacterial, fungal, and parasitic infections; inflammatory bowel disease; intravascular coagulation; irritable bowel syndrome; liver fibrosis; Lyme arthritis; meningoencephalitis; myocarditis; osteoporosis; pancreatitis; Parkinson's disease; pelvic inflammatory disease; pain (especially inflammation-related pain); periodontitis; peritonitis; penile nodules; pilonidal disease; psoriasis; psoriatic arthritis (PsA); renal fibrosis; rheumatoid arthritis; scleroderma or systemic sclerosis; stroke; surgical adhesions; systemic lupus erythematosus (SLE); generalized juvenile idiopathic arthritis (JIA); trauma (hand). The combination includes compounds of the present invention as defined above, or pharmaceutically acceptable salts thereof, and one or more other therapeutic agents.

[0483] Examples of these other therapeutic agents may include, but are not limited to, corticosteroids (topical or systemic), vitamin D analogs, anthralin, retinoids, calcineurin inhibitors, salicylic acid, methotrexate, cyclosporine, leflunomide, sulfasalazine, azathioprine, etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), uterginumab (Sidano), golimumab (Simponi), and PDE inhibitors. Pharmaceutical formulations (such as aprescribing), thioguanine, hydroxyurea, dimethyl fumarate, JAK inhibitors including TYK2 inhibitors (such as ruxolitinib, tofacitinib, olatinib, baricitinib, figatitinib, cedutinib, gondotinib, lintatinib, molotinib, paritinib, PF-04965842, utpatinib, peficixitinib, fentatinib, BMS-986165), and NSAIDs (such as naproxen and indomethacin).

[0484] In another aspect of the invention, compounds of the invention or pharmaceutically acceptable salts thereof are provided in combination with one or more other therapeutic agents.

[0485] In this document, when the term "combination" is used, it should be understood that it means simultaneous, separate, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means separate application. In yet another aspect of the invention, "combination" means sequential application. When application is sequential or separate, a delay in applying the second component should not, for example, cause a loss of the beneficial effects of the combination.

[0486] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents, and a pharmaceutically acceptable diluent or carrier.

[0487] The one or more additional therapeutic agents may comprise additional compounds of the present invention. Therefore, in one embodiment, a pharmaceutical composition comprising two compounds of the present invention or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable diluent or carrier is provided.

[0488] The combinations mentioned above can be conveniently presented for use in the form of pharmaceutical formulations, and therefore pharmaceutical formulations comprising the combinations as defined above together with pharmaceutically acceptable diluents or carriers represent another aspect of the invention.

[0489] This combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially, or separately. In one embodiment, the individual compounds are administered simultaneously in the combined pharmaceutical formulation.

[0490] Such combination therapies employ compounds of the present invention within the dosage range described herein, as well as other pharmaceutically active agents within the approved dosage range or in the relevant published literature at dosages.

[0491] General procedures:

[0492] Methods for preparing the compounds of the present invention are illustrated in the following examples. Starting materials were prepared according to procedures known in the art or shown herein, or were commercially available. Commercially available reagents were used without further purification. The reaction was carried out at ambient temperature (or room temperature) (typically 17°C–27°C), excluding the reaction temperature.

[0493] Those skilled in the art will understand that the reaction temperature, reaction time, and reagent volume may differ from those described herein.

[0494] The compound names have been generated using ChemDraw Professional version 20.0.0.41.

[0495] The compound described in this invention is composed of 1 For characterization by 1H NMR spectroscopy, spectra were recorded on a JEOLE CX300 (300 MHz), JEOL ECX400 (400 MHz), or Bruker Avance III Ultra Shield 400 (400 MHz) instrument. Spectra were recorded at ambient temperature, excluding temperature. Chemical shift values ​​are expressed in parts per million (ppm). The following abbreviations are used for NMR signal multiplicity: s = singlet, b = broad peak, t = triplet, q = quartet, m = multiplet, d = doublet.

[0496] When the compounds described in this invention are characterized by LCMS data, the retention time and molecular weight are determined using the conditions listed below.

[0497] Method 1: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: XBridge C18, 2.5 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 1.30 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2%-98% B over 0.80 min, held at 98% B until 1.30 min.

[0498] Method 2: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: XBridge C18, 2.5 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 1.40 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2% - 98% B over 1.20 min, held at 98% B until 1.40 min.

[0499] Method 3: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 4.60 min. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia [eluent C; continuous at 5%]. Gradient: 2%-95% B with A and 5% C over 4.0 min, held at 95% B and 5% C until 4.60 min, column temperature 40 °C.

[0500] Method 4: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 1.40 min. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia [eluent C; continuous at 5%]. Gradient: 2%-95% B with A and 5% C over 1.2 min, held at 95% B and 5% C until 1.40 min, column temperature 40 °C.

[0501] Method 5: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: XBridge C18, 2.5 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 4.60 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2%-98% B over 4.0 min, held at 98% B until 4.60 min.

[0502] Method 6: Waters Acquity UPLC system (binary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 4.6 min. Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2%-98% B over 4.0 min, held at 98% B until 4.60 min, column temperature 40 °C.

[0503] Method 7: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: XBridge C18, 2.5 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 5.00 min. Conditions: 2% ammonia [eluent D], MeCN [eluent C], water [eluent A]. Gradient: 2%-95% C (in A) and 5% C over 4.50 min, held at 95% C to 5.00 min, column temperature 40 °C.

[0504] Method 8: Waters Acquity UPLC system (binary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 1.4 min. Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2%-98% B over 1.2 min, held at 98% B until 1.40 min, column temperature 40 °C.

[0505] Method 9: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: CSH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.7 mL / min). Run time: 5.00 min. Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2%-95% B over 4.50 min, held at 95% B until 5.00 min.

[0506] Method 10: Waters Acquity UPLC system (binary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: XBridge BEH C18, 2.5 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 4.80 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent A], MeCN [eluent B]. Gradient: 2%-98% B over 4.0 min, held at 98% B until 4.70 min.

[0507] Method 11: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: XBridge BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia [eluent C; continuous at 5%]. Gradient: 5%-95% B over 4.50 min, held at 95% B to 5.00 min, column temperature 40 °C.

[0508] Method 12: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: XBridge BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia [eluent C; continuous at 5%]. Gradient: 2%-95% B over 4.0 min, held at 95% B for 4.60 min, column temperature 40 °C.

[0509] Method 13: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: CSH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% formic acid in water [eluent D; 5% continuous]. Gradient: 2%-95% B over 4.0 min, held at 95% B for 4.60 min, column temperature 40 °C.

[0510] Method 14: Agilent 6140 series quadrupole mass spectrometer with a composite source (monitoring at 254 nm). Column: Phenomenex C18(2)-HST column, 2.5 μm, 50 x 2.0 mm (flow rate 1.0 mL / min). Conditions: Mobile phase A contained 0.1% formic acid in 18 MΩ water; mobile phase B contained 0.1% formic acid in acetonitrile. Gradient: 1%-100% B over 3.75 min.

[0511] Method 15: Agilent 6140 series quadrupole mass spectrometer with a composite source (monitoring at 254 nm). Column: Phenomenex C18(2)-HST column, 2.5 μm, 50 x 2.0 mm (flow rate 1.0 mL / min). Conditions: Mobile phase A contained 0.1% formic acid in 18 MΩ water; mobile phase B contained 0.1% formic acid in acetonitrile. Gradient: 1%-100% B over 5.5 min.

[0512] Method 16: Agilent 6140 series quadrupole mass spectrometer with a composite source (monitoring at 254 nm). Column: Phenomenex C18(2)-HST column, 2.5 μm, 50 x 2.0 mm (flow rate 1.0 mL / min). Conditions: Mobile phase A contained 5 mM ammonium acetate in 18 MΩ water; mobile phase B contained 5 mM ammonium acetate in 18 MΩ water / 5 mM ammonium acetate in acetonitrile (9:1). Gradient: 5%-100% B over 3.5 min.

[0513] Method 17: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2%-95% B over 4.0 min, held at 95% B for 4.60 min, column temperature 40 °C.

[0514] Method 18: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: XBridge BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia [eluent C; continuous at 5%]. Gradient: 4.5 min 2%-95% B, held at 95% B for 5.00 min, column temperature 40 °C.

[0515] Method 19: Agilent 6140 series quadrupole mass spectrometer with a composite source (monitoring at 254 nm). Column: Phenomenex C18 1.7 μm, 50 x 2.1 mm. Conditions: Mobile phase A contains 0.1% formic acid in 18 MΩ water, and mobile phase B contains 0.1% formic acid in HPLC-grade acetonitrile (flow rate 0.8 mL / min). Gradient: 5%-95% B over 5 min.

[0516] Method 20: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 1.40 min. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia [eluent C; continuous at 5%]. Gradient: 50%-95% B with A and 5% C over 1.2 min, held at 95% B and 5% C until 1.40 min, column temperature 40 °C.

[0517] Method 21: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% formic acid in water [eluent D; 5% for continuity]. Gradient: 2%-20% B in 3.0 min, to 95% B in 4.0 min, held at 95% B for 4.60 min, column temperature 40 °C.

[0518] Method 22: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and QDa mass spectrometer detector). Column: BEH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 1.40 min. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia [eluent C; continuous at 5%]. Gradient: 2%-50% B with A and 5% C in 1.0 min, to 95% B in 1.8 min, held at 95% B and 5% C for 2.0 min, column temperature 40 °C.

[0519] Method 23: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: Acquity UPLC CSH C18, 1.7 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Conditions: Water [eluent A], MeCN [eluent B], 2% formic acid in water [eluent D; 5% for continuity]. Gradient: 2%-20% B in 1.0 min, to 95% B in 1.8 min, held at 95% B for 2.0 min, column temperature 40 °C.

[0520] Method 24: Waters Acquity UPLC H-Class system (quaternary pump, PDA (210-350 nm) and SQD mass spectrometer detector). Column: XBridge C18, 2.5 μm, 2.1 x 50 mm (flow rate 0.8 mL / min). Run time: 1.80 min. Conditions: 10 mM ammonium bicarbonate pH 10 [eluent A], MeCN [eluent B]. Gradient: 2%-50% B over 1.00 min, held at 98% B until 1.80 min, column temperature 40 °C.

[0521] Method 25: Agilent 1260. Column: XSelect CSH C18. 2.5 μm, 4.6 x 30 mm. Conditions: 0.1% formic acid [eluent A], MeCN [eluent B] (flow rate 2.5 mL / min). Gradient: 5%-95% B over 4 min, column temperature 40 °C.

[0522] Method 26: Agilent 1260 (binary pump, HiP injector, column chamber, DAD: 260 + / - 90 nm, G6150MSD: ESI); column: Cortecs C18, 2.6 μm, 30 x 2.1 mm. Conditions: 0.1% NH3 [eluent A] in water, MeCN [eluent B] (flow rate 1.35 mL / min). Gradient: 5%-100% B over 2.5 min, held at 100% B for 3 min, column temperature 40 °C.

[0523] Method 27: Agilent 1260 (quaternary pump, HiP injector, column chamber, DAD: 260 + / - 90 nm, G6150MSD: ESI); column: Cortecs C18, 2.6 μm, 30 x 2.1 mm. Conditions: 0.1% formic acid [eluent A] in water, MeCN [eluent B] (flow rate 1.35 mL / min). Gradient: 5%-100% B over 2.5 min, held at 100% B for 3 min, column temperature 40 °C.

[0524] Method 28: Agilent 1260 (Waters Acquity PDA 210-400nm and Waters Acquity QDa detector). Column: Waters BEH C18 column, 1.7μm, 30 x 2.1mm. Conditions: 0.1% NH3 [eluent A] and MeCN [eluent B] in water (flow rate 0.77mL / min). Gradient: 2%-100% B over 3 min, column temperature 40℃.

[0525] Method 29: Agilent 1260 (Agilent VWD or DAD detector - set at 254nm, and Agilent MSD detector); column: X-Bridge BEH C18. 2.5 μm, 4.6 x 30 mm. Conditions: 0.1% NH3 [eluent A] and MeCN [eluent B] in water (flow rate 2.5 mL / min). Gradient: 5%-95% B over 4 min, column temperature 40 °C.

[0526] Preparative HPLC is performed using a variety of preparative systems or mass-oriented automated preparation (MDAP) systems with variable wavelength UV detection, as listed below:

[0527] Method 1: Waters Fractionlynx preparative HPLC system with Waters 3100 mass spectrometer detector (2545 pump, 2998 UV / VIS detector, 2767 liquid processor). Column: Waters XBridge OBD C18 column, XSelectCSH C18 (5 μm, 19 x 150 mm) or as specified. Conditions: Eluent selected from MeOH, MeCN, and modifiers selected from formic acid (0.1%) and ammonium hydroxide (0.1%) as specified. Gradient selected as specified.

[0528] Method 2: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters system fluid organizer, Waters 515ACD pump, Waters 2998 photodiode array detector) was used with a Waters XBridge Prep OBD C18 (5 μm, 19 mm x 50 mm id) column and a flow rate of 20 mL / min. Alkaline reversed-phase HPLC (water / acetonitrile / 0.005 M ammonia solution) was used with a standard gradient from 10% acetonitrile / 90% water to 95% acetonitrile / 5% water. UV detection (e.g., 254 nM) was used for fraction collection from the HPLC.

[0529] Method 3: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters system fluid organizer, Waters 515 ACD pump, Waters 2998 photodiode array detector) was used with a Waters XBridge Prep OBD C18 (5 μm, 19 mm x 50 mm id) column and a flow rate of 20 mL / min. Acidic reversed-phase HPLC (water / acetonitrile / 0.1% formic acid) was used with a standard gradient from 5% acetonitrile / 95% water to 95% acetonitrile / 5% water. UV detection (e.g., 254 nM) was used for fraction collection from the HPLC.

[0530] Method 4: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters system fluid organizer, Waters 515ACD pump, Waters 2998 photodiode array detector) was used with a Waters XBridge Prep OBD C18 (5 μm, 19 mm x 50 mm id) column and a flow rate of 20 mL / min. Acidic reversed-phase HPLC (water / acetonitrile / 0.1% trifluoroacetic acid) was used with a standard gradient from 5% acetonitrile / 95% water to 95% acetonitrile / 5% water. UV detection (e.g., 254 nm) was used for fraction collection from the HPLC.

[0531] Method 5: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters system fluid organizer, Waters 515 ACD pump, Waters 2998 photodiode array detector), using a Waters X-Select CSH C18 ODB prep column ( The column (5 μm, 30 mm x 100 mm) was eluted with a 0.1% formic acid gradient in water-MeCN at a flow rate of 40 mL min⁻¹ for 12.5 min. Throughout the method, an on-column dilution pump provided 2 mL min⁻¹ of MeCN, which is included in the following MeCN percentages. Gradient information: 0.0–0.5 min, 25% MeCN; 0.5–10.5 min, from 25% MeCN to 55% MeCN; 10.5–10.6 min, from 55% MeCN to 100% MeCN; 10.6–12.5 min, held at 100% MeCN. UV detection was performed across all wavelengths using a PDA detector, as well as QDA and ELS detectors.

[0532] Method 6: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters system fluid organizer, Waters 515 ACD pump, Waters 2998 photodiode array detector), using a Waters XBridge BEH C18 ODB prep column ( The column (5 μm, 30 mm x 100 mm) was eluted with a 0.3% ammonia gradient in water-MeCN at a flow rate of 40 mL min⁻¹ for 12.5 min. Throughout the method, an on-column dilution pump provided 2 mL min⁻¹ of MeCN, which is included in the following MeCN percentages. Gradient information: 0.0–0.5 min, 30% MeCN; 0.5–10.5 min, from 30% MeCN to 60% MeCN; 10.5–10.6 min, from 60% MeCN to 100% MeCN; 10.6–12.5 min, maintained at 100% MeCN. UV detection was performed across all wavelengths using a PDA detector, as well as QDA and ELS detectors.

[0533] Preparative supercritical fluid chromatography (SFC) was performed on a Waters Investigator SFC comprising a Waters 05962 fluid delivery module, a Waters 07419 autosampler, a Waters 2489 UV / Vis detector, a Waters 08005 column oven, a Waters 279002192 heat exchanger, a Waters ABPR-20A back pressure regulator, and a Waters 08127 fractionation collection module. The general method used liquid CO2 (Airproducts) and a suitable modifier as described. UV detection was performed at 254 nm.

[0534] abbreviation:

[0535]

[0536]

[0537]

[0538] Intermediate 1: 5-(4-aminophenyl)-1,6-dimethylpyridin-2(1H)-one

[0539] XPhos PdG2 (0.47 g, 0.59 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (15.6 g, 71.3 mmol, CAS: 214360-73-3), 5-bromo-1,6-dimethylpyridin-2-one (12.0 g, 59.4 mmol, CAS: 889865-54-7), and 2M potassium carbonate (99 mL, 178 mmol) in degassed ethanol (300 mL) at room temperature. The mixture was heated at 85 °C for 1 h, then diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The organic matter was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was then purified by rapid column chromatography (eluting with 60%–100% EtOAc in heptane, followed by 0%–15% MeOH in EtOAc) to give the title compound (10 g). LCMS (Method 4): 0.46 min, 215.0 [M+H) + .

[0540] Intermediate 1.1: 5-(4-amino-2-fluorophenyl)-1,6-dimethylpyridin-2(1H)-one

[0541] A suspension of 5-bromo-1,6-dimethylpyridin-2-one (1.2 g, 5.8 mmol, CAS: 889865-54-7), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (1.4 g, 5.8 mmol, CAS: 819057-45-9), sodium carbonate (1.5 g, 14.6 mmol), and Pd(dppf)Cl2 (0.47 g, 0.58 mmol) in degassed water (10 mL) / 1,4-dioxane (40 mL) was heated at 80 °C for 4 h. The reaction mixture was then passed through... The sample was filtered and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 100% EtOAc) to provide the title compound (0.43 g). LCMS (Method 3): 1.07 min, 233.1 [M+H] + .

[0542] Intermediate 1.2: 4-(4-aminophenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0543] XPhos (85 mg, 0.18 mmol) and XPhos Pd G2 (70 mg, 0.09 mmol) were added to a stirred suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (0.2 mg, 0.89 mmol, CAS: 214360-73-3) and 4-bromo-1,6-dihydropyrrolo[2,3-c]pyridin-7-one (0.19 mg, 0.89 mmol, CAS: 1361481-62-0) in degassed ethanol (24 mL) and a solution of tripotassium phosphate (1.8 M aqueous, 1.5 mL, 2.7 mmol). The reaction mixture was then heated at 100 °C for 1 h by microwave irradiation. The solvent was removed under vacuum and the residue was ground with toluene. The crude product was purified twice by rapid column chromatography (eluting with 5%–10% MeOH in DCM) to give the title compound (0.13 g). LCMS (Method 4): 0.44 min, 226.07 [M+H] + .

[0544] Intermediate 1.3: 4-(4-aminophenyl)pyridine-2(1H)-one

[0545] The title compound (80 mg) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (277 mg, 1.26 mmol, CAS: 214360-73-3), 4-bromo-1H-pyridin-2-one (0.2 g, 1.2 mmol, CAS: 36953-37-4), sodium carbonate (0.30 g, 2.9 mmol), and Pd(dppf)Cl2 (84 mg, 0.11 mmol) in degassed water (8 mL) / 1,4-dioxane (14 mL) at 80 °C for 2 h. The crude product was purified by rapid column chromatography (eluting with 5% MeOH in EtOAc, followed by elution with 5% MeOH in DCM). LCMS (Method 4): 0.36 min, 187.1 [M+H] + .

[0546] Intermediate 1,4: 4-(imidazo[1,2-a]pyridin-5-yl)aniline

[0547] The title compound (61 mg) was prepared by microwave irradiation at 85 °C for 1 h from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.33 g, 1.5 mmol, CAS: 214360-73-3), 5-bromoimidazolo[1,2-a]pyridine (0.25 g, 1.3 mmol, CAS: 69214-09-1) in degassed ethanol (7.6 mL), 1.8 M tripotassium phosphate aqueous solution (2.1 mL, 3.8 mmol), and XPhosPd G2 (20 mg, 0.03 mmol) in 7.6 mL of degassed ethanol, 81 mg of bromoimidazolo[1,2-a]pyridine, 1.3 mmol of bromoimidazolo[1,2-a]pyridine, 2 ... TM Purification was performed using rapid column chromatography (25 g silica gel column, eluted with 40%-100% EtOAc in heptane). LCMS (Method 4): 0.56 min, 210.1 [M+H] + .

[0548] Intermediate 1.6: 4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)aniline

[0549] The title compound (1.1 g) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (2.2 g, 10.2 mmol, CAS: 214360-73-3), 4-bromo-1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole (3 g, 10.2 mmol, CAS: 1457073-32-3), Xphos Pd G2 (240 mg, 0.31 mmol), and tripotassium phosphate (4.2 g, 31 mmol) in ethanol (44 ml) by microwave irradiation at 80 °C for 1 h. TM Purification was performed using rapid column chromatography (100g silica column, eluted with 0%-100% EtOAc in heptane). 1 H NMR(400MHz,MeOD)δ:7.11–7.03(m,2H),7.03–6.95(m,2H),6.93–6.84(m,2H),6.82–6.74(m,2H),5.21(s,2H),3.77(s,3H),2.16(d,6H).

[0550] Intermediate 1.7: 2-(4-(4-aminophenyl)pyridin-3-yl)-1-(pyrrolidone-1-yl)ethyl-1-one

[0551] Intermediate 1.7a: 2-(4-chloro-3-pyridinyl)-1-pyrrolidine-1-yl-ethyl ketone

[0552] Add 2-(4-chloro-3-pyridyl)acetic acid hydrochloric acid (0.52 g, 2.5 mmol, CAS: 1803562-33-5), triethylamine (1.05 mL, 7.54 mmol), and pyrrolidine (0.31 mL, 3.8 mmol, CAS: 123-75-1) to a stirred solution of MeCN (10 mL) and EtOAc (15 mL) at 0 °C. (50% w / w in EtOAc; 3.2 mL, 5.0 mmol). The reaction mixture was stirred at room temperature for 3 h, then diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The combined organic matter was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (0.38 g), which was used without further purification. LCMS (Method 22): 0.70 min, 189.1 [M-Cl]. + .

[0553] Intermediate 1.7: 2-(4-(4-aminophenyl)pyridin-3-yl)-1-(pyrrolidone-1-yl)ethyl-1-one

[0554] The title compound (0.2 g) was prepared from intermediate 1.7a (0.34 g, 1.6 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.41 g, 1.9 mmol, CAS: 214360-73-3), XPhos PdG2 (123 mg, 0.15 mmol) and potassium carbonate solution (2 M aqueous, 3.1 mL, 6.3 mmol) by heating at 100 °C for 2 h. The crude product was subjected to Biotage Isolera One. TM Purified by rapid column chromatography (40 g Silicycle column, eluted with 0%-20% MeOH in EtOAc). LCMS (Method 22): 0.66 min, 282.1 [M+H] +

[0555] Intermediate 1.8: 6'-amino-1,2-dimethyl-[3,3'-bipyridine]-6(1H)-one

[0556] The title compound (0.23 g) was prepared from 5-(4,4,5,5-methyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.25 g, 1.1 mmol, CAS: 827614-64-2), 5-bromo-1,6-dimethylpyridin-2-one (0.3 g, 1.1 mmol, CAS: 889865-54-7), XPhos Pd G2 (18 mg, 0.02 mmol), and tripotassium phosphate solution (1.8 M aqueous, 1.9 mL, 3.3 mmol) by microwave irradiation at 85 °C for 1 h. The crude product was purified by reversed-phase column chromatography on a Biotage Isolera One (30 g C18 column, eluted with 1%–40% MeCN / 0.1% ammonia (in H2O / 0.1% ammonia solution)). LCMS (Method 4): 0.36 min, 216.1 [M+H] + .

[0557] Intermediate 1.9: 3',5'-dimethyl-[3,4'-bipyridine]-6-amine

[0558] The title compound (0.22 g) was prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.25 g, 1.1 mmol, CAS: 827614-64-2), 4-chloro-3,5-dimethylpyridine (0.16 g, 1.1 mmol, CAS: 143798-73-6), XPhos Pd G2 (18 mg, 0.02 mmol), and potassium carbonate solution (1.8 M aqueous, 1.9 mL, 3.4 mmol) by microwave irradiation at 85 °C for 2 h. The crude product was subjected to Biotage Isolera One. TM Purified by reversed-phase column chromatography (30g C18 column, eluted with 10%-70% MeCN / 0.1% ammonia (in H2O / 0.1% ammonia solution)). LCMS (Method 4): 0.49 min, 200.1 [M+H] + .

[0559] Intermediate 1.17: 4-(3,5-dimethylpyridin-4-yl)aniline

[0560] Water (8.4 mL) and ethanol (17 mL) were added to a mixture of 4-chloro-3,5-dimethylpyridine (0.93 g, 6.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (1.4 g, 6.6 mmol), X Phos Pd G2 (52 mg, 0.07 mmol), and K2CO3 (2.7 g, 19.7 mmol). The reaction mixture was degassed with argon and then stirred at 85 °C for 1 h. The mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was passed through a Biotage Isolera. TM The sample was purified by rapid column chromatography (4 g silica gel column, eluted with 0%-10% MeOH in DCM) to provide the title compound (1.3 g). 1 ¹H NMR (400MHz, CDCl₃) δ: 8.34–8.19 (m, 2H), 6.92–6.80 (m, 2H), 6.80–6.67 (m, 2H), 2.03 (t, 6H), NH₄⁺ not observed.

[0561] Intermediate 1.18: 5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-amine

[0562] Intermediate 1.18a: 4-bromo-1-[(4-methoxyphenyl)methyl]-3,5-dimethylpyrazole

[0563] Add 1-(bromomethyl)-4-methoxybenzene (0.57 g, 2.9 mmol, CAS: 3398-16-1) to a solution of 4-bromo-3,5-dimethyl-1H-pyrazole (0.5 g, 2.9 mmol, CAS: 3398-16-1) and potassium carbonate (0.39 g, 2.9 mmol) in acetone (10 mL). Heat the mixture at 55 °C for 18 h. Concentrate the reaction mixture under vacuum. Partition the residue between EtOAc and brine. Dry the organic matter with Na₂SO₄, filter, and concentrate under vacuum. Pass the crude product through Biotage Isolera One. TM The compound was purified by rapid column chromatography (12 g silica column, eluted with 0%-30% EtOAc in heptane) to give the title compound (0.53 g). 1 H NMR(400MHz, CDCl3)δ:7.08–7.01(m,2H),6.87–6.81(m,2H),5.16(s,2H),3.78(s,3H),2.23(s,3H),2.15(s,3H).

[0564] Intermediate 1.18b: N-[5-[1-[(4-methoxyphenyl)methyl]-3,5-dimethyl-pyrazol-4-yl]-2-pyridyl]tert-butyl carbamate

[0565] The title compound (0.61 g) was prepared from intermediate 1.18a (0.49 g, 1.7 mmol) and N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-2-pyridyl]carbamate tert-butyl ester (0.53 g, 1.7 mmol, CAS: 910462-31-6), XPhos Pd G2 (26 mg, 0.03 mmol), and tripotassium phosphate solution (1.8 M aqueous, 2.8 mL, 5.0 mmol) under reflux for 19 h. The crude product was purified by rapid column chromatography (eluting with 0%–80% EtOAc in heptane). LCMS (Method 14): 1.88 min, 409.2 [M+H] + .

[0566] Intermediate 1.18: 5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-amine

[0567] HCl (4 M in 1,4-dioxane; 0.54 mL, 2.2 mmol) was added to a solution of intermediate 1.18b (0.6 g, 1.5 mmol) in 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature for 20 h, then a further portion of HCl (4 M in 1,4-dioxane; 2.4 mL, 9.6 mmol) was added, and the mixture was stirred again at room temperature for 2.5 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in DCM and washed with saturated aqueous NaHCO3 and brine. The combined organics were concentrated under vacuum. The crude product was purified by rapid column chromatography (20%–100% EtOAc in heptane) to provide the title compound (0.27 g). 1 H NMR(400MHz, CDCl3)δ:7.89(dd,1H),7.29–7.20(m,1H),7.08–7.00(m,2H),6.83–6.75( m,2H),6.48(dd,1H),5.13(s,2H),4.34(s,2H),3.72(s,3H),2.17(s,3H),2.07(s,3H).

[0568] Intermediate 1.23: tert-butyl 4-(4-aminophenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylate

[0569] Ethanol (2 mL) and water (0.5 mL) were added to a mixture of tert-butyl 4-bromo-3,5-dimethylpyrazole-1-carboxylate (0.2 g, 0.73 mmol, CAS: 1040276-87-6), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.16 g, 0.73 mmol), K₂CO₃ (0.4 g, 2.9 mmol), and Xphos Pd G₂ (57 mg, 0.07 mmol). The reaction mixture was degassed with argon and then stirred at 85 °C for 1 h. The mixture was extracted with EtOAc, dried over MgSO₄, filtered, and concentrated under vacuum. The crude product was passed through a Biotage Isolera. TM The title compound (70 mg) was purified by rapid column chromatography (40 g silica gel column, eluted with 0%-10% MeOH in DCM). 1 H NMR(400MHz, CDCl3)δ:7.04–6.95(m,2H),6.77–6.70(m,2H),3.49(s,2H),2.42(s,3H),2.23(s,3H),1.66(s,9H).

[0570] Intermediate 1.25: 5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine-2-amine

[0571] The title compound (0.35 g) was prepared from 5-iodopyridin-2-amine (1.1 g, 5 mmol, CAS: 20511-12-0), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazole (1.1 g, 5 mmol, CAS: 1047644-76-7), XPhos Pd G2 (79 mg, 0.1 mmol), and tripotassium phosphate solution (1.8 M aqueous, 8.3 mL, 15 mmol) under reflux for 20 h. The crude product was subjected to Biotage Isolera One. TM Purified by rapid column chromatography (40g silica gel column, eluted with 0%-10% MeOH in DCM). LCMS (Method 14): 1.06 min, 189.2 [M+H] + .

[0572] Intermediate 1.44: 5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-amine

[0573] Tributyl-(3,5-dimethyltriazol-4-yl)stanane (2.2 g, 5.6 mmol, CAS: 1047637-17-1), triethylamine (1.2 mL, 8.4 mmol), and copper iodide (I) (80 mg, 0.42 mmol) were added to a solution of N-(5-iodo-2-pyridyl)carbamate (0.9 g, 2.8 mmol, CAS: 375853-79-5) in 1,4-dioxane (14 mL). The reaction mixture was degassed with argon for 5 min, then tetrakis(triphenylphosphine)palladium (0) (0.33 g, 0.28 mmol) was added, and the reaction mixture was heated at 120 °C for 20 h. The reaction was concentrated under vacuum, and the residue was partitioned between EtOAc and water. The organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to Biotage Isolera One. TM The title compound (0.3 g) was purified by rapid column chromatography (100 g silica column, eluted with 0%-100% EtOAc in heptane). 1 H NMR (400MHz, MeOD) δ: 8.28 (dd, 1H), 8.05 (dd, 1H), 7.82 (dd, 1H), 3.97 (s, 3H), 2.28 (s, 3H), 1.55 (s, 9H).

[0574] Intermediate 1.44a: 2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridine

[0575] Add 1,4-dimethyl-1H-1,2,3-triazole (4.6 g, 48 mmol, CAS: 60166-43-0), 2,2-dimethylpropionic acid (0.73 g, 7.2 mmol), K₂CO₃ (6.6 g, 48 mmol), and PEPPSI to a solution of 5-bromo-2-chloropyridine (4.6 g, 24 mmol, CAS: 53939-30-3) in DMA (100 mL). TM -IPr catalyst (0.33 g, 0.28 mmol). The mixture was heated at 120 °C for 20 h. The reaction was concentrated under vacuum and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc, and the combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to Biotage Isolera One. TM The compound was purified by rapid column chromatography (340 g silica gel column, eluted with 0%-70% EtOAc in heptane) to give the title compound (1.6 g). 1H NMR (400MHz, CDCl3) δ: 8.39 (dd, 1H), 7.63 (dd, 1H), 7.51 (dd, 1H), 3.97 (s, 3H), 2.33 (s, 3H).

[0576] Intermediate 1.57: 6-(3,5-dimethylisoxazol-4-yl)pyridine-3-amine

[0577] The title compound (0.18 g) was prepared from 2-chloropyridin-5-amine (1 g, 7.8 mmol, CAS: 5350-93-6), (3,5-dimethylisoxazol-4-yl)boronic acid (3.8 mg, 27 mmol, CAS: 16114-47-9), Pd(dppf)Cl2 (0.57 g, 0.78 mmol), and sodium carbonate (3.3 g, 31 mmol) by microwave irradiation at 145 °C for 3 h. The crude product was subjected to Biotage Isolera One... TM Purification was performed by reversed-phase column chromatography (50 g C18 column, eluted with 5%-100% MeCN in aqueous buffer containing 0.005 M NH4OH). LCMS (Method 14): 1.21 min, 190.2 [M+H] + .

[0578] Intermediate 1.59: 5-(5-methylpyrimidin-4-yl)pyridin-2-amine

[0579] The title compound (0.24 g) was prepared from 4-chloro-5-methylpyrimidine (0.25 g, 2.0 mmol, CAS: 51957-32-5), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.43 mg, 2.0 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.14 g, 0.19 mmol), and sodium carbonate (0.62 mg, 5.8 mmol) by heating at 80 °C for 3 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One TM Rapid column chromatography (20g silica gel column, eluted with 0-7% MeOH in DCM) and Biotage Isolera One TM Purification was performed using rapid column chromatography (4g silica gel column, 0-7% MeOH in DCM). 1 H NMR (400MHz, CDCl3) δ: 9.10 (s, 1H), 8.59 (s, 1H), 8.47 (dd, 1H), 7.88 (dd, 1H), 6.64 (dd, 1H), 4.75 (s, 2H), 2.47 (d, 3H).

[0580] Intermediate 1.61: 5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridine-2-amine

[0581] The title compound (0.2 g) was prepared from 4-bromo-3-(methoxymethyl)-5-methylisoxazole (0.57 g, 2.76 mmol, CAS: 1000894-06-3), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.67 g, 3.0 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.23 g, 0.28 mmol), and potassium carbonate (1.1 g, 8.3 mmol) by heating at 120 °C for 1 h according to the procedure described for intermediate 1.1. The crude product was subjected to BiotageIsolera One TM Purified by rapid column chromatography (40 g silica gel column, eluted with 0%-100% EtOAc in heptane). LCMS (Method 14): 1.18 min, 220.2 [M+H2O] + .

[0582] Intermediate 1.62: 2-chloro-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine

[0583] Intermediate 1.62a: 5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-2-methoxypyridine

[0584] A solution of dimethylacetamide dimethyl acetal (0.18 g, 13.3 mmol, CAS: 18871-66-4) and acetylhydrazine (0.98 g, 13.3 mmol, CAS: 1068-57-1) in acetonitrile (5 mL) was heated to 50 °C and held for 30 min. Then, 6-methoxypyridine-3-amine (0.15 g, 12.1 mmol, CAS: 6628-77-9), acetic acid (7.5 mL), and acetonitrile (2.5 mL) were added. The reaction mixture was heated to 120 °C and held for 20 h, then concentrated under vacuum. The crude product was ground with diethyl ether to give the title compound (0.72 g). LCMS (Method 14): 1.24 min, 205.2 [M+H] + .

[0585] Intermediate 1.62b: 5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2(1H)-one

[0586] HBr (48% aqueous; 7.5 mL, 66 mmol) was added to a solution of intermediate 1.62a (0.68 g, 3.3 mmol) in acetic acid (7.7 mL). The reaction mixture was heated to 80 °C and held for 6 h, then concentrated under vacuum. The residue was azeotropically eluted from a mixture of EtOAc and heptane (1:1). The crude product was ground with diethyl ether to give the title compound (0.65 g). 1 H NMR (400MHz, MeOD) δ: 8.05 (d, 1H), 7.73 (dd, 1H), 6.75 (d, 1H), 2.53 (s, 6H).

[0587] Intermediate 1.62: 2-chloro-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine

[0588] Phosphorus oxychloride (2.5 mL, 26 mmol) was added to intermediate 1.62b (0.5 g, 2.6 mmol), and the reaction was heated under reflux for 20 h. The mixture was concentrated under vacuum, and then a mixture of MeOH / H2O (1:1) was slowly added. The crude product was subjected to Biotage Isolera One. TM Purification was performed by rapid column chromatography (20 g silica column, eluted with 0%-10% MeOH in DCM) to give the title compound (0.41 g). LCMS (Method 14): 1.22 min, 209.2 [M+H] + .

[0589] Intermediate 1.64: 6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine-3-amine

[0590] The title compound (0.91 g) was prepared from 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazole (0.13 g, 5.5 mmol, CAS: 1047644-76-7), 6-chloropyridin-3-amine (0.71 g, 5.5 mmol, CAS: 5350-93-6), XPhos Pd G2 (87 mg, 0.11 mmol), and tripotassium phosphate (2.5 M aqueous; 6.6 mL, 16.6 mmol) and heated under reflux for 24 h according to the procedure described for intermediate 1. The crude product was subjected to Biotage IsoleraOne... TM Purified by rapid column chromatography (20 g silica gel column, eluted with 10% MeOH in DCM). LCMS (Method 14): 1.22 min, 189.2 [M+H] + .

[0591] Intermediate 1.65: 4-Methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine

[0592] The title compound (0.85 g) was prepared from 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazole (1.7 g, 8 mmol, CAS: 847818-74-0), 5-bromo-4-methylpyridin-2-amine (1 g, 5.3 mmol, CAS: 98198-48-2), Pd(dppf)Cl2 (0.19 mg, 0.27 mmol), and sodium carbonate (2.3 g, 21 mmol) by heating at 120 °C for 16 h according to the procedure described for intermediate 1.1. TM Purification was performed by rapid column chromatography (12 g silica column, eluted with 0%-10% MeOH in DCM). LCMS (Method 19): 0.52 min, 189.2 [M+H] + .

[0593] Intermediate 1.66: 2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-amine

[0594] The title compound (0.66 g) was prepared from 2-chloropyrimidin-5-amine (603 mg, 4.66 mmol, CAS: 56621-90-0), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazole (1.0 g, 4.7 mmol, CAS: 1047644-76-7), XPhos Pd G2 (73 mg, 0.09 mmol), and tripotassium phosphate (2.5 M aqueous; 5.6 mL, 16.6 mmol) under reflux for 24 h. The crude product was subjected to Biotage Isolera One. TM Purified by rapid column chromatography (20 g silica gel column, eluted with 10% MeOH in DCM). LCMS (Method 19): 1.25 min, 190.2 [M+H] + .

[0595] Intermediate 1.69: 5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridine-2-amine

[0596] Intermediate 1.69a: 4-bromo-5-(methoxymethyl)-3-methylisoxazole

[0597] 5-(methoxymethyl)-3-methylisoxazole (1.1 g, 8.3 mmol, CAS: 13999-31-0) was dissolved in DMF (13 mL) and NBS (1.8 g, 9.9 mmol) was added in a single batch. The reaction was heated at 55 °C for 20 h under argon atmosphere. The reaction was cooled to room temperature, diluted with diethyl ether, and washed with water and brine. The organic matter was dried over Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (1.7 g). 1 H NMR (400MHz, MeOD) δ: 4.53 (s, 2H), 3.37 (s, 3H), 2.28 (s, 3H).

[0598] Intermediate 1.69: 5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridine-2-amine

[0599] The title compound (0.22 g) was prepared from intermediate 1.69a (1.6 g, 7.8 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (1.9 g, 8.5 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.63 g, 0.78 mmol), and potassium carbonate (3.2 g, 23 mmol) by heating at 120 °C for 1 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One... TM Purification was performed using rapid column chromatography (40g silica gel column, eluted with 0%-100% EtOAc in heptane). 1 H NMR (400MHz, MeOD) δ: 7.91 (dd, 1H), 7.49 (dd, 1H), 6.67 (dd, 1H), 4.45 (s, 2H), 3.36 (s, 3H), 2.28 (s, 3H).

[0600] Intermediate 1.70: 3'-methoxy-2'-methyl-[3,4'-bipyridine]-6-amine

[0601] The title compound (0.2 g) was prepared from 4-chloro-3-methoxy-2-methylpyridine (0.50 g, 3.2 mmol, CAS: 107512-34-5), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine-2-amine (0.7 g, 3.2 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.23 g, 0.32 mmol), and sodium carbonate (1.0 g, 9.5 mmol) by heating at 80 °C for 3 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One TMPurification was performed using rapid column chromatography (10g silica column, eluted with 0%-5% MeOH in DCM). 1 H NMR (400MHz, CDCl3) δ: 8.23 ​​(s, 1H), 8.18 (d, 1H), 7.70 (dd, 1H), 7.21 (d, 1H), 6.53 (d, 1H), 6.24 (s, 2H), 3.43 (s, 3H), 2.45 (s, 3H).

[0602] Intermediate 1.71: 2',3'-dimethyl-[3,4'-bipyridine]-6-amine

[0603] The title compound (0.5 g) was prepared from 4-bromo-2,3-dimethylpyridine (0.50 g, 2.7 mmol, CAS: 259807-91-5), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine-2-amine (0.59 g, 2.7 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.2 g, 0.27 mmol), and sodium carbonate (0.85 g, 8.1 mmol) by heating at 80 °C for 3 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One TM Purification was performed using rapid column chromatography (10g silica column, eluted with 0%-5% MeOH in DCM). 1 H NMR (400MHz, CDCl3) δ: 8.33 (d, 1H), 8.04 (dd, 1H), 7.40 (dd, 1H), 6.97 (d, 1H), 6.58 (dd, 1H), 4.59 (br s, 2H), 2.58 (s, 3H), 2.22 (s, 3H).

[0604] Intermediate 1.72: 2',5'-dimethyl-[3,4'-bipyridine]-6-amine

[0605] The title compound (0.17 g) was prepared from 4-chloro-2,5-dimethylpyridine (0.50 g, 3.5 mmol, CAS: 22282-80-0), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine-2-amine (0.78 g, 3.5 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.26 g, 0.35 mmol), and sodium carbonate (1.1 g, 10.6 mmol) by heating at 80 °C for 20 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One TMPurification was performed using rapid column chromatography (10g silica gel column, eluted with 0%-5% MeOH in DCM) and SCX column chromatography (5g, washed with MeOH and eluted with 2M methylamine). 1 H NMR(400MHz, DMSO-d6)δ:8.29(s,1H),7.96(d,1H),7.47(dd,1H),7.07(s,1H),6.52(dd,1H),6.15(br s,2H),2.43(s,3H),2.22(s,3H).

[0606] Intermediate 1.76: 2-chloro-5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine

[0607] Intermediate 1.76a: 1-Ethyl-4-methyl-1H-1,2,3-triazole

[0608] A solution of 1,1-dimethoxypropane-2-one (1 g, 8.5 mmol, CAS: 6342-56-9) and 4-toluenesulfonyl hydrazine (1.6 g, 8.5 mmol, CAS: 1576-35-8) in MeOH (2 mL) was stirred at room temperature for 10 min. Ethylamine (4.7 mL, 9.3 mmol) and Et3N (1.3 mL, 9.3 mmol) were added, and the mixture was heated at 140 °C for 5 min by microwave irradiation. The mixture was concentrated under vacuum, and the residue was dissolved in DCM and H2O. The phases were separated, and the aqueous layer was extracted with DCM. The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (0.99 g), which was used without further purification. 1 H NMR (400MHz, CDCl3) δ: 7.30 (s, 1H), 4.38 (qt, 2H), 2.38–2.33 (m, 3H), 1.54 (tt, 3H).

[0609] Intermediate 1.76: 2-chloro-5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine

[0610] According to the procedure described for intermediate 1.44a, from intermediate 1.76a (0.98 g, 8.8 mmol), 5-bromo-2-chloropyridine (0.85 g, 4.4 mmol, CAS: 53939-30-3), PEPPSI TM The title compound (0.27 g) was prepared by heating at 130 °C for 2 h with IPr catalyst (60 mg, 0.09 mmol), 2,2-dimethylpropionic acid (0.14 g, 1.3 mmol), and potassium carbonate (1.2 g, 8.8 mmol). The crude product was then subjected to Biotage Isolera One... TMPurification was performed by rapid column chromatography (10 g silica column, eluted with 0%-70% EtOAc in heptane) and reversed-phase preparative HPLC (Method 2). LCMS (Method 14): 1.55 min, 223.6 [M+H2O] + .

[0611] Intermediate 1.77: 4-(5-chloropyrazin-2-yl)-3,5-dimethylisoxazole

[0612] The title compound (0.52 g) was prepared from 2-bromo-5-chloro-pyrazine (1 g, 5.2 mmol, CAS: 912773-21-8), (3,5-dimethylisoxazol-4-yl)boronic acid (1.1 g, 7.8 mmol, CAS: 16114-47-9), Pd(dppf)Cl2 (0.19 mg, 0.26 mmol), and sodium carbonate (2.2 g, 21 mmol) by heating at 120 °C for 16 h according to the procedure described for intermediate 1.1. TM Purified by rapid column chromatography (12 g silica column, eluted with 0%-10% MeOH in DCM). LCMS (Method 19): 2.09 min, 210.2 [M+H] + .

[0613] Intermediate 1.80: 2-chloro-5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine

[0614] According to the procedure described for intermediate 1.44a, from 1-cyclopropyl-4-methyltriazole (1.1 g, 8.8 mmol, CAS: 2370890-05-2), 5-bromo-2-chloropyridine (0.85 g, 4.4 mmol, CAS: 53939-30-3), PEPPSI TM The title compound (0.26 g) was prepared by heating at 130 °C for 2 h with IPr catalyst (60 mg, 0.09 mmol), 2,2-dimethylpropionic acid (0.14 g, 1.3 mmol), and potassium carbonate (1.2 g, 8.8 mmol). The crude product was then subjected to Biotage Isolera One... TM Purification was performed by rapid column chromatography (10 g silica column, eluted with 0%-70% EtOAc in heptane) and reversed-phase preparative HPLC (Method 2). LCMS (Method 14): 1.55 min, 223.6 [M+H2O] + .

[0615] Intermediate 1.81: 5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridine-2-amine

[0616] The title compound (0.56 g) was prepared from 5-bromo-3-fluoro-pyridin-2-amine (1.0 g, 5.2 mmol, CAS: 748812-37-5), (3,5-dimethylisoxazol-4-yl)boronic acid (0.89 g, 6.3 mmol, CAS: 16114-47-9), Pd(dppf)Cl2 (0.19 g, 0.26 mmol), and sodium carbonate (0.22 g, 21 mmol) by heating at 80 °C for 16 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One... TM Purification was performed by rapid column chromatography (25 g silica gel column, eluted with 0%-2% MeOH in DCM). LCMS (Method 14): 1.26 min, 208.2 [M+H] + .

[0617] Intermediate 1.84: 2-chloro-5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidine

[0618] The title compound (0.16 g) was prepared from 5-bromo-2-chloropyrimidine (0.25 g, 1.3 mmol, CAS: 32779-36-5), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazole (0.34 g, 1.5 mmol, CAS: 1047644-76-7), tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mmol), and potassium carbonate (0.36 g, 2.6 mmol) according to the procedure described for intermediate 1.44. The crude product was subjected to Biotage Isolera One. TM Purification was performed by rapid column chromatography (12 g silica column, eluted with 0%-2% MeOH in DCM). LCMS (Method 14): 1.51 min, 209.2 [M+H] + .

[0619] Intermediate 1.92: 5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridine-2-amine

[0620] Intermediate 1.92a: 1-Cyclopropyl-2,2-Diethoxy-ethyl ketone

[0621] A solution of 2,2-diethoxy-N-methoxy-N-methylacetamide (3.35 g, 17.5 mmol, CAS: 1378705-69-1) in anhydrous THF (80 mL) was cooled to -78 °C under argon. A solution of magnesium bromo(cyclopropyl)magnesium (1 M in MeTHF; 21 mL, 21 mmol, CAS: 23719-80-4) was slowly added, and the mixture was stirred at -78 °C for 3 h. The reaction was quenched by adding saturated aqueous NH4Cl and extracted with EtOAc. The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (3.0 g). 1 H NMR (400MHz, CDCl3) δ: 4.71 (s, 1H), 3.76–3.54 (m, 4H), 2.41–2.33 (m, 1H), 1.30–1.20 (m, 6H), 1.09–1.04 (m, 2H), 1.01–0.91 (m, 2H).

[0622] Intermediate 1.92b: 4-Cyclopropyl-1-methyl-1H-1,2,3-triazole

[0623] 4-Toluenesulfonylhydrazine (2.8 g, 15.1 mmol, CAS: 1576-35-8) was added to a stirred solution of intermediate 1.92a (2 g, 11.6 mmol) in MeOH (25 mL), and the mixture was stirred at room temperature for 1 h. A further portion of 4-toluenesulfonylhydrazine (0.64 g, 3.4 mmol) was added, and the mixture was stirred at room temperature for 1 h. Then, methylamine (1.3 mL, 15.1 mmol) and triethylamine (2.1 mL, 15.1 mmol) were added, and the mixture was stirred at room temperature for 5 min, followed by heating at 140 °C for 5 min by microwave irradiation. The mixture was concentrated under vacuum, and the residue was dissolved in water and DCM. The aqueous layer was extracted with DCM, and the combined organic matter was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was subjected to Biotage Isolera One. TM The sample was purified by rapid column chromatography (40 g silica gel column, eluted with 2%-65% EtOAc in heptane) to provide the title compound (0.66 g). 1 H NMR (400MHz, CDCl3) δ: 7.20 (s, 1H), 4.02 (s, 3H), 1.97-1.89 (m, 1H), 0.96-0.90 (m, 2H), 0.84-0.79 (m, 2H).

[0624] Intermediate 1.92: 5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridine-2-amine

[0625] Under argon atmosphere, 5-bromo-2-chloropyridine (1.4 g, 7.3 mmol, CAS: 53939-30-3), palladium(II) acetate (55 mg, 0.24 mmol), potassium carbonate (0.67 g, 4.9 mmol), and triphenylphosphine (0.13 g, 0.49 mmol) were added to a solution of intermediate 1.92b (0.3 g, 2.4 mmol) in toluene (6.1 mL), 5-bromo-2-chloropyridine (55 mg, 0.24 mmol), 5-bromo-2-chloropyridine (0.47 g, 2.4 mmol), and the reaction mixture was stirred at 120 °C for 40 h. A further fraction of palladium(II) acetate (55 mg, 0.24 mmol), triphenylphosphine (0.13 g, 0.49 mmol), potassium carbonate (0.34 g, 2.5 mmol), and 5-bromo-2-chloropyridine (0.47 g, 2.4 mmol) was added, and the reaction mixture was stirred at 120 °C for 72 h. The reaction mixture was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then passed through Biotage Isolera One. TM The sample was purified by rapid column chromatography (12 g silica column, eluted with 2%-80% EtOAc in heptane) to provide the title compound (0.22 g). 1 H NMR(400MHz, CDCl3)δ:8.48(dd,1H),7.73(dd,1H),7.52(dd,1H),3.96(s,3H),1.77–1.66(tt,1H),1.07–1.00(m,2H),0.97–0.87(m,2H).

[0626] Intermediate 1.93: 5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-amine

[0627] The title compound (1.1 g) was prepared from 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazole (2.3 g, 9.5 mmol, CAS: 1430057-83-2), 5-bromopyridin-2-amine (1.1 g, 6.40 mmol, CAS: 1072-97-5), XPhos Pd G2 (0.25 g, 0.32 mmol), and tripotassium phosphate (0.5 M aqueous, 25 mL, 13 mmol) and heated to 60 °C for 18 h, according to the procedure described for intermediate 1. The crude product was purified by rapid column chromatography (eluting with 0%–5% MeOH in DCM). 1 H NMR (400MHz, CDCl3) δ: 8.04 (dd, 1H), 7.46–7.39 (m, 2H), 6.56 (dd, 1H), 4.71 (s, 2H), 3.73 (s, 3H).

[0628] Intermediate 1.98: 6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridine-3-amine

[0629] The title compound (1 g) was prepared from 6-bromo-5-fluoro-pyridin-3-amine (1 g, 5.2 mmol, CAS: 1256276-41-1), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazole (1.7 g, 7.9 mmol, CAS: 1047644-76-7), Pd(dppf)Cl2 (0.38 g, 0.52 mmol), and sodium carbonate (2.2 g, 21 mmol) by microwave irradiation at 120 °C for 1 h. The crude product was subjected to BiotageIsolera One... TM Purification was performed using rapid column chromatography (20g silica gel column, eluted with 20%-100% EtOAc in heptane). 1 HNMR (400MHz, CDCl3) δ: 8.05 (s, 1H), 7.37 (s, 1H), 6.86–6.74 (m, 1H), 3.82 (s, 3H), 2.01 (d, 3H).

[0630] Intermediate 1.109: 2-(5-(6-chloropyridin-3-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-N , N-dimethylamine Acetamide

[0631] Intermediate 1.109a: N,N-dimethyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)acetamide

[0632] Add to a solution of 2-(4-methyltriazol-1-yl)acetic acid (0.11 g, 8.1 mmol, CAS: 887405-58-5) and N-methylmethylamine (2 M in THF; 12 mL, 24 mmol) in DMF (25 mL). (50% w / w solution in EtOAc; 7.2 mL, 12 mmol). The reaction mixture was stirred at room temperature for 20 h, then concentrated under vacuum. The residue was diluted with DCM and washed with aqueous saturated NaHCO3. The aqueous layer was extracted with DCM, and the combined organic matter was washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product was subjected to Biotage Isolera One. TM Purification was performed by rapid column chromatography (40 g silica column, eluted with 0%–10% MeOH in DCM) to provide the title compound (0.7 g). LCMS (Method 14): 1.01 min, 169.2 [M+H] + .

[0633] Intermediate 1.109: 2-(5-(6-chloropyridin-3-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-N,N-dimethylacetamide

[0634] A solution of intermediate 1.109a (0.64 g, 3.1 mmol), 5-bromo-2-chloropyridine (0.59 g, 3.1 mmol, CAS: 53939-30-3), 2,2-dimethylpropionic acid (94 mg, 0.92 mmol), palladium(II) acetate (69 mg, 0.31 mmol), and potassium carbonate (0.85 g, 6.1 mmol) in DMA (12 mL) was heated at 120 °C for 1 h by microwave irradiation. The reaction mixture was cooled to room temperature, diluted with EtOAc, and quenched with aqueous saturated NH4Cl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic compounds were washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude product was subjected to Biotage IsoleraOne. TM Purification was performed by rapid column chromatography (20 g silica column, eluted with 0%-100% EtOAc in heptane, followed by elution with 0%-10% MeOH in DCM) to provide the title compound (71 mg). 1 H NMR (400MHz, CDCl3) δ: 8.40 (dd, 1H), 7.80 (dd, 1H), 7.46 (dd, 1H), 5.05 (s, 2H), 3.07 (s, 3H), 2.96 (s, 3H), 2.33 (s, 3H).

[0635] Intermediate 1.112: 5-(6-aminopyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxynitrile

[0636] The title compound (0.21 g) was prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.53 g, 2.4 mmol, CAS: 827614-64-2), 5-bromo-1-methylpyrazol-4-carboxynitrile (0.3 g, 1.6 mmol, CAS: 1269293-80-2), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and sodium carbonate (0.68 g, 6.5 mmol) by microwave irradiation at 120 °C for 1 h. The crude product was subjected to Biotage Isolera One... TM Purification was performed by reversed-phase column chromatography (20 g silica gel column, eluted with 0%-100% EtOAc in heptane, then eluted with 0%-10% MeOH in DCM). LCMS (Method 14): 0.78 min, 200.2 [M+H) + .

[0637] Intermediate 1.114: 5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridine-2-amine

[0638] Divide the mixture into three separate batches and heat a mixture of 2,4,5-trimethyl-4H-pyrazole-3-one hydrochloride (1.5 g, 9.2 mmol, CAS: 1285259-23-5), N-phenyl-bis(trifluoromethanesulfonylimide) (3.5 g, 9.7 mmol), and sodium carbonate (2.9 g, 27.6 mmol) in THF (33 mL) at 110 °C for 6 min by microwave irradiation. Cool the mixture to room temperature, then add 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine-2-amine (3.1 g, 14 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.34 g, 0.46 mmol), and water (15 mL), and heat the mixture at 110 °C for 45 min by microwave irradiation. These batches were combined and the mixture was filtered through a diatomaceous earth pad. The solvent was concentrated under vacuum, and the crude product was purified by rapid column chromatography (eluting with 0%–5% MeOH in DCM) to provide the title compound (1.4 g). LCMS (Method 14): 0.97 min, 203.2 [M+H] + .

[0639] Intermediate 1.115: 5-(3,5-dimethylisothiazo-4-yl)pyridine-2-amine

[0640] The title compound (0.14 g) was prepared from 4-iodo-3,5-dimethylisothiazolium (0.2 g, 0.82 mmol, CAS: 113234-27-8), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.18 g, 0.82 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (59 mg, 0.08 mmol), and potassium carbonate (0.34 g, 2.5 mmol) by heating at 100 °C for 18 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One... TM Purification was performed using rapid column chromatography (40g silica column, eluted with 2%-10% MeOH in DCM). 1 H NMR (400MHz, CDCl3) δ: 7.94 (s, 1H), 7.32 (dd, 1H), 6.61 (d, 1H), 4.60 (s, 2H), 2.39 (s, 3H), 2.33 (s, 3H).

[0641] Intermediate 1.126: 6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)pyridine-3-amine

[0642] Water (1 mL), Pd-170 (26 mg, 0.04 mmol), and potassium carbonate (0.24 g, 1.7 mmol) were added to a stirred solution of 6-chloropyridin-3-amine (0.1 g, 0.8 mmol, CAS: 5350-93-6) and 2-[[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (0.58 g, 1.4 mmol, CAS: 1000801-22-8) in 1,4-dioxane (4 mL). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with brine, and extracted with EtOAc. The combined organic matter was passed through a phase separator and concentrated under vacuum. The crude product was subjected to Teledyne ISCO. The title compound (0.21 g) was purified by rapid column chromatography (12 g silica gel column, eluted with 0%-100% 3:1 EtOAc:EtOH (in isohexane)) to provide a brown oily substance. LCMS (Method 28): 1.42 min, 319.5 [M+H] + .

[0643] Intermediate 1.133: 6'-amino-1,2,4-trimethyl-[3,3'-bipyridine]-6(1H)-one

[0644] The title compound (90 mg) was prepared from 5-bromo-1,4,6-trimethylpyridin-2-one (0.1 g, 0.48 mmol, CAS: 1380389-40-1), (6-amino-3-pyridyl)boronic acid (0.1 g, 0.73 mmol, CAS: 851524-96-4), Pd-170 (20 mg, 0.03 mmol), and potassium carbonate (0.13 g, 0.96 mmol) according to the procedure described for intermediate 1.126. The crude product was subjected to Teledyne ISCO... Purification was performed by rapid column chromatography (12 g silica column, eluted with 0%-10% MeOH in DCM). LCMS (Method 29): 0.44 min, 230.2 [M+H] + .

[0645] Intermediate 1.135: 5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine-2-amine

[0646] The title compound (79 mg) was prepared from 4-bromo-1,3,5-trimethylpyrazole (0.1 g, 0.55 mmol, CAS: 15801-69-1), (6-amino-3-pyridyl)boronic acid (0.11 g, 0.83 mmol, CAS: 851524-96-4), Pd-170 (22 mg, 0.03 mmol), and potassium carbonate (0.15 g, 1.1 mmol) according to the procedure described for intermediate 1.126. The crude product was subjected to Teledyne ISCO... Purification was performed by rapid column chromatography (12 g silica column, eluted with 0%-10% MeOH in DCM). LCMS (Method 26): 0.53 min, 203.2 [M+H] + .

[0647] Intermediate 1.138: 5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridine-2-amine

[0648] The title compound (0.45 g) was prepared from 5-iodo-1-methyl-4-(trifluoromethyl)-1H-pyrazole (0.75 g, 2.7 mmol, CAS: 2137730-49-3), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.82 g, 3.3 mmol, CAS: 827614-64-2), Pd(dppf)Cl2 (0.2 g, 0.27 mmol), and potassium carbonate (1.1 g, 8.2 mmol) by heating at 80 °C for 18 h according to the procedure described for intermediate 1.1. The crude product was subjected to BiotageIsolera One TM The sample was purified by rapid column chromatography (50 g silica gel column, eluted with 2%–4% MeOH in DCM) followed by purification via an SCX column (10 g, washed with MeOH and eluted with 2 M methylamine). LCMS (Method 14): 1.18 min, 243.2 [M+H] + .

[0649] Intermediate 2: ((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0650] At room temperature under an argon atmosphere, intermediate 1 (79 mg, 0.37 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (50 mg, 0.18 mmol, CAS: 1187224-06-1, prepared according to the method described in WO2020011731), and triethylamine (0.1 mL, 0.55 mmol) in a solution of EtOAc (0.74 mL) and acetonitrile (0.49 mL) were added to a solution of EtOAc containing 50% w / w of the acetonitrile. Solution (0.33 mL, 0.55 mmol). The reaction mixture was stirred for 4 h, then diluted with saturated aqueous NaHCO3 and extracted into EtOAc (x2). The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (eluting with 10% MeOH in EtOAc) to give the title compound (55 mg). LCMS (Method 4): 0.97 min, 468.3 [M+H]+.

[0651] Intermediate 2.1: ((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl) tert-butyl amino(1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0652] According to the procedure described for intermediate 2, intermediate 1.1 (0.4 g, 1.7 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.27 g, 0.98 mmol, CAS: 1187224-06-1), triethylamine (0.54 mL, 3.9 mmol) and The title compound (71 mg) was prepared by passing the crude product through Biotage Isolera One (50% w / w solution in EtOAc; 2.5 mL, 3.9 mmol). TM Purified by automated reversed-phase column chromatography (60 g C18 column, 0.1% ammonia / MeCN (in pH 11 0.1% ammonia / H2O)). LCMS (Method 4): 1.06 min, 486.2 [M+H]+.

[0653] Intermediate 2.2: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(7-oxo-6,7-di) Hydrogen-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)ethyl)tert-butyl carbamate

[0654] HATU (0.52 g, 1.4 mmol) was added to a stirred solution of intermediate 1,2 (86 mg, 0.38 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.1 g, 0.38 mmol, CAS: 1187224-06-1), and triethylamine (0.48 mL, 3.4 mmol) in DMF (4.3 mL), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted into EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 5% MeOH in DCM) to provide the title compound (0.12 g). LCMS (Method 3): 2.39 min, 479.3 [M+H] + .

[0655] Intermediate 2.3: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(2-oxo-1,2-dihydro) 4-yl)phenyl)amino)ethyl)tert-butyl carbamate

[0656] The title compound (49 mg) was prepared from intermediate 1.3 (60 mg, 0.32 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (87 mg, 0.32 mmol, CAS: 1187224-06-1), HATU (0.14 g, 0.35 mmol), and triethylamine (0.09 mL, 0.64 mmol) according to the procedure described for intermediate 2.2. The crude product was purified by rapid column chromatography (eluting with 5% MeOH in DCM). LCMS (Method 3): 2.26 min, 440.3 [M+H] + .

[0657] Intermediate 2.4: ((S)-2-((4-(imidazo[1,2-a]pyridin-5-yl)phenyl)amino)-1-((1r,4S)-4- tert-butyl methylcyclohexyl-2-oxoethyl)carbamate

[0658] According to the procedure described for intermediate 2, from intermediate 1,4 (56 mg, 0.24 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (64 mg, 0.24 mmol, CAS: 1187224-06-1), triethylamine (0.12 mL, 0.89 mmol) and The title compound (49 mg) was prepared by passing the crude product through Biotage Isolera One (50% w / w solution in EtOAc; 0.53 mL, 0.89 mmol). TM Purification was performed by rapid column chromatography (25 g Silacycle silica column, eluted with 30%-100% EtOAc in heptane). LCMS (Method 4): 1.03 min, 463.3 [M+H] + .

[0659] Intermediate 2.6: ((S)-2-((4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl) tert-butyl amino(1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0660] The title compound (0.6 g) was prepared from intermediates 1.6 (0.35 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.31 g, 1.1 mmol, CAS: 1187224-06-1), HATU (0.52 mg, 1.4 mmol), and triethylamine (0.48 mL, 3.4 mmol) according to the procedure described for intermediate 2.2, except in an EtOAc / MeCN (2:1) solvent mixture. The crude product was subjected to Biotage Isolera One... TMPurified by rapid column chromatography (20 g ZIP sphere silica column, eluted with 20%-100% EtOAc in heptane). LCMS (Method 16): 3.12 min, 561.2 [M+H] + .

[0661] Intermediate 2.7: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(3-(2-oxo-2-(pyridine)) 1-yl)ethyl)pyridin-4-yl)phenyl)amino)ethyl)tert-butyl carbamate

[0662] According to the procedure described for intermediate 2, from intermediate 1.78 (83 mg, 0.29 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (81 mg, 0.29 mmol, CAS: 1187224-06-1), triethylamine (0.12 mL, 0.89 mmol) and The title compound (98 mg) was prepared by (50% w / w solution in EtOAc; 0.53 mL, 0.89 mmol). The crude product was purified by rapid column chromatography (using 10%–20% MeOH in EtOAc). LCMS (Method 4): 0.97 min, 535.3 [M+H). + .

[0663] Intermediate 2.8: ((S)-2-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6- tert-butyl carbamate (1r,4S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0664] BTFFH (0.17 g, 0.54 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.13 g, 0.47 mmol, CAS: 1187224-06-1) and DIPEA (0.28 mL, 1.6 mmol) in 1,2-dichloroethane (4.2 mL), and the reaction mixture was stirred at room temperature under argon for 1 h. Intermediate 1.8 (78 mg, 0.36 mmol) was added, and the reaction mixture was heated at 80 °C for 2 h under microwave. The reaction mixture was diluted with water and brine and extracted three times into DCM. The combined organic matter was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was passed through Biotage Isolera One. TM Purification was performed by automated reversed-phase column chromatography (30 g C18 column, eluted with 5%–85% MeCN in 0.1% ammonia / MeCN (pH 11, 0.1% ammonia / H2O)) to provide the title compound (18 mg). LCMS (Method 4): 0.95 min, 469.3 [M+H2O] + .

[0665] Intermediate 2.9: ((S)-2-((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)- 4-Methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0666] The title compound (60 mg) was prepared from intermediate 1.9 (0.11 g, 0.55 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.18 g, 0.66 mmol, CAS: 1187224-06-1), DIPEA (0.43 mL, 2.5 mmol), and BTFFH (0.21 g, 0.66 mmol) according to the procedure described for intermediate 2.8. The crude product was purified by MDAP (Method 1: 20%–90% MeCN in 0.1% NH4OH). LCMS (Method 4): 1.07 min, 453.3 [M+H] + .

[0667] Intermediate 2.12: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(tetrahydro-2H-pyran- 4-yl)phenyl)amino)ethyl)tert-butyl carbamate

[0668] The title compound (0.13 g) was prepared from 4-(tetrahydro-2H-pyran-4-yl)aniline (64 mg, 0.36 mmol, CAS: 62071-40-3), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (98 mg, 0.36 mmol, CAS: 1187224-06-1), HATU (0.15 g, 0.40 mmol), and triethylamine (0.1 mL, 0.72 mmol) except in an EtOAc / MeCN (2:1) solvent mixture, except for the procedure described for intermediate 2.2. The crude product was used directly. LCMS (Method 12): 2.83 min, 331.2 [M-Boc+H] + .

[0669] Intermediate 2.13: ((S)-2-((4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)- 4-Methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0670] According to the procedure described for intermediate 2, from 4-(4-aminophenyl)tetrahydro-2H-pyran-4-ol (51 mg, 0.26 mmol, CAS: 1002726-77-3) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (72 mg, 0.26 mmol, CAS: 1187224-06-1), triethylamine (0.11 mL, 0.79 mmol) and The title compound (93 mg) was prepared by diluting a 50% w / w solution in EtOAc (0.5 mL, 0.79 mmol). The crude product was used directly without further purification. LCMS (Method 4): 0.94 min, 347.0 [M-Boc+H] +.

[0671] Intermediate 2.14: ((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4- tert-butyl methylcyclohexyl-2-oxoethyl)carbamate

[0672] According to the procedure described for intermediate 2.1, from 4-(3,6-dihydro-2H-pyran-4-yl)aniline (0.1 g, 0.57 mmol, CAS: 1039053-21-8) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.16 g, 0.57 mmol, CAS: 1187224-06-1), triethylamine (0.24 mL, 1.7 mmol) and The title compound (65 mg) was prepared by passing the crude product through Biotage Isolera One (50% w / w solution in EtOAc; 1.1 mL, 1.7 mmol). TM Purification was performed by rapid column chromatography (25 g Siliacycle silica gel column, eluted with 10%-100% EtOAc in heptane). LCMS (Method 4): 1.10 min, 329.2 [M-Boc+H2O] + .

[0673] Intermediate 2.15: ((S)-2-((4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-((1r,4S)-4- tert-butyl methylcyclohexyl-2-oxoethyl)carbamate

[0674] According to the procedure described for intermediate 2, from 4-(3,5-dimethylisoxazol-4-yl)aniline (55 mg, 0.29 mmol, CAS: 2155-99-9) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (76 mg, 0.28 mmol, CAS: 1187224-06-1), triethylamine (0.12 mL, 0.84 mmol) and The title compound (84 mg) was prepared by passing the crude product via Biotage IsoleraOne (50% w / w solution in EtOAc; 0.5 mL, 0.84 mmol). TM Purification was performed using rapid column chromatography (4g silica gel column, eluted with 0%-25% EtOAc in heptane). 1H NMR(400MHz, CDCl3)δ:8.19(s,1H),7.62–7.55(m,2H),7.17(d,2H),5.14(s,1H),4.02(t,1H),2.37(s,3H),2 .24(s,3H),1.84(d,5H),1.46(s,9H),1.34–1.27(m,1H),1.21–1.04(m,2H),1.00–0.90(m,2H),0.88(d,3H).

[0675] Intermediate 2.16: ((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r, 4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0676] Under argon atmosphere, EEDQ (84 mg, 0.35 mmol) was added to a solution of 5-(3,5-dimethylisoxazol-4-yl)pyridine-2-amine (59 mg, 0.3 mmol, CAS: 1177269-12-3) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (85 mg, 0.3 mmol, CAS: 1187224-06-1) in tetrahydrofuran (3 mL). The mixture was stirred for 64 h, concentrated under vacuum, and then partitioned between EtOAc and saturated NaHCO3. The organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (5 g silica gel column, eluted with 0%-50% EtOAc in heptane) to provide the title compound (23 mg). LCMS (Method 14): 2.02 min, 443.3 [M+H] + .

[0677] Intermediate 2.18: ((S)-2-((5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine- 2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate tert-butyl ester

[0678] The title compound (39 mg) was prepared from intermediate 1.18 (50 mg, 0.16 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (53 mg, 0.19 mmol, CAS: 1187224-06-1) and EEDQ (60 mg, 0.24 mmol) according to the procedure described for intermediate 2.16. A further portion of EEDQ (60 mg, 0.24 mmol) was added, and the mixture was stirred for another 24 h before post-processing. The crude product was purified by rapid column chromatography (4 g silica gel column, eluted with 0%–25% EtOAc in heptane). LCMS (Method 14): 2.09 min, 562.2 [M+H] + .

[0679] Intermediate 2.25: ((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0680] The title compound (19 mg) was prepared from intermediate 1.25 (65 mg, 0.35 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.11 g, 0.41 mmol, CAS: 1187224-06-1) and EEDQ (0.13 g, 0.52 mmol) according to the procedure described for intermediate 2.16. The crude product was purified by rapid column chromatography (5 g silica gel column, eluted with 20%–80% EtOAc in heptane). LCMS (Method 14): 1.99 min, 442.2 [M+H] + .

[0681] Intermediate 2.27: (S)-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino tert-butyl 2-oxoethyl carbamate

[0682] The title compound (67 mg) was prepared from 5-(3,5-dimethylisoxazol-4-yl)pyridine-2-amine (110 mg, 0.58 mmol, CAS: 1177269-12-3), (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (150 mg, 0.58 mmol, CAS: 109183-71-3), IIDQ (354 mg, 1.17 mmol), and DIPEA (0.41 mL, 2.3 mmol) according to the procedure described for intermediate 2.16, except that IIDQ (0.35 g, 1.2 mmol) was used and heating was carried out at 90 °C for 16 h. TM Purified by rapid column chromatography (12 g silica column, eluted with 0%-100% EtOAc in heptane). LCMS (Method 14): 1.99 min, 429.2 [M+H] + .

[0683] Intermediate 2.34: (S)-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino tert-butyl 2-oxoethyl carbamate

[0684] The title compound (0.2 g) was prepared from 5-(3,5-dimethylisoxazol-4-yl)pyridin-2-amine (0.43 g, 2.2 mmol, CAS: 1177269-12-3) and (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.61 g, 2.2 mmol, CAS: 1228542-19-5) and EEDQ (0.61 g, 2.5 mmol) according to the procedure described for intermediate 2.16. The crude product was subjected to Biotage Isolera One. TMPurified by rapid column chromatography (40 g silica gel column, eluted with 0%-3% MeOH in DCM). LCMS (Method 14): 2.00 min, 443.2 [M+H] + .

[0685] Intermediate 2.38: (S)-(1-cyclohexyl-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl) tert-butyl phenylamino)-2-oxoethyl)carbamate

[0686] The title compound (0.28 g) was prepared from intermediate 1 (0.18 g, 0.86 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (0.2 g, 0.78 mmol, CAS: 109183-71-3), DIPEA (0.2 g, 1.6 mmol), and HATU (0.4 g, 1.1 mmol) according to the procedure described for intermediate 2.2. The crude product was used directly. LCMS (Method 14): 1.75 min, 454.2 [M+H] + .

[0687] Intermediate 2.44: ((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)- 1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0688] Under an argon atmosphere, DIPEA (0.15 g, 1.1 mmol) and HATU (0.3 g, 0.79 mmol) were added to a stirred solution of intermediate 1.44 (0.12 g, 0.62 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 g, 0.56 mmol, CAS: 1187224-06-1) in anhydrous DMF (0.77 mL). The mixture was heated at 50 °C for 44 h. The reaction mixture was diluted with MeOH (1 mL) and then purified by Biotage Isolera One. TM Purification was performed by reversed-phase column chromatography (30 g KP-C18_HS Biotage SNAP column, eluted with 5%–100% MeCN in aqueous buffer containing 0.005 M NH4OH) to provide the title compound (35 mg). LCMS (Method 14): 1.83 min, 443.3 [M+H] + .

[0689] Intermediate 2.44 was obtained: ((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino Alternative pathways for tert-butyl carbamate (1r,4S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0690] Intermediate 2.44a: ((S)-2-amino-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0691] DIPEA (3.2 mL, 18.4 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (1 g, 3.7 mmol, CAS: 1187224-06-1) in anhydrous DMF (5 mL), followed by ammonium chloride (0.99 g, 18.4 mmol). The mixture was stirred at ambient temperature for 20 h. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was milled in DCM to provide the title compound (0.85 g). 1 H NMR(400MHz,DMSO-d6)δ:7.25(s,1H),6.97(s,1H),6.50(d,1H),3.77–3.68(m,1H),1. 69–1.44(m,5H),1.38(s,9H),1.27–1.21(m,1H),1.07–0.92(m,2H),0.90–0.75(m,5H).

[0692] Intermediate 2.44: ((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0693] Xantphos (58 mg, 0.1 mmol) and Cs₂CO₃ (0.98 g, 3 mmol) were added to a suspension of intermediates 1.44a (0.3 g, 1.5 mmol) and 2.44a (0.27 g, 1.0 mmol) in degassed anhydrous 1,4-dioxane (14 mL). The mixture was degassed with argon for 5 min, followed by the addition of tris(dibenzylacetone)dipalladium(0) (46 mg, 0.05 mmol) and degassed for 5 min. The vial was sealed and the reaction mixture was heated to 100 °C and maintained for 18 h. The mixture was diluted with EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organic matter was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was passed through Biotage Isolera One. TM The title compound (0.12 g) was purified by rapid column chromatography (20 g silica gel, eluted with 30%-100% EtOAc in heptane). 1H NMR(400MHz,MeOD)δ:8.39(dd,1H),8.32(dd,1H),7.88(dd,1H),4.09(d,1H),3.98(s,3 H),2.29(s,3H),1.84–1.65(m,5H),1.45(s,9H),1.36–1.10(m,3H),1.03–0.81(m,5H).

[0694] Intermediate 2.51: (S)-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino (2-oxoethyl)

[0695] tert-butyl carbamate

[0696] Under an argon atmosphere, HATU (0.83 mg, 2.2 mmol) was added to a solution of intermediate 1.25 (0.62 g, 3.3 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.4 g, 1.6 mmol, CAS: 1228542-19-5), and DIPEA (0.4 g, 3.1 mmol) in anhydrous DMF (2.6 mL). The mixture was heated at 50 °C for 24 h. The mixture was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to Biotage Isolera One. TM Purification was performed by rapid column chromatography (40 g silica gel column, eluted with 0%-50% EtOAc in heptane) to provide the title compound (0.28 g). LCMS (Method 14): 1.85 min, 442.2 [M+H] + .

[0697] Intermediate 2.54: ((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r, 4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0698] The title compound (0.13 g) was prepared from 2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-amine (0.18 g, 0.95 mmol, CAS: 1094246-50-0), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 mg, 0.55 mmol, CAS: 1187224-06-1), DIPEA (0.14 g, 1.1 mmol), and HATU (0.29 g, 0.77 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TMPurified by rapid column chromatography (10 g silica gel column, eluted with 30% EtOAc in heptane). LCMS (Method 14): 1.93 min, 443.2 [M+H] + .

[0699] Intermediate 2.57: ((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r, 4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0700] The title compound (0.13 g) was prepared from intermediate 1.57 (0.18 g, 0.95 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 mg, 0.55 mmol, CAS: 1187224-06-1), DIPEA (0.14 g, 1.1 mmol), and HATU (0.29 g, 0.77 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (10 g silica gel column, eluted with 30% EtOAc in heptane). LCMS (Method 14): 1.93 min, 443.2 [M+H] + .

[0701] Intermediate 2.59: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-((5-(5-methylpyrimidin-4-yl)pyridine- 2-yl)amino)-2-oxoethyl)carbamate tert-butyl ester

[0702] The title compound (0.14 g) was prepared from intermediate 1.59 (0.24 g, 1.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.17 g, 0.62 mmol, CAS: 1187224-06-1), DIPEA (0.16 g, 1.2 mmol), and HATU (0.33 g, 0.87 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purification was performed by rapid column chromatography (20 g silica gel column, eluted with 0%-3% MeOH in DCM). LCMS (Method 14): 1.88 min, 440.2 [M+H] + .

[0703] Intermediate 2.61: ((S)-2-((5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-yl)amino tert-butyl carbamate (1r,4S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0704] The title compound (0.12 g) was prepared from intermediate 1.61 (0.2 g, 0.9 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.16 g, 0.6 mmol, CAS: 1187224-06-1), DIPEA (0.17 mg, 1.2 mmol), and HATU (0.32 g, 0.84 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (20 g silica gel column, eluted with 0%-50% EtOAc in heptane). LCMS (Method 14): 1.99 min, 473.2 [M+H] + .

[0705] Intermediate 2.62a: (S)-(2-amino-1-cycloheptyl-2-oxoethyl) tert-butyl carbamate

[0706] DIPEA (0.36 g, 2.8 mmol) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.25 g, 0.92 mmol, CAS: 1228542-19-5) in anhydrous THF (11 mL) at 0 °C, followed by dropwise addition of isobutyl chloroformate (176 mg, 1.29 mmol). The mixture was stirred at 0 °C for 30 min, followed by dropwise addition of ammonium hydroxide solution (30%, 0.22 g, 1.8 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under vacuum and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was ground in diethyl ether to provide the title compound (75 mg). 1 H NMR(400MHz, DMSO-d6)δ:7.25(s,1H),6.97(s,1H),6.48(d,1H),3.78–3.69(m,1H),1.74–1.46(m,20H).

[0707] Intermediate 2.62: (S)-(1-cycloheptyl-2-((5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine-2- tert-butyl carbamate (2-( ...

[0708] Xantphos (6.4 mg, 11 μmol) and Cs₂CO₃ (109 mg, 0.33 mmol) were added to a suspension of intermediate 1.62 (35 mg, 0.17 mmol) and intermediate 2.62a (30 mg, 0.11 mmol) in degassed anhydrous 1,4-dioxane (1.4 mL). The mixture was degassed with argon for 5 min, followed by the addition of tris(dibenzylacetone)dipalladium(O) (5.1 mg, 6 μmol) and degassed for another 5 min. The vial was sealed and the reaction mixture was heated at 100 °C for 18 h. The mixture was diluted with EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organic matter was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was passed through a Biotage Isolera One filter. TM Purification was performed by rapid column chromatography (4 g silica gel column, eluted with 0%–10% MeOH in DCM) to provide the title compound (40 mg). LCMS (Method 19): 2.36 min, 443.2 [M+H] + .

[0709] Intermediate 2.63: (S)-(1-(4,4-difluorocyclohexyl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrazol) tert-butyl 2-(2-yl)amino)2-oxoethyl)carbamate

[0710] The title compound (0.29 g) was prepared from intermediates 1.25 (0.39 g, 2.1 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (0.17 g, 0.62 mmol, CAS: 394735-65-0), DIPEA (0.26 g, 2.1 mmol), and HATU (0.55 g, 1.4 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purification was performed by rapid column chromatography (10 g silica gel column, eluted with 0%-2% MeOH in DCM), followed by purification by SCX column (washed with MeOH and eluted with 2M methylamine). LCMS (Method 14): 2.56 min, 464.2 [M+H] + .

[0711] Intermediate 2.64: ((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0712] The title compound (0.34 g) was prepared from intermediates 1.64 (0.31 g, 1.7 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.22 g, 0.81 mmol, CAS: 1187224-06-1), DIPEA (0.21 g, 1.6 mmol), and HATU (0.46 g, 1.2 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (10 g silica gel column, eluted with 100% EtOAc in heptane). LCMS (Method 19): 2.73 min, 442.2 [M+H] + .

[0713] Intermediate 2.65: ((S)-2-((4-methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0714] The title compound (0.23 g) was prepared from intermediates 1.65 (0.21 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.2 g, 0.74 mmol, CAS: 1187224-06-1), DIPEA (0.19 g, 1.5 mmol), and HATU (0.39 g, 1.0 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (12 g silica column, eluted with 0%-12% MeOH in DCM). LCMS (Method 14): 1.92 min, 442.2 [M+H] + .

[0715] Intermediate 2.66: ((S)-2-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0716] The title compound (0.50 g) was prepared from intermediate 1.66 (0.49 g, 2.6 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.35 g, 1.3 mmol, CAS: 1187224-06-1), DIPEA (0.45 mL, 2.6 mmol), and HATU (0.69 g, 1.8 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TMPurified by rapid column chromatography (12 g silica column, eluted with 100% EtOAc in heptane). LCMS (Method 19): 2.82 min, 443.2 [M+H] + .

[0717] Intermediate 2.67: (S)-(1-cycloheptayl-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridine-2- tert-butyl carbamate (2-( ...

[0718] The title compound (0.18 g) was prepared in a similar procedure to that for intermediate 2.62a from intermediate 1.44a (0.3 g, 1.5 mmol), intermediate 2.62a (0.27 g, 1.0 mmol), Xantphos (58 mg, 0.10 mmol), Cs₂CO₃ (976 mg, 3.00 mmol), and tris(dibenzylacetone)dipalladium(0) (46 mg, 0.05 mmol). The crude product was subjected to Biotage IsoleraOne. TM Purified by rapid column chromatography (20 g silica gel, 50%-100% EtOAc in heptane). LCMS (Method 19): 1.62 min, 443.2 [M+H]. + .

[0719] Intermediate 2.69: (S)-(1-cycloheptyl-2-((5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridine tert-butyl 2-(2-yl)amino)2-oxoethyl)carbamate

[0720] The title compound (90 mg) was prepared from intermediates 1.69 (0.13 g, 0.61 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.11 g, 0.41 mmol, CAS: 1228542-19-5), DIPEA (0.14 mL, 0.81 mmol), and HATU (0.21 g, 0.57 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (12 g silica gel column, eluted with 0%-60% EtOAc in heptane). LCMS (Method 19): 2.89 min, 473.2 [M+H] + .

[0721] Intermediate 2.70: ((S)-2-((3'-methoxy-2'-methyl-[3,4'-bipyridine]-6-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0722] The title compound (0.11 g) was prepared from intermediate 1.70 (0.18 g, 0.83 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 g, 0.55 mmol, CAS: 1187224-06-1), DIPEA (0.19 mL, 1.1 mmol), and HATU (0.29 g, 0.77 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purification was performed by rapid column chromatography (10 g silica gel column, eluted with 0%-2% MeOH in DCM), followed by purification via SCX column (washed with MeOH and eluted with 2M methylamine). LCMS (Method 19): 2.40 min, 469.2 [M+H] + .

[0723] Intermediate 2.71: ((S)-2-((2',3'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)- 4-Methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0724] The title compound (0.19 g) was prepared from intermediate 1.71 (0.26 g, 1.3 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.18 g, 0.65 mmol, CAS: 1187224-06-1), DIPEA (0.17 g, 1.3 mmol), and HATU (0.34 g, 0.9 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (10 g silica gel column, eluted with 0%-2% MeOH in DCM), followed by purification by SCX column (washed with MeOH and eluted with 2M methylamine). LCMS (Method 14): 1.54 min, 453.2 [M+H] + .

[0725] Intermediate 2.72: ((S)-2-((2',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)- 4-Methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0726] The title compound (102 mg) was prepared from intermediate 1.72 (171 mg, 0.86 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (155 mg, 0.57 mmol, CAS: 1187224-06-1), DIPEA (0.3 mL, 1.71 mmol), and HATU (304 mg, 0.80 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One...TM Purified by rapid column chromatography (4 g silica gel column, eluted with 0%–10% MeOH in DCM), followed by ion exchange purification (eluting SCX with MeOH, then eluting with 2M ammonia in MeOH). LCMS (Method 14): 1.57 min, 453.2 [M+H] + .

[0727] Intermediate 2.76: (S)-(1-cycloheptayl-2-((5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine tert-butyl 2-(2-yl)amino)2-oxoethyl)carbamate

[0728] The title compound (31 mg) was prepared from intermediate 1.76 (0.27 g, 1.2 mmol), intermediate 2.62a (0.22 g, 0.81 mmol), Xantphos Pd G3 (39 mg, 0.04 mmol), and Cs2CO3 (0.8 g, 2.4 mmol) in a procedure similar to that for intermediate 2.62. The crude product was subjected to Biotage Isolera One. TM Purified by rapid column chromatography (20 g silica gel column, eluted with 0%-100% EtOAc in heptane). LCMS (Method 14): 1.87 min, 457.2 [M+H] + .

[0729] Intermediate 2.77: (S)-(1-cycloheptayl-2-((5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine tert-butyl 2-(2-yl)amino)2-oxoethyl)carbamate

[0730] The title compound (31 mg) was prepared from intermediate 1.7 (0.2 g, 0.96 mmol), intermediate 2.62a (0.2 g, 0.74 mmol), Xantphos Pd G3 (70 mg, 0.07 mmol), and Cs2CO3 (0.72 g, 2.2 mmol) in a procedure similar to that for intermediate 2.62. The crude product was used directly. LCMS (Method 14): 1.87 min, 457.2 [M+H] + .

[0731] Intermediate 2.80: (S)-(1-cycloheptyl-2-((5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine tert-butyl 2-(2-yl)amino)2-oxoethyl)carbamate

[0732] The title compound (18 mg) was prepared from intermediates 1.80 (0.15 g, 0.67 mmol), 2.62a (0.14 g, 0.52 mmol), Xantphos Pd G3 (49 mg, 0.05 mmol), and Cs2CO3 (0.5 g, 1.5 mmol) in a procedure similar to that for intermediate 2.62. The crude product was subjected to Biotage Isolera One. TMPurified by rapid column chromatography (10 g silica gel, 0%-100% EtOAc in heptane). LCMS (Method 14): 1.98 min, 469.2 [M+H] + .

[0733] Intermediate 2.81: (S)-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl) tert-butyl (amino)-2-oxoethyl)carbamate

[0734] The title compound (23 mg) was prepared from intermediate 1.81 (0.34 g, 1.7 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.3 g, 1.1 mmol, CAS: 1228542-19-5), DIPEA (0.39 mL, 2.2 mmol), and HATU (0.5 g, 1.3 mmol) according to the procedure described for intermediate 2.51. Further portions of (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.3 g, 1.1 mmol, CAS: 1228542-19-5), HATU (0.5 g, 1.3 mmol), and DIPEA (0.39 mL, 2.2 mmol) were added, and the reaction mixture was stirred at 50 °C for 24 h. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (10 g silica gel column, eluted with 0%-30% EtOAc in heptane). LCMS (Method 14): 1.97 min, 461.2 [M+H] + .

[0735] Intermediate 2.84: (S)-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)amino tert-butyl 2-oxoethyl carbamate

[0736] The title compound (59 mg) was prepared from intermediate 1.84 (0.14 g, 0.67 mmol), intermediate 2.62a (0.12 g, 0.44 mmol), Xantphos (26 mg, 0.044 mmol), Cs₂CO₃ (0.43 g, 1.3 mmol), and tris(dibenzylacetone)dipalladium(0) (20 mg, 0.022 mmol) according to the procedure described for intermediate 2.62. The crude product was subjected to Biotage IsoleraOne. TM Purified by rapid column chromatography (12 g silica gel, 0%–3% MeOH in DCM). LCMS (Method 14): 1.86 min, 443.2 [M+H]. + .

[0737] Intermediate 2.85: (S)-(1-cycloheptyl-2-((5-(4-hydroxy-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl) tert-butyl (amino)-2-oxoethyl)carbamate

[0738] The title compound (30 mg) was prepared from 5-(4-benzyloxy-2-methylpyrazol-3-yl)pyridine-2-amine (35 mg, 0.12 mmol, CAS: 2151907-63-8), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (50 mg, 0.18 mmol, CAS: 1228542-19-5), DIPEA (0.06 mL, 0.37 mmol), and HATU (77 mg, 0.2 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (4 g silica gel column, eluted with 0%-50% EtOAc in heptane). LCMS (Method 14): 2.13 min, 534.2 [M+H] + .

[0739] Intermediate 2.88: (S)-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino tert-butyl 2-oxoethyl carbamate

[0740] The title compound (0.48 g) was prepared from intermediate 1.57 (0.42 g, 2.2 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.3 g, 1.1 mmol, CAS: 1228542-19-5), DIPEA (0.39 mL, 2.2 mmol), and HATU (0.63 g, 1.7 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (20 g silica gel column, eluted with 0%-100% EtOAc in heptane). LCMS (Method 14): 2.00 min, 443.2 [M+H] + .

[0741] Intermediate 2.92: (S)-(1-cycloheptyl-2-((5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridine tert-butyl 2-(2-yl)amino)2-oxoethyl)carbamate

[0742] The title compound (51 mg) was prepared from intermediate 1.92 (88 mg, 0.33 mmol), intermediate 2.62a (80 mg, 0.3 mmol), Xantphos (17 mg, 0.03 mmol), Cs₂CO₃ (0.29 g, 0.89 mmol), and tris(dibenzylacetone)dipalladium(0) (14 mg, 0.015 mmol) according to the procedure described for intermediate 2.62. Additional portions of tris(dibenzylacetone)dipalladium(0) (14 mg, 0.015 mmol), Xantphos (17 mg, 0.03 mmol), and Cs₂CO₃ (0.29 g, 0.89 mmol) were added, and the mixture was stirred at 100 °C for 18 h. The crude product was passed through Biotage Isolera One. TM Purified by rapid column chromatography (20 g silica gel column, eluted with 2%-80% EtOAc in heptane). LCMS (Method 19): 2.81 min, 469.2 [M+H] + .

[0743] Intermediate 2.93: (S)-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cyclo hepta-2-oxoethyl) tert-butyl carbamate

[0744] The title compound (0.72 g) was prepared from intermediate 1.93 (1.1 g, 5.3 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.8 g, 2.9 mmol, CAS: 1228542-19-5), DIPEA (1.0 mL, 5.9 mmol), and HATU (1.6 g, 4.2 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage IsoleraOne... TM Purified by rapid column chromatography (100 g silica gel column, eluted with 0%-100% EtOAc in heptane). LCMS (Method 19): 2.96 min, 462.2 [M+H] + .

[0745] Intermediate 2.96: (S)-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino tert-butyl 2-oxoethyl carbamate

[0746] The title compound (0.5 g) was prepared from intermediates 1.25 (0.79 g, 4.2 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (0.54 g, 2.1 mmol, CAS: 109183-71-3), DIPEA (0.73 mL, 4.2 mmol), and HATU (1.1 g, 2.9 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage IsoleraOne... TMPurified by rapid column chromatography (100g silica column, eluted with 100% EtOAc). 1 H NMR(400MHz, CDCl3)δ:8.65(s,1H),8.37(dd,1H),8.25(dd,1H),7.67(dd,1H),7.40(d,1H),5.08(s,1H),4.12( m,1H),3.77(s,3H),2.01(d,3H),1.77(s,3H),1.66(s,2H),1.47(s,9H),1.26–1.18(m,3H),1.18–1.01(m,3H).

[0747] Intermediate 2.98: ((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)- 1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0748] The title compound (0.49 g) was prepared from intermediate 1.98 (0.79 g, 3.7 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.5 g, 1.8 mmol, CAS: 1187224-06-1), DIPEA (0.64 mL, 3.7 mmol), and HATU (1.1 g, 2.8 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (20 g silica gel column, eluted with 0%-100% EtOAc in heptane). LCMS (Method 14): 2.02 min, 460.2 [M+H2O] + .

[0749] Intermediate 2.101: (S)-(2-((5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl- 1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)tert-butyl carbamate Intermediate 2.101a: (S)-(1-cycloheptayl-2-oxo-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-2-yl)amino)ethyl)tert-butyl carbamate

[0750] The title compound (0.59 g) was prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.81 g, 3.7 mmol, CAS: 827614-64-2), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.5 g, 1.8 mmol, CAS: 1228542-19-5), DIPEA (0.64 mL, 3.7 mmol), and HATU (2 g, 2.6 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TMPurified by rapid column chromatography (40 g silica gel column, eluted with 2%-80% EtOAc in heptane). LCMS (Method 15): 2.36 min, 392.2 [M-C6H] 14 +H] + .

[0751] Intermediate 2.101b: 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazole

[0752] To a solution of (5-bromo-1-methyl-1H-pyrazol-4-yl)methanol (0.38 g, 2 mmol, CAS: 1415638-13-9) in DMF (15 mL), tert-butyldimethylchlorosilyl (0.36 g, 2.4 mmol) was added, followed by imidazole (0.34 g, 5 mmol). The mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to Biotage Isolera One chromatography. TM The sample was purified by rapid column chromatography (20 g silica gel column, eluted with 2%-40% EtOAc in heptane) to provide the title compound (0.54 g). 1 HNMR (400MHz, CDCl3) δ: 7.50 (s, 1H), 4.52 (s, 2H), 3.86 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H).

[0753] Intermediate 2.101: (S)-(2-((5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)tert-butyl carbamate

[0754] The title compound (0.11 g) was prepared from intermediates 2.101a (0.12 mg, 0.24 mmol), 2.101b (89 mg, 0.29 mmol), Pd(dppf)Cl2 (20 mg, 0.02 mmol), and potassium carbonate (0.1 g, 0.73 mmol) by heating at 100 °C for 18 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (20 g silica gel column, eluted with 2%-70% EtOAc in heptane). LCMS (Method 15): 3.47 min, 572.2 [M+H]. + .

[0755] Intermediate 2.102: (S)-(1-cyclopentyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino tert-butyl 2-oxoethyl carbamate

[0756] The title compound (48 mg) was prepared from intermediate 1.25 (0.1 g, 0.53 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cyclopentyl-acetic acid (0.14 g, 0.56 mmol, CAS: 109183-72-4), DIPEA (0.19 mL, 1.1 mmol), and HATU (0.3 g, 0.8 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Teledyne ISCO... Purified by rapid column chromatography (12 g silica column, eluted with 0%-100% EtOAc in isohexane). LCMS (Method 25): 2.26 min, 414.3 [M+H] + .

[0757] Intermediate 2.103: (1-(bicyclo[2.2.1]heptane-2-yl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl) 2-yl)amino)-2-oxoethyl)carbamate tert-butyl ester

[0758] The title compound (60 mg) was prepared from intermediate 1.25 (77 mg, 0.41 mmol), 2-(tert-butoxycarbonylamino)-2-norbornen-2-yl-acetic acid (0.1 g, 0.37 mmol, CAS: 182292-11-1), DIPEA (0.13 mL, 0.74 mmol), and HATU (0.21 g, 0.56 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Teledyne ISCO... Purification was performed by rapid column chromatography (12 g silica column, eluted with 0%-100% EtOAc in isohexane). LCMS (Method 26): 1.50 min, 440.20 [M+H]+.

[0759] Intermediate 2.104: (2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1- ((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)tert-butyl carbamate

[0760] Intermediate 2.104a: 5-((1r,4r)-4-(trifluoromethyl)cyclohexyl)imidazoline-2,4-dione

[0761] A solution of trans-4-(trifluoromethyl)cyclohexane-1-carboxaldehyde (0.93 g, 5.2 mmol, CAS: 133261-34-4), sodium cyanide (0.51 g, 10.3 mmol), and ammonium carbonate (1.5 g, 15.5 mmol) in MeOH (3 mL) and then in water (3 mL) was degassed with argon and heated at 60 °C for 48 h. The reaction mixture was cooled to room temperature and carefully quenched with HCl (1 M aqueous; 8 mL). HCl (5 M aqueous) was carefully added until the pH was about 4-5. The mixture was filtered, and the solid was washed with water to give the title compound (0.73 g). LCMS (Method 19): 1.82 min, 249.2 [MH] + .

[0762] Intermediate 2.104b: 2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-2-ureoacetic acid

[0763] A solution of intermediate 2.104a (0.73 g, 2.9 mmol) in sodium hydroxide (5 M aqueous; 3.8 mL, 18.9 mmol) was heated under reflux for 18 h. The reaction mixture was cooled to room temperature, and the pH was adjusted to approximately 5–6 by dropwise addition of HCl (5 M aqueous). The mixture was filtered, and the solid was ground with diethyl ether to provide the title compound (0.3 g). LCMS (Method 14): 1.46 min, 269.2 [M + H₂] + .

[0764] Intermediate 2.104c: 2-((tert-butoxycarbonyl)amino)-2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)acetic acid

[0765] Sodium hydroxide (6M aqueous; 0.56 mL, 3.4 mmol) was added to a suspension of intermediate 2.104b (0.3 g, 1.1 mmol) in water (3.4 mL). The mixture was heated at 110 °C for 48 h. A further portion of sodium hydroxide (134 mg, 3.4 mmol) was added, and the mixture was heated again at 110 °C for 72 h. The reaction mixture was acidified to pH 6 by dropwise addition of HCl (5 M aqueous). Sodium carbonate (0.36 g, 3.4 mmol) was added to the mixture, followed by THF (4 mL) and BOC anhydride (0.37 g, 1.7 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was adjusted to pH 5 with HCl (1 M aqueous) and diluted with water, then extracted with EtOAc. The aqueous phase was acidified to pH 1 and extracted with EtOAc. The combined organic matter was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was ground with heptane to provide the title compound (0.22 g). LCMS (Method 14): 1.83 min, 324.0 [MH] - .

[0766] Intermediate 2.104: (2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)tert-butyl carbamate

[0767] The title compound (0.22 g) was prepared from intermediate 1.25 (0.25 g, 1.3 mmol), intermediate 2.104c (0.22 g, 0.66 mmol), DIPEA (72 mg, 1.3 mmol), and HATU (0.35 g, 0.93 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One. TM Purified by rapid column chromatography (40 g silica gel column, eluted with 0%-1.5% MeOH in DCM). LCMS (Method 14): 1.96 min, 496.2 [M+H] + .

[0768] Intermediate 2.109: (S)-(1-cycloheptayl-2-((5-(1-(2-(dimethylamino)-2-oxoethyl)-4-methyl) 1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)tert-butyl carbamate

[0769] The title compound (55 mg) was prepared from intermediate 1.109 (0.11 g, 0.38 mmol), intermediate 2.62a (68 mg, 0.25 mmol), XantPhos (15 mg, 0.03 mmol), Cs2CO3 (0.25 g, 0.75 mmol), and tris(dibenzylacetone)dipalladium(0) (12 mg, 0.01 mmol) according to the procedure described for intermediate 2.62. The crude product was subjected to Biotage IsoleraOne. TM Purified by rapid column chromatography (10g silica gel, 0%-100% EtOAc in heptane). 1 H NMR(400MHz, CDCl3)δ:8.87(s,1H),8.37(dd,1H),8.30(dd,1H),7.80(dd,1H),5.03(s,2H),4.21(s,1 H),3.05(s,3H),2.96(s,4H),2.32(s,3H),2.17(d,1H),1.83–1.65(m,4H),1.60(d,2H),1.47(s,15H).

[0770] Intermediate 2.112: ((S)-2-((5-(4-cyano-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0771] The title compound (70 mg) was prepared from intermediate 1.112 (0.21 g, 1.0 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.14 g, 0.51 mmol, CAS: 1187224-06-1), DIPEA (0.18 mL, 1.0 mmol), and HATU (0.29 g, 0.77 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (20g silica gel column, eluted with 0%-100% EtOAc in heptane). LCMS (Method 14): 1.99 min, 453.2 [M+H] + . Intermediate 2.114: (S)-(1-cyclohepty-2- oxo-2-((5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)ethyl)

[0772] tert-butyl carbamate

[0773] The title compound (70 mg) was prepared from intermediate 1.114 (0.85 g, 4.2 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.67 g, 2.5 mmol, CAS: 1228542-19-5), DIPEA (0.86 mL, 4.9 mmol), and HATU (0.32 g, 3.5 mmol) according to the procedure described for intermediate 2.51. The crude product was purified by rapid column chromatography (eluting with 20%–100% EtOAc in heptane). LCMS (Method 14): 2.07 min, 456.2 [M+H] + .

[0774] Intermediate 2.115: ((S)-2-((5-(3,5-dimethylisothiazo-4-yl)pyridin-2-yl)amino)-1-((1r, 4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0775] The title compound (0.11 g) was prepared from intermediate 1.115 (0.14 g, 0.66 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.1 g, 0.37 mmol, CAS: 1187224-06-1), DIPEA (0.13 mL, 0.74 mmol), and HATU (0.2 g, 0.52 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (20 g silica gel column, eluted with 20%-100% EtOAc in heptane). LCMS (Method 15): 3.09 min, 459.2 [M+H] + .

[0776] Intermediate 2.118: ((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0777] The title compound (0.48 g) was prepared from intermediate 1.93 (0.46 g, 2.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.4 g, 1.4 mmol, CAS: 1187224-06-1), DIPEA (0.49 mL, 2.8 mmol), and HATU (0.75 g, 2.0 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (40 g silica gel column, eluted with 10%-50% EtOAc in heptane). LCMS (Method 15): 3.04 min, 462.2 [M+H] + .

[0778] Intermediate 2.124: ((S)-2-((5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl- 1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butylcarbamate ester

[0779] Intermediate 2.124a: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-yl)amino)ethyl)tert-butyl carbamate

[0780] The title compound (0.69 g) was prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-amine (0.8 g, 3.7 mmol, CAS: 827614-64-2), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.5 g, 1.8 mmol, CAS: 1187224-06-1), DIPEA (0.64 mL, 3.7 mmol), and HATU (0.98 g, 2.6 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One TM Purification was performed by rapid column chromatography (25 g silica gel column, eluted with 2%-100% EtOAc in heptane). LCMS (Method 15): 2.41 min for boric acid, 392.2 [M+H]. + .

[0781] Intermediate 2.124: ((S)-2-((5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0782] The title compound (0.27 g) was prepared from intermediates 2.124a (0.32 g, 0.67 mmol), 2.101b (0.27 g, 0.87 mmol), Pd(dppf)Cl2 (49 mg, 0.07 mmol), and potassium carbonate (0.28 g, 2.0 mmol) by heating at 110 °C for 18 h according to the procedure described for intermediate 1.1. The crude product was subjected to Biotage Isolera One... TM Purified by rapid column chromatography (50 g silica gel column, eluted with 2%-70% EtOAc in heptane). LCMS (Method 15): 3.49 min, 572.2 [M+H] + .

[0783] Intermediate 2.126: (S)-(1-cyclohexyl-2-((6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethyl) 2-(oxy)methyl)-1H-pyrazole-4-yl)pyridin-3-yl)amino)-2-oxoethyl)tert-butyl carbamate

[0784] The title compound (37 mg) was prepared from intermediate 1.126 (0.15 g, 0.43 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (0.14 g, 0.52 mmol, CAS: 109183-71-3), DIPEA (0.24 mL, 1.4 mmol), and HATU (0.2 g, 0.51 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Teledyne ISCO... Purified by rapid column chromatography (12 g silica column, eluted with 0%-100% 3:1 EtOAc:EtOH (in isohexane)). LCMS (Method 28): 2.04 min, 558.5 [M+H). + .

[0785] Intermediate 2.127: (S)-(1-cycloheptayl-2-((6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethyl) 2-(oxy)methyl)-1H-pyrazole-4-yl)pyridin-3-yl)amino)-2-oxoethyl)tert-butyl carbamate

[0786] The title compound (0.9 g) was prepared from intermediate 1.126 (0.55 g, 1.5 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.57 g, 2.1 mmol, CAS: 1228542-19-5), DIPEA (0.8 mL, 4.6 mmol), and HATU (0.8 g, 2.1 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Teledyne ISCO... Purified by rapid column chromatography (24 g silica gel column, eluted with 0%-100% 3:1 EtOAc:EtOH (in isohexane)). LCMS (Method 28): 2.14 min, 572.4 [M+H] + . Intermediate 2.130: ((S)-2-((6-(3,5-dimethyl-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)

[0787] pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[0788] The title compound (0.36 g) was prepared from intermediate 1.126 (0.22 g, 0.59 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.2 g, 0.74 mmol, CAS: 1187224-06-1), DIPEA (0.32 mL, 1.8 mmol), and HATU (0.29 g, 0.76 mmol) according to the procedure described for intermediate 2.51. An additional portion of (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (40 mg, 0.15 mmol, CAS: 1187224-06-1) and HATU (56 mg, 0.15 mmol) was added, and the mixture was stirred at 50 °C for 3 h. The crude product was subjected to Teledyne ISCO... Purified by rapid column chromatography (24 g silica gel column, eluted with 0%-100% 3:1 EtOAc:EtOH (in isohexane)). LCMS (Method 26): 1.95 min, 572.4 [M+H] + .

[0789] Intermediate 2.133: (S)-(1-cycloheptayl-2-oxo-2-((1',2',4'-trimethyl-6'-oxo-1',6'-di) Hydrogen-[3,3'-bipyridine]-6-yl)amino)ethyl)tert-butyl carbamate

[0790] The title compound (0.36 g) was prepared from intermediate 1.133 (30 mg, 0.13 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.12 g, 0.43 mmol, CAS: 1228542-19-5), DIPEA (0.14 mL, 0.8 mmol), and HATU (0.22 g, 0.59 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Teledyne ISCO... Purified by rapid column chromatography (12 g silica gel column, eluted with 0%-100% EtOAc in isohexane). LCMS (Method 28): 1.63 min, 483.3 [M+H] + .

[0791] Intermediate 2.134: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((1',2',4'-trimethyl- 6'-Oxo-1',6'-Dihydro-[3,3'-Bipyridine]-6-yl)amino)ethyl)tert-butyl carbamate

[0792] The title compound (30 mg) was prepared from intermediate 1.133 (90 mg, 0.39 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (32 mg, 0.12 mmol, CAS: 1187224-06-1), DIPEA (0.04 mL, 0.23 mmol), and HATU (68 mg, 0.18 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Teledyne ISCO... Purified by rapid column chromatography (12 g silica column, eluted with 0%-100% EtOAc in isohexane). LCMS (Method 28): 1.64 min, 483.3 [M+H] + .

[0793] Intermediate 2.135: (S)-(1-cycloheptyl-2-oxo-2-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrazol) tert-butyl 2-pyridylaminoethylcarbamate

[0794] The title compound (30 mg) was prepared from intermediate 1.135 (79 mg, 0.38 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptyl-acetic acid (0.1 g, 0.38 mmol, CAS: 1228542-19-5), DIPEA (0.13 mL, 0.75 mmol), and HATU (0.17 g, 0.46 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Teledyne ISCO... Purified by rapid column chromatography (12 g silica column, eluted with 0%-100% EtOAc in isohexane). LCMS (Method 27): 1.54 min, 456.2 [M+H] + .

[0795] Intermediate 2.136: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(1,3,5-trimethyl- 1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)tert-butyl carbamate

[0796] The title compound (30 mg) was prepared from intermediate 1.135 (46 mg, 0.23 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (62 mg, 0.23 mmol, CAS: 1187224-06-1), DIPEA (0.08 mL, 0.46 mmol), and HATU (95 mg, 0.25 mmol) according to the procedure described for intermediate 2.51. The crude product was used without further purification. LCMS (Method 27): 1.55 min, 456.2 [M+H] + .

[0797] Intermediate 2.138: ((S)-2-((5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)amino tert-butyl carbamate (1r,4S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0798] The title compound (0.22 g) was prepared from intermediate 1.138 (0.46 g, 1.9 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.26 g, 0.94 mmol, CAS: 1187224-06-1), DIPEA (0.33 mL, 1.9 mmol), and HATU (0.54 g, 1.4 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One... TM Rapid column chromatography (50g silica gel column, eluted with 0%-3% MeOH in DCM) and Biotage Isolera One TM Purified by rapid column chromatography (50 g silica gel column, eluted with 0%-30% EtOAc in heptane). LCMS (Method 14): 2.11 min, 496.2 [M+H] + .

[0799] Intermediate 2.139: (2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-(dispiro) [2.1.2 5 .2 3 Nonane-4-yl)-2-oxoethyl) tert-butyl carbamate

[0800] Intermediate 2.139a: 4-(methoxymethylene)bispirol [2.1.2] 5 .2 3 nonane

[0801] At 0 °C, n-butyllithium (2.5 M in hexane; 2.2 mL, 5.5 mmol) was slowly added to a solution of (methoxymethyl)triphenylphosphonium chloride (1.9 g, 5.5 mmol) in THF (6 mL). The mixture was stirred for 20 min, and then dispirol [2.1.2] was added to tetrahydrofuran (4 mL). 5 .2 3 Nonane-4-one (0.5 g, 3.7 mmol, CAS: 1004-54-2). The mixture was heated at 60 °C for 20 h, then cooled to room temperature and quenched with water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were passed through a phase separation column and then concentrated under vacuum. The crude product was passed through Biotage Isolera One. TM The title compound was purified by rapid column chromatography (10 g silica column, eluted with 100% DCM) to provide the title compound as an impurity mixture, which was subjected to the same reaction conditions described below.

[0802] At 0 °C, n-butyllithium (2.5 M in hexane; 1.5 mL, 3.7 mmol) was slowly added to a solution of (methoxymethyl)triphenylphosphonium chloride (1.3 g, 3.7 mmol) in THF (4 mL). The mixture was stirred for 20 min, followed by the addition of a crude mixture as a solution in tetrahydrofuran (2 mL). The mixture was heated at 60 °C for 20 h, then cooled to room temperature and quenched with water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were passed through a phase separation column and then concentrated under vacuum. The crude product was passed through a Biotage Isolera One. TM The sample was purified by rapid column chromatography (10 g silica column, eluted with 100% DCM) to provide the title compound (0.56 g). 1 H NMR (400MHz, CDCl3) δ: 5.32 (s, 1H), 3.40 (s, 3H), 1.74 (d, 4H), 1.38 (q, 2H), 0.76–0.68 (m, 2H), 0.65 (q, 2H), 0.62–0.56 (m, 2H).

[0803] Intermediate 2.139b: Two-screw [2.1.2] 5 .2 3 Nonane-4-carboxaldehyde

[0804] To a solution of intermediate 2.139a (70 mg, 0.43 mmol) in THF (0.5 mL), HCl (5 M aqueous; 0.5 mL, 2.5 mmol) in water (0.5 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixture was extracted with DCM, passed through a phase separation column, and concentrated under vacuum to provide the title compound (67 mg), which was used without further purification. 1 HNMR (400MHz, CDCl3) δ9.45(d,1H),3.51(t,2H),2.60(tt,2H),2.39(ddt,2H),1.88–1.79(m,3H),0.78–0.70(m,2H),0.48–0.44(m,2H).

[0805] Intermediate 2.139c: 5-(dispiro[2.1.2]) 5 .2 3 (nonane-4-yl)imidazoline-2,4-dione

[0806] A mixture of intermediate 2.139b (0.2 g, 1.3 mmol), ammonium carbonate (0.37 mg, 3.9 mmol), and sodium cyanide (95 mg, 1.9 mmol) in MeOH (5 mL) and water (5 mL) was added to a microwave-safe vial. The vial was sealed and the mixture was heated to 60 °C and maintained for 2 days. The mixture was cooled to room temperature and then acidified to pH 3 with HCl (1 M aqueous). The volatiles were concentrated under vacuum, and the aqueous residue was extracted with DCM. The organic matter was passed through a phase separation column and concentrated under vacuum. The crude product was milled with DCM to provide the title compound (35 mg). LCMS (Method 14): 1.50 min, 221.2 [M + H] + .

[0807] Intermediate 2.139d: 2-((tert-butoxycarbonyl)amino)-2-(dispiro[2.1.2] 5 .2 3 Nonane-4-yl)acetic acid

[0808] A solution of intermediate 2.139c (0.5 g, 2.3 mmol) in NaOH (5 M aqueous; 25 mL, 125 mmol) and water (25 mL) was heated under reflux for 3 days. The mixture was cooled to room temperature and then acidified to pH 3 with HCl (12 M aqueous). Potassium carbonate was added to adjust the pH to approximately 8, followed by the addition of THF (150 mL), then BOC anhydride (1.4 g, 6.8 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic matter was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was passed through Biotage Isolera One. TM Purification was performed by rapid column chromatography (40 g silica gel column, eluted with 0%–10% MeOH in DCM) to provide the title compound (0.27 g). LCMS (Method 14): 2.11 min, 1.89 min, 294.2 [MH] - .

[0809] Intermediate 2.139: (2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-(dispiro[2.1.2]) 5 .2 3 Nonane-4-yl)-2-oxoethyl) tert-butyl carbamate

[0810] The title compound (0.22 g) was prepared from intermediate 1.25 (45 mg, 0.24 mmol), intermediate 2.139d (47 mg, 0.16 mmol), DIPEA (0.06 mL, 0.32 mmol), and HATU (85 mg, 0.22 mmol) according to the procedure described for intermediate 2.51. The crude product was subjected to Biotage Isolera One. TM Purified by rapid column chromatography (10g silica gel column, eluted with 0%-10% MeOH in DCM). LCMS (Method 14): 2.05 min, 466.2 [M+H] + .

[0811] Intermediate 3: (S ) -2-amino-N-(4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-2- ((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride

[0812] The solution of intermediate 2 (73 mg, 0.16 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to provide the title compound (0.11 g). LCMS (Method 4): 0.76 min, 368.2 [M + H₂] + .

[0813] Intermediate 3.1: (S)-2-amino-N-(4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluoro phenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride

[0814] The solution of intermediate 2.1 (60 mg, 0.12 mmol) in HCl (4 M in 1,4-dioxane; 3 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to provide the title compound (70 mg). LCMS (Method 3): 0.86 min, 384.2 [MH] + .

[0815] Intermediate 3.2: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(7-oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetamide hydrochloride

[0816] The solution of intermediate 2.2 (0.12 g, 0.25 mmol) in HCl (3 M in 1,4-dioxane; 15 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum to provide the title compound (0.11 g). LCMS (Method 4): 0.73 min, 379.3 [M + H] + .

[0817] Intermediate 3.3: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(2-oxo-1,2-dihydropyridine) (Pyridine-4-yl)phenyl)acetamide hydrochloride

[0818] The solution of intermediate 2.3 (49 mg, 0.11 mmol) in HCl (3 M in 1,4-dioxane; 10 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum to provide the title compound (40 mg). LCMS (Method 4): 0.68 min, 340.2 [M + H) + .

[0819] Intermediate 3.4: (S)-2-amino-N-(4-(imidazo[1,2-a]pyridin-5-yl)phenyl)-2-((1r,4S)-4- (Methylcyclohexyl)acetamide hydrochloride

[0820] The solution of intermediate 2.4 (32 mg, 0.07 mmol) in HCl (3 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under vacuum to provide the title compound (28 mg). LCMS (Method 4): 0.84 min, 363.2 [M + H] + .

[0821] Intermediate 3.6: (S)-2-amino-N-(4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl) phenyl)-2-((1r,4S)-4-methylcyclohexyl)acetamide hydrochloride

[0822] Intermediate 2.6 (0.69 g, 1.2 mmol) was stirred for 16 h at room temperature in a solution of HCl (4 M in 1,4-dioxane; 3.1 mL) and 1,4-dioxane (2 mL). The reaction mixture was concentrated under vacuum, and the crude product was passed through a Biotage Isolera. TM Purification was performed by rapid column chromatography (20 g silica column, eluted with 30%–100% EtOAc in heptane) to provide the title compound (0.4 g). LCMS (Method 14): 1.57 min, 461.2 [M+H] + .

[0823] Intermediate 3.6a: (S)-N-(2-((4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)benzene (4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0824] To a solution of intermediate 3.6 (370 mg, 0.80 mmol) in MeCN (4 mL) and EtOAc (12 mL), 2-methylpyrazol-3-carboxylic acid (101 mg, 0.80 mmol, CAS: 16034-46-1), HATU (367 mg, 0.96 mmol), and triethylamine (0.34 mL, 2.41 mmol) were added, and the reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, partitioned between saturated aqueous NaHCO3 and EtOAc, and separated. The organic matter was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was subjected to a Biotage Isolera. TMThe title compound (400 mg) was purified by rapid column chromatography (120 g silica column, 30%-100% EtOAc in heptane). 1 H NMR(400MHz,MeOD)δ:7.67–7.60(m,2H),7.47(d,1H),7.22(s,2H),7.12–7.04(m,2H),6.92–6.84(m,3H),5.22(s,2H),4.44(d,1H),4.08(s,3H) ,3.77(s,3H),2.21(s,3H),2.18(s,3H),1.94(d,1H),1.88–1.84(m,1H) ,1.77(d,3H),1.35–1.27(m,2H),1.17(d,1H),0.98(q,2H),0.90(d,3H).

[0825] Intermediate 3.7: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(3-(2-oxo-2-(pyrrole)) Alkyl-1-yl)ethyl)pyridin-4-yl)phenyl)acetamide dihydrochloride

[0826] The solution of intermediate 2.7 (98 mg, 0.18 mmol) in HCl (4 M in 1,4-dioxane; 1.4 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum to provide the title compound (95 mg). LCMS (Method 4): 0.77 min, 435.3 [M + H) + .

[0827] Intermediate 3.8: (S)-2-amino-N-(1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine] [Pyridine]-6-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride

[0828] The solution of intermediate 2.8 (18 mg, 0.04 mmol) in HCl (3 M in 1,4-dioxane; 3 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under vacuum to provide the title compound (16 mg). LCMS (Method 4): 0.75 min, 369.2 [M + H] + .

[0829] Intermediate 3.9: (S)-2-amino-N-(3',5'-dimethyl-[3,4'-bipyridin]-6-yl)-2-((1r,4S)- 4-Methylcyclohexyl)acetamide dihydrochloride

[0830] The solution of intermediate 2.9 (60 mg, 0.13 mmol) in HCl (3 M in 1,4-dioxane; 3 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to provide the title compound (57 mg). LCMS (Method 4): 0.90 min, 353.2 [M + H] + .

[0831] Intermediate 3.12: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(4-(tetrahydro-2H-pyran-4-) phenylacetamide hydrochloride

[0832] The solution of intermediate 2.12 (0.13 g, 0.3 mmol) in HCl (4 M in 1,4-dioxane; 0.8 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum, and the residue was ground with diethyl ether (5 mL) to provide the title compound (75 mg). LCMS (Method 12): 2.20 min, 331 [M + H] + .

[0833] Intermediate 3.13: (S)-2-amino-N-(4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-2-((1r,4S)- 4-Methylcyclohexyl)acetamide

[0834] The suspension of intermediate 2.13 (0.1 g, 0.22 mmol) in HCl (4 M in 1,4-dioxane; 0.56 mL) was stirred at room temperature for 35 min. The reaction mixture was diluted with water and passed through Biotage Isolera One. TM Purification was performed by reversed-phase column chromatography (30 g C18 column, eluted with 5%–100% 0.1% ammonia MeCN in 0.1% ammonia / water) to provide the title compound (54 mg). LCMS (Method 4): 0.70 min, 347.2 [M+H] + .

[0835] Intermediate 3.14: (S)-2-amino-N-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-2-((1r,4S)-4- (Methylcyclohexyl)acetamide

[0836] The suspension of intermediate 2.14 (0.23 g, 0.54 mmol) in HCl (4 M in 1,4-dioxane; 1.5 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water and passed through Biotage Isolera One. TM Purification was performed by reversed-phase column chromatography (30 g C18 column, eluted with 5%–100% 0.1% ammonia MeCN in 0.1% ammonia / water) to provide the title compound (0.11 g). LCMS (Method 4): 0.91 min, 329.0 [M+H] + .

[0837] Intermediate 3.15: (S)-2-amino-N-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-((1r,4S)-4- (Methylcyclohexyl)acetamide hydrochloride

[0838] A solution of intermediate 2.15 (81 mg, 0.18 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to provide the title compound (70 mg). LCMS (Method 14): 1.44 min, 342.2 [M + H] + .

[0839] Intermediate 3.16: (S)-2-amino-N-(5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)-2-((1r, 4S)-4-methylcyclohexyl ) Acetamide

[0840] A solution of intermediate 2.16 (0.28 g, 0.62 mmol) in HCl (4 M in 1,4-dioxane; 5 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH (6 mL) and passed through an SCX column (5 g, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.19 mg). LCMS (Method 14): 1.40 min, 343.2 [M + H] + .

[0841] Intermediate 3.18: (S)-2-amino-N-(5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl) Pyridin-2-yl)-2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride

[0842] The solution of intermediate 2.18 (37 mg, 0.07 mmol) in HCl (4 M in 1,4-dioxane; 0.17 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to provide the title compound (33 mg). 1 H NMR(400MHz, DMSO-d6)δ:11.03(s,1H),8.36–8.24(m,4H),8.12(d,1H),7.78(dd,1H),7.20–7.14(m,2H),6.95–6.88(m,2H),5. 21(s,2H),3.95–3.86(m,1H),3.73(s,3H),2.22(s,3H),2.17(s,3H),1.84–1.61(m,5H),1.30–1.04(m,3H),0.94–0.83(m,5H).

[0843] Intermediate 3.18a: N-((S)-2-((5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyrazol (Pyridine-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0844] 2-Methylpyrazol-3-carboxylic acid (9.2 mg, 0.07 mmol, CAS: 16034-46-1), HATU (28 mg, 0.07 mmol), and triethylamine (0.03 mL, 0.2 mmol) were added to a solution of intermediate 3.18 (33 mg, 0.07 mmol) in EtOAc (0.39 mL) and MeCN (0.39 mL) at 0 °C. The mixture was stirred at 0 °C for 20 h, and then the solvent was removed under vacuum. The residue was dissolved in DCM and washed with saturated aqueous NaHCO3. The organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 20%–80% EtOAc in heptane) to provide the title compound (24 mg). LCMS (Method B): 2.78 min, 570.2 [M+H] + .

[0845] Intermediate 3.25: (S)-2-amino-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-2- ((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride

[0846] A solution of intermediate 2.25 (28 mg, 0.06 mmol) in HCl (4 M in 1,4-dioxane; 0.75 mL) was stirred at room temperature for 45 min. The reaction mixture was concentrated under vacuum to provide the title compound (24 mg). LCMS (Method 14): 1.38 min, 342.3 [M + H] + .

[0847] Intermediate 3.27: (S)-2-amino-2-cyclohexyl-N-(5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl) Acetamide

[0848] A solution of intermediate 2.27 (0.6 g, 1.4 mmol) in HCl (4 M in 1,4-dioxane; 6 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH (6 mL) and passed through an SCX column (5 g, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.45 mg). LCMS (Method 14): 1.36 min, 329.2 [M+H] + .

[0849] Intermediate 3.34: (S)-2-amino-2-cycloheptyl-N-(5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl) Acetamide

[0850] The intermediate 2.34 (0.2 g, 0.38 mmol) was stirred in HCl (4 M in 1,4-dioxane; 4 mL) for 1 h at room temperature. The reaction mixture was concentrated under vacuum, and the residue was suspended in EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted twice with EtOAc, and the combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (0.15 g). LCMS (Method 14): 1.35 min, 343.2 [M+H] + .

[0851] Intermediate 3.38: (S)-2-amino-2-cyclohexyl-N-(4-(1,2-dimethyl-6-oxo-1,6-dihydropyridine- 3-yl)phenyl)acetamide hydrochloride

[0852] The suspension of intermediate 2.38 (0.26 g, 0.57 mmol) in HCl (4 M in 1,4-dioxane; 0.14 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under vacuum to provide the title compound (0.28 g). LCMS (Method 14): 1.27 min, 354.2 [M + H] + .

[0853] Intermediate 3.44: (S)-2-amino-N-(5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)- 2-((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride

[0854] A solution of intermediate 2.44 (35 mg, 0.08 mmol) in HCl (4 M in 1,4-dioxane; 1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to provide the title compound (32 mg). LCMS (Method 14): 1.32 min, 343.3 [M + H] + .

[0855] Intermediate 3.49a: (S)-6-((1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl) (amino)-2-oxoethyl ) tert-butyl carbamoyl 3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

[0856] HATU (88 mg, 0.23 mmol) and DIPEA (0.1 mL, 0.58 mmol) were added to 2-tert-butoxycarbonyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-6-carboxylic acid (61 mg, 0.23 mmol, CAS: 1363380-86-2) in anhydrous DCM (1.5 mL). The mixture was stirred at room temperature for 5 min, followed by the addition of intermediate 3.27 (70 mg, 0.19 mmol). The reaction mixture was stirred again at room temperature under an argon atmosphere for 20 h, then diluted with DCM and washed with saturated aqueous NaHCO3. The organic matter was washed with brine, passed through a hydrophobic sintered tube, and concentrated under vacuum. The crude product was purified by rapid column chromatography (12 g silica gel, eluted with 0%–80% EtOAc in heptane) to give the title compound (41 mg). LCMS (Method 14): 2.71 min, 577.4 [M+H]+.

[0857] Intermediate 3.51: (S)-2-amino-2-cycloheptyl-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine-2- Acetamide

[0858] The suspension of intermediate 2.51 (0.36 g, 0.81 mmol) in HCl (4 M in 1,4-dioxane; 7 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (0.3 g). LCMS (Method 14): 1.35 min, 342.2 [M+H] + .

[0859] Intermediate 3.54: (S)-2-amino-N-(2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)-2-((1r, 4S)-4-methylcyclohexyl)acetamide

[0860] A solution of intermediate 2.54 (0.24 g, 0.54 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (97 mg). LCMS (Method 14): 1.42 min, 344.2 [M + H] + .

[0861] Intermediate 3.57: (S)-2-amino-N-(6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)-2-((1r, 4S)-4-methylcyclohexyl)acetamide

[0862] A solution of intermediate 2.57 g (0.13 g, 0.29 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (93 mg). LCMS (Method 14): 1.43 min, 343.2 [M + H] + .

[0863] Intermediate 3.59: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(5-(5-methylpyrimidin-4-yl) pyridin-2-yl)acetamide

[0864] A solution of intermediate 2.5g (0.13 g, 0.3 mmol) in HCl (4 M in 1,4-dioxane; 0.08 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (93 mg). LCMS (Method 14): 1.32 min, 340.2 [M + H] + .

[0865] Intermediate 3.61: (S)-2-amino-N-(5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridine-2- 2-((1r,4S)-4-methylcyclohexyl)acetamide

[0866] A solution of intermediate 2.61 (0.12 g, 0.25 mmol) in HCl (4 M in 1,4-dioxane; 0.08 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum, and the residue was diluted with saturated aqueous NaHCO3 and extracted into ethyl acetate. The aqueous phase was extracted with EtOAc, and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (82 mg). LCMS (Method 14): 1.37 min, 373.2 [M+H] + .

[0867] Intermediate 3.62: (S)-2-amino-2-cycloheptyl-N-(5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine (Pyridine-2-yl)acetamide dihydrochloride

[0868] The intermediate 2.62 (34 mg, 0.08 mmol) was stirred in HCl (4 M in 1,4-dioxane; 0.19 mL) at room temperature for 18 h. The reaction mixture was concentrated under vacuum and the crude product was purified by rapid column chromatography (eluting with 2%–100% MeOH in DCM) to provide the title compound (23 mg). 1H NMR(400MHz,MeOD)δ:8.60(s,1H),8.49(d,1H),8.18–8.04(m,1H),4.13–4.07(m,1H),2.52(d,6H),2.25(s,1H),1.94–1.39(m,12H).

[0869] Intermediate 3.63: (S)-2-amino-2-(4,4-difluorocyclohexyl)-N-(5-(1,4-dimethyl-1H-pyrazole-5- 2-pyridine-2-yl)acetamide

[0870] The intermediate 2.63 (0.29 g, 0.6 mmol) was stirred for 18 h at room temperature in HCl (4 M in 1,4-dioxane; 1.6 mL) and 1,4-dioxane (5 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.19 g). LCMS (Method 19): 1.63 min, 364.2 [M + H] + .

[0871] Intermediate 3.64: (S)-2-amino-N-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)-2- ((1r,4S)-4-methylcyclohexyl)acetamide

[0872] A solution of intermediate 2.64 (0.34 g, 0.77 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (239 mg). LCMS (Method 19): 1.68 min, 342.2 [M + H] + .

[0873] Intermediate 3.65: (S)-2-amino-N-(4-methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2- ((1r,4S)-4-methylcyclohexyl)acetamide

[0874] The intermediate 2.65 (0.23 g, 0.51 mmol) was stirred for 19 h at room temperature in HCl (4 M in 1,4-dioxane; 1.3 mL) and 1,4-dioxane (10 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (0.5 g, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.12 g). LCMS (Method 14): 1.29 min, 342.2 [M + H] + .

[0875] Intermediate 3.66: (S)-2-amino-N-(2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-2- ((1r,4S)-4-methylcyclohexyl)acetamide

[0876] A solution of intermediate 2.66 (0.5 g, 0.89 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.27 g). LCMS (Method 14): 1.41 min, 343.2 [M + H] + .

[0877] Intermediate 3.67: (S)-2-amino-2-cycloheptyl-N-(5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl) ) pyrene (Pyridine-2-yl)acetamide

[0878] The intermediate 2.67 (0.14 g, 0.31 mmol) was stirred in HCl (4 M in 1,4-dioxane; 2.5 mL) for 3 h at room temperature. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (2 g, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.1 g). 1 H NMR(400MHz,MeOD)δ:8.41–8.33(m,2H),7.89(dd,1H),3.99(s,3H),3.44(d,1H),2.29(s,3H),2.10–1.97(m,1H),1.81–1.34(m,12H).

[0879] Intermediate 3.69: (S)-2-amino-2-cycloheptyl-N-(5-(5-(methoxymethyl)-3-methylisoxazole-4- 2-pyridine-2-yl)acetamide dihydrochloride

[0880] A solution of intermediate 2.69 g (90 mg, 0.19 mmol) in HCl (4 M in 1,4-dioxane; 0.48 mL) and 1,4-dioxane (3 mL) was stirred at room temperature for 40 h. The reaction mixture was concentrated under vacuum to provide the title compound (0.1 g). LCMS (Method 19): 1.810 min, 373.2 [M + H] + .

[0881] Intermediate 3.70: (S)-2-amino-N-(3'-methoxy-2'-methyl-[3,4'-bipyridine]-6-yl)-2- ((1r,4S)-4-methylcyclohexyl ) Acetamide

[0882] A solution of intermediate 2.70 (0.11 g, 0.24 mmol) in HCl (4 M in 1,4-dioxane; 0.6 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (86 mg). LCMS (Method 19): 1.50 min, 369.2 [M + H] + .

[0883] Intermediate 3.71: (S)-2-amino-N-(2',3'-dimethyl-[3,4'-bipyridin]-6-yl)-2-((1r,4S)- 4-Methylcyclohexyl)acetamide

[0884] The intermediate 2.71 (0.19 g, 0.43 mmol) was stirred for 4 h at room temperature in HCl (4 M in 1,4-dioxane; 1.1 mL) and 1,4-dioxane (3 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.13 g). 1 H NMR(400MHz, CDCl3)δ:10.05(s,1H),8.42–8.32(m,2H),8.25(dd,1H),7.66(dd,1H),6.99(d,1H),3.45(d,1H),2.59(s,3H),2. 21(s,3H),2.06–1.95(m,1H),1.78–1.71(m,3H),1.60(m,1H),1.35–1.22(m,2H),1.16(m,1H),1.09–0.91(m,2H),0.88(d,3H).

[0885] Intermediate 3.72: (S)-2-amino-N-(2',5'-dimethyl-[3,4'-bipyridine]-6-yl)-2-((1r,4S)- 4-Methylcyclohexyl)acetamide

[0886] The intermediate 2.72 (0.1 g, 0.23 mmol) was stirred for 18 h at room temperature in HCl (4 M in 1,4-dioxane; 0.56 mL) and 1,4-dioxane (3 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (77 mg). LCMS (Method 14): 1.24 min, 353.2 [M + H] + .

[0887] Intermediate 3.76: (S)-2-amino-2-cycloheptayl-N-(5-(1-ethyl-4-methyl-1H-1,2,3-triazole-5- 2-pyridine-2-yl)acetamide

[0888] A solution of intermediate 2.76 (31 mg, 0.068 mmol) in HCl (4 M in 1,4-dioxane; 0.17 mL) and 1,4-dioxane (10 mL) was stirred at room temperature for 19 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (0.5 g, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (19 mg). LCMS (Method 19): 1.67 min, 357.2 [M + H] + .

[0889] Intermediate 3.77: (S)-2-amino-2-cycloheptyl-N-(5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl) Acetamide

[0890] The intermediate 2.77 (20 mg, 0.05 mmol) was stirred at room temperature for 19 h in HCl (4 M in 1,4-dioxane; 0.17 mL), 1,4-dioxane (5 mL), and MeOH (5 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (0.1 g, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (16 mg). LCMS (Method 14): 1.36 min, 344.2 [M + H] + .

[0891] Intermediate 3.80: (S)-2-amino-2-cycloheptayl-N-(5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazole-5- 2-pyridine-2-yl)acetamide

[0892] A solution of intermediate 2.80 (18 mg, 0.04 mmol) in HCl (4 M in 1,4-dioxane; 0.05 mL) and 1,4-dioxane (5 mL) was stirred at room temperature for 19 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (0.1 g, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (16 mg). LCMS (Method 14): 1.35 min, 369.2 [M + H] + .

[0893] Intermediate 3.81: (S)-2-amino-2-cycloheptyl-N-(5-(3,5-dimethyl) different Oxazol-4-yl ) -3-Fluoropyridine- 2-yl)acetamide

[0894] The intermediate 2.81 (0.22 g, 0.49 mmol) was stirred for 18 h at room temperature in HCl (4 M in 1,4-dioxane; 1.2 mL) and 1,4-dioxane (3 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (99 mg). LCMS (Method 14): 1.36 min, 361.2 [M + H] + .

[0895] Intermediate 3.84: (S)-2-amino-2-cycloheptyl-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidine-2- Acetamide

[0896] A solution of intermediate 2.84 (59 mg, 0.13 mmol) in HCl (4 M in 1,4-dioxane; 1 mL) was stirred at room temperature for 1 h. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (51 mg). LCMS (Method 14): 1.27 min, 343.2 [M+H] + .

[0897] Intermediate 3.85: (S)-2-amino-2-cycloheptyl-N-(5-(4-hydroxy-1-methyl-1H-pyrazol-5-yl)pyridine- 2-yl)acetamide

[0898] Boron tribromide (1 M in DCM; 0.17 mL, 0.17 mmol) was added to a solution of intermediate 2.85 (30 mg, 0.06 mmol) in 10 mL of DCM at 0 °C. The mixture was heated to room temperature, and then another portion of boron tribromide (0.56 mL, 0.56 mmol) was added, and the mixture was stirred at room temperature for 8 h. Another portion of boron tribromide (0.56 mL, 0.56 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with water and neutralized with 1 M NaOH solution, extracted with DCM, and the phases were separated using a phase separation column. The organic layer was concentrated under vacuum to provide the title compound (21 mg). LCMS (Method 14): 1.24 min, 344.2 [M+H] + .

[0899] Intermediate 3.88: (S)-2-amino-2-cycloheptyl-N-(6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl) Acetamide

[0900] The intermediate 2.88 g (0.44 g, 0.99 mmol) was stirred in HCl (4 M in 1,4-dioxane; 5 mL) and 1,4-dioxane (5 mL) at room temperature for 2 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.3 g). LCMS (Method 14): 1.34 min, 343.2 [M + H] + .

[0901] Intermediate 3.92: (S)-2-amino-2-cycloheptyl-N-(5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazole-5- 2-pyridine-2-yl)acetamide

[0902] A solution of intermediate 2.92 (53 mg, 0.09 mmol) in HCl (4 M in 1,4-dioxane; 1 mL) and 1,4-dioxane (5 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (46 mg). LCMS (Method 19): 1.70 min, 369.2 [M+H] + .

[0903] Intermediate 3.93: (S)-2-amino-N-(5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-cyclo heptaethyl acetamide

[0904] A solution of intermediate 2.93 (0.58 g, 1.1 mmol) in HCl (4 M in 1,4-dioxane; 5.6 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (10 g column, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.38 g). LCMS (Method 19): 1.78 min, 362.2 [M + H] + .

[0905] Intermediate 3.96: (S)-2-amino-2-cyclohexyl-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine-2- Acetamide

[0906] A solution of intermediate 2.96 g (0.5 g, 1.2 mmol) in HCl (4 M in 1,4-dioxane; 2.9 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (0.38 g). 1H NMR(400MHz,MeOD)δ:8.35–8.28(m,2H),7.81(dd,1H),7.38(d,1H),3.74(s,3H),3.36(d,1H),2.01(d,3H),1.81–1.65(m,6H),1.45–1.11(m,5H).

[0907] Intermediate 3.98: (S)-2-amino-N-(6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)- 2-(4-methylcyclohexyl) ) Acetamide

[0908] The intermediate 2.98 g (0.49 g, 1.1 mmol) was stirred for 5 h at room temperature in HCl (4 M in 1,4-dioxane; 5.3 mL) and 1,4-dioxane (4 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (10 g column, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.33 g). LCMS (Method 14): 1.35 min, 360.2 [M + H] + .

[0909] Intermediate 3.101: (S)-2-amino-2-cycloheptyl-N-(5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl) pyridin-2-yl)acetamide

[0910] The solution of intermediate 2.101 (70 mg, 0.12 mmol) in HCl (4 M in 1,4-dioxane; 0.15 mL) and 1,4-dioxane (2 mL) was stirred at room temperature for 3 h. A further portion of HCl (4 M in 1,4-dioxane; 0.15 mL) was added, and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (36 mg). LCMS (Method 15): 1.45 min, 358.2 [M+H] + .

[0911] Intermediate 3.102: (S)-2-amino-2-cyclopentyl-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine-2- Acetamide

[0912] The intermediate 2.102 (48 mg, 0.12 mmol) was stirred for 18 h at room temperature in HCl (4 M in 1,4-dioxane; 0.3 mL) and 1,4-dioxane (1 mL). The reaction mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous NaHCO3 and DCM. The phases were separated, and the aqueous layer was extracted with DCM. The combined organics were washed with water and brine, separated by a phase separation column, and concentrated under vacuum to provide the title compound (34 mg). LCMS (Method 26): 1.02 min, 314.2 [M + H2]. + .

[0913] Intermediate 3.103: 2-amino-2-(bicyclo[2.2.1]heptane-2-yl)-N-(5-(1,4-dimethyl-1H-pyrazole- 5-yl)pyridin-2-yl)acetamide

[0914] The intermediate 2.103 (60 mg, 0.13 mmol) was stirred for 18 h at room temperature in HCl (4 M in 1,4-dioxane; 0.33 mL) and 1,4-dioxane (1 mL). The reaction mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous NaHCO3 and DCM. The phases were separated, and the aqueous layer was extracted with DCM. The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (30 mg). LCMS (Method 26): 1.30 min, 340.3 [M+H] + .

[0915] Intermediate 3.104: 2-amino-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-((1r, 4r)-4-(trifluoromethyl)cyclohexyl)acetamide

[0916] A solution of intermediate 2.104 (0.22 g, 0.44 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (0.16 g). LCMS (Method 14): 1.30 min, 396.2 [M + H] + .

[0917] Intermediate 3.109: (S)-2-amino-2-cycloheptayl-N-(5-(1-(2-(dimethylamino)-2-oxoethyl)- 4-Methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)acetamide

[0918] The intermediate 2.109 (55 mg, 0.1 mmol) was stirred at room temperature for 17 h in HCl (4 M in 1,4-dioxane; 0.48 mL) and 1,4-dioxane (1.5 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (2 g column, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (36 mg). LCMS (Method 14): 1.25 min, 414.2 [M + H] + .

[0919] Intermediate 3.112: (S)-2-amino-N-(5-(4-cyano-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2- ((1r,4S)-4-methylcyclohexyl)acetamide

[0920] The intermediate 2.112 (71 mg, 0.14 mmol) was stirred for 5 h at room temperature in HCl (4 M in 1,4-dioxane; 0.71 mL) and 1,4-dioxane (1 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (2 g column, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (44 mg). LCMS (Method 14): 1.33 min, 353.2 [M + H] + .

[0921] Intermediate 3.114: (S)-2-amino-2-cycloheptyl-N-(5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridine- 2-yl)acetamide

[0922] A solution of intermediate 2.114 (0.36 g, 0.78 mmol) in HCl (4 M in 1,4-dioxane; 0.98 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (10 g column, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum to provide the title compound (0.29 g). LCMS (Method 14): 1.35 min, 356.2 [M + H] + .

[0923] Intermediate 3.115: (S)-2-amino-N-(5-(3,5-dimethylisothiazo-4-yl)pyridin-2-yl)-2-((1r, 4S)-4-methylcyclohexyl)acetamide

[0924] A solution of intermediate 2.115 (0.1 g, 0.23 mmol) in HCl (4 M in 1,4-dioxane; 2 mL) was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (77 mg). LCMS (Method 15): 1.77 min, 359.2 [M+H] + .

[0925] Intermediate 3.118: (S)-2-amino-N-(5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)-2- ((1r,4S)-4-methylcyclohexyl)acetamide

[0926] Intermediate 2.118 (0.48 g, 0.93 mmol) was stirred for 3 h at room temperature in a solution of HCl (4 M in 1,4-dioxane; 2 mL) and 1,4-dioxane (2 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (10 g column, washed with MeOH and eluted with 2 M methylamine). The solvent was removed under vacuum. The crude product was passed through a Biotage Isolera One. TM Purification was performed by rapid column chromatography (10 g silica column, eluted with 0%-5% 2M methylamine in DCM) to provide the title compound (0.28 g). LCMS (Method 15): 1.77 min, 362.2 [M+H] + .

[0927] Intermediate 3.124: (S)-2-amino-N-(5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridine-2- 2-((1r,4S)-4-methylcyclohexyl)acetamide

[0928] The solution of intermediate 2.124 (0.27 g, 0.47 mmol) in HCl (4 M in 1,4-dioxane; 0.59 mL) and 1,4-dioxane (11.5 mL) was stirred at room temperature for 3 h. A further portion of HCl (4 M in 1,4-dioxane; 0.59 mL) was added, and the mixture was stirred at room temperature for another 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (0.17 g). LCMS (Method 15): 1.48 min, 358.2 [M+H] + .

[0929] Intermediate 3.126: (S)-2-amino-2-cyclohexyl-N-(6-(3,5-dimethyl-1H-pyrazol-4-yl) ) Pyridine-3- Acetamide dihydrochloride

[0930] A solution of intermediate 2.126 (37 mg, 0.05 mmol) in HCl (4 M in 1,4-dioxane; 0.5 mL), 1,4-dioxane (0.5 mL), and MeOH (1 mL) was stirred at 40 °C for 3 h. The mixture was concentrated under vacuum to provide the title compound (30 mg). LCMS (Method 28): 1.03 min, 328.3 [M + H] + .

[0931] Intermediate 3.127: (S)-2-amino-2-cycloheptyl-N-(6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridine-3- Acetamide dihydrochloride

[0932] The intermediate 2.127 (0.9 g, 1.6 mmol) was stirred for 1 h at room temperature in HCl (4 M in 1,4-dioxane; 5 mL), 1,4-dioxane (5 mL), and MeOH (20 mL). The mixture was concentrated under vacuum to provide the title compound (0.76 g). LCMS (Method 28): 1.14 min, 342.3 [M + H] + .

[0933] Intermediate 3.130: (S)-2-amino-N-(6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2- ((1r,4S)-4-methylcyclohexyl)acetamide dihydrochloride

[0934] A solution of intermediate 2.130 (0.36 g, 0.62 mmol) in HCl (4 M in 1,4-dioxane; 2.2 mL) and MeOH (5 mL) was stirred at 40 °C for 20 h. The mixture was concentrated under vacuum to provide the title compound (0.34 g). LCMS (Method 28): 1.16 min, 342.3 [M + H] + .

[0935] Intermediate 3.133: (S)-2-amino-2-cycloheptayl-N-(1',2',4'-trimethyl-6'-oxo-1',6'-di) Hydrogen-[3,3'-bipyridine]-6-yl)acetamide

[0936] The intermediate 2.133 (30 mg, 0.06 mmol) was stirred for 18 h at room temperature in HCl (4 M in 1,4-dioxane; 0.16 mL) and 1,4-dioxane (0.5 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (1 g column, washed with MeOH and eluted with 5% methylamine). The solvent was removed under vacuum to provide the title compound (25 mg). LCMS (Method 29): 1.27 min, 383.3 [M + H] + .

[0937] Intermediate 3.134: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(1',2',4'-trimethyl- 6'-Oxo-1',6'-Dihydro-[3,3'-Bipyridine]-6-yl)acetamide

[0938] The intermediate 2.134 (30 mg, 0.06 mmol) was stirred for 18 h at room temperature in HCl (4 M in 1,4-dioxane; 0.15 mL) and 1,4-dioxane (0.5 mL). The reaction mixture was concentrated under vacuum, and the residue was dissolved in MeOH and passed through an SCX column (1 g column, washed with MeOH and eluted with 5% methylamine). The solvent was removed under vacuum to provide the title compound (16 mg). LCMS (Method 28): 1.23 min, 383.4 [M + H] + .

[0939] Intermediate 3.135: (S)-2-amino-2-cycloheptyl-N-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine- 2-yl)acetamide

[0940] A solution of intermediate 2.135 (71 mg, 0.16 mmol) in HCl (4 M in 1,4-dioxane; 0.39 mL) and 1,4-dioxane (1 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum and the residue was partitioned between saturated aqueous NaHCO3 and DCM. The phases were separated using a phase separation column, and the organic matter was concentrated under vacuum to provide the title compound (65 mg). LCMS (Method 26): 1.30 min, 356.3 [M + H] + .

[0941] Intermediate 3.136: (S)-2-amino-2-((1r,4S)-4-methylcyclohexyl)-N-(5-(1,3,5-trimethyl- 1H-pyrazol-4-yl)pyridin-2-yl)acetamide

[0942] The intermediate 2.136 (80 mg, 0.16 mmol) was stirred for 18 h at room temperature in HCl (4 M in 1,4-dioxane; 0.4 mL) and 1,4-dioxane (1 mL). The reaction mixture was concentrated under vacuum and the residue was partitioned between saturated aqueous NaHCO3 and DCM. The phases were separated using a phase separation column, and the organic matter was concentrated under vacuum to provide the title compound (46 mg). LCMS (Method 28): 1.37 min, 356.3 [M + H] + .

[0943] Intermediate 3.138: (S)-2-amino-N-(5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridine-2- 2-((1r,4S)-4-methylcyclohexyl)acetamide

[0944] The intermediate 2.138 (0.11 g, 0.21 mmol) was stirred for 1 h at room temperature in HCl (4 M in 1,4-dioxane; 1 mL) and DCM (0.5 mL). The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (85 mg). LCMS (Method 14): 1.42 min, 396.2 [M + H] + .

[0945] Intermediate 3.139: 2-amino-N-(5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)-2-(dispiro) [2.1.2 5 .2 3 nonan-4-yl)acetamide

[0946] The intermediate 2.139 (30 mg, 0.06 mmol) was stirred for 18 h at room temperature in a solution of HCl (4 M in 1,4-dioxane; 0.08 mL) and 1,4-dioxane (5 mL). The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was passed through Biotage Isolera One. TMPurification was performed by rapid column chromatography (10 g silica column, eluted with 0%–10% MeOH in DCM) to provide the title compound (16 mg). LCMS (Method 14): 1.36 min, 366.2 [M+H] + .

[0947] Intermediate 4.17: 4-(4,4-difluorocyclohexyl)-2-(1-methyl-1H-pyrazol-5-yl)oxazol-5(4H)-one

[0948] Under argon atmosphere at -10°C, a solution of 2-(2-methylpyrazol-3-yl)-4H-oxazol-5-one (200 mg, 1.2 mmol CAS: 2256070-09-2) in THF (10 mL) was added to a mixture of titanium tetrachloride (IV) (1 M in DCM; 4.8 mL, 4.8 mmol) in THF (10 mL), followed by the addition of a solution of 4,4-difluorocyclohexanone (179 mg, 1.3 mmol CAS: 22515-18-0) in THF (5 mL). The mixture was stirred at -10°C for 30 min, followed by the dropwise addition of pyridine (0.59 mL, 7.3 mmol), and then the mixture was stirred at -10°C to room temperature for 16 h. The mixture was quenched by the addition of saturated aqueous NH4Cl and then extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was passed through Biotage Isolera TM The title compound (240 mg) was purified by rapid column chromatography (10 g silica column, eluted with 0%-30% EtOAc in heptane). 1 H NMR(400MHz, CDCl3)δ:7.55(d,1H),6.90(d,1H),4.28(s,3H),3.30–3.19(m,2H),3.08–2.97(m,2H),2.22–2.05(m,4H).

[0949] Intermediate 4.19: 4-(4,4-dimethylcyclohexylene)-2-(1-methyl-1H-pyrazol-5-yl)oxazol-5(4H)- ketone

[0950] The title compound (0.17 g) was prepared from 2-(2-methylpyrazol-3-yl)-4H-oxazol-5-one (0.19 g, 1.1 mmol, CAS: 22515-18-0) and 4,4-dimethylcyclohexanone (0.13 g, 1 mmol, CAS: 4255-62-3) according to the procedure described for intermediate 4.17. LCMS (Method 14): 2.07 min, 274.2 [M+H] + .

[0951] Intermediate 4.20: 4-(4,4-difluorocyclohexyl)-2-(1-methyl-1H-pyrazol-5-yl)oxazol-5(4H)-one

[0952] The mixture of intermediate 4.17 (60 mg, 0.210 mmol) in THF (10 mL) was subjected to a 10% Pd / C column at 50 bar and 70 °C. Hydrogenation. The crude product is passed through Biotage Isolera One. TM The title compound (45 mg) was purified by rapid column chromatography (4 g silica gel column, eluted with 0%-10% MeOH in DCM). 1 H NMR(400MHz, CDCl3)δ:7.57(d,1H),6.84(d,1H),4.35(d,1H),4.26(s,3H),2.30–2.00(m,4H),1.91–1.64(m,4H),1.62–1.58(m,1H).

[0953] Intermediate 4.22: 4-Cyclopentyl-2-(1-methyl-1H-pyrazol-5-yl)oxazol-5(4H)-one

[0954] The title compound (0.14 g) was prepared from 2-(2-methylpyrazol-3-yl)-4H-oxazol-5-one (0.3 g, 0.76 mmol, CAS: 22515-18-0) and cyclooctanone (96 mg, 0.76 mmol, CAS: 696-71-9) according to the procedure described for intermediate 4.17. 1 H NMR(400MHz, CDCl3)δ:7.53(d,1H),6.86(d,1H),4.29(s,3H),3.02–2.95(m,2H) ,2.91–2.83(m,2H),1.92(tdd,4H),1.45–1.31(m,2H),1.26(s,2H),0.85(d,2H).

[0955] Intermediate 5.17: N-(1-(4,4-difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino 2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0956] Acetic acid (0.1 mL, 1.8 mmol) was added to a mixture of intermediate 4.17 (50 mg, 0.18 mmol) and intermediate 1.17 (41 mg, 0.21 mmol) in THF (10 mL) under argon atmosphere. The reaction mixture was heated at 100 °C for 30 min by microwave irradiation. The reaction mixture was concentrated under vacuum and purified by rapid column chromatography (50% EtOAc in heptane) to give the title compound (80 mg). 1H NMR(400MHz,MeOD)δ:8.28(s,2H),7.78(d,2H),7.52(d,1H),7.20–7.13(m,2H),6. 99(d,1H),4.12(s,3H),2.77(t,2H),2.54(t,2H),2.17–2.10(m,4H),2.08(s,6H).

[0957] Intermediate 5.19: N-(1-(4,4-dimethylcyclohexylene)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl) (amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0958] The title compound (30 mg) was prepared from intermediates 4.19 (51 mg, 0.19 mmol) and 1.17 (41 mg, 0.21 mmol) according to the procedure described for intermediate 5.17. LCMS (Method 14): 1.50 min, 472.2 [M+H] + .

[0959] Intermediate 5.21: N-(2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)- 1-(4,4-Dimethylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0960] The title compound (75 mg) was prepared from intermediate 4.19 (50 mg, 0.18 mmol) and intermediate 1 (43 mg, 0.20 mmol) according to the procedure described for intermediate 5.17. LCMS (Method 14): 1.72 min, 488.2 [M+H] + .

[0961] Intermediate 5.22: N-(1-cyclooxyoctyl-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxo (Ethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0962] The title compound (50 mg) was prepared from intermediates 4.22 (41 mg, 0.15 mmol) and 1.17 (30 mg, 0.15 mmol) according to the procedure described for intermediate 5.17. LCMS (Method 14): 1.51 min, 472.2 [M+H] + .

[0963] Intermediate 5.23: N-(1-cyclooxyoctyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2- (Oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0964] The title compound (14 mg) was prepared from intermediate 4.22 (51 mg, 0.19 mmol) and intermediate 1.23 (54 mg, 0.11 mmol) according to the procedure described for intermediate 5.17. 1H NMR(400MHz,MeOD)δ:7.66–7.57(m,2H),7.49(dd,1H),7.28–7.20(m,2H),6.95(d,1H),4.10(d, 3H),2.71–2.64(m,2H),2.47–2.39(m,2H),2.23(s,6H),1.85(s,2H),1.77(s,2H),1.59(s,6H).

[0965] Synthesis of the Implementation Examples

[0966] Example 1: N-((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)- 1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0967]

[0968] HATU (125 mg, 0.33 mmol) was added to a stirred solution of intermediate 3 (110 mg, 0.27 mmol), 2-methylpyrazol-3-carboxylic acid (41 mg, 0.33 mmol, CAS: 16034-46-1), and triethylamine (0.15 mL, 1.1 mmol) in EtOAc (0.9 mL) and acetonitrile (0.5 mL) under an argon atmosphere at 0 °C. The reaction mixture was heated to room temperature and stirred for 2 h, then diluted with saturated aqueous sodium bicarbonate and extracted into EtOAc (x2). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to rapid column chromatography on silica gel (eluting with 10% MeOH in EtOAc) followed by chromatography on Biotage Isolera One. TM Purification was performed using automated reversed-phase column chromatography (200-400 nm diode array detector, 30 g C18 column, eluted with 10%-80% MeCN (containing 0.1% NH3 aqueous solution) in water containing 0.1% NH3 aqueous solution). Fractions containing the desired product were combined, and the solvent was removed by lyophilization to give the title compound (37 mg). LCMS (Method 3): 2.05 min, 476.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ:10.29(s,1H),8.52(d,1H),7.69(d,2H),7.46(d,1H),7.29(d,1H),7.21(d,2H),7.07(d,1H),6. 34(d,1H),4.38(t,1H),4.03(s,3H),3.50(s,3H),2.30(s,3H),1.90-1.54(m,5H),1.37-0.98(m,3H),0.94-0.81(m,5H).

[0969] Example 2: N-((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl) (amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0970]

[0971] The title compound (23 mg) was prepared in MeCN / DMF from intermediate 3.1 (52 mg, 0.12 mmol) and 2-methylpyrazol-3-carboxylic acid (23 mg, 0.19 mmol, CAS: 16034-46-1), HATU (71 mg, 0.19 mmol), and triethylamine (0.1 mL, 0.74 mmol). The crude product was subjected to Biotage Isolera One. TM Purification was performed by rapid column chromatography (25 g Silicycle column, eluted with 10%-60% EtOAc in heptane). The compound was dissolved in a mixture of DCM / MeOH (95:5) and washed with 10% LiCl solution followed by H2O. The organic layer was concentrated under vacuum, and the residue was dissolved in hot EtOAc followed by washing with H2O. The organic layer was filtered through a phase separation column, and the organic matter was concentrated under vacuum. LCMS (Method 3): 2.14 min, 494.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:10.51(s,1H),8.57(d,1H),7.72(dd,1H),7.46(d,1 H),7.42(dd,1H),7.27-7.21(m,2H),7.07(d,1H),6.35(d,1H),4.36(dd,1H), 4.03(s,3H),3.51(s,3H),2.21(d,3H),2.12-1.75(m,2H),1.75-1.65(m,2H) ,1.62-1.54(m,1H),1.37-1.13(m,2H),1.10-0.98(m,1H),0.95-0.79(m,5H).

[0972] Example 3: 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide

[0973]

[0974] The title compound (50 mg) was prepared in MeCN / DMF from intermediate 3.2 (0.1 g, 0.22 mmol), 2-methylpyrazol-3-carboxylic acid (28 mg, 0.22 mmol, CAS: 16034-46-1), HATU (84 mg, 0.22 mmol), and triethylamine (0.12 mL, 0.89 mmol). The crude product was subjected to Biotage Isolera One. TM Purified by reversed-phase column chromatography (25 g C18 column, with 10%–50% 0.1% ammonia / MeCN (at pH 11 0.1% ammonia / H2O)). LCMS (Method 18): 2.19 min, 487.4 [M+H2O] + ; 1 H NMR(400MHz,DMSO-d6)δ:12.24(s,1H),11.21(d,1H),10.38(s,1H),8.61(d,1H),7.80(d,2H),7.58(d,2H),7.54(d,1H),7.42(dd,1H),7 .14(d,1H),7.00(d,1H),6.51(dd,1H),4.42(t,1H),4.06(s,3H),1.91-1.55(m,5H),1.34-1.13(m,2H),1.02(m,1H),0.93-0.78(m,5H).

[0975] Example 4: 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(2-oxo- 1,2-Dihydropyridine-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide

[0976]

[0977] The title compound (13 mg) was prepared in MeCN / DMF from intermediate 3.3 (30 mg, 0.08 mmol), 2-methylpyrazol-3-carboxylic acid (10 mg, 0.08 mmol, CAS: 16034-46-1), HATU (30 mg, 0.08 mmol), and triethylamine (0.03 mL, 0.24 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One. TM Reversed-phase column chromatography (25g C18 column, eluted with 10%-50% 0.1% ammonia / MeCN (in pH 11 0.1% ammonia / H2O)) and Biotage Isolera OneTM Purification was performed using rapid column chromatography (5g ZIP silica column, eluted with 0%-10% MeOH in DCM). LCMS (Method 3): 1.84 min, 448.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:11.66(s,1H),10.51(s,1H),8.63(d,1H),7.82(d,2H),7.75(d,2H),7.54(d,1H),7.49(d,1H),7.14(d, 1H),6.62(d,1H),6.55(d,1H),4.42(t,1H),4.05(s,3H),1.90-1.51(m,5H),1.35-1.11(m,2H),1.02(m,1H),0.92-0.77(m,5H).

[0978] Example 5: N-((S)-2-((4-(imidazo[1,2-a]pyridin-5-yl)phenyl)amino)-1-((1r,4S)-4- (methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0979]

[0980] The title compound (14 mg) was prepared from intermediate 3.4 (28 mg, 0.07 mmol), 2-methylpyrazol-3-carboxylic acid (8.7 mg, 0.07 mmol, CAS: 16034-46-1), HATU (32 mg, 0.08 mmol), and triethylamine (0.02 mL, 0.17 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One... TM Purified by reversed-phase column chromatography (30 g C18 column, eluted with 30%-70% 0.1% ammonia / MeCN (at pH 11, 0.1% ammonia / H2O)). LCMS (Method 12): 2.23 min, 471.3 [M+H2O] + ; 1 H NMR(400MHz,DMSO-d6)δ:10.50(d,1H),8.58(dd,1H),7.91-7.79(m,3H),7.73-7.54(m,4H),7.50-7.44(m,1H),7.39-7.28(m,1H),7.11- 7.04(m,1H),6.88(dd,1H),4.41(dd,1H),4.08-4.00(m,3H),1.96-1.52(m,5H),1.38-1.18(m,2H),1.13-1.01(m,1H),0.93-0.80(m,5H).

[0981] Example 6: N-((S)-2-((4-(3,5-dimethyl-1H-pyrazole-4-yl)phenyl)amino)-1-((1r,4S)- (4-Methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0982]

[0983] The solution of intermediate 3.6a (200 mg, 0.35 mmol) in MeOH (80 mL) was subjected to a Pd(OH)₂ / C column chromatography at 60 bar and 60 °C. Hydrogenation was carried out for 14 consecutive runs. The mixture was concentrated in a vacuum and then passed through BiotageIsolera One. TM Purified by automated reversed-phase column chromatography (200-400 nm diode array detector, 10 g C18 column, eluted with 5%-100% MeCN / 0.1% ammonia (in H2O / 0.1% ammonia solution)) to give the title compound (25 mg). LCMS (Method 15): 2.32 min, 448.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:12.20(s,1H),10.21(s,1H),8.51(d,1H),7.70–7.62(m,2H),7.46(d,1H),7.25 –7.17(m,2H),7.07(d,1H),4.38(t,1H),4.03(s,3H),2.17(s,6H),1.90–1.56(m,5H),1.32–0.79(m,8H).

[0984] Example 7: 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(3-(2-oxo) 2-(pyrrolidone-1-yl)ethyl)pyridin-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide

[0985]

[0986] The title compound (47 mg) was prepared from intermediate 3.7 (93 mg, 0.18 mmol), 2-methylpyrazol-3-carboxylic acid (28 mg, 0.22 mmol, CAS: 16034-46-1), HATU (84 mg, 0.22 mmol), and triethylamine (0.1 mL, 0.73 mmol) according to the procedure described for Example 1. The crude product was purified by rapid column chromatography (eluting with 25% MeOH in EtOAc) and MDAP (Method 1: 38% MeCN in 0.1% NH4OH). LCMS (Method 3): 2.05 min, 543.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ:10.36(s,1H),8.55(d,1H),8.46(d,1H),8.43(s,1H),7.72(d,2H),7.46(d,1H),7.28(d,2H),7.22(d,1H),7.07 (d,1H),4.38(t,1H),4.03(s,3H),3.58(s,2H),3.26-3.17(m,4H),1.91-1.54(m,9H),1.37-1.15(m,2H),1.04(m,1H),0.94-0.81(m,5H).

[0987] Example 8: N-((S)-2-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6- (1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0988]

[0989] The title compound (3.2 mg) was prepared from intermediate 3.8 (16 mg, 0.04 mmol), 2-methylpyrazol-3-carboxylic acid (16 mg, 0.04 mmol, CAS: 16034-46-1), HATU (18 mg, 0.05 mmol), and triethylamine (0.01 mL, 0.1 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One... TM Purified by reversed-phase column chromatography (12 g C18 column, eluted with 10%–70% 0.1% ammonia / MeCN (at pH 11, 0.1% ammonia / H2O)). LCMS (Method 12): 1.96 min, 477.3 [M + H2O] + ; 1 H NMR(400MHz,DMSO-d6)δ:10.71(s,1H),8.48(s,1H),8.24(s,1H),8.14(s,1H),7.71(dd,1H),7.47(d,1H),7.35(d,1H),7.04(d,1H),6.38 (d,1H),4.53(dd,1H),4.02(s,3H),3.52(s,3H),2.31(s,3H),1.88-1.54(m,5H),1.36-1.19(m,2H),1.17-1.00(m,1H),0.88-0.81(m,5H).

[0990] Example 9: N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)- (4-Methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[0991]

[0992] The title compound (33 mg) was prepared from intermediate 3.9 (57 mg, 0.13 mmol), 2-methylpyrazol-3-carboxylic acid (17 mg, 0.13 mmol, CAS: 16034-46-1), HATU (61 mg, 0.16 mmol), and triethylamine (0.05 mL, 0.33 mmol) according to the procedure described for Example 1. The crude product was purified by MDAP (Method 1: 40%–70% MeCN in 0.1% NH4OH). LCMS (Method 12): 2.29 min, 461.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:10.77(s,1H),8.50(d,1H),8.36(s,2H),8.22-8.19(m,2H),7.69(dd,1H),7.47(d,1H),7.04(d,1H),4 .54(t,1H),4.02(s,3H),2.03(s,6H),1.90-1.75(m,2H),1.75-1.55(m,3H),1.37-1.19(m,2H),1.08(m,1H),0.95-0.80(m,5H).

[0993] Example 10: N-((S)-2-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6- (1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide

[0994]

[0995] The title compound (2 mg) was prepared from intermediate 3.8 (11 mg, 0.03 mmol), 2-ethylpyrazol-3-carboxylic acid (3.9 mg, 0.03 mmol, CAS: 400755-43-3), HATU (13 mg, 0.03 mmol), and triethylamine (0.01 mL, 0.07 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One... TM Purified by reversed-phase column chromatography (12 g C18 column, eluted with 10%–70% 0.1% ammonia / MeCN (at pH 11, 0.1% ammonia / H2O)). LCMS (Method 12): 2.07 min, 491.3 [M + H2O] + ; 1H NMR(400MHz,DMSO-d6)δ:10.71(s,1H),8.49(d,1H),8.24(d,1H),8.14(d,1H) ,7.71(dd,1H),7.48(d,1H),7.35(d,1H),7.00(d,1H),6.38(d,1H),4.52(dd,1 H),4.45(m,2H),3.52(s,3H),2.31(s,3H),1.88-1.78(m,2H),1.73-1.65(m,2H ),1.63-1.55(m,1H),1.38-1.20(m,5H),1.16-1.02(m,1H),0.93-0.81(m,5H).

[0996] Example 11: N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)- (4-Methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide

[0997]

[0998] The title compound (25 mg) was prepared in DCM from intermediate 3.9 (42 mg, 0.1 mmol), 2-ethylpyrazol-3-carboxylic acid (17 mg, 0.12 mmol, CAS: 400755-43-3), HATU (5.1 mg, 0.12 mmol), and triethylamine (0.05 mL, 0.35 mmol). The crude product was purified by MDAP (Method 1: 40%–80% MeCN in 0.1% NH4OH). LCMS (Method 12): 2.42 min, 475.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:10.76(s,1H),8.50(d,1H),8.36(s,2H),8.23-8.18(m,2H),7.69(dd,1H),7.49(d,1H),7.01(d,1H),4 .54(t,1H),4.46(m,2H),2.03(s,6H),1.90-1.76(m,2H),1.76-1.57(m,3H),1.37-1.20(m,5H),1.09(m,1H),0.90-0.80(m,5H).

[0999] Example 12: 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(tetrahydro- 2H-pyran-4-yl)phenyl)amino)ethyl)-1H-pyrazole-5-carboxamide

[1000]

[1001] The title compound (20 mg) was prepared from intermediate 3.12 (65 mg, 0.18 mmol), 2-methylpyrazol-3-carboxylic acid (22 mg, 0.18 mmol, CAS: 16034-46-1), HATU (67 mg, 0.18 mmol), and triethylamine (0.05 mL, 0.35 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One... TM Purified by reversed-phase column chromatography (30 g C18 column, eluted with 10%-70% MeCN in 0.1 M NH4HCO3 buffer at pH 10). LCMS (Method 12): 2.38 min, 439.3 [M+H2O] + ; 1 H NMR(300MHz, CDCl3)δ:7.60(s,1H),7.47-7.41(m,3H),7.18(d,2H),6.65(d,1H),6.58(d,1H),4.40(t,1H),4.14(s,3H), 4.07(m,1H),4.03(m,1H),3.56-3.44(m,2H),2.78-2.64(m,1H),1.90-1.66(m,9H),1.35-1.05(m,3H),1.02-0.82(m,5H).

[1002] Example 13: N-((S)-2-((4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)- (4-Methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1003]

[1004] The title compound (29 mg) was prepared from intermediate 3.13 (54 mg, 0.16 mmol), 2-methylpyrazol-3-carboxylic acid (20 mg, 0.16 mmol, CAS: 16034-46-1), HATU (71 mg, 0.19 mmol), and triethylamine (0.07 mL, 0.47 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One... TM Purified by reversed-phase column chromatography (25 g C18 column, eluted with 10%–70% 0.1% ammonia / MeCN (at pH 11, 0.1% ammonia / H2O)). LCMS (Method 12): 1.90 min, 452.8 [MH] - ; 1H NMR(400MHz,DMSO-d6)δ:10.15(s,1H),8.48(d,1H),7.57(d,2H),7.45(d,1 H),7.40(d,2H),7.05(d,1H),4.95(s,1H),4.37(t,1H),4.02(s,3H),3.80-3 .72(m,2H),3.72-3.65(m,2H),2.00-1.73(m,4H),1.72-1.63(m,2H),1.57(m ,1H),1.53-1.46(m,1H),1.24-1.12(m,2H),1.03(m,1H),0.92-0.80(m,5H).

[1005] Example 14: N-((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4- (methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1006]

[1007] The title compound (5.2 mg) was prepared from intermediate 3.14 (0.11 g, 0.3 mmol), 2-methylpyrazol-3-carboxylic acid (38 mg, 0.3 mmol, CAS: 16034-46-1), HATU (0.14 g, 0.36 mmol), and triethylamine (0.13 mL, 0.9 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One... TM Purified by reversed-phase column chromatography (25 g C18 column, eluted with 5%–80% 0.1% ammonia / MeCN (pH 11, 0.1% ammonia / H2O)). LCMS (Method 3): 2.39 min, 435.2 [MH]. - ; 1 H NMR(400MHz,DMSO-d6)δ:10.24(s,1H),8.52(d,1H),7.62(d,2H),7.46(d,1H),7.40(d,2H),7.07(d,1H),6.19(m, 1H),4.37(t,1H),4.21(m,2H),4.02(s,3H),3.81(t,2H),1.90-1.53(m,6H),1.33-0.95(m,4H),0.93-0.78(m,5H).

[1008] Example 15: N-((S)-2-((4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-((1r,4S)-4- (methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1009]

[1010] The title compound (38 mg) was prepared from intermediate 3.15 (69 mg, 0.2 mmol), 2-methylpyrazol-3-carboxylic acid (28 mg, 0.22 mmol, CAS: 16034-46-1), HATU (85 mg, 0.22 mmol), and triethylamine (0.1 mL, 0.71 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One... TM Purification was performed by rapid column chromatography (12 g silica column, 0%-2% MeOH in DCM) and reversed-phase preparative HPLC (Method 2). LCMS (Method 10): 2.68 min, 450.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.91(s,1H),7.58(d,2H),7.44(d,1H),7.20(d,2H),6.68(d,1H),6.60(d,1H),4.44(t,1H),4.14(s,3H ),2.36(s,3H),2.23(s,3H),1.96-1.81(m,3H),1.81-1.69(m,2H),1.31(m,1H),1.16(m,2H),1.03-0.90(m,2H),0.87(d,3H).

[1011] Example 16: N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r, 4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1012]

[1013] The title compound (8.5 mg) was prepared from intermediate 3.16 (19 g, 0.05 mmol), 2-methylpyrazol-3-carboxylic acid (7.1 mg, 0.06 mmol, CAS: 16034-46-1), HATU (22 mg, 0.06 mmol), and triethylamine (0.01 mL, 0.18 mmol) according to the procedure described for Example 1. The crude product was subjected to Biotage Isolera One... TM Purification was performed by rapid column chromatography (4 g silica gel column, eluted with 0%-2% MeOH in DCM) and reversed-phase preparative HPLC (Method 2). LCMS (Method 10): 2.61 min, 451.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ:10.75(s,1H),8.48(d,1H),8.36(m,1H),8.18(m,1H),7.83(m,1H),7.47(d,1H),7.04(d,1H),4. 54(t,1H),3.33(s,3H),2.41(s,3H),2.23(s,3H),1.90-1.54(m,5H),1.35-1.17(m,2H),1.07(m,1H),0.95-0.80(m,5H).

[1014] Example 17: (S)-N-(1-(4,4-difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino 2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1015]

[1016] A solution of intermediate 5.17 (80 mg, 0.17 mmol) in MeOH (10 mL) was subjected to chromatography at 50 bar and 60 °C using a 10% Pd / C column. Hydrogenation. The mixture is concentrated in a vacuum and the crude compound is passed through a preparative SFC (Synthetic Fusion Process). Purified using AD-H, 5 μM, 10 mm x 250 mm id column, 15 mL / min, with 20% IPA + 1% diethylamine and CO2 as eluent, to give the title compound (2.3 mg), presumed to be stereochemical based on activity data. LCMS (Method 14): 1.84 min, 482.2 [M+H] + ; 1 ¹H NMR (400MHz, MeOD) δ: 8.30 (s, 2H), 7.79 (d, 2H), 7.52 (d, 1H), 7.18 (d, 2H), 6.95 (d, 1H), 4.60 (d, 1H), 4.13 (s, 3H), 2.21–1.98 (m, 10H), 1.94–1.75 (m, 3H), 1.67–1.46 (m, 2H). Other inactive enantiomers (3.7 mg) were also isolated.

[1017] Example 18: N-((S)-2-((5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1018]

[1019] According to the procedure described for Example 6, intermediate 3.18a (20 mg, 0.04 mmol) was obtained and a 10% Pd / C column was used in... The title compound (3.9 mg) was prepared by hydrogenation. The crude product was purified by reversed-phase preparative HPLC (Method 2). LCMS (Method 15): 2.31 min, 450.2 [M+H]+; 1 H NMR(400 MHz,MeOD)δ:8.27(dd,1H),8.19(d,1H),7.75(dd,1H),7.51(d,1H),6.94(d,1H),4.57(d,1H),4.12(s,3H ),2.29(s,6H),1.99-1.88(m,2H),1.88-1.77(m,3H),1.46-1.17(m,3H),1.09-0.96(m,2H),0.94(d,3H).

[1020] Example 19: (S)- N -(1-(4,4-dimethylcyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl) (amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1021]

[1022] The intermediate 5.19 (30 mg, 0.06 mmol) solution in MeOH (5 mL) was subjected to chromatography at 50 bar and 60 °C using a 10% Pd / C column. Hydrogenation. The mixture was concentrated under vacuum and the crude compound was subjected to rapid column chromatography (eluting with 5% MeOH in DCM) and preparati...

Claims

1. A compound of formula I (I) in: X 1 X 2 X 3 and X 4 The two in the middle are CR 5 And both are N; or X 1 X 2 X 3 and X 4 The three of them are CR 5 And the other is N; Y is , , or , in It is the attachment point to the rest of the compound of formula I and Y is optionally substituted by one or more substituents independently selected from: halogen, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups selected from the following: , , and , in * It is R 1 and R 2 Attached carbon atoms, and each R 17 Independently selected from hydrogen, fluorine, methyl, and trifluoromethyl; R 3 It is hydrogen; R 4 Selected from one of the following groups: and , in: It is the attachment point to the rest of the compound of formula I; R 18 Independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 and C 1-3 Alkylene-R 11 ; R 19 Independently selected from hydrogen and C 1-4 Alkyl and C 1-3 Alkylene-R 11 ;and p is 0, 1, or 2; Where R 4 When it is a bicyclic group and p is 1 or 2, each R 18 The substituents may be present on either ring of the bicyclic group; R 5 It is hydrogen, fluorine, chlorine, methyl, methoxy, or trifluoromethyl; R 11 It is hydroxyl, halogen, C 1-4 Alkoxy, cyano, NR 12 R 13 C(O)R 14 , aryl or heteroaryl, wherein the term "aryl" refers to phenyl, biphenyl or naphthyl, and the term "heteroaryl" refers to a monocyclic or bicyclic group containing 5 to 12 ring members and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 14 It is hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy or NR 15 R 16 ; R 6 R 7 R 12 and R 13 Independently selected from hydrogen and C 1-4 alkyl; R 15 and R 16 Independently selected from hydrogen and C 1-4 Alkyl; or R 15 and R 16 Together with the nitrogen atoms to which they are attached, they form 3 to 7-membered heterocyclic rings, which optionally contain additional heteroatoms selected from O, S, and N and optionally are C 1-4 Alkyl substitution; Or its pharmaceutically acceptable salt.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 It is N and X 2 X 3 and X 4 It is CH.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is: ， in It is the attachment point to the rest of the compound of formula I.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 17 Each time it appears, it is independently selected from hydrogen, fluorine, and methyl.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Together with the carbon atoms to which they are attached, they form the following groups: ， in * It is R 1 and R 2 Attached carbon atoms, and each R 17 It is independently selected from hydrogen, fluorine, and methyl.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from one of the following groups: and , in: It is the attachment point to the rest of the compound of formula I; R 18 Independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 and C 1-3 Alkylene-R 11 ; R 19 Independently selected from hydrogen, C 1-4 Alkyl and C 1-3 Alkylene-R 11 ;and p is 0, 1, or 2; Where R 4 When it is a bicyclic group and p is 1 or 2, each R 18 The substituents may be present on either ring of the bicyclic group.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 18 Independently selected from hydroxyl, fluorine, chlorine, methyl, methoxy, CF3, NR 6 R 7 and C 1-3 Alkylene-R 11 And R 19 It is independently selected from hydrogen and methyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structural formulas: IE, IF, IG, IH, IJ, IK, IL, or IM: ， Among them, Y and R 1 R 2 R 3 R 4 and R 5 It is as defined in claim 1; each R 17 Independently selected from halogen groups, C 1-2 Alkyl and C 1-2 Halogenated alkyl; R 20 and R 21 It is independently selected from hydrogen, fluorine, methyl and trifluoromethyl; and n is 0.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R 5 It is hydrogen.

10. A compound selected from: N-((S)-2-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-(1-Cyclooctyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide; N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazol-4-carboxamide; N-(1-Cyclooctyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide; (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide; (S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide; (S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-((S)-2-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-(methoxymethyl)isoxazole-4-carboxamide; N-((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; 6-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamide)-2-((1r,4S)-4-methylcyclohexyl)acetamide)-3',5'-dimethyl-[3,4'-bipyridine] 1'-oxide; 3-Ethyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-((5-(5-methylpyrimidin-4-yl)pyridin-2-yl)amino)-2-oxoethyl)isoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-1,2,3-triazol-5-carboxamide; N-((S)-2-((5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-(4,4-difluorocyclohexyl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; 1-Methyl-N-((S)-2-((4-methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazol-5-carboxamide; N-((S)-2-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((3'-methoxy-2'-methyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((2',3'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((2',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; N-((S)-2-((2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1-Ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-methylisoxazol-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1-Cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(4-hydroxy-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-1,2,3-triazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(4-Cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; (S)-N-(2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-cycloheptyl-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cyclopentyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-(1-(bicyclo[2.2.1]heptane-2-yl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)-1-ethyl-1H-pyrazol-5-carboxamide; N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethyl)-3-ethylisoxazole-4-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(1-(2-(dimethylamino)-2-oxoethyl)-4-methyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-isopropylisoxazol-4-carboxamide; 3-(tert-butyl)-N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)isoxazole-4-carboxamide; N-((S)-2-((5-(4-cyano-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-(trifluoromethyl)isoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-oxo-2-((5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-((S)-2-((5-(3,5-dimethylisothiazo-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-2-((5-(3,5-dimethylisothiazo-4-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; N-((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; N-((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide; N-((S)-2-((5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; N-((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide; N-((S)-2-((6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazol-5-carboxamide; 1-Ethyl-N-((S)-2-((5-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazol-5-carboxamide; N-((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide; (S)-N-(1-Cyclohexyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-1,2,3-triazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; N-((S)-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; N-((S)-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazol-5-carboxamide; N-((S)-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide; (S)-N-(1-Cycloheptyl-2-oxo-2-((1',2',4'-trimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6-yl)amino)ethyl)-1-methyl-1H-pyrazole-5-carboxamide; 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((1',2',4'-trimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)amino)ethyl)-1H-pyrazole-5-carboxamide; (S)-N-(1-Cycloheptyl-2-oxo-2-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)-1-methyl-1H-pyrazol-5-carboxamide; 1-Methyl-N-((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)-1H-pyrazol-5-carboxamide; (S)-N-(1-Cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide; 1-Methyl-N-((S)-2-((5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazol-5-carboxamide; and N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-(dispiro[2.1.2]) 5 .2 3 Nonane-4-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; Or its pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising the compound of claim 1 or 10 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

12. Use of the compound of claim 1 or 10 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or disorder associated with IL-17A activity, said disease or disorder being selected from ankylosing spondylitis, axial spondyloarthritis, enthesitis-associated arthritis, psoriasis, psoriatic arthritis, hidradenitis suppurativa, and rheumatoid arthritis.

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