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 further relates to processes for preparing these compounds, pharmaceutical compositions containing them and their use 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 them, and their use in treating 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 major effector cytokine of the T-helper-17 (Th17) cell lineage.

[0004] IL-17A is a variable glycosylated, disulfide-linked 34-38 kDa homodimeric glycoprotein that shares approximately 50% homology with its closest family member, IL-17F. Both can be secreted as either homodimers or heterodimers of IL-17AF [KF Geoghegan et al., Protein Expression and Purification 2013, 87, 27-34; JK Kolls 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 the expression of pro-inflammatory mediators such as IL-17A. Furthermore, multiple cell types from the innate and adaptive immune systems have been identified as sources of IL-17A. These include mast cells, neutrophils, NK cells, NKT cells, CD8+ T cells, δγT cells, macrophages, and type 3 innate lymphocytes [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 heteromer receptor complexes IL-17RA and IL-17RC, despite varying affinities. Although multiple cell types have been reported to express the IL-17RA subunit, the highest response to IL-17A is observed in epithelial cells, endothelial cells, keratinocytes, and fibroblasts [TAMoseley et al. / CytokineGrowthFactor Reviews. 2003, 14, 155-174; SLGaffen / Nature RevImmunol 2009, 9, 556-567; RMOnishi and SLGaffen / Immunology 2010, 129, 311-321].

[0007] The binding of IL-17A to its receptor activates multiple 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), leading 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 attraction and activation of cells of the innate immune system to the site of inflammation completes the induction of the inflammatory loop, which can also be synergistically mediated by other cytokines such as TNFα, IFN-γ and IL-1β [SLGaffen, Arthritis Research & Therapy 2004, 6, 240-247].

[0008] These IL-17-mediated biological processes are involved in the pathology or autoimmune pathology of many human diseases with immune components, such as psoriasis, ankylosing spondylitis, axial spondylitis, 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, Peyronie's disease, celiac disease, gallbladder disease, pilonidal disease, peritonitis, multiple sclerosis, Guillain-Barré syndrome, irritable bowel syndrome, inflammatory bowel disease, and Castleman's disease. Disease), pelvic inflammatory disease, systemic juvenile idiopathic arthritis (JIA), rheumatoid arthritis, giant cell arteritis, graft-versus-host disease, discoid lupus erythematosus, systemic lupus erythematosus, lupus nephritis, vasculitis, insulin-dependent type 1 diabetes, autoimmune diabetes, diabetic lipid progressive necrosis, gangrenous pyoderma, hidradenitis suppurativa, papulopustular acne, 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). In addition, 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). Furthermore, due to the key regulatory role of IL-17A in host defense, related pathological conditions also include viral, bacterial, fungal, and parasitic infections. A correlation was also observed between serum IL-17 levels upon admission to the intensive care unit and the development of sepsis, suggesting that increased IL-17 may increase susceptibility to infection-related sepsis complications and endotoxin shock [Ahmed et al., Eur J Trauma Emerg Surg 2018, 44(4):621-626].Its role in sepsis has also been shown to extend to patients with sepsis-induced acute respiratory distress syndrome (ARDS) and acute lung injury [Ding et al., Oncotarget 2017, 8(55): 93704-93711]. More recently, inhibition of IL-17 has also been shown to be useful for the prevention of acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) [Pacha, Sallman & Evans., NatRev 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 patients with psoriasis have also shown a positive correlation with disease severity, as measured by the Psoriasis Area and Severity Index (PASI) score [L. Zhang et al., Clin Immunol 2010, 135, 108-117]. Serum IL-17A levels 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 of antibodies targeting IL-17A or IL-17RA provide final validation, observing excellent efficacy [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, allogeneic transplant 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, secukinumab and ixekizumab, have shown evidence of positive efficacy in treating palmoplantar and nail psoriasis [A. Gottlieb et al., J Am Acad Dermatol 2016, 76, 70-80; A. Menter et al., J Eur Acad Dermatol Venereol 2017, 31, 1686-1692; C. Paul et al., J Eur Acad Dermatol Venereol 2014, 28, 1670-1675]; PsA [P. Mease et al., Ann Rheum Dis 2018, 77, 890-897; P. Nash et al., Lancet 2017, 389, 2317-2327] and AS [K. Pavelka et al., Arthritis Res Ther 2017, 19, 285; A. Deodhar et al., Arthritis Rheumatol 2018, doi:10.1002 / art.40753. Proof-of-concept studies using secukinumab in MS have also shown encouraging signs of efficacy [E. Havdrova et al., J Neurol 2016, 263, 1287-1295].

[0013] IL-17A expression is 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, WO2010062858 and WO 2011163452; CSDe Paiva et al., Mucosal Immunol 2009, 2, 243-253], and Th17 cells have been shown to be elevated in active uveitis and scleritis [A. Amadi-Obi et al., Nat Med 2007, 13, 711-718]. IL-17A levels in tears are associated with the clinical severity of dry eye in patients with a range of systemic autoimmune or inflammatory diseases, including Schogren's syndrome (…). Stevens-Johnson 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., J Int Med Res 2010, 38, 611-619; D. Lemancewicz et al., Med Sci Monit 2012, 18, BR 54-59; S. LeGouvello 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., ClinCancer Res 2014, 20, 2885-2897; MH. Lee et al., Oncotarget 2018, 9, 9825-9837.

[0016] In summary, modulating the IL-17A pathway, particularly by inhibiting the interaction between IL-17A and its receptor IL-17RA, could be considered a target for treating 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 chemical compounds that supposedly modulate the activity of IL-17 and can be used to treat medical conditions, including inflammatory diseases.

[0018] Nevertheless, there remains a continued need for compounds that can attenuate 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 a pharmaceutical composition 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 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 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 disorders.

[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 compounds or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating diseases with 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 methods for treating diseases with immune components or autoimmune pathologies (such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and neurodegenerative disorders, the methods comprising administering to a subject requiring such treatment a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or 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 can be obtained by synthetic methods as defined herein, or obtained directly by synthetic methods as defined herein.

[0031] On the other hand, the present invention provides novel intermediates as defined herein, which are applicable to 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 predisposed 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., preventing, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; and (3) alleviating or reducing the disease, i.e. leading to the disappearance of the state, disorder, or condition or at least one of its clinical or subclinical symptoms.

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

[0037] In this specification, the term "alkyl" refers to an aliphatic hydrocarbon group and includes both straight-chain and branched alkyl groups. References to individual alkyl groups such as "propyl" refer only to the straight-chain form, and references to individual branched alkyl groups such as "isopropyl" refer only to the branched form. 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 butylene.

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

[0040] The term "C" used as a prefix m-n "" 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 in which one or more hydrogen atoms are replaced by halogen (e.g., fluorine) atoms. Examples of haloalkyl and haloalkoxy groups include fluoroalkyl and fluoroalkoxy groups such as -CHF2, -CH2CF3, or perfluoroalkyl / alkoxy groups such as -CF3, -CF2CF3, or -OCF3.

[0044] The terms "carbocyclic group," "carbocyclic," or "carbocyclic" refer to one or more non-aromatic saturated or partially saturated monocyclic or fused, bridged, or spirobicyclic carbocyclic systems. Monocyclic carbocyclic systems contain about 3 to 12 (suitably 3 to 7) ring atoms. Bicyclic carbocyclic systems contain 7 to 17 carbon atoms in the ring, suitably 7 to 12 carbon atoms. Bicyclic carbocyclic systems can be fused, spirocyclic, or bridged ring systems.

[0045] 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, with 1 to 5 (suitably 1, 2, or 3) heteroatoms 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, spirocyclic, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as ethylene oxide, oxetyl, tetrahydrofuranyl, dioxetylhexyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, oxetyl, pyrrolidinyl, piperidinyl, piperazineyl, tetrahydrotriazineyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiaran, and hexahydrothiophene. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxthiazolyl, 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. Suitable heterocyclic groups with one or two oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolyl, 2-thiopyrrolyl, 2-oxoimidazoyl, 2-thioimidazoyl, 2-oxopyridinyl, 2,5-dioxopyrrolyl, 2,5-dioxoimidazoyl, 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 azo-butyl, 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 groups 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 by any suitable atom, such as through a carbon or nitrogen atom. Appropriately, the terms “heterocyclic group,” “heterocyclic,” or “heterocyclic” will refer to a 4, 5, 6, or 7-membered monocyclic ring as defined above.

[0046] "Bridging 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 bridging 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.

[0047] A “spirocyclic bicyclic system” refers to a system in which two rings share a common spirocarbon atom, meaning that the 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.

[0048] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic group incorporating one or more (e.g., 1-4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryls are monocyclic and bicyclic groups containing 5 to 12 ring members, and more typically 5 to 10 ring members. Heteroaryls can be, for example, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic, such as a bicyclic structure formed by fused 5- and 6-membered rings or two fused 6-membered rings. Each ring may contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Typically, the number of basic nitrogen atoms present in a heteroaryl group, including any amino substituents in the ring, will be less than five. Nitrogen-containing heteroaryl groups can exist as corresponding N-oxides. A specific example of such heteroaryl groups is pyridine N-oxide. Appropriately, the terms "heteroaryl" or "heteroarylene" will refer to a 5- or 6-membered monocyclic heteroaryl ring as defined above.

[0049] 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-pyrazol[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazol[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl.

[0050] 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.

[0051] Non-limiting examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0052] The bicyclic heteroaryl group can be, for example, selected from the following groups:

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

[0054] A pyridine ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0055] A pyrimidine ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0056] Pyrrole rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

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

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

[0059] An imidazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0060] Oxazole rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

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

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

[0063] An isothiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

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

[0065] Furan rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0066] Cyclohexyl rings fused with 5- or 6-membered heteroaromatic rings containing 1, 2, or 3 cyclic heteroatoms; and

[0067] A cyclopentyl ring fused with a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 cyclic heteroatoms.

[0068] 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, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indazinyl, indololinyl, isoindololinyl, purine (e.g., adenine, guanine), indazole, benzodioxolane, pyrrolopyridine, and pyrazolopyridyl.

[0069] Specific, non-limiting examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxane, quinazinyl, benzooxazinyl, benzodiazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, terolinyl, phthalazinyl, naphthidyl, and pteridylyl.

[0070] 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.

[0071] This specification also uses several compound terms to describe groups that incorporate more than one functional group. Those skilled in the art will understand such terms. For example, heterocyclic C 1-4 Alkyl groups include C14 groups substituted with heterocyclic groups. 1-4 alkyl.

[0072] The term "optionally substituted" refers to substituted and unsubstituted groups, structures, or molecules.

[0073] When the optional substituents are selected from "one or more" groups, this definition should be understood to include all substituents being selected from a single specified group or substituents being selected from two or more specified groups. It should be understood that when multiple substituents are present, the selected substituents may be the same or different.

[0074] When a range of values ​​is given, it should be understood that the range includes the endpoints.

[0075] The phrase “compounds of the present invention” means those compounds disclosed herein, including both general and specific ones.

[0076] The compounds of the present invention

[0077] In a first aspect, the present invention provides compounds of formula I:

[0078]

[0079] in:

[0080] X 1 X 2 X 3 and X 4 Each is CR independently 5 Or N;

[0081] Y is an aryl or heteroaryl group, each of which is 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-

[0082] N(C 1-3 Alkyl)2, and C 1-4 Haloalkyl; and wherein when Y is a 5- or 6-membered heteroaryl ring, the ring is optionally fused to a 5- or 6-membered cycloalkyl or heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 alkylene-

[0083] 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 2 :

[0085] (A) are all phenyl groups optionally substituted by one or more substituents independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Alkoxy groups and C 1-4 Halogenated alkyl, wherein the phenyl group is optionally bonded by a bond or C 1-2 Alkyl groups are connected; or

[0086] (B) Together with the carbon atoms to which they are attached, they form a 4- to 10-membered cycloalkyl or a 4- to 10-membered heterocyclic ring, wherein the cycloalkyl or heterocyclic ring:

[0087] 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 groups and C 1-4 Halogenated alkoxy groups;

[0088] b. Optionally contains one or two C=C double bonds;

[0089] c. C atoms optionally connected to two carbon atoms in the ring 1-3 Alkylene bridging; and

[0090] d. Optional earth snails are attached to one or more independently selected Cs 3-6 cycloalkyl;

[0091] R 3 Is it hydrogen, fluorine, or C? 1-4 alkyl;

[0092] R 4 yes:

[0093] (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: hydroxyl, halogen, 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, 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, C1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 and CO2R 10 ;

[0094] (B) Optionally replaced by hydroxyl, halogen, C 1-4 Alkoxy, cyano, NR 6 R 7 C(O)NR 8 R 9 or CO2R 10 Replacement C 1-6 alkyl;

[0095] (C) A 5- or 6-membered heteroaryl ring, said ring fused to a 5- or 6-membered cycloalkyl or heterocyclic ring, said cycloalkyl or heterocyclic ring 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;

[0096] (D) A 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic ring, said ring fused to a phenyl or 5- or 6-membered heteroaryl ring, said ring optionally being 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; or

[0097] (E) A partially unsaturated heterocycle, optionally fused to a 5- or 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 1-4Halogenated 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;

[0098] R 5 It is hydrogen, halogen, C 1-4 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 R13 is 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, said rings optionally containing a subset selected from O,

[0104] Additional heteroatoms of S and N and optionally C 1-4 Alkyl substitution;

[0105] Or its pharmaceutically acceptable salt.

[0106] The compound according to formula (I) can exist as a mixture of stereoisomers. Preferably, the compound according to formula (I) has the following structure:

[0107]

[0108] Where X 1 X 2 X 3 X 4 Y, R 1 R 2 R 3 and R 4 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 in any of paragraphs (1) to (78) above or below. For the avoidance of doubt, the invention includes combinations of two or more substituents as defined in paragraphs (1) to (78):

[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 3and X 4 The three are CR 5 And the other one 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 Both are CH;

[0121] (12) Y is an aryl or heteroaryl group, each optionally substituted by one or more substituents independently selected from the following: 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 groups 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 groups and C 1-2 Halogenated alkyl groups;

[0124] (15) Y is a 5- to 6-membered heteroaryl ring optionally substituted by one or more substituents independently selected from the following: 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 of which is 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 groups and C 1-2 Halogenated alkyl groups;

[0128] (19) Y is a pyrazolyl, pyrroleyl, isoxazolyl, oxadiazolyl or triazolyl group, which is substituted by one or more substituents independently selected from the following: 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 1-2Alkylene-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, which is substituted by one or more substituents independently selected from the following: 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 All are phenyl groups optionally substituted by one or more substituents independently selected from the following: halogen, C 1-2 Alkyl, C 1-2 Alkoxy groups and C 1-2 Halogenated alkyl, wherein the phenyl group is optionally bonded by a bond or C 1-2 Alkyl groups are connected;

[0137] (24)R 1 and R 2 All are phenyl groups optionally substituted by one or more substituents independently selected from the following: halogen, methyl, and methoxy, wherein the phenyl group is optionally substituted by a bond or C-linker. 1-2 Alkyl groups are connected;

[0138] (25)R 1 and R 2 All are phenyl groups that are optionally substituted by one or more substituents independently selected from the following: halogen, methyl, and methoxy;

[0139] (26)R 1 and R 2 All are phenyl groups that are optionally substituted by one or more substituents independently selected from the following: fluorine and methyl;

[0140] (27)R 1 and R 2 All are phenyl groups optionally substituted by one or more substituents independently selected from the following: halogen, C 1-2 Alkyl, C 1-2 Alkoxy groups and C 1-2 Haloalkyl, wherein the phenyl group is linked by a bond;

[0141] (28)R 1 and R2 Together with the carbon atoms to which they are attached, they form 4- to 10-membered cycloalkyl rings or 4- to 10-membered heterocyclic rings (such as 1,3-dioxanealkyl or 1,4-dioxanealkyl), wherein the cycloalkyl or heterocyclic rings are:

[0142] a. Optionally substituted by one or more substituents independently selected from the following: halogen, C 1-2 Alkyl, C 1-2 Alkoxy groups and C 1-2 Halogenated alkyl groups;

[0143] b. Optionally contains one or two C=C double bonds;

[0144] c. C atoms optionally connected to two carbon atoms in the ring 1-3 Alkylene bridging; and

[0145] d. Optional earth snails are attached to one or more independently selected Cs 3-5 cycloalkyl;

[0146] (29)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:

[0147] a. Optionally substituted by one or more substituents independently selected from the following: halogen, C 1-2 Alkyl, C 1-2 Alkoxy groups and C 1-2 Halogenated alkyl groups;

[0148] b. Optionally contains one or two C=C double bonds;

[0149] c. C atoms optionally connected to two carbon atoms in the ring 1-3 Alkylene bridging; and

[0150] d. Optional earth snails are attached to one or more independently selected Cs 3-5 cycloalkyl;

[0151] (30)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:

[0152] a. Optionally substituted by one or more substituents independently selected from the following: fluorine, methyl, trifluoromethyl, and methoxy;

[0153] b. Optionally contains one or two C=C double bonds;

[0154] c. C atoms optionally connected to two carbon atoms in the ring 1-3Alkylene bridging; and

[0155] d. Optional earth snails are attached to one or more independently selected Cs 3-5 cycloalkyl;

[0156] (31)R 1 and R 2 Together with the carbon atoms to which they are attached, they form 5- to 8-membered cycloalkyl rings, wherein the cycloalkyl rings are:

[0157] a. Substituted by one or more substituents independently selected from the following: fluorine, trifluoromethyl, and methyl;

[0158] b. Optionally contains one or two C=C double bonds;

[0159] c. C atoms optionally connected to two carbon atoms in the ring 1-3 Alkylene bridging; and

[0160] d. Optional snails are attached to one or two Cs. 3-5 Cycloalkyl groups (such as one or two cyclopropyl groups);

[0161] (32)R 1 and R 2 Together with the carbon atoms to which they are attached, they form 5- to 8-membered cycloalkyl rings, wherein the cycloalkyl rings are:

[0162] a. Substituted by a methyl substituent;

[0163] b. Optionally contains one or two C=C double bonds;

[0164] c. C atoms optionally connected to two carbon atoms in the ring 1-3 Alkylene bridging; and

[0165] d. Optional earth snails are attached to C 3-5 cycloalkyl;

[0166] (33)R 1 and R 2 Together with the carbon atoms to which they are attached, they form a cyclohexyl ring, wherein the cyclohexyl ring:

[0167] a. Substituted by one or more substituents independently selected from the following: fluorine, trifluoromethyl, and methyl;

[0168] b. Optionally contains one or two C=C double bonds;

[0169] c. C atoms optionally connected to two carbon atoms in the ring 1-3 Alkylene bridging; and

[0170] d. Optional earth snails are attached to C 3-5cycloalkyl;

[0171] (34)R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups selected from the following:

[0172]

[0173] Where * represents R 1 and R 2 The attached carbon atom, each R that appears 17 Independently selected from halogen groups, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkyl groups and C 1-2 Haloalkoxy group, and m is 0, 1, 2 or 3;

[0174] (35)R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups selected from the following:

[0175]

[0176] Where * represents R 1 and R 2 The attached carbon atom, each R that appears 17 It is independently selected from fluorine, methyl, trifluoromethyl and methoxy, and m is 0, 1 or 2;

[0177] (36)R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups selected from the following:

[0178]

[0179] Where * represents R 1 and R 2 The attached carbon atoms, and each R that appears 17 It is independently selected from hydrogen, fluorine, methyl, trifluoromethyl, and methoxy;

[0180] (37)R 1 and R 2 Together with the carbon atoms to which they are attached, they form the following:

[0181]

[0182] Where * represents R 1 and R 2 The attached carbon atoms, and each R 17 Independently selected from hydrogen, fluorine, methyl, and trifluoromethyl;

[0183] (38)R 3 It is hydrogen, fluorine, or methyl;

[0184] (39)R 3 It is hydrogen;

[0185] (40)R 3 It is methyl;

[0186] (41)R 4 yes:

[0187] (A) 5 to 10 aryl groups or C 3-7 Cycloalkyl 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 1-4 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, C 1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 and CO2R 10 ;

[0188] (B) Optionally replaced by hydroxyl, halogen, C 1-4 Alkoxy, cyano, NR 6 R 7 or CO2R 10 Replacement C 1-6 alkyl;

[0189] (C) A 5- or 6-membered heteroaryl ring, said ring fused to a 5- or 6-membered cycloalkyl or heterocyclic ring, said cycloalkyl or heterocyclic ring 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 R9 CO2R 10 C 1-3 Alkylene-R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0190] (D) A 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic ring, said ring fused to a phenyl or 5- or 6-membered heteroaryl ring, said ring optionally being 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; or

[0191] (E) A partially unsaturated heterocycle, optionally fused to a 5- or 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-R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0192] (42)R 4 yes:

[0193] (A) A 5- to 10-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, 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;

[0194] (C) A 5- or 6-membered heteroaryl ring, said ring fused to a 5- or 6-membered cycloalkyl or heterocyclic ring, said cycloalkyl or heterocyclic ring 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;

[0195] (D) A 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic ring, said ring fused to a phenyl or 5- or 6-membered heteroaryl ring, said ring optionally being 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; or

[0196] (E) A partially unsaturated heterocycle, optionally fused to a 5- or 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-R 11 C 3-7 cycloalkyl and heterocyclic groups;

[0197] (43)R 4 yes:

[0198] (A) A 5- to 10-membered heteroaryl group, optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Halogenated alkyl, cyano, NR 6 R 7 C(O)NR 8 R 9 CO2R 10 C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl;

[0199] (C) A 5- or 6-membered heteroaryl ring, said ring fused to a 5- or 6-membered cycloalkyl or heterocyclic ring, said cycloalkyl or heterocyclic ring 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

[0200] (E) A partially unsaturated heterocycle, optionally fused to a 5- or 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-R 11 ;

[0201] (44)R 4 yes:

[0202] (A) A 5- to 10-membered heteroaryl group, optionally substituted by one or more substituents independently selected from: hydroxyl, halogen, 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 and C 3-7 cycloalkyl; or

[0203] (E) A partially unsaturated heterocycle, optionally fused to a 5- or 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-R 11 ;

[0204] (45)R 4 It is a 5- to 10-membered heteroaryl group, C 3-7 Cycloalkyl or 3 to 12-membered heterocyclic rings, each optionally substituted by one or more substituents independently selected from: 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 ;

[0205] (46)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: 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 ;

[0206] (47)R 4 It is a 5- to 10-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from the following: 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 C3-7 cycloalkyl;

[0207] (48)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 the following: fluorine, chlorine, methyl, methoxy, trifluoromethoxy, cyano, NR. 6 R 7 CH2-R 11 and cyclopropyl;

[0208] (49)R 4 It is a 6- to 10-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from the following: halogen, C 1-4 Alkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkyl, cyano, NR 6 R 7 and C 1-3 Alkylene-R 11 ;

[0209] (50)R 4 It is C 3-7 The cycloalkyl ring is 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 ;

[0210] (51)R 4 It is C 3-5 The cycloalkyl ring is 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 ;

[0211] (52)R 4 It is a 3- to 7-membered heterocyclic ring, optionally substituted by one or more substituents independently selected from the following: 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-R11 ;

[0212] (53)R 4 It is a 3- to 7-membered heterocyclic ring, optionally substituted by one or more substituents independently selected from the following: hydroxyl, methyl, methoxy, cyano, NR. 6 R 7 、 and C(O)NR 8 R 9 ;

[0213] (54)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 C 1-6 alkyl;

[0214] (55)R 4 It is optionally coated with hydroxyl, fluorine, NR 6 R 7 or CO2R 10 Replacement C 2-5 alkyl;

[0215] (56)R 4 It is a 5- or 6-membered heteroaryl ring, said ring fused to a 5- or 6-membered cycloalkyl or heterocyclic ring, said cycloalkyl or heterocyclic ring being 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;

[0216] (57)R 4 It is a 5- or 6-membered heteroaryl ring, said ring being fused to a 5-membered cycloalkyl or heterocyclic ring, said cycloalkyl or heterocyclic ring being optionally substituted by one or more substituents independently selected from the following: chlorine, fluorine, methyl, methoxy and cyano;

[0217] (58)R 4 It is a 5- or 6-membered cycloalkyl or 5- or 6-membered heterocyclic ring, said ring being fused to a phenyl or 5- or 6-membered heteroaryl ring, said ring being 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;

[0218] (59)R 4It is a partially unsaturated heterocycle, optionally fused to a 5- or 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;

[0219] (60)R 4 It is a partially unsaturated heterocycle, optionally substituted by one or more substituents independently selected from: fluorine, oxo, and C. 1-2 alkyl;

[0220] (61)R 4 It is a partially unsaturated heterocycle, which is optionally substituted by one or more substituents independently selected from the following: oxo and methyl;

[0221] (62)R 4 It is a partially unsaturated 6-membered N-containing heterocycle that is substituted by one or more substituents independently selected from the following: oxo and methyl groups;

[0222] (63)R 4 It is a partially unsaturated heterocyclic ring fused to a 5- or 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from: fluorine, oxo, and C. 1-2 alkyl;

[0223] (64)R 4 It is a partially unsaturated heterocycle that is fused to a 5- or 6-membered heteroaryl ring and optionally substituted by one or more substituents independently selected from the following: oxo and methyl;

[0224] (65)R 4 It is a partially unsaturated 6-membered N-containing heterocycle that fuses to a 5-membered N-containing heteroaryl ring and is optionally bounded by one or more

[0225] Each substituent is independently selected from the following: oxo group and methyl group;

[0226] (66)R 4 Selected from the following groups:

[0227]

[0228] in:

[0229] It is the attachment point to the rest of the compound of Formula I;

[0230] R 18 Independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Halogenated alkyl, cyano, NR 6 R 7 C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl;

[0231] R 19 Independently selected from hydrogen and C 1-4 Alkyl, C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl; and

[0232] p is 0, 1, or 2;

[0233] Where R 4 When it is a bicyclic group and p is 1 or 2, then each R 18 Substituents may be present on the ring of the bicyclic group;

[0234] (67)R 4 Selected from the following groups:

[0235]

[0236] in:

[0237] It is the attachment point to the rest of the compound of Formula I;

[0238] 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;

[0239] R 19 Independently selected from hydrogen and C 1-4 Alkyl, C 1-3 Alkylene-R 11 and C 3-7 cycloalkyl; and

[0240] p is 0, 1, or 2;

[0241] Where R 4 When it is a bicyclic group and p is 1 or 2, then each R 18 Substituents may be present on the ring of the bicyclic group;

[0242] (68)R 4Selected from the following groups:

[0243]

[0244] in:

[0245] It is the attachment point to the rest of the compound of Formula I;

[0246] R 18 Independently selected from hydroxyl, fluorine, chlorine, methyl, methoxy, CF3, NR 6 R 7 C 1-3 Alkylene-R 11 and cyclopropyl;

[0247] R 19 Independently selected from hydrogen, methyl, and cyclopropyl; and

[0248] p is 0, 1, or 2;

[0249] Where R 4 When it is a bicyclic group and p is 1 or 2, then each R 18 Substituents may be present on the ring of the bicyclic group;

[0250] (69)R 5 It is hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, or cyano;

[0251] (70)R 5 It is hydrogen, fluorine, chlorine, or methyl;

[0252] (71)R 5 It is hydrogen;

[0253] (72)R 5 It is fluorine;

[0254] (73)R 11 It is hydroxyl, halogen, methoxy, cyano, NR 12 R 13 C(O)R 14 Or aryl;

[0255] (74)R 11 It is hydroxyl, methoxy, cyano, NR 12 R 13 C(O)R 14 Or phenyl;

[0256] (75)R 14 Is it hydroxyl, methoxy, or NR? 15 R 16 ;

[0257] (76)R14 It is NR 15 R 16 ;

[0258] (77)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 1-4 Alkyl substitution;

[0259] (78)R 15 and R 16 Together with the nitrogen atoms to which they are attached, they form 5- to 6-membered heterocyclic rings, which optionally contain additional heteroatoms selected from O, S or N and optionally substituted with methyl groups.

[0260] Appropriately, X 1 To X 4 As defined in any of paragraphs (1) to (11) above. In one implementation, X 1 To X 4 As defined in any of paragraphs (6) to (7) and (10) to (11) above. In yet another implementation, X 1 To X 4 As defined in paragraph (11) above. In yet another implementation, X 1 To X 4 As defined in paragraph (7) above.

[0261] Appropriately, 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 yet another embodiment, Y is as defined in paragraph (22) above.

[0262] Appropriately, R 1 and R 2 As defined in any of paragraphs (23) to (37) above. In one implementation, R 1 and R 2 As defined in any of paragraphs (26) and (34) to (37) above. Preferably, R 1 and R 2 As defined in paragraph (37) above.

[0263] Appropriately, R 3 As defined in any of paragraphs (38) to (40) above. Preferably, R 3 As defined in paragraph (39) above.

[0264] Appropriately, R 4As defined in any of paragraphs (41) to (68) above. In one implementation, R 4 As defined in any of paragraphs (67) to (68) above. Preferably, R 4 As defined in paragraph (68) above.

[0265] Appropriately, R 5 As defined in any of paragraphs (69) to (72) above. Preferably, R 5 As defined in paragraph (71) above.

[0266] Appropriately, R 11 As defined in any of paragraphs (73) to (74) above. Preferably, R 11 As defined in paragraph (74) above.

[0267] Appropriately, R 14 As defined in any of paragraphs (75) to (76) above. Preferably, R 14 As defined in paragraph (76) above.

[0268] Appropriately, R 15 and R 16 As defined in any of paragraphs (77) to (78) above. Preferably, R 15 and R 16 As defined in paragraph (78) above.

[0269] In yet another group of compounds, the compounds have one of the following structural formulas: IA, IB, IC, or ID:

[0270]

[0271] Where X 1 To X 4 Y and R 4 As defined above; each R 17 Independently selected from hydrogen, halogen groups (such as fluorine), C 1-2 Alkyl (such as methyl), C 1-2 Alkoxy and C 1-2 Haloalkyl; and n is 1, 2, 3 or 4.

[0272] In yet another group of compounds, the compounds have one of the above structural formulas IA, IB, IC, or ID, wherein X 1 To X 4 As defined in any of paragraphs (1) to (11) above; Y as defined in any of paragraphs (12) to (22) above; R 4 As defined in any of paragraphs (41) to (68) above; each R 17Independently selected from hydrogen, halogen groups (such as fluorine), C 1-2 Alkyl (such as methyl), C 1-2 Alkoxy groups and C 1-2 Haloalkyl; and n is 1, 2, 3 or 4.

[0273] In yet another group of compounds, the compounds have the above-shown structural formula IA, wherein X 1 To X 4 As defined in any of paragraphs (6) to (7) or (10) to (11) above; Y as defined in any of paragraphs (19) to (22) above; and R 4 As defined in any of paragraphs (67) to (68) above. In yet another group of compounds, the compound has the above-shown structural formula IA, wherein X 1 To X 4 As defined in paragraph (11) above; Y as defined in paragraph (22) above; and R 4 As defined in paragraph (68) above.

[0274] In yet another group of compounds, the compounds have the above-shown structural formula IB, wherein X 1 To X 4 As defined in either paragraph (6) to (7) or (10) to (11) above; and R 4 As defined in any of paragraphs (67) to (68) above. In yet another group of compounds, the compound has the above-shown structural formula IA, wherein X 1 To X 4 As defined in paragraph (11) above; and R 4 As defined in paragraph (68) above.

[0275] In yet another group of compounds, the compounds have the above-shown structural formula IC, wherein X 1 To X 4 As defined in paragraphs (6) to (7) or (10) to (11) above; Y as defined in paragraphs (19) to (22) above; R 4 As defined in any of paragraphs (67) to (68) above; each R 17 Independently selected from hydrogen, fluorine, methyl, methoxy, and C 1-2 Haloalkyl; and n is 1, 2, 3 or 4. In yet another group of compounds, the compounds have the above-shown structural formula IC, wherein X 1 To X 4 As defined in paragraph (11) above; Y as defined in paragraph (22) above; R 4 As defined in paragraph (68) above; each R 17It is independently selected from hydrogen, fluorine, methyl, and trifluoromethyl; and n is 1, 2, 3, or 4.

[0276] In yet another group of compounds, the compounds have the above-shown structural formula ID, where X 1 To X 4 As defined in any of paragraphs (6) to (7) or (10) above, up to (11); R 4 As defined in any of paragraphs (67) to (68) above; each R 17 Independently selected from hydrogen, fluorine, methyl, methoxy, and C 1-2 Haloalkyl; and n is 1, 2, 3 or 4. In yet another group of compounds, the compounds have the above-shown structural formula ID, where X 1 To X 4 As defined in paragraph (11) above; R 4 As defined in paragraph (68) above; each R 17 It is independently selected from hydrogen, fluorine, methyl, and trifluoromethyl; and n is 1, 2, 3, or 4.

[0277] In yet another group of compounds, the compounds have one of the following structural formulas: IE, IF, IG, IH, IJ, IK, IL, or IM:

[0278]

[0279]

[0280] Among them, Y and R 1 R 2 R 3 R 4 , and R 5 As defined above; each R 17 Independently selected from halogen groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups 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 groups and C 1-4 Halogenated alkoxy group; and m is 0 to 4.

[0281] In yet another group of compounds, the compounds have 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 2As defined in any of paragraphs (23) to (37) above; R 3 As defined in any of paragraphs (38) to (40) above; R 4 As defined in any of paragraphs (41) to (68) above; each R 5 Independently as defined in any of paragraphs (69) to (72) above; each R 17 Independently selected from halogen groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups 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 groups and C 1-4 Halogenated alkoxy group; and m is 0 to 4.

[0282] In yet another group of compounds, the compounds have the above-shown structural formulas IE, IF, IG, or IH, wherein Y is as defined in any of paragraphs (19) to (22) above; R 1 and R 2 As defined in any of paragraphs (31) to (37) above; R 3 As defined in any of paragraphs (38) to (40) above; R 4 As defined in any of paragraphs (67) to (68) above; and each R 5 Independently as defined in any of paragraphs (70) to (71) above. In yet another group of compounds, the compounds have the above-shown structural formulas IE, IF, IG, or IH, wherein Y is as defined in paragraph (22) above; R 1 and R 2 As defined in paragraph (37) above; R 3 As defined in paragraph (39) above; R 4 As defined in paragraph (68) above; and each R 5 As defined in paragraph (71) above.

[0283] In yet another group of compounds, the compounds have the above-shown structural formulas IJ, IK, IL, or IM, wherein Y is as defined in any of paragraphs (19) to (22) above; R 4 As defined in any of paragraphs (67) to (68) above; each R 5 Independently as defined in any of paragraphs (70) to (71) above; each R 17 Independently selected from fluorine, methyl, methoxy, and C 1-2 Halogenated alkyl; R20 and R 21 Independently selected from hydrogen, fluorine, methyl, ethyl, methoxy, C 1-2 Halogenated alkyl groups and C 1-2 Haloalkoxy; and m is 0 to 4. In yet another group of compounds, the compounds have the above-shown structural formulas IJ, IK, IL, or IM, wherein Y is as defined in paragraph (22) above; R 4 As defined in paragraph (68) above; each R 5 As defined in paragraph (71) 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 m is 0 to 3.

[0284] The specific compounds of this invention include any one of the following:

[0285] (S)-N-(1-((4-(2,3-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 1);

[0286] (S)-N-(1-((4-(3-chloropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 2);

[0287] (S)-N-(1-((4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 3);

[0288] (S)-1-methyl-N-(1-((4-(3-methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 4);

[0289] (S)-1-methyl-N-(1-oxo-3,3-diphenyl-1-((4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)amino)propyl-2-yl)-1H-pyrazole-5-carboxamide (Example 5);

[0290] (S)-N-(1-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 6);

[0291] (S)-1-methyl-N-(1-((4-(3-(methylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 7);

[0292] (S)-N-(1-((4-(3-(dimethylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 8);

[0293] (S)-N-(1-((4-(3,5-dimethoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 9);

[0294] (S)-N-(1-((4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 10);

[0295] (S)-1-methyl-N-(1-((4-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 11);

[0296] (S)-N-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 12);

[0297] (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 13);

[0298] (S)-N-(1-((4-(3,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 14);

[0299] (S)-N-(1-((3-fluoro-4-(3-methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 15);

[0300] (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 16);

[0301] (S)-N-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 17);

[0302] N-((2S)-1-((3-fluoro-4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 18);

[0303] (S)-N-(1,1-bis(4-fluorophenyl)-3-((4-(3-methoxypyridin-4-yl)phenyl)amino)-3-oxopropyl-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 19);

[0304] (S)-N-(1-((4-(3-methoxypyridin-4-yl)-3-methylphenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 20);

[0305] (S)-N-(1-((4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 21);

[0306] (S)-N-(1-((4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 22);

[0307] (S)-N-(1-((2-fluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 23);

[0308] (S)-N-(1-((3-fluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 24);

[0309] (S)-3-methoxy-4-(4-(2-(1-methyl-1H-pyrazole-5-carbamoyl)-3,3-diphenylpropionamido)phenyl)pyridine 1-oxide (Example 25);

[0310] (S)-3,5-dimethyl-4-(4-(2-(1-methyl-1H-pyrazol-5-carbamoyl)-3,3-diphenylpropionamido)phenyl)pyridine 1-oxide (Example 26);

[0311] (S)-3,5-dimethoxy-4-(4-(2-(1-methyl-1H-pyrazole-5-carbamate)-3,3-diphenylpropionamido)phenyl)pyridine 1-oxide (Example 27);

[0312] (S)-3-fluoro-5-methoxy-4-(4-(2-(1-methyl-1H-pyrazol-5-carbamoyl)-3,3-diphenylpropionamido)phenyl)pyridine 1-oxide (Example 28);

[0313] (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3,5-difluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 29);

[0314] (S)-N-(1-((3,5-difluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 30);

[0315] (S)-N-(1-((4-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazol-5-carboxamide (Example 31);

[0316] (S)-N-(1-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazol-5-carboxamide (Example 32);

[0317] 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 33);

[0318] (S)-1-ethyl-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 34);

[0319] (S)-N-(1-((3-fluoro-4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 35);

[0320] (S)-N-(1-((4-(3-fluoropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 36);

[0321] (S)-N-(1-((4-(2,5-dimethylpyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 37);

[0322] (S)-N-(1-((4-(2,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 38);

[0323] (S)-N-(1-((4-(imidazo[1,2-a]pyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 39);

[0324] (S)-N-(1-((4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 40);

[0325] (S)-N-(1-((4-(imidazo[1,2-a]pyrimidin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 41);

[0326] (S)-N-(1-((4-(3-(hydroxymethyl)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 42);

[0327] (S)-N-(1-((4-(3-cyanopyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 43);

[0328] (S)-N-(1-((4-(6,7-dihydro-5H-cyclopentadien[b]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 44);

[0329] (S)-1-methyl-N-(1-((3-methyl-4-(pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 45);

[0330] (S)-1-(difluoromethyl)-N-(1-((4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 46);

[0331] (S)-N-(1-((3-methoxy-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 47);

[0332] (S)-N-(1-((3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 48);

[0333] (S)-1-methyl-N-(1-oxo-1-((4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 49);

[0334] (S)-1-methyl-N-(1-((4-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 50);

[0335] (S)-1-methyl-N-(1-((4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 51);

[0336] (S)-1-methyl-N-(1-oxo-1-((4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-3,3-diphenylpropyl-2-yl)-1H-pyrazole-5-carboxamide (Example 52);

[0337] (S)-N-(1-((4-(3-(hydroxymethyl)pyridin-4-yl)-3-methoxyphenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 53);

[0338] (S)-N-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 54);

[0339] (S)-N-(1-((3-chloro-4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 55);

[0340] (S)-N-(1-((4-(2,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 56);

[0341] (S)-N-(1-((4-(2,3-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 57);

[0342] (S)-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 58);

[0343] (S)-1-ethyl-N-(1-((3-fluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazol-5-carboxamide (Example 59);

[0344] (S)-N-(1-((4-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 60);

[0345] (S)-N-(1-((4-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 61);

[0346] (S)-N-(1-((3-fluoro-4-(1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazol-5-carboxamide (Example 62);

[0347] (S)-N-(1-((3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 63);

[0348] (S)-N-(1-((3-fluoro-4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 64);

[0349] (S)-N-(1-((3-fluoro-4-(3-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazol-5-carboxamide (Example 65);

[0350] (S)-N-(1-((3-fluoro-4-(5-oxo-5,6-dihydro-1,6-naphthid-8-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 66);

[0351] (S)-1-ethyl-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 67);

[0352] (S)-N-(1-((3-fluoro-4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 68);

[0353] (S)-N-(1-((3-fluoro-4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-7-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 69);

[0354] (S)-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 70);

[0355] (S)-N-(1-((3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 71);

[0356] (S)-N-(1-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6-yl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 72);

[0357] (S)-N-(1-((3',5'-dimethyl-[3,4'-bipyridin]-6-yl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 73);

[0358] (S)-1-methyl-N-(1-((4-(5-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1H-pyrazol-5-carboxamide (Example 74);

[0359] (S)-N-(1-((3-fluoro-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazol-5-carboxamide (Example 75);

[0360] (S)-N-(1-((4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 76);

[0361] (S)-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridin-2-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 77);

[0362] (S)-1-methyl-N-(1-oxo-1-((4-(3-(2-oxo-2-(pyrrolidone-1-yl)ethyl)pyridin-4-yl)phenyl)amino)-3,3-diphenylprop-2-yl)-1H-pyrazole-5-carboxamide (Example 78);

[0363] (S)-4-(4-(2-(1-methyl-1H-pyrazole-5-carbamate)-3,3-diphenylpropamido)phenyl)-3-(2-oxo-2-(pyrrolidone-1-yl)ethyl)pyridine-1-oxide (Example 79);

[0364] (S)-N-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 80);

[0365] (S)-N-(1-((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Example 81);

[0366] N-(1-(9H-fluorene-9-yl)-2-((4-(3-methoxypyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 82);

[0367] 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 83);

[0368] 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 84);

[0369] 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 85);

[0370] 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 86);

[0371] 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 87);

[0372] 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 (Example 88);

[0373] 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 89);

[0374] 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 (Example 90);

[0375] N-((S)-2-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 91);

[0376] N-((S)-2-((3',5'-dimethyl-[3,4'-bipyridinyl]-6-yl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 92);

[0377] 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 93);

[0378] 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 94);

[0379] 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 95);

[0380] 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 96);

[0381] 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 97);

[0382] N-(1-(4,4-difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 98);

[0383] 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 99);

[0384] N-(1-(4,4-dimethylcyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 100);

[0385] 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 101);

[0386] 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 102);

[0387] N-(1-Cyclooctyl-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 103);

[0388] N-(1-Cyclooctyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 104);

[0389] N-(1-Cyclooctyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 105);

[0390] 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 106);

[0391] 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 107);

[0392] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 108);

[0393] 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 109);

[0394] 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 110);

[0395] 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 111);

[0396] 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 112);

[0397] 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 113);

[0398] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 114);

[0399] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 115);

[0400] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide (Example 116);

[0401] (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 117);

[0402] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 118);

[0403] (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 119);

[0404] 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 120);

[0405] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide (Example 121);

[0406] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 122);

[0407] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 123);

[0408] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 124);

[0409] 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 125);

[0410] 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 126);

[0411] 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 127);

[0412] (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 128);

[0413] (S)-N-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 129);

[0414] (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 130);

[0415] 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 131);

[0416] (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 132);

[0417] (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 133);

[0418] (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 134);

[0419] 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 135);

[0420] (S)-N-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 136);

[0421] (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 137);

[0422] 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 138);

[0423] 6-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamyl)-3',5'-dimethyl-[3,4'-bipyridine]1'-oxide (Example 139);

[0424] 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 140);

[0425] (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 141);

[0426] 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 142);

[0427] (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 143);

[0428] (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 144);

[0429] 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 145);

[0430] 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 146);

[0431] 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 147);

[0432] (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 148);

[0433] (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 149);

[0434] (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 150);

[0435] 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 151);

[0436] 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 (Example 152);

[0437] 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 153);

[0438] 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 154);

[0439] 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 155);

[0440] 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 156);

[0441] (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 157);

[0442] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 158);

[0443] 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 159);

[0444] 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 160);

[0445] (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 161);

[0446] (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 162);

[0447] (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 163);

[0448] (S)-N-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 164);

[0449] (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 165);

[0450] (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 166);

[0451] 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 167);

[0452] 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 168);

[0453] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (Example 169);

[0454] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-methylisoxazol-4-carboxamide (Example 170);

[0455] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazol-4-carboxamide (Example 171);

[0456] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 172);

[0457] (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 173);

[0458] (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 174);

[0459] (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 175);

[0460] (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 176);

[0461] (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 177);

[0462] (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 178);

[0463] 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 179);

[0464] 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 180);

[0465] (S)-N-(1-cyclohexyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-methylisoxazole-4-carboxamide (Example 181);

[0466] (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 182);

[0467] (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 183);

[0468] N-(1-(bicyclo[2.2.1]hept-2-yl)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazol-5-carboxamide (Example 184);

[0469] 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 185);

[0470] 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 186);

[0471] 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 187);

[0472] 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 188);

[0473] 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 189);

[0474] (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 190);

[0475] 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 191);

[0476] 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 192);

[0477] 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 193);

[0478] 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 194);

[0479] (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 195);

[0480] 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 196);

[0481] 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 197);

[0482] (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 198);

[0483] 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 199);

[0484] 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 200);

[0485] 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 201);

[0486] (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 202);

[0487] 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 203);

[0488] 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 204);

[0489] 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 205);

[0490] 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 206);

[0491] (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 207);

[0492] (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 208);

[0493] (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 209);

[0494] (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide (Example 210);

[0495] 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 211);

[0496] 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 212);

[0497] 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 213);

[0498] (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 (Example 214);

[0499] 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 215);

[0500] (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 216);

[0501] 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 217);

[0502] (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 218);

[0503] 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 219); or

[0504] N-(2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1-(dispiro[2.1.2]) 5 .2 3 (Non-4-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Example 220);

[0505] Or its pharmaceutically acceptable salt.

[0506] Typically, the various functional groups and substituents constituting the compounds of this invention are selected such that the molecular weight of the compound does not exceed 1000. More generally, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600.

[0507] Suitable or preferred features of any compound of the present invention may also be suitable features of any other aspect.

[0508] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of sufficiently basic compounds of the present invention, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid. Additionally, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present invention are alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; ammonium salts; or salts with organic bases that provide physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine.

[0509] Compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of atoms, 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." When a compound has an asymmetric center (e.g., it is bonded to four different groups), a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S sequencing rules of Cahn and Prelog or by rotating the molecular polarization plane, and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0510] The compounds of this invention may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R) or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both its individual enantiomers and mixtures thereof, racemic or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolving racemic forms. Some compounds of this invention may have geometric isomer centers (E- and Z-isomers). It should be understood that this invention includes all optical diastereomers and geometric isomers and mixtures thereof.

[0511] The present invention also includes compounds of the invention as defined herein that contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H(D), and 3H(T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 16O and 18O; and so on.

[0512] It should also be understood that some compounds of the present invention can exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention includes all such solvated forms.

[0513] It should also be understood that some compounds of the present invention may exhibit polymorphism, and the present invention includes all such forms.

[0514] The compounds of the present invention can exist in many different tautomer forms, and references to the compounds of the present invention include all such forms. However, for the avoidance of ambiguity, when a compound can exist in one of several tautomer forms and only one is specifically described or shown, all other tautomer forms are included in the compounds of the present invention. Examples of tautomer forms include ketone-, enol-, and enolate-forms, such as in, for example, the following tautomer pairs: ketone / enol (described below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / aci-nitro.

[0515]

[0516] Compounds of the present invention containing amine functional groups can also form N-oxides. References herein to compounds of formula I containing amine functional groups also include N-oxides. When a compound contains multiple amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, page number. More specifically, N-oxides can be formed using the LWDeady procedure (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in, for example, an inert solvent such as dichloromethane.

[0517] The compounds of this invention can be administered as prodrugs, which decompose in the human or animal body to release the compounds of this invention. Prodrugs can be used to modify the physical or pharmacokinetic properties of the compounds of this invention. Prodrugs can be formed when the compounds of this invention contain suitable groups or substituents, and the modifying groups can be attached to said groups or substituents. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl group of the compounds of this invention, and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino group of the compounds of this invention.

[0518] Therefore, the present invention includes compounds of Formula I as defined above, when they are obtainable through organic synthesis and when they are obtainable in humans or animals through the cleavage of their prodrugs. Thus, the present invention includes compounds of Formula I produced by organic synthesis and also such compounds produced in humans or animals through the metabolism of precursor compounds, i.e., compounds of Formula I can be synthetically produced or metabolically produced compounds.

[0519] synthesis

[0520] In the description of the synthesis methods below and in the reference synthesis methods for preparing the starting materials, it should be understood that those skilled in the art can choose all the proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, experimental duration and post-treatment procedures.

[0521] Those skilled in the field of organic synthesis can understand that the functional groups present on different parts of a molecule must be compatible with the reagents and reaction conditions used.

[0522] The necessary starting materials can be obtained through standard procedures in organic chemistry. The preparation of such starting materials combines the following representative method variations and is described in the accompanying examples. Alternatively, the necessary starting materials can be obtained through procedures similar to those described within the scope of the general skill of an organic chemist.

[0523] It should be understood that during the synthesis of the compounds of the present invention in the methods defined below, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent them from undergoing undesirable reactions. Skilled chemists should understand when such protection is needed and how to place such protecting groups in the appropriate positions and subsequently remove them.

[0524] For examples of protecting groups, see one of the many general texts on the 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 suitable for removing the protecting groups in question, chosen so that the removal of the protecting groups can be achieved with minimal interference from groups elsewhere in the molecule.

[0525] Therefore, if the reactants include groups such as amino, carboxyl, or hydroxyl groups, it may be desirable to protect the groups in some of the reactions mentioned herein.

[0526] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups like acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; or aromatic acyl groups, such as 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, alkoxycarbonyl, or aromatic acyl groups can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide or sodium hydroxide). Alternatively, acyl groups such as tert-butoxycarbonyl can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl can be removed, for example, by hydrogenation on a catalyst such as carbon-supported palladium or by treatment with a Lewis acid such as BF3·OEt2. Suitable alternative protecting groups for primary amino groups are, for example, phthalyl groups, which can be removed by treatment with an alkylamine such as dimethylaminopropylamine or with hydrazine.

[0527] Those skilled in the art will recognize that the compounds of the present invention can be prepared in a variety of known ways. Compounds of Formula I can be prepared by the methods given below, by the methods given experimentally, or by similar methods. The described routes 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 should also be understood that the partitioning of nucleophiles and electrophiles is not limited to that described herein, and in some cases, reversing the 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).

[0528] Where R 1 R 2 R 3 R 4 X 1 X 2 X 3 X 4 And Y, as previously defined, a compound of formula I or a pharmaceutically acceptable salt thereof, can be reacted by making a carboxylic acid of formula III or a suitable reactive derivative thereof (where R) 1 R 2 R 3 And Y as defined in Formula I) and amine of Formula II (where R) 4 X 1 X 2 X 3 and X 4 Prepared by reaction as defined in Formula I (Scheme A, step i).

[0529] 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 as defined above) can be made by making an amine of formula IV (where R) 1 R 2 R 3 R 4 X 1 X 2 X 3 and X 4 Prepared by reacting a carboxylic acid of formula V or a suitable reactive derivative of a carboxylic acid (where Y is as defined in formula I) as described above (Scheme A, step ii).

[0530] Option A

[0531]

[0532] Compounds of formula III can be obtained by using an amine of formula VI with appropriate protection (where R... 1 R 2 and R 3 Scheme B, step i) is prepared by reacting a carboxylic acid of formula V or a suitable reactive derivative of a carboxylic acid (where Y is as defined in formula I) as described above with the carboxylic acid of formula V.

[0533] Compounds of formula IV can be reacted by a suitably protected carboxylic acid of formula VI or a suitably protected carboxylic acid derivative (where R... 1 R 2 and R 3 As defined in Formula I above) and amines of Formula II (where R) 4 X 1 X 2 X 3 and X 4 Prepared by reaction as defined in Formula I (Scheme B, step ii).

[0534] Option B

[0535]

[0536] Suitable reactive derivatives of carboxylic acids of formulas III, V, and VI include, for example: acyl halides formed by reacting an acid with an inorganic acyl chloride such as thionyl chloride; mixed acid anhydrides formed by reacting an acid with a chloroformate such as isobutyl chloroformate; esters formed by reacting an acid with an alcohol in the presence of an acid or a base; activated esters formed by reacting an acid with a phenol such as pentafluorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; or products formed by reacting an acid with an amide coupling agent such as dicyclohexylcarbodiimide. When carboxylic acids of formulas III and V are converted to esters (e.g., by reacting an acyl chloride with an organic alcohol such as methanol), this can be done by reacting a suitable amine in the presence of an organometallic activator (e.g., a Grignard reagent such as isopropyl magnesium bromide). Typically, this is done in a suitable solvent such as DMF, ethyl acetate, or MeCN in the presence of a nonnucleophilic base such as triethylamine, 2,4,6-trimethylpyridine, or N,N-diisopropylethylamine with an amide coupling agent such as HATU or Treat carboxylic acids of formula III and amines of formula II, or carboxylic acids of formula V and amines of formula IV, or appropriately protected carboxylic acids of formula VI and amines of formula II.

[0537] Those skilled in the art will understand that converting amino acids of formula VI into compounds of formulas III and IV will require suitable synthetic strategies, which may involve multiple steps. Those skilled in the art will be able to identify such synthetic strategies, which may include the selection, preparation, and removal of suitable protecting groups.

[0538] Natural and non-natural amino acids of formula VI and their derivatives (where R 1 R 2 and R 3 (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. Ansano, Chem Rev, 2007, 107, 4584; (b) R. R. Williams and J. A. Hendrix, Chem Rev, 1992, 92, 889; and (c) R. R. Duthaler, Tetrahedron, 1994, 50, 1539.

[0539] Carboxylic acids of formula V or their derivatives (wherein 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, such as 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.

[0540] Option C

[0541]

[0542] Amines of formula II (where R) 4 X 1 X 2 X 3 and X 4 (As defined in Formula I above) is commercially available or can be prepared by methods known to those skilled in the art.

[0543] Compounds of formula II can be prepared from compounds of formula VII, wherein R 4 As defined in Equations I and VIII, where X 1 X 2 X 3 and X 4 As defined in Equation I, and where Z 1 and Z 2 It promotes R 4Functional groups that form bonds with phenyl / heteroaryl rings, and said functional groups are replaced / eliminated during the bond-forming reaction (Scheme C, step i). 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 can be the Suzuki reaction, and Z... 1 or Z 2 One is boric acid or borate ester, and the other is a halide. Typically, compounds of formula VII and VIII (where Z) are used. 1 or Z 2 One of them is boric acid or borate ester and the other is a halide) combined and reacted 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.

[0544] Amines of formula II can also be prepared from compounds of formula IX, wherein R 4 X 1 X 2 X 3 and X 4 As defined in equation I above, and Z 3 It is a functional group that can be converted into an amine by known methods (Scheme C, step ii). Examples of known methods include: reduction, where Z 3 For example, azides or nitro groups; rearrangements, where Z 3 It is, for example, a primary amide (Hoffmann rearrangement), a carboxylic acid (Schmidt rearrangement), or an acyl azide (Curtius rearrangement); or a CN bond formation, wherein Z 3 It is H or a halide, such as nitration, followed by reduction or amination (e.g., Buchwald-Hartwig reaction).

[0545] Compounds of formula IX (where R) 4 X 1 X 2 X 3 and X 4 As defined in Formula I above, and as described herein, it is commercially available or can be prepared by methods known to those skilled in the art.

[0546] Pharmaceutical Composition

[0547] The compounds of the present invention will generally, but not necessarily, be formulated into pharmaceutical compositions before administration to a patient. 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.

[0548] 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, such as in the form of 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 as unit dosage forms, the pharmaceutical compositions of the present invention typically contain 1 mg to 1000 mg.

[0549] The compositions of the present invention may be in the form suitable for oral use (e.g., as tablets, capsules, pouches, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, small capsules and flat capsules), in the form suitable for topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams and gels), in the form suitable for transdermal administration (e.g., via transdermal patches), in the form suitable for inhalation administration (e.g., as dry powders, aerosols, suspensions and solutions), in the form suitable for blow-in administration (e.g., as finely dispersed powders), or in the form suitable for parenteral administration (e.g., as sterile aqueous or oil solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0550] As used herein, "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or medium relating to imparting the form or consistency of a pharmaceutical composition. When blended, 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 invention when administered to a patient, as well as interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. Furthermore, each excipient must, of course, have sufficiently high purity to be pharmaceutically acceptable.

[0551] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0552] An effective amount of the compound of the present invention for treating proliferative diseases is sufficient to alleviate symptoms of proliferative diseases in warm-blooded animals, particularly humans, slow the progression of proliferative diseases, or reduce the risk of worsening in patients with proliferative disease symptoms.

[0553] The amount of active ingredient combined with one or more excipients to produce a single dosage form must vary depending on the host being treated and the specific route of administration. For example, a formulation intended for oral administration in humans will typically contain, for example, 0.5 mg to 0.5 g (more appropriately 0.5 to 100 mg, e.g., 1 to 30 mg) of the active ingredient, which is mixed with an appropriate and convenient amount of excipients, the amount of which can vary from about 5% to about 98% by weight of the total composition.

[0554] Based on well-known medical principles, the dosage of compounds 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.

[0555] When the compounds of the present invention are used for therapeutic or prophylactic purposes, they are typically administered such that a daily dose, for example, ranging from 0.1 mg / kg to 75 mg / kg body weight, is received, and if necessary, in divided doses. Generally, a lower dose is administered when the administration is via a parenteral route. Thus, for example, for intravenous or intraperitoneal administration, a dose, for example, ranging from 0.1 mg / kg to 30 mg / kg body weight, is typically used. Similarly, for inhalation administration, a dose, for example, ranging from 0.05 mg / kg to 25 mg / kg body weight, is used. Oral administration may also be suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention.

[0556] Application route

[0557] The compounds of the present invention or pharmaceutical compositions comprising the active compound may be administered to a subject via any convenient route of administration, whether systemic / peripheral or local (i.e., at the site of desired action).

[0558] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by chewing gum, membranes, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, by aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intrasacral, intraperitoneal, intratracheal, subcutaneous, intra-articular, subarachnoid, and intrasternal; and via, for example, subcutaneous or intramuscular implantation of a reservoir or depository.

[0559] Therapeutic uses and applications

[0560] The compounds of the present invention are high-affinity binders of human IL-17A and effective modulators of human IL-17A activity, and are therefore beneficial as therapeutic compounds for the treatment or prevention of human ailments caused by IL-17A activity.

[0561] The compounds of this invention are high-affinity binders of human IL-17A and effective modulators of human IL-17A activity, and can be beneficially used as pharmacological standards for developing new biological assays and identifying new pharmacological agents. Therefore, the compounds of this invention can be usefully used as radioligands for the determination of pharmacologically active compounds.

[0562] 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.

[0563] 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.

[0564] In another aspect, the present invention relates to the use of the compounds of the 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.

[0565] 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.

[0566] Examples of specific diseases or disorders that compounds of formula (I) and their pharmaceutically acceptable salts may be used to treat include, but are not limited to, any of the following: acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spinal joint disorders, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes and other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid tumors such as melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, and hematologic malignancies, 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-related endotoxic shock, exophthalmos, fibrotic disorders including pulmonary fibrosis, and gallbladder disease. Giant cell arteritis, graft-versus-host disease, heart disease including ischemic diseases such as myocardial infarction and atherosclerosis, hepatoblastoma, hypoacidity, immune-mediated inflammatory disorders of the central and peripheral nervous systems such as multiple sclerosis and Guillain-Barré syndrome, infections (viral, bacterial, fungal, and parasitic), 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, Peroni disease, 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.

[0567] IL-17 activity modulators can be administered to inhibit or reduce the severity of ocular inflammatory disorders (WO 2009 / 089036), such as ocular surface inflammatory disorders, including dry eye syndrome (DES). 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, corneal prosthesis surgery, corneal and ocular surface inflammatory disorders, conjunctival scarring disorders, ocular autoimmune disorders, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye disease, conjunctivitis, and microbial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Shogren's syndrome, Shogren's syndrome-associated keratoconjunctivitis sicca, non-Shogren's syndrome-associated keratoconjunctivitis sicca, keratoconjunctivitis sicca, Shogren's syndrome, dry eye, tear film disorders, decreased tear secretion, aqueous tear deficiency (ATD), meibomian gland dysfunction, and evaporation loss.

[0568] Combination therapy

[0569] The compounds of the present invention can be administered alone as monotherapy or in combination with one or more other therapeutic agents. The selection of such one or more other therapeutic agents will, of course, vary depending on the disease or condition to be treated and its severity.

[0570] It is common to use combination therapies to treat certain conditions.

[0571] According to one specific aspect of the invention, a combination suitable for treating diseases or conditions in which IL-17 activity is involved is provided, the combination comprising the compound of the invention as defined above or a pharmaceutically acceptable salt thereof and another therapeutic agent.

[0572] According to this aspect of the invention, suitable for the prevention or treatment of combinations of the following: acute lung injury, Alzheimer's disease, ankylosing spondylitis, axial spondyloarthritis and other spinal joint diseases, arthritis, asthma (including severe asthma), atopic dermatitis, autoimmune diabetes and other autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid tumors such as melanoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, and hematologic malignancies, especially acute myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), Kassman disease, and other related conditions. 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-related endotoxic shock, exophthalmos, fibrotic disorders including pulmonary fibrosis, gallbladder disease, giant cell arteritis, graft-versus-host disease, heart disease including ischemic diseases such as myocardial infarction and atherosclerosis, hepatoblastoma, hypoacidity, immune-mediated inflammatory disorders of the central and peripheral nervous systems such as multiple sclerosis and Guillain-Barré syndrome, infections (diseases) (Toxins, bacteria, fungi, and parasites), 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, Peronis disease, 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 1 diabetes, ulcerative colitis, uveitis, vasculitis, dry eye syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, corneal prosthesis surgery, corneal and ocular surface inflammatory disorders, conjunctival scarring disorders, ocular autoimmune disorders, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye disease, conjunctivitis, and microbial keratitis, wherein the combination comprises the compound of the present invention as defined above or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.

[0573] Examples of these other therapeutic agents may include, but are not limited to, corticosteroids (topical or systemic), vitamin D analogs, anthraquinone, retinoids, calcineurin inhibitors, salicylic acid, methotrexate, cyclosporine, leflunomide, sulfasalazine, azathioprine, etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), uteroximateb (Stellara), golimumab (Simponi), guselkumab, PDE inhibitors (such as apremilast), thioguanine, hydroxyurea, dimethyl fumarate, JAK inhibitors, including TYK2 inhibitors (such as ruxo). Including tinib, tofacitinib, olatinib, baricitinib, filgotinib, cemodulinib, gandotinib, letautinib, momelotiib, peficitiib, pyridatinib, BMS-986165, and NSAIDs (such as naproxen and indomethacin).

[0574] In another aspect of the invention, a combination of the compound of the invention or a pharmaceutically acceptable salt thereof with one or more other therapeutic agents is provided.

[0575] In this document, the term "combination" is understood to mean simultaneous, individual, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means individual application. In yet another aspect of the invention, "combination" means sequential application. In the case of sequential or individual application, a delay in the application of the second component should not negate the beneficial effects of the combination.

[0576] According to another aspect of the invention, a pharmaceutical composition is provided comprising a combination of the compound of the invention or a pharmaceutically acceptable salt thereof with one or more other therapeutic agents, combined with a pharmaceutically acceptable diluent or carrier.

[0577] The one or more additional therapeutic agents may include yet another compound of the present invention. Therefore, in one embodiment, a pharmaceutical composition is provided comprising two compounds of the present invention or pharmaceutically acceptable salts thereof, combined with a pharmaceutically acceptable diluent or carrier.

[0578] 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.

[0579] Such combination therapy can be achieved by administering individual components simultaneously, sequentially, or individually. In one embodiment, the individual compounds are administered simultaneously as a combined pharmaceutical formulation.

[0580] Such combination therapies use compounds of the present invention within the dosage range described herein and other pharmaceutically active agents within the approved dosage range or as described in relevant published references.

[0581] General procedures:

[0582] The method for preparing the compounds of the present invention is described in the following examples. Starting materials were prepared according to procedures known in the art or as described herein, or were commercially available. Commercial reagents without further purification were used. The reactions were carried out at ambient temperature (or room temperature), typically 17°C–27°C, excluding the reaction temperature.

[0583] Those skilled in the art will understand that the reaction temperature, reaction time, and reagent quantity may differ from those described herein.

[0584] Compound names were generated using ChemDraw Professional version 20.0.0.41.

[0585] The compounds described in this invention are obtained by... 1 For characterization using 1H NMR spectroscopy, spectra were recorded on a JEOL ECX300 (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 the multiplicity of the NMR signal: s = singlet, b = broad, t = triplet, q = quartet, m = multiply, d = doublet.

[0586] 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.

[0587] Method 1: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210-350nm) and QDa mass detector). Column: XBridge C18, 2.5μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 1.30min. Conditions: 10mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2%-98% B for 0.80min, held at 98% B until 1.30min.

[0588] Method 2: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210-350nm) and QDa mass detector). Column: XBridge C18, 2.5μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 1.40min. Conditions: 10mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2%-98% B for 1.20min, held at 98% B for 1.40min.

[0589] Method 3: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210-350nm) and QDa mass detector). Column: BEH C18, 1.7μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 4.60min. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; always 5%]. Gradient: 2%-95% B (containing A and 5% C) for 4.0min, held at 95% B 5% C for 4.60min, column temperature 40℃.

[0590] Method 4: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210-350nm) and QDa mass detector). Column: BEH C18, 1.7μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 1.40min. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; always 5%]. Gradient: 2%-95% B with A and 5% C for 1.2min, held at 95% B 5% C for 1.40min, column temperature 40°C.

[0591] Method 5: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210-350nm) and QDa mass detector). Column: XBridge C18, 2.5μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 4.60min. Conditions: 10mM ammonium bicarbonate pH 10 [eluent C], MeCN [eluent B]. Gradient: 2%-98% B for 4.0min, held at 98% B for 4.60min.

[0592] Method 6: Waters Acquity UPLC system (binary pump with PDA (210-350nm) and QDa mass detector). Column: Acquity UPLC CSH C18, 1.7μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 4.6min. Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2%-98% B for 4.0min, held at 98% B for 4.60min, column temperature 40℃.

[0593] Method 7: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350nm) and SQD mass detector). Column: XBridge C18, 2.5μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 5.00min. Conditions: 2% ammonia [eluent D] in water, MeCN [eluent C], water [eluent A]. Gradient: 2%-95% C in A (containing 5% D) for 4.50min, held at 95% C for 5.00min, column temperature 40℃.

[0594] Method 8: Waters Acquity UPLC system (binary pump with PDA (210-350nm) and QDa mass detector). Column: Acquity UPLC CSH C18, 1.7μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 1.4min. Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2%-98% B for 1.2min, held at 98% B for 1.40min, column temperature 40℃.

[0595] Method 9: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350nm) and SQD mass detector). Column: CSH C18, 1.7μm, 2.1x50mm (flow rate 0.7mL / min). Run time: 5.00min. Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2%-95% B for 4.50min, held at 95% B for 5.00min.

[0596] Method 10: Waters Acquity UPLC system (binary pump with PDA (210-350nm) and QDa mass detector). Column: XBridge BEH C18, 2.5μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 4.80 min. Conditions: 10mM ammonium bicarbonate pH 10 [eluent A], MeCN [eluent B]. Gradient: 2%-98% B for 4.0 min, held at 98% B for 4.70 min.

[0597] Method 11: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350 nm) and SQD mass 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 in water [eluent C; always 5%]. Gradient: 5%-95% B for 4.50 min, held at 95% B for 5.00 min, column temperature 40 °C.

[0598] Method 12: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350 nm) and SQD mass 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 in water [eluent C; always 5%]. Gradient: 2%-95% B for 4.0 min, held at 95% B for 4.60 min, column temperature 40 °C.

[0599] Method 13: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350 nm) and SQD mass 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; always 5%]. Gradient: 2%-95% B for 4.0 min, held at 95% B for 4.60 min, column temperature 40 °C.

[0600] Method 14: Agilent 6140 series quadrupole mass spectrometer with multi-mode 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 3.75 min.

[0601] Method 15: Agilent 6140 series quadrupole mass spectrometer with multi-mode 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 contains 0.1% formic acid in 18 MΩ water; mobile phase B contains 0.1% formic acid in acetonitrile. Gradient: 1%-100% B 5.5 min.

[0602] Method 16: Agilent 6140 series quadrupole mass spectrometer with multi-mode 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 3.5 min.

[0603] Method 17: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210-350nm) and QDa mass detector). Column: Acquity UPLC CSH C18, 1.7μm, 2.1x50mm (flow rate 0.8mL / min). Conditions: Water + 0.1% formic acid [eluent A], MeCN + 0.1% formic acid [eluent B]. Gradient: 2%-95% B for 4.0 min, held at 95% B for 4.60 min, column temperature 40℃.

[0604] Method 18: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350 nm) and SQD mass 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 in water [eluent C; always 5%]. 2%-95% B for 4.5 min, held at 95% B for 5.00 min, column temperature 40 °C.

[0605] Method 19: Agilent 6140 series quadrupole mass spectrometer with multi-mode 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 for 5 min.

[0606] Method 20: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210-350nm) and QDa mass detector). Column: BEH C18, 1.7μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 1.40min. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; always 5%]. Gradient: 50%-95% B (containing A and 5% C) for 1.2min, held at 95% B 5% C for 1.40min, column temperature 40°C.

[0607] Method 21: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350 nm) and SQD mass 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; always 5%]. Gradient: 2%-20% B for 3.0 min, at 4.0 min to 95% B, held at 95% B for 4.60 min, column temperature 40 °C.

[0608] Method 22: Waters Acquity UPLC H-Class system (quaternary pump with PDA (210-350nm) and QDa mass detector). Column: BEH C18, 1.7μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 1.40min. Conditions: Water [eluent A], MeCN [eluent B], 2% ammonia in water [eluent C; always 5%]. Gradient: 2%-50% B (containing A and 5% C) 1.0min, 1.8min to 95% B, 95% B 5% C held to 2.0min, column temperature 40°C.

[0609] Method 23: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350 nm) and SQD mass 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; always 5%]. Gradient: 2%-20% B for 1.0 min, at 1.8 min to 95% B, held at 95% B for 2.0 min, column temperature 40 °C.

[0610] Method 24: Waters Acquity UPLC H-Class system (binary pump with PDA (210-350nm) and SQD mass detector). Column: XBridge C18, 2.5μm, 2.1x50mm (flow rate 0.8mL / min). Run time: 1.80min. Conditions: 10mM ammonium bicarbonate pH 10 [eluent A], MeCN [eluent B]. Gradient: 2%-50% B for 1.00min, held at 98% B for 1.80min, column temperature 40°C.

[0611] 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 for 4 min, column temperature 40 °C.

[0612] Method 26: Agilent 1260 (binary pump, HiP sampler, column chamber, DAD: 260 + / - 90 nm, G6150 MSD: ESI); column: Cortecs C18, 2.6 μm, 30 x 2.1 mm. Conditions: 0.1% NH3 [eluent A] and MeCN [eluent B] in water (flow rate 1.35 mL / min). Gradient: 5% - 100% B for 2.5 min, hold at 100% B for 3 min, column temperature 40 °C.

[0613] Method 27: Agilent 1260 (quaternary pump, HiP sampler, column chamber, DAD: 260 + / - 90 nm, G6150 MSD: 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 for 2.5 min, hold at 100% B for 3 min, column temperature 40 °C.

[0614] Method 28: Agilent 1260 (Waters Acquity PDA 210-400nm and Waters Acquity QDa detector). Column: Waters BEH C18 column, 1.7μm, 30x2.1mm. Conditions: 0.1% NH3 [eluent A] and MeCN [eluent B] in water (flow rate 0.77mL / min). Gradient: 2%-100% B for 3 min, column temperature 40℃.

[0615] Method 29: Agilent 1260 (Agilent VWD or DAD detector (at 254 nm) 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 for 4 min, column temperature 40 °C.

[0616] Preparative HPLC was performed using a variety of preparative systems with variable wavelength UV detection or quality-guided AutoPrep (MDAP) systems, as listed below:

[0617] Method 1: Waters Fractionlynx preparative HPLC system (2545 pump, 2998 UV / VIS detector, 2767 liquid processor) with a Waters 3100 mass detector. Column: Waters XBridge OBD C18 column, XSelect CSHC18 (5 μm, 19 x 150 mm) or as specified. Conditions: Eluent selected from MeOH and MeCN; modifier selected from formic acid (0.1%) and ammonium hydroxide (0.1%) as specified. Gradient as specified.

[0618] Method 2: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 2998 photodiode array detector) was performed using a Waters XBridge Prep OBD C18, 5 μm, 19 mm x 50 mm id column at 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 to collect fractions from the HPLC.

[0619] Method 3: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters Systems Fluidics Organiser, 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 at 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 to collect fractions from the HPLC.

[0620] Method 4: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 2998 photodiode array detector) was performed using a Waters XBridge Prep OBD C18, 5 μm, 19 mm x 50 mm id column at 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 to collect fractions from the HPLC.

[0621] Method 5: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 2998 photodiode array detector), using a Waters X-Select CSH C18 ODB preparative column. A 5 μm, 30 mm x 100 mm column was used, with a flow rate of 40 mL min⁻¹, eluted with a 0.1% formic acid-MeCN gradient in water for 12.5 min. An At-column dilution pump was used to deliver 2 mL min⁻¹ of MeCN throughout the method, which was contained in the following MeCN percentages: Gradient information: 0.0–0.5 min, 25% MeCN; 0.5–10.5 min, ramping from 25% MeCN to 55% MeCN; 10.5–10.6 min, ramping from 55% MeCN to 100% MeCN; 10.6–12.5 min, maintained at 100% MeCN. UV detection was performed at all wavelengths using a PDA, as well as QDA and ELS detectors.

[0622] Method 6: Waters HPLC (Waters 2767 sample manager, Waters 2545 binary gradient module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 2998 photodiode array detector), using a Waters XBridge BEH C18 ODB preparative column. A 5 μm, 30 mm x 100 mm column was used, with a flow rate of 40 mL min⁻¹, eluted with a 0.3% ammonia-MeCN gradient in water for 12.5 min. An At-column dilution pump was used to deliver 2 mL min⁻¹ of MeCN throughout the method, which was contained in the following MeCN percentages: Gradient information: 0.0–0.5 min, 30% MeCN; 0.5–10.5 min, ramping from 30% MeCN to 60% MeCN; 10.5–10.6 min, ramping from 60% MeCN to 100% MeCN; 10.6–12.5 min, maintained at 100% MeCN. UV detection was performed at all wavelengths using a PDA, as well as QDA and ELS detectors.

[0623] 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 uses liquid CO2 (Airproducts) and a suitable modifier as specified. UV detection was performed at 254 nm.

[0624] abbreviation:

[0625]

[0626]

[0627]

[0628] Intermediate 1.1: 4-(2,3-dimethylpyridin-4-yl)aniline

[0629] A suspension of 4-bromo-2,3-dimethylpyridine (3.3 g, 18 mmol, CAS: 259807-91-5), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (3.9 g, 18 mmol, CAS: 214360-73-3), potassium carbonate (6.1 g, 44 mmol), and Pd(dppf)Cl2 (1.3 g, 1.8 mmol) in 1,4-dioxane (20 mL) and water (3 mL) was heated at 70 °C for 15 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 (2.6 g). LCMS (Method 1): 0.64 min, 199.1 [M+H] +

[0630] Intermediate 1.2: 4-(3-chloropyridin-4-yl)aniline

[0631] The title compound (0.18 g) was prepared from 3-chloro-4-iodopyridine (0.25 g, 1.0 mmol, CAS: 77332-79-7), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.23 g, 1.0 mmol, CAS: 214360-73-3), Pd(dppf)Cl2 (0.85 g, 1.0 mmol), and sodium carbonate (0.33 g, 3.1 mmol) by heating at 80 °C for 4 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 2): 0.63 min, 205.1 [M+H] +

[0632] Intermediate 1.3: 4-(3-methoxypyridin-4-yl)aniline

[0633] XPhos Pd G2 (1.8 g, 0.23 mmol) was added to a solution of (3-methoxy-4-pyridyl)boric acid (0.7 g, 4.6 mmol, CAS: 1008506-24-8), 4-iodoaniline (1.0 g, 4.6 mmol, CAS: 540-37-4), and potassium phosphate (2.9 g, 13 mmol) in water (7 mL) and ethanol (7 mL), and the reaction was heated to 80 °C for 6 h. The reaction mixture was diluted with water, and the crude product was extracted into EtOAc. The combined organic matter was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane) to provide the title compound (0.25 g). LCMS (Method 2): 0.54 min, 201.1 [M+H] +

[0634] Intermediate 1,4: 4-(3-methylpyridin-4-yl)aniline

[0635] The title compound (61 mg) was prepared from 4-chloro-3-methylpyridine hydrochloride (0.20 g, 1.2 mmol, CAS: 19524-08-4), 4-aminophenylborate salt (0.17 g, 1.2 mmol, CAS: 80460-73-7), Pd(dppf)Cl2 (0.10 g, 0.12 mmol), and sodium carbonate (0.39 g, 3.7 mmol) by heating at 80 °C for 3 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 60%–80% EtOAc in heptane). LCMS (Method 2): 0.57 min, 185.1 [M+H] +

[0636] Intermediate 1.5: 4-(3-(trifluoromethyl)pyridin-4-yl)aniline

[0637] The title compound (75 mg) was prepared from 4-chloro-3-(trifluoromethyl)pyridine hydrochloride (0.20 g, 0.92 mmol, CAS: 732306-24-0), 4-aminophenylborate salt (0.17 g, 1.0 mmol, CAS: 80460-73-7), Pd(dppf)Cl2 (34 mg, 0.05 mmol), and sodium carbonate (0.39 g, 3.7 mmol) by heating at 80 °C for 6 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 2): 0.71 min, 239.1 [M+H] +

[0638] Intermediate 1.6: 4-(3,5-dimethylpyridin-4-yl)aniline

[0639] Pd(dppf)Cl2 (0.21 g, 0.28 mmol) was added to a stirred suspension of 4-chloro-3,5-dimethylpyridine (0.40 g, 2.8 mmol, CAS: 143798-73-6), 4-aminophenylborate salt (0.59 g, 3.4 mmol, CAS: 80460-73-7), and sodium carbonate (0.96 g, 9.0 mmol) in degassed water (8 mL) and 1,4-dioxane (8 mL), and then heated at 120 °C for 2 h by microwave irradiation. The reaction mixture was then subjected to... The sample was filtered and washed with EtOAc. The filtrate was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 10%–30% EtOAc in DCM) to provide the title compound (0.15 g). LCMS (Method 3): 1.42 min, 199.1 [M+H] +

[0640] Intermediate 1.7: 4-(4-aminophenyl)-N-methylpyridine-3-amine Intermediate 1.7a: (E)-N-(4-iodopyridin-3-yl)methaneimine methyl ester

[0641] A suspension of 4-iodopyridin-3-amine (2.0 g, 9.1 mmol, CAS: 105752-11-2) in trimethyl orthoformate (20 mL, 182 mmol) and TFA (0.04 mL, 0.52 mmol) was heated under reflux for 2 h. The reaction mixture was concentrated under vacuum to provide the title compound (2.4 g), which was used without further purification. LCMS (Method 2): 0.66 min, 262.9 [M+H] +

[0642] Intermediate 1.7b: 4-Iodo-N-methylpyridin-3-amine

[0643] LiAlH4 (5.2 mL, 5.2 mmol in 1 M THF) was added dropwise to a suspension of intermediate 1.7a (2.6 g, 9.9 mmol) in anhydrous THF (20 mL) at -5 °C under argon atmosphere. The reaction was stirred at -5 °C for 30 min, then warmed to 0 °C and quenched with a saturated aqueous solution of NH4Cl. The mixture was diluted with EtOAc and then... The sample was filtered through a pad, washed with EtOAc, and the filtrate was dried over MgSO4, filtered again, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane) to provide the title compound (0.58 g). LCMS (Method 2): 0.60 min, 234.9 [M+H] +

[0644] Intermediate 1.7: 4-(4-aminophenyl)-N-methylpyridine-3-amine

[0645] The title compound (0.14 g) was prepared from intermediate 1.7b (0.15 g, 0.64 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.15 g, 0.71 mmol, CAS: 214360-73-3), Pd(dppf)Cl2 (47 mg, 0.06 mmol), and potassium carbonate (0.22 g, 1.6 mmol) by heating at 70 °C for 16 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 100% EtOAc) and by reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 30g C18 column, eluting with 0-40% MeCN in 0.1M NH4HCO3 buffer at pH 10. LCMS (Method 2): 0.50 min, 200.1M [M+H2O]+

[0646] Intermediate 1.8: 4-(4-aminophenyl)-N,N-dimethylpyridine-3-amine Intermediate 1.8a: 4-iodo-N,N-dimethylpyridin-3-amine

[0647] Sodium hydride (60% dispersion in mineral oil, 0.27 g, 6.8 mmol) was added to a solution of 4-iodopyridin-3-amine (0.5 g, 2.3 mmol, CAS: 105752-11-2) in anhydrous DMF (40 mL) at room temperature under argon atmosphere. The mixture was stirred at room temperature for 30 min, then cooled to 0 °C, and iodomethane (0.42 mL, 6.8 mmol) was added dropwise over 10 min at 0 °C, and the reaction was stirred at 0 °C for 3 h. The mixture was quenched with 2 M NaOH aqueous solution and extracted into EtOAc. The combined organic matter was washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 20% EtOAc in hexane) to provide the title compound (0.35 g). LCMS (Method 2): 0.70 min, 248.9 [M+H] +

[0648] Intermediate 1.8: 4-(4-aminophenyl)-N,N-dimethylpyridine-3-amine

[0649] The title compound (75 mg) was prepared from intermediate 1.8a (0.15 g, 0.60 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.13 g, 0.60 mmol, CAS: 214360-73-3), Pd(dppf)Cl2 (44 mg, 0.06 mmol), and potassium carbonate (0.21 g, 1.5 mmol) by heating at 70 °C for 16 h according to the procedure described for intermediate 1.1. The crude product was subjected to reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 30g C18 column (eluting with 0-40% MeCN in 0.1M NH4HCO3 buffer at pH 10) and by rapid column chromatography (eluting with 90% EtOAc in hexane). LCMS (Method 2): 0.63 min, 214.1 [M+H] +

[0650] Intermediate 1.9: 4-(3,5-dimethoxypyridin-4-yl)aniline

[0651] The title compound (0.18 g) was prepared from 4-bromo-3,5-dimethoxy-pyridine (0.20 g, 0.92 mmol, CAS: 1033610-45-5), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.22 g, 1.0 mmol, CAS: 214360-73-3), Pd(dppf)Cl2 (0.10 g, 0.14 mmol), and potassium carbonate (0.32 g, 2.3 mmol) by heating at 90 °C for 16 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 100% EtOAc). LCMS (Method 2): 0.52 min, 231.1 [M+H] +

[0652] Intermediate 1.10: 4-(3-fluoro-5-methoxypyridin-4-yl)aniline

[0653] The title compound (0.17 g) was prepared from 4-bromo-3-fluoro-5-methoxypyridine (0.20 g, 0.97 mmol, CAS: 1256825-73-6), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.23 g, 1.1 mmol, CAS: 214360-73-3), Pd(dppf)Cl2 (71 mg, 0.10 mmol), and potassium carbonate (0.33 g, 2.4 mmol) by heating at 80 °C for 16 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 60% EtOAc in hexane). LCMS (Method 2): 0.58 min, 219.1 [M+H] +

[0654] Intermediate 1.11: 5-(4-aminophenyl)-6-methylpyridin-2(1H)-one

[0655] The title compound (0.14 g) was prepared from 5-bromo-6-methylpyridin-2-phenol (0.50 g, 2.6 mmol, CAS: 54923-31-8), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.63 g, 3.0 mmol, CAS: 214360-73-3), Pd(dppf)Cl2 (97 mg, 0.13 mmol), and sodium carbonate (0.85 g, 8.0 mmol) by heating at 80 °C for 20 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting in heptane with 50%–100% EtOAc). LCMS (Method 2): 0.38 min, 201.1 [M+H] +

[0656] Intermediate 1.12: 5-(4-aminophenyl)-1,4-dimethylpyridine-2(1H)-oneIntermediate 1.12a: 5-bromo-1,4-dimethylpyridin-2(1H)-one

[0657] Potassium carbonate (0.52 g, 3.8 mmol) was added to a suspension of 5-bromo-4-methylpyridine-2-phenol (0.15 g, 0.80 mmol, CAS: 164513-38-6) in acetone (10 mL), followed by the addition of methyl iodoform (0.22 mL, 3.6 mmol). The resulting mixture was stirred at room temperature for 6 h. The precipitate was removed by filtration, the mixture was washed with acetone, and the liquid was concentrated to dryness under vacuum. The crude product was purified by rapid column chromatography (eluting with 0–15% MeOH in EtOAc) to give the title compound (0.20 g).

[0658] LCMS (Method 4): 0.48 min, 204.0 [M+H] +

[0659] Intermediate 1.12: 5-(4-aminophenyl)-1,4-dimethylpyridine-2(1H)-one

[0660] The title compound (0.11 g) was obtained from intermediate 1.12a (0.20 g, 0.97 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.23 g, 1.1 mmol, CAS: 214360-73-3), Pd(dppf)Cl2 (79 mg, 0.10 mmol), and sodium carbonate (0.31 g, 2.9 mmol) by heating at 80 °C for 4 h according to the procedure described for intermediate 1.1. The crude product was then subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 0.42 min, 215.1 [M+H] +

[0661] Intermediate 1.13: 5-(4-aminophenyl)-1,6-dimethylpyridin-2(1H)-one Intermediate 1.13a: 5-bromo-1,6-dimethylpyridin-2(1H)-one

[0662] Potassium carbonate (1.7 g, 13 mmol) was added to a suspension of 5-bromo-6-methylpyridine-2-phenol (0.5 g, 2.7 mmol, CAS: 54923-31-8) in acetone (33 mL), followed by the addition of methyl iodide (0.74 mL, 12 mmol), and the resulting mixture was stirred at room temperature for 6 h. The precipitate was removed by filtration, the mixture was washed with acetone, and the liquid was concentrated to dryness under vacuum. The crude product was analyzed by rapid column chromatography in Biotage Isolera One. TMPurification was performed (30 g ZIP-coated silica column, 60%–100% EtOAc in heptane, followed by elution in EtOAc at 0–10% MeOH) to give the title compound (0.37 g). LCMS (Method 4): 0.52 min, 203.9 [M+H) +

[0663] Intermediate 1.13: 5-(4-aminophenyl)-1,6-dimethylpyridin-2(1H)-one

[0664] The title compound (0.13 g) was prepared from intermediate 1.13a (0.17 g, 0.79 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.41 g, 1.9 mmol, CAS: 214360-73-3), XPhos Pd G2 (12 mg, 0.02 mmol), and potassium carbonate (0.31 g, 4.7 mmol) by heating at 85 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%–100% EtOAc in heptane, followed by elution with 0–10% MeOH in EtOAc. LCMS (Method 4): 0.50 min, 215.1 [M+H] +

[0665] Intermediate 1.14: 4-(3,5-dimethylpyridin-4-yl)-3-fluoroaniline

[0666] The title compound (0.1 g) was prepared from 4-chloro-3,5-dimethylpyridine (0.20 g, 1.4 mmol, CAS: 143798-73-6), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.37 g, 1.6 mmol, CAS: 819057-45-9), Pd(dppf)Cl2 (51 mg, 0.07 mmol), and sodium carbonate (0.45 g, 4.2 mmol) according to the procedure described for intermediate 1.6 and by heating at 120 °C for 1 h under microwave irradiation. The crude product was purified by rapid column chromatography (eluting in heptane with 50%–100% EtOAc). LCMS (Method 4): 0.66 min, 217.1 [M+H] +

[0667] Intermediate 1.15: 3-Fluoro-4-(3-methylpyridin-4-yl)aniline

[0668] The title compound (0.17 g) was prepared from 4-chloro-3-methylpyridine hydrochloride (0.25 g, 1.5 mmol, CAS: 19524-08-4), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.36 g, 1.5 mmol, CAS: 819057-45-9), Pd(dppf)Cl2 (111.5 mg, 0.15 mmol), and sodium carbonate (0.57 g, 5.4 mmol) according to the procedure described for intermediate 1.6 and by heating at 120 °C for 1 h under microwave irradiation. The crude product was purified on silica gel by rapid column chromatography (eluting with 70% EtOAc in heptane). LCMS (Method 4): 0.62 min, 203.0 [M+H] +

[0669] Intermediate 1.16: 5-(4-amino-2-fluorophenyl)-1,6-dimethylpyridin-2(1H)-one

[0670] The title compound (0.16 g) was prepared from intermediate 1.13a (0.23 g, 1.14 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.27 g, 1.14 mmol, CAS: 819057-45-9), Pd(dppf)Cl2 (83 mg, 0.11 mmol), and sodium carbonate (0.30 g, 2.9 mmol) by heating at 80 °C for 5 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 2% MeOH in EtOAc). LCMS (Method 3): 1.07 min, 233.1 [M+H] +

[0671] Intermediate 1.17: 5-(4-amino-2-fluorophenyl)-1,4-dimethylpyridin-2(1H)-one

[0672] The title compound (0.19 g) was prepared from intermediate 1.12a (0.28 g, 1.4 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.33 g, 1.4 mmol, CAS: 819057-45-9), Pd(dppf)Cl2 (0.10 g, 0.14 mmol), and sodium carbonate (0.37 g, 3.5 mmol) by heating at 80 °C for 5 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography on silica gel (eluting with 2% MeOH in EtOAc). LCMS (Method 4): 0.49 min, 233.1 [M+H] +

[0673] Intermediate 1.18: 3-fluoro-4-(3-fluoro-5-methoxypyridin-4-yl)aniline

[0674] The title compound (0.26 g) was prepared from 4-bromo-3-fluoro-5-methoxypyridine (0.24 g, 1.1 mmol, CAS: 1256825-73-6), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.30 g, 1.3 mmol, CAS: 819057-45-9), Pd(dppf)Cl2 (83 mg, 0.11 mmol), and potassium carbonate (0.39 g, 2.9 mmol) by heating at 85 °C for 16 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 4): 0.69 min, 237.0 [M+H] +

[0675] Intermediate 1.20: 4-(3-methoxypyridin-4-yl)-3-methylaniline Intermediate 1.20a: N-(4-(3-methoxypyridin-4-yl)-3-methylphenyl)acetamide

[0676] The title compound (0.27 g) was prepared from N-(4-bromo-3-methyl-phenyl)acetamide (0.23 g, 0.99 mmol, CAS: 90914-81-1), (3-methoxy-4-pyridyl)boronic acid (0.15 g, 0.99 mmol, CAS: 1008506-24-8), Pd(dppf)Cl2 (0.81 g, 0.10 mmol), and sodium carbonate (0.31 g, 3.0 mmol) by heating at 80 °C for 3 h according to the procedure described for intermediate 1.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 2): 0.54 min, 257.1 [M+H] +

[0677] Intermediate 1.20: 4-(3-methoxypyridin-4-yl)-3-methylaniline

[0678] A solution of intermediate 1.20a (0.25 g, 0.98 mmol) in MeOH (15 mL) and sodium hydroxide (2 M aqueous solution; 2.5 mL, 4.9 mmol) were stirred at 80 °C for 4 h. The mixture was diluted with water and extracted into EtOAc. The combined organic matter was dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (130 mg), which was used without further purification. LCMS (Method 2): 0.56 min, 215.1 [M + H] +

[0679] Intermediate 1.21: 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)aniline

[0680] The title compound (0.53 g) was prepared from 4-bromo-1H-pyrrolo[2,3-b]pyridine (0.50 g, 2.5 mmol, CAS: 348640-06-2), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.61 g, 2.8 mmol, CAS: 214360-73-3), Pd(dppf)Cl2 (93 mg, 0.13 mmol), and sodium carbonate (0.81 g, 7.6 mmol) by heating at 80 °C for 2 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 66% EtOAc in heptane). LCMS (Method 2): 0.54 min, 210.1 [M+H] +

[0681] Intermediate 1.22: 4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline

[0682] Borate dimethyl sulfide complex (0.27 mL, 2.9 mmol) was added dropwise to a stirred solution of intermediate 1.21 (0.1 g, 0.48 mmol) in 2 mL of THF at room temperature under an argon atmosphere, and the mixture was stirred at 80 °C for 16 h in a sealed tube. The reaction was quenched at 0 °C with MeOH, then with water and ethanolamine, and then heated under reflux for 2 min. The mixture was extracted with EtOAc, and the combined organic matter was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to reversed-phase column chromatography in Biotage Isolera One. TM Purification (16 g C18 column, eluted with 25%–50% MeCN in 0.1 M NH₄HCO₃ buffer at pH 10) was performed to provide the title compound (35 mg). LCMS (Method 5): 1.05 min, 212.1 [M + H₂] +

[0683] Intermediate 1.23: 2-Fluoro-4-(3-methoxypyridin-4-yl)aniline

[0684] The title compound (0.16 g) was prepared from (3-methoxy-4-pyridyl)boronic acid (0.25 g, 1.6 mmol, CAS: 1008506-24-8), 2-fluoro-4-iodoaniline (0.39 g, 1.7 mmol, CAS: 29632-74-4), XPhos Pd G2 (76 mg, 0.10 mmol), and potassium phosphate (1.0 g, 4.9 mmol) according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in hexane). LCMS (Method 2): 0.59 min, 219.1 [M+H] +

[0685] Intermediate 1.24: 3-Fluoro-4-(3-methoxypyridin-4-yl)aniline

[0686] The title compound (0.15 g) was prepared from (3-methoxy-4-pyridyl)boronic acid (0.25 g, 1.6 mmol, CAS: 1008506-24-8), 3-fluoro-4-iodoaniline (0.39 g, 1.7 mmol, CAS: 656-66-6), XPhos Pd G2 (76 mg, 0.10 mmol), and potassium phosphate (1.0 g, 4.9 mmol) according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting with 60% EtOAc in hexane). LCMS (Method 2): 0.57 min, 219.1 [M+H] +

[0687] Intermediate 1.29: 5-(4-amino-2,6-difluorophenyl)-1,6-dimethylpyridin-2(1H)-one

[0688] Intermediate 1.29a: 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)aniline

[0689] 4,4,5,5-Tetramethyl-1,3,2-dioxane (2.3 mL, 16 mmol) was added dropwise to a solution of 4-bromo-3,5-difluoroaniline (1.1 g, 5.3 mmol, CAS: 203302-95-8), triethylamine (3.0 mL, 21 mmol), and XPhos Pd G2 (42 mg, 0.06 mmol) in degassed anhydrous toluene (33 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 4 h. The mixture was then passed through... Filter, wash with EtOAc, dilute with water and extract into EtOAc. Wash the combined organic matter with water and brine, dry to MgSO4, filter and concentrate under vacuum. Perform rapid column chromatography on Biotage Isolera One. TMPurification (120 g ZIP-coated silica column, eluted with 0-45% EtOAc in heptane) was performed to provide the title compound (0.86 g). LCMS (Method 3): 1.14 min, 254.0 [MH] -

[0690] Intermediate 1.29: 5-(4-amino-2,6-difluorophenyl)-1,6-dimethylpyridin-2(1H)-one

[0691] XPhos Pd G2 (20 mg, 0.02 mmol) was added to a solution of intermediate 1.13a (0.1 g, 0.49 mmol) and intermediate 1.29a (0.15 g, 0.59 mmol) in a mixture of degassed 1,4-dioxane (3 mL) and degassed potassium phosphate (2 M aqueous solution; 0.74 mL, 1.5 mmol) at room temperature and under argon atmosphere. The reaction mixture was heated to 45 °C and intermediate 1.29a (3 x 35 mg, 0.42 mmol) was added in portions over 3 h. The reaction mixture was then passed through... Filter and wash with EtOAc. Dilute the filtrate with water and extract the crude product into EtOAc. Wash the combined organic matter with water and brine, dry to MgSO4, filter and concentrate under vacuum, and extract the crude product by rapid column chromatography in Biotage IsoleraOne. TM Purification (45 g ZIP-coated silica column, eluted with 20%–100% EtOAc in heptane) to provide the title compound (0.10 g). LCMS (Method 3): 1.19 min, 251.0 [M+H) +

[0692] Intermediate 1.30: 3,5-Difluoro-4-(3-methoxypyridin-4-yl)aniline

[0693] The title compound (0.11 g) was prepared from (3-methoxy-4-pyridyl)boronic acid (0.17 g, 1.1 mmol, CAS: 1008506-24-8), 4-bromo-3,5-difluoroaniline (0.27 g, 1.3 mmol, CAS: 203302-95-8), XPhos Pd G2 (85 mg, 0.11 mmol), and potassium phosphate (2 M aqueous solution; 1.8 mL, 3.2 mmol) according to the procedure described for intermediate 1.29. The crude product was purified by rapid column chromatography (eluting in heptane with 40%–100% EtOAc). LCMS (Method 3): 1.47 min, 237.1 [M+H] +

[0694] Intermediate 1.31: 4-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)aniline hydrochloride

[0695] Intermediate 1.31a: (4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)tert-butyl carbamate hydrochloride

[0696] The title compound (0.27 g) was prepared from tert-butyl carbamate (0.44 g, 1.4 mmol, CAS: 330793-01-6) of (4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)carbamate (0.20 g, 1.1 mmol, CAS: 3398-16-1), XPhos Pd G2 (9 mg, 0.01 mmol), and potassium carbonate (1.8 M aqueous solution; 1.9 mL, 3.4 mmol) according to the procedure described for intermediate 1.3 and by microwave irradiation. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 20%-100% EtOAc in heptane. LCMS (Method 4): 0.84 min, 288.2 [M+H] +

[0697] Intermediate 1.31b: (4-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)tert-butyl carbamate

[0698] Bromotoluene (0.10 mL, 0.83 mmol) was added to a solution of intermediate 1.31a (0.27 g, 0.83 mmol) and potassium carbonate (0.29 g, 2.1 mmol) in acetone (20 mL), and the reaction was heated at 55 °C for 3 days. The solvent was concentrated under vacuum, and the crude product was analyzed by rapid column chromatography in Biotage Isolera One. TM Purification was performed (30 g ZIP-coated silica column, eluted with 30%–100% EtOAc in heptane) to give the title compound (0.11 g). LCMS (Method 4): 1.06 min, 378.3 [M + H) +

[0699] Intermediate 1.31: 4-(1-benzyl-3,5-dimethyl-1H-pyrazole-4-yl)aniline hydrochloride

[0700] A solution of intermediate 1.31b (0.11 g, 0.25 mmol) in HCl (3 M in 1,4-dioxane; 4.0 mL, 0.25 mmol) was stirred at room temperature for 2 h. The solvent was concentrated under vacuum to give the title compound (78 mg). The crude product was used without further purification. LCMS (Method 4): 0.82 min, 278.2 [M + H] +

[0701] Intermediate 1.34: 6-(4-amino-2-fluorophenyl)pyridazine-3(2H)-one

[0702] The title compound (0.13 g) was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.18 g, 0.77 mmol, CAS: 819057-45-9), 3-chloro-1H-pyridazin-6-one (0.1 g, 0.77 mmol, CAS: 19064-67-6), XPhos Pd G2 (12 mg, 0.02 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 1.28 mL, 2.3 mmol) according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (20%–100% EtOAc in heptane, followed by elution with 10% MeOH in DCM). LCMS (Method 4): 0.38 min, 206.2 [M+H] +

[0703] Intermediate 1.35: 4-(4-amino-2-fluorophenyl)pyridine-2(1H)-one

[0704] The title compound (0.29 g) was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.3 g, 1.3 mmol, CAS: 819057-45-9), 4-bromo-1H-pyridin-2-one (0.2 g, 1.2 mmol, CAS: 36953-37-4), Pd(dppf)Cl2 (84 mg, 0.11 mmol), and sodium carbonate (0.31 mg, 2.9 mmol) by heating at 80 °C for 4 h according to the procedure described for intermediate 1.6. The crude product was purified by rapid column chromatography (eluting with 5% MeOH in EtOAc). LCMS (Method 4): 0.39 min, 205.0 [M+H] +

[0705] Intermediate 1.37: 4-(2,5-dimethylpyrimidin-4-yl)aniline

[0706] The title compound (0.24 g) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.31 g, 1.4 mmol, CAS: 214360-73-3), 4-chloro-2,5-dimethylpyrimidine (0.2 g, 1.4 mmol, CAS: 75712-74-2), Pd(dppf)Cl2 (0.12 mg, 0.14 mmol), and sodium carbonate (0.45 g, 4.2 mmol) by heating at 80 °C for 4 h according to the procedure described for intermediate 1.6. The crude product was purified by rapid column chromatography (eluting with 40%–50% EtOAc in heptane). LCMS (Method 2): 0.49 min, 200.1 [M+H] +

[0707] Intermediate 1.40: 4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline

[0708] The title compound (0.25 g) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.28 g, 1.3 mmol, CAS: 214360-73-3), 4-chloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.2 g, 1.3 mmol, CAS: 16372-08-0), Pd(dppf)Cl2 (0.11 g, 0.13 mmol), and sodium carbonate (0.41 g, 3.9 mmol) by heating at 80 °C for 3 h according to the procedure described for intermediate 1.6. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 2): 0.40 min, 213.1 [M+H] +

[0709] Intermediate 1.41: 4-(imidazo[1,2-a]pyrimidin-3-yl)aniline

[0710] The title compound (0.21 g) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)aniline (0.33 g, 1.5 mmol, CAS: 214360-73-3), 3-bromoimidazolo[1,2-a]pyrimidine (0.3 g, 1.5 mmol, CAS: 6840-45-5), Pd(dppf)Cl2 (62 mg, 0.08 mmol), and sodium carbonate (1 M aqueous solution, 4.5 mL, 4.5 mmol) by heating at 60 °C for 2 h according to the procedure described for intermediate 1.6. The crude product was purified by rapid column chromatography (eluting with 5% MeOH in EtOAc). LCMS (Method 2): 0.39 min, 211.1 [M+H] +

[0711] Intermediate 1.42: (4-(4-aminophenyl)pyridin-3-yl)methanol hydrochloride

[0712] Intermediate 1.42a: N-[4-(3-formyl-4-pyridyl)phenyl]tert-butyl carbamate

[0713] The title compound (0.4 g) was prepared from 4-chloropyridin-3-carboxaldehyde (0.2 g, 1.4 mmol, CAS: 114077-82-6], N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]carbamate tert-butyl ester (0.45 g, 1.4 mmol), Pd(dppf)Cl2 (0.12 mg, 0.14 mmol), and sodium carbonate (0.45 g, 4.3 mmol) by heating at 80 °C for 4 h according to the procedure described for intermediate 1.6. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 2): 0.82 min, 299.1 [M+H] +

[0714] Intermediate 1.42b: N-[4-[3-(hydroxymethyl)-4-pyridyl]phenyl]tert-butyl carbamate

[0715] Sodium borohydride (51 mg, 1.4 mmol) was added to a solution of intermediate 1.42a (0.2 g, 0.67 mmol) in MeOH (3 mL), and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water and extracted into EtOAc. The combined organic compounds were dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (0.16 g), which was used without further purification. LCMS (Method 2): 0.70 min, 30 1.1 [M+H] +

[0716] Intermediate 1.42: (4-(4-aminophenyl)pyridin-3-yl)methanol hydrochloride

[0717] Intermediate 1.42b (0.16 g, 0.54 mmol) was mixed with HCl (3 M, 4 mL, 0.54 mmol in 1,4-dioxane) and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to provide the title compound (0.13 g), which was used without further purification. LCMS (Method 2): 0.40 min, 201.1 [M+H] +

[0718] Intermediate 1.44: 4-(6,7-dihydro-5H-cyclopentadien[b]pyridin-4-yl)aniline

[0719] The title compound (65 mg) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)aniline (0.18 g, 0.81 mmol, CAS: 214360-73-3), 4-chloro-6,7-dihydro-5H-cyclopentadieno[b]pyridine (0.13 g, 0.81 mmol, CAS: 54664-55-0), Pd(dppf)Cl2 (66 mg, 0.08 mmol), and sodium carbonate (0.26 g, 2.4 mmol) by heating at 80 °C for 5 h according to the procedure described for intermediate 1.6. The crude product was purified by rapid column chromatography (eluting in heptane with 50%–100% EtOAc). LCMS (Method 2): 0.62 min, 211.1 [M+H] +

[0720] Intermediate 1.47: 3-Methoxy-4-(3-Methoxypyridin-4-yl)aniline

[0721] The title compound (32 mg) was prepared from (3-methoxy-4-pyridyl)boronic acid (0.13 g, 0.82 mmol, CAS: 1008506-24-8), 4-bromo-3-methoxy-aniline (0.17 g, 0.82 mmol, CAS: 19056-40-7), Pd(dppf)Cl2 (66 mg, 0.08 mmol), and sodium carbonate (0.26 g, 2.5 mmol) by heating at 80 °C for 16 h according to the procedure described for intermediate 1.6. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 2): 0.52 min, 231.1 [M+H] +

[0722] Intermediate 1.48: 6-(4-amino-2-fluorophenyl)-2-methylpyridazine-3(2H)-one

[0723] The title compound (0.15 g) was prepared from (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.18 g, 0.77 mmol, CAS: 819057-45-9), 6-chloro-2-methylpyridazin-3-one (0.11 g, 0.77 mmol, CAS: 10071-38-2), XPhos Pd G2 (12 mg, 0.02 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 1.3 mL, 2.3 mmol) according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting in heptane with 50%–100% EtOAc). LCMS (Method 4): 0.48 min, 220.0 [M+H)+

[0724] Intermediate 1.51: 5-(4-aminophenyl)-1-methylpyridin-2(1H)-one

[0725] The title compound (0.18 g) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.26 g, 1.2 mmol, CAS: 214360-73-3), 5-bromo-1-methylpyridin-2-one (0.2 g, 1 mmol, CAS: 81971-39-3), Pd(dppf)Cl2 (87 mg, 0.11 mmol), and sodium carbonate (0.34 g, 3.2 mmol) according to the procedure described for intermediate 1.6. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30 g ZIP column with silica beads, in heptane with 60%–100% EtOAc, followed by elution with 7% MeOH in EtOAc. LCMS (Method 24): 0.64 min, 201.1 [M+H] +

[0726] Intermediate 1.52: 4-(4-aminophenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0727] 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 tripotassium phosphate solution (1.8 M aqueous solution, 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] +

[0728] Intermediate 1.53: 4-(4-amino-2-methoxyphenyl)pyridin-3-yl)methanol dihydrochloride

[0729] N-[4-[3-(hydroxymethyl)-4-pyridyl]-3-methoxy-phenyl]carbamate tert-butyl ester (0.1 mg, 0.17 mmol, CAS: 1622889-96-6) was dispersed in HCl (3 M, 2.3 mL, 6.9 mmol in CPME) under an argon atmosphere and stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to provide the title compound (52 mg), which was used without further purification. LCMS (Method 2): 0.42 min, 231.1 [M+H] +

[0730] Intermediate 1.54: 5-(4-amino-2-(trifluoromethyl)phenyl)-1,6-dimethylpyridin-2(1H)-one

[0731] The title compound (0.11 g) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3-(trifluoromethyl)aniline (0.18 g, 0.63 mmol, CAS: 1259285-61-4), 5-bromo-1,6-dimethyl-pyridin-2-one (0.13 mg, 0.63 mmol, CAS: 889865-54-7), XPhos Pd G2 (12 mg, 0.02 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 1 mL, 1.9 mmol) by heating at 100 °C for 1.5 h according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting with 100% EtOAc). LCMS (Method 3): 1.38 min, 283.1 [M+H] +

[0732] Intermediate 1.55: 3-chloro-4-(3,5-dimethylpyridin-4-yl)aniline

[0733] The title compound (96 mg) was prepared from 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.34 g, 1.3 mmol, CAS: 877160-63-9), 4-chloro-3,5-dimethylpyridine (0.17 g, 1.2 mmol, CAS: 143798-73-6), XPhos Pd G2 (95 mg, 0.12 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 1.8 mL, 3.6 mmol) according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using an 80g ZIP silica column, eluted with 5%-70% EtOAc in DCM. LCMS (Method 4): 0.74 min; 233.1 [M+H] +

[0734] Intermediate 1.56: 4-(2,5-dimethylpyridin-4-yl)-3-fluoroaniline

[0735] The title compound (0.29 g) was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.36 g, 1.5 mmol, CAS: 819057-45-9), 4-chloro-2,5-dimethylpyridine (0.22 g, 1.5 mmol, CAS: 22282-80-0), XPhos Pd G2 (12 mg, 0.02 mmol), and potassium carbonate solution (1.8 M aqueous solution, 2.5 mL, 4.5 mmol) according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting with 90% EtOAc in heptane). LCMS (Method 3): 1.64 min, 217.1 [M+H] +

[0736] Intermediate 1.57: 4-(2,3-dimethylpyridin-4-yl)-3-fluoroaniline

[0737] The title compound (0.18 g) was prepared from 4-bromo-2,3-dimethylpyridine (0.25 g, 1.3 mmol, CAS: 259807-91-5), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.32 g, 1.3 mmol, CAS: 819057-45-9), Pd(dppf)Cl2 (98 mg, 0.13 mmol), and potassium carbonate (0.46 g, 3.4 mmol) by heating at 80 °C for 16 h according to the procedure described for intermediate 1.1. The crude product was purified by rapid column chromatography (eluting with 90% EtOAc in heptane). LCMS (Method 4): 0.68 min, 217.1 [M+H] +

[0738] Intermediate 1.59: 4-(1-benzyl-3-methyl-1H-pyrazole-4-yl)-3-fluoroaniline

[0739] The title compound (0.5 g) was prepared from a mixture of 1-benzyl-4-bromo-5-methyl-1H-pyrazole (CAS: 916080-12-1) and 1-benzyl-4-bromo-3-methyl-1H-pyrazole (0.5 g, 2.2 mmol, CAS: 137968-32-2) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.5 g, 2.2 mmol, CAS: 819057-45-9), XPhos Pd G2 (35 mg, 0.04 mmol) and potassium phosphate (2 M aqueous solution; 3.7 mL, 6.6 mmol) according to the procedure described for intermediate 1.3, as a mixture of positional isomers of 4-(1-benzyl-5-methyl-1H-pyrazole-4-yl)-3-fluoroaniline. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g SiliCycle silica column, eluted with 50%-100% EtOAc in heptane. LCMS (Method 4): 0.83 min, 282.1 [M+H] +

[0740] Intermediate 1.60: 4-(3,5-dimethylisoxazol-4-yl)-3-fluoroaniline

[0741] The title compound (0.15 g) was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.77 g, 3.2 mmol, CAS: 819057-45-9), 4-bromo-3,5-dimethylisoxazole (0.38 mL, 3.2 mmol, CAS: 10558-25-5), XPhos Pd G2 (51 mg, 0.06 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 5.4 mL, 9.6 mmol) by heating at 100 °C for 2 h according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting with 30%–50% EtOAc in heptane) and reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 60g C18 column, eluted in water containing 0.1% formic acid and 0-50% MeCN in 0.1% formic acid. LCMS (Method 3): 1.52 min, 207.0 [M+H] +

[0742] Intermediate 1.62: 4-(1-benzyl-1H-pyrazole-4-yl)-3-fluoroaniline

[0743] The title compound (0.22 g) was prepared from 1-benzyl-4-bromopyrazole (0.4 g, 1.7 mmol, CAS: 50877-41-3) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.4 g, 1.7 mmol, CAS: 819057-45-9), XPhos Pd G2 (27 mg, 0.03 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 2.8 mL, 5.1 mmol) according to the procedure described for intermediate 1.3, heated at 90 °C for 1 h. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 12g ZIP silica column, eluted with 30%-100% EtOAc in heptane. LCMS (Method 4): 0.80 min, 268.1 [M+H] +

[0744] Intermediate 1.63: 5-(4-amino-2-fluorophenyl)-1-methylpyrimidin-2(1H)-one

[0745] The title compound (0.1 g) was prepared from 5-bromo-1-methylpyrimidin-2-one (0.25 g, 1.3 mmol, CAS: 14248-01-2) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.4 g, 1.7 mmol, CAS: 819057-45-9), XPhosPd G2 (20 mg, 0.03 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 2.1 mL, 3.9 mmol) by microwave irradiation at 120 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 45g ZIP silica column, eluted with 0-15% MeOH in DCM. LCMS (Method 21): 0.93 min, 220.3 [M+H] +

[0746] Intermediate 1.64: 5-(4-amino-2-fluorophenyl)pyrimidin-2(1H)-one

[0747] The title compound (0.26 g) was prepared from 5-bromo-1H-pyrimidin-2-one (0.4 g, 2.3 mmol, CAS: 38353-06-9) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.7 g, 3 mmol, CAS: 819057-45-9), XPhos Pd G2 (36 mg, 0.05 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 3.8 mL, 6.9 mmol) by microwave irradiation at 120 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using an 80g ZIP silica column, eluted with 0-20% MeOH in DCM. LCMS (Method 21): 0.66 min, 206.0 [M+H] +

[0748] Intermediate 1.66: 8-(4-amino-2-fluorophenyl)-1,6-naphthidium-5(6H)-one

[0749] The title compound (0.52 g) was prepared from 8-bromo-6H-1,6-naphthidin-5-one (0.11 g, 4.9 mmol, CAS: 155057-97-9) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.12 g, 5.1 mmol, CAS: 819057-45-9), XPhos Pd G2 (77 mg, 0.1 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 8.1 mL, 15 mmol) by heating at 100 °C for 2 h according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (33%–100% EtOAc in heptane, followed by elution in DCM with 10%–50% MeOH (containing 5% triethylamine)) and then milled in heptane. LCMS (Method 3): 0.88 min, 256.0 [M+H] +

[0750] Intermediate 1.67: 5-(4-amino-2-fluorophenyl)pyridazine-3(2H)-one

[0751] The title compound (0.24 g) was prepared from 4-iodo-1H-pyridazin-6-one (0.5 g, 2.3 mmol, CAS: 825633-94-1) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.59 g, 2.5 mmol, CAS: 819057-45-9), XPhos PdG2 (35 mg, 0.05 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 3.8 mL, 6.8 mmol) by heating at 100 °C for 20 h according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting with 0-10% MeOH in EtOAc) followed by grinding with heptane. LCMS (Method 13): 0.79 min, 206.0 [M+H] +

[0752] Intermediate 1.68: 3-fluoro-4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)aniline

[0753] The title compound (0.6 mg) was prepared from 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.5 mg, 2.2 mmol, CAS: 425380-37-6) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.52 g, 2.2 mmol, CAS: 819057-45-9), XPhos Pd G2 (0.17 g, 0.22 mmol), and potassium phosphate (1.8 M aqueous solution; 3.7 mL, 6.6 mmol) according to the procedure described for intermediate 1.3. The crude product was purified on silica gel by rapid column chromatography (eluting with 40% EtOAc in heptane). LCMS (Method 4): 0.69 min, 258.0 [M+H] +

[0754] Intermediate 1.69: 7-(4-amino-2-fluorophenyl)-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one

[0755] The title compound (0.26 g) was prepared from 7-bromo-3,5-dihydroimidazo[4,5-c]pyridin-4-one (0.42 g, 2.0 mmol, CAS: 163452-70-8) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.51 g, 2.2 mmol, CAS: 819057-45-9), XPhos Pd G2 (62 mg, 0.08 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 3.3 mL, 5.9 mmol) by microwave irradiation at 120 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting in DCM with 10%–20% MeOH (containing 5% Et3N)). LCMS (Method 21): 0.63 min, 245.0 [M+H] +

[0756] Intermediate 1.71: 6-(4-amino-2-fluorophenyl)-1-methylpyridin-2(1H)-one

[0757] The title compound (0.19 g) was prepared from 6-bromo-1-methylpyridin-2-one (0.19 g, 1.0 mmol, CAS: 163452-70-8) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.24 g, 1.0 mmol, CAS: 819057-45-9), XPhos Pd G2 (32 mg, 0.04 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 1.7 mL, 3.0 mmol) according to the procedure described for intermediate 1.3 by microwave irradiation at 85 °C for 1 h. The crude product was subjected to rapid column chromatography using Biotage Isolera One. TM Purification (25 g SiliCycle silica column, eluted with 40%-100% EtOAc in heptane). LCMS (Method 4): 0.49 min, 219.1 [M+H] +

[0758] Intermediate 1.72: 6'-amino-1,2-dimethyl-[3,3'-bipyridine]-6(1H)-one

[0759] The title compound (0.23 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), 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 solution, 1.9 mL, 3.3 mmol) according to the procedure described for intermediate 1.3 by microwave irradiation at 85 °C for 1 h. The crude product was subjected to reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 30g C18 column, eluting with 1%–40% MeCN / MeCN in H2O / 0.1% ammonia solution. LCMS (Method 4): 0.36 min, 216.1 [M+H] +

[0760] Intermediate 1.73: 3',5'-dimethyl-[3,4'-bipyridine]-6-amine

[0761] 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 solution, 1.9 mL, 3.4 mmol) by microwave irradiation at 85 °C for 2 h according to the procedure described for intermediate 1.3. The crude product was subjected to reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 30g C18 column, eluting with 10%-70% MeCN / MeCN in H2O / 0.1% ammonia solution. LCMS (Method 4): 0.49 min, 200.1 [M+H] +

[0762] Intermediate 1.74: 4-(1-benzyl-5-methyl-1H-pyrazole-4-yl)aniline

[0763] From 1-benzyl-4-bromo-5-methyl-1H-pyrazole (CAS: 916080-12-1) and 1-benzyl-4-bromo-3-methyl-1H-pyrazole (0.54 g, 2.2 mmol, CAS: 137968-32-2) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.57 g, 2.6 mmol, CAS: 214360-73-3), XPhos Pd The title compound (0.57 g) was prepared by microwave irradiation at 85 °C for 1 h, according to the procedure described for intermediate 1.3, from a mixture of G2 (34 mg, 0.04 mmol) and tripotassium phosphate solution (1.8 M aqueous solution, 3.6 mL, 6.5 mmol), as a mixture of positional isomers of 4-(1-benzyl-3-methyl-1H-pyrazol-4-yl)aniline. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g SiliCycle silica column, eluted with 30%-100% EtOAc in heptane. LCMS (Method 4): 0.75 min, 264.1 [M+H] + , 0.77 min, 264.1 [M+H] +

[0764] Intermediate 1.75: 4-(4-amino-2-fluorophenyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridine- 7-keto

[0765] The title compound (0.14 g) was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.32 g, 1.4 mmol, CAS: 819057-45-9), 4-bromo-6-methyl-1H-pyrazolo[3,4-c]pyridin-7-one (0.28 g, 1.3 mmol, CAS: 1446236-51-6), XPhos Pd G2 (48 mg, 0.06 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 2.1 mL, 3.7 mmol) according to the procedure described for intermediate 1.3 by microwave irradiation at 120 °C for 1.5 h. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 40g ZIP silica column, eluted with 25%-100% EtOAc in heptane. LCMS (Method 3): 0.98 min, 259.1 [M+H] +

[0766] Intermediate 1.76: 4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)aniline

[0767] The title compound (0.21 g) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)aniline (0.19 g, 0.88 mmol, CAS: 214360-73-3) and 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.2 g, 0.88 mmol, CAS: 425380-37-6), XPhos Pd G2 (14 mg, 0.02 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 1.5 mL, 2.6 mmol) according to the procedure described for intermediate 1.3 by microwave irradiation at 100 °C for 30 min. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g ZIP silica column, eluted with 50%-100% EtOAc in heptane. LCMS (Method 4): 0.61 min, 240.1 [M+H] +

[0768] Intermediate 1.77: 6-(4-amino-2-fluorophenyl)-1-benzylpyridine-2(1H)-one

[0769] Intermediate 1.77a: 1-Benzyl-6-chloro-pyridin-2-one

[0770] Bromotoluene (0.18 mL, 1.5 mmol, CAS: 100-39-0) was added to a solution of 6-chloropyridine-2-phenol (0.2 g, 1.5 mmol, CAS: 16879-02-0) and potassium carbonate (0.53 g, 3.9 mmol) in acetone (15 mL), and the reaction was heated to 55 °C for 24 h. The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was analyzed by rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25 g SiliCycle silica column, eluted with 40%–100% EtOAc in heptane to give the title compound (0.2 g). 1 ¹H NMR (400 MHz, DMSO-d6) δ: 7.74 (t, 1H), 7.43 (d, 2H), 7.33 (td, 3H), 7.07 (d, 1H), 6.86 (d, 1H), 5.28 (s, 2H). Intermediate 1.77: 6-(4-amino-2-fluorophenyl)-1-benzylpyridine-2(1H)-one

[0771] The title compound (0.2 g) was prepared from intermediate 1.77a (0.2 g, 0.93 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.2 g, 0.93 mmol, CAS: 819057-45-9), XPhos Pd G2 (15 mg, 0.02 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 1.6 mL, 2.8 mmol) by microwave irradiation at 85 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g SiliCycle silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 1.06 min, 295.1 [M+H] +

[0772] Intermediate 1.78: 2-(4-(4-aminophenyl)pyridin-3-yl)-1-(pyrrolidone-1-yl)ethyl-1-one

[0773] Intermediate 1.78a: 2-(4-chloro-3-pyridinyl)-1-pyrrolidine-1-yl-ethyl ketone

[0774] Add 2-(4-chloro-3-pyridyl)acetic acid hydrochloride (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 2-(4-chloro-3-pyridyl)acetic acid hydrochloride (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) in 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 a saturated aqueous solution of 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]. +

[0775] Intermediate 1.78: 2-(4-(4-aminophenyl)pyridin-3-yl)-1-(pyrrolidone-1-yl)ethyl-1-one

[0776] The title compound (0.2 g) was prepared from intermediate 1.78a (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 Pd G2 (123 mg, 0.15 mmol) and potassium carbonate solution (2 M aqueous solution, 3.1 mL, 6.3 mmol) by heating at 100 °C for 2 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 40g SiliCycle silica column, eluted with 0-20% MeOH in EtOAc. LCMS (Method 22): 0.66 min, 282.1 [M+H] +

[0777] Intermediate 1.80: 6-(4-amino-2-fluorophenyl)pyrimidin-4(3H)-one

[0778] The title compound (0.2 g) was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (1.1 g, 4.6 mmol, CAS: 819057-45-9) and 4-chloro-1H-pyrimidin-6-one (0.5 g, 3.8 mmol, CAS: 4765-77-9), XPhos Pd G2 (90 mg, 0.11 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 6.4 mL, 11.5 mmol) by microwave irradiation at 85 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting in EtOAc with 0–10% MeOH). LCMS (Method 23): 0.73 min, 206 [M+H] +

[0779] Intermediate 1.84: 4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)aniline

[0780] 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 (0.24 mg, 0.31 mmol), and tripotassium phosphate (4.2 g, 31 mmol) by microwave irradiation at 80 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TMPurification (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).

[0781] Intermediate 1.87: 4-(4-aminophenyl)pyridine-2(1H)-one

[0782] The title compound (80 mg) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (0.28 g, 1.3 mmol, CAS: 214360-73-3), 4-bromo-1H-pyridin-2-one (0.2 g, 1.2 mmol, CAS: 36953-37-4), Pd(dppf)Cl2 (84 mg, 0.11 mmol), and sodium carbonate (0.30 g, 2.9 mmol) by heating at 80 °C for 2 h according to the procedure described for intermediate 1.6. The crude product was purified by rapid column chromatography (eluting with 5% MeOH in EtOAc, then eluting with 5% MeOH in DCM). LCMS (Method 4): 0.36 min, 187.1 [M+H] +

[0783] Intermediate 1.88: 4-(imidazo[1,2-a]pyridin-5-yl)aniline

[0784] The title compound (61 mg) was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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), XPhos Pd G2 (20 mg, 0.03 mmol), and tripotassium phosphate solution (1.8 M aqueous solution, 2.1 mL, 3.8 mmol) by microwave irradiation at 85 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g SiliCycle silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 0.56 min, 210.1 [M+H] +

[0785] Intermediate 1.99: 5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-amine

[0786] Intermediate 1.99a: 4-bromo-1-[(4-methoxyphenyl)methyl]-3,5-dimethylpyrazole

[0787] 1-(bromomethyl)-4-methoxybenzene (0.57 g, 2.9 mmol, CAS: 3398-16-1) was added 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). The mixture was heated at 55 °C for 18 h. The reaction mixture was concentrated under vacuum. The residue was partitioned between EtOAc and brine. The organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was analyzed by rapid column chromatography in Biotage Isolera One. TM Purification (12 g silica column, eluted with 0-30% EtOAc in heptane) was performed 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).

[0788] Intermediate 1.99b: N-[5-[1-[(4-methoxyphenyl)methyl]-3,5-dimethyl-pyrazol-4-yl]-2-pyridyl]tert-butyl carbamate

[0789] The title compound (0.61 g) was prepared from intermediate 1.99a (0.49 g, 1.7 mmol), 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 solution, 2.8 mL, 5.0 mmol) under reflux for 19 h according to the procedure described for intermediate 1.3. The crude product was purified by rapid column chromatography (eluting in heptane with 0-80% EtOAc). LCMS (Method 14): 1.88 min, 409.2 [M+H] +

[0790] Intermediate 1.99: 5-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-amine

[0791] HCl (4 M in 1,4-dioxane; 0.54 mL, 2.2 mmol) was added to a solution of intermediate 1.99b (0.6 g, 1.5 mmol) in 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature for 20 h, then another portion of HCl (4 M in 1,4-dioxane; 2.4 mL, 9.6 mmol) was added and the mixture was stirred at room temperature for another 2.5 h. The reaction mixture was concentrated under vacuum and the residue was dissolved in DCM and washed with saturated aqueous NaHCO3 solution 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).

[0792] Intermediate 1.104: tert-butyl 4-(4-aminophenyl)-3,5-dimethyl-1H-pyrazole-1-carboxylate

[0793] The title compound (70 mg) was prepared from tert-butyl 4-bromo-3,5-dimethylpyrazol-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, CAS: 214360-73-3), potassium carbonate (0.4 g, 2.9 mmol), and Xphos Pd G2 (57 mg, 0.07 mmol) by heating at 85 °C for 1 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification (40g silica 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).

[0794] Intermediate 1.106: 5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine-2-amine

[0795] 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 solution, 8.3 mL, 15 mmol) under reflux for 20 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 40 g silica column, eluted with 0-10% MeOH in DCM. LCMS (Method 14): 1.06 min, 189.2 [M+H] +

[0796] Intermediate 1.125: 5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridine-2-amine

[0797] 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 was heated at 120 °C for 20 h. The reaction mixture 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 analyzed by rapid column chromatography in Biotage IsoleraOne. TM Purification (100 g silica column, 0-100% EtOAc in heptane) was performed to provide the title compound (0.3 g). 1 HNMR(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).

[0798] Intermediate 1.125a: 2-chloro-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridine

[0799] 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 solution 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 analyzed by rapid column chromatography in Biotage Isolera One. TM Purification (340 g silica column, 0-70% EtOAc in heptane) was performed to provide the title compound (1.6 g). 1 H NMR (400MHz, CDCl3) δ: 8.39 (dd, 1H), 7.63 (dd, 1H), 7.51 (dd, 1H), 3.97 (s, 3H), 2.33 (s, 3H).

[0800] Intermediate 1.138: 6-(3,5-dimethylisoxazol-4-yl)pyridine-3-amine

[0801] 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 according to the procedure described for intermediate 1.6. The crude product was subjected to reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 50g C18 column, eluted with 5%-100% MeCN (containing 0.005M NH4OH) in aqueous buffer. LCMS (Method 14): 1.21 min, 190.2 [M+H] +

[0802] Intermediate 1.140: 5-(5-methylpyrimidin-4-yl)pyridin-2-amine

[0803] 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 1.6. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification (using a 20g silica column, eluting with 0-7% MeOH in DCM) and by rapid column chromatography in Biotage IsoleraOne TM Purification (4g silica 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).

[0804] Intermediate 1.142: 5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridine-2-amine

[0805] 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 rapid column chromatography in Biotage Isolera One. TM Purification (40 g silica column, eluted with 0-100% EtOAc in heptane). LCMS (Method 14): 1.18 min, 220.2 [M+H) +

[0806] Intermediate 1.143: 2-chloro-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine

[0807] Intermediate 1.143a: 5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-2-methoxypyridine

[0808] 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 for 30 min, followed by the addition of 6-methoxypyridine-3-amine (0.15 g, 12.1 mmol, CAS: 6628-77-9), acetic acid (7.5 mL), and acetonitrile (2.5 mL). The reaction was heated to 120 °C for 20 h, and then concentrated under vacuum. The crude product was ground with diethyl ether to provide the title compound (0.72 g). LCMS (Method 14): 1.24 min, 205.2 [M+H] +

[0809] Intermediate 1.143b: 5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2(1H)-one

[0810] HBr (48% aqueous solution; 7.5 mL, 66 mmol) was added to a solution of intermediate 1.143a (0.68 g, 3.3 mmol) in acetic acid (7.7 mL). The reaction mixture was heated to 80 °C for 6 h and then concentrated under vacuum. The residue was azeotropically treated with a mixture of EtOAc and heptane (1:1). The crude product was milled with diethyl ether to provide 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).

[0811] Intermediate 1.143: 2-chloro-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridine

[0812] Phosphorus oxychloride (2.5 mL, 26 mmol) was added to intermediate 1.143b (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 MeOH / H2O (1:1) mixture was slowly added. The crude product was analyzed by rapid column chromatography in Biotage Isolera One. TM Purification (20 g silica column, eluted with 0–10% MeOH in DCM) to provide the title compound (0.41 g). LCMS (Method 14): 1.22 min, 209.2 [M + H2] +

[0813] Intermediate 1.145: 6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridine-3-amine

[0814] 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 PdG2 (87 mg, 0.11 mmol), and tripotassium phosphate (2.5 M aqueous solution; 6.6 mL, 16.6 mmol) according to the procedure described for intermediate 1.3 and heated under reflux for 24 h. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 20 g silica column, eluted with 10% MeOH in DCM. LCMS (Method 14): 1.22 min, 189.2 [M+H] +

[0815] Intermediate 1.146: 4-Methyl-5-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine

[0816] 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 1.6. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 12 g silica column, eluted with 0-10% MeOH in DCM. LCMS (Method 19): 0.52 min, 189.2 [M + H₂] +

[0817] Intermediate 1.147: 2-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidin-5-amine

[0818] 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 PdG2 (73 mg, 0.09 mmol), and tripotassium phosphate (2.5 M aqueous solution; 5.6 mL, 16.6 mmol) under reflux for 24 h according to the procedure described for intermediate 1.3. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 20 g silica column, eluted with 10% MeOH in DCM. LCMS (Method 19): 1.25 min, 190.2 [M + H₂] +

[0819] Intermediate 1.150: 5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridine-2-amine Intermediate 1.150a: 4-bromo-5-(methoxymethyl)-3-methylisoxazole

[0820] 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 under argon for 20 h. 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).

[0821] Intermediate 1.150: 5-(5-(methoxymethyl)-3-methylisoxazol-4-yl)pyridine-2-amine

[0822] The title compound (0.22 g) was prepared from intermediate 1.150a (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 rapid column chromatography in Biotage Isolera One. TM Purification (40g silica column, eluted with 0-100% EtOAc in heptane). 1H 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)

[0823] Intermediate 1.151: 3'-methoxy-2'-methyl-[3,4'-bipyridine]-6-amine

[0824] 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 1.6. The crude product was subjected to rapid column chromatography in Biotage IsoleraOne. TM Purification was performed using a 10g silica column, eluted with 0-5% MeOH in DCM. 1 HNMR(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).

[0825] Intermediate 1.152: 2',3'-dimethyl-[3,4'-bipyridine]-6-amine

[0826] 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 1.6. The crude product was subjected to rapid column chromatography in Biotage IsoleraOne. TM Purification was performed using a 10g silica column, eluted with 0-5% MeOH in DCM. 1H 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).

[0827] Intermediate 1.153: 2',5'-dimethyl-[3,4'-bipyridine]-6-amine

[0828] 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 1.6. The crude product was subjected to rapid column chromatography in Biotage IsoleraOne. TM Purification on a 10g silica column, eluted with 0-5% MeOH in DCM, and on an SCX column (5g, washed with MeOH and eluted with 2M methanol-ammonia). 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).

[0829] Intermediate 1.157: 2-chloro-5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine Intermediate 1.157a: 1-Ethyl-4-methyl-1H-1,2,3-triazole

[0830] A solution of 1,1-dimethoxypropane-2-one (1 g, 8.5 mmol, CAS: 6342-56-9) and 4-methylbenzenesulfonylhydrazine (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. 1H NMR (400MHz, CDCl3) δ: 7.30 (s, 1H), 4.38 (qt, 2H), 2.38–2.33 (m, 3H), 1.54 (tt, 3H).

[0831] Intermediate 1.157: 2-chloro-5-(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine

[0832] From intermediate 1.157a (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) according to the procedure described for intermediate 1.125a. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 10 g silica column, eluting with 0-70% EtOAc in heptane, and by reversed-phase preparative HPLC (Method 2). LCMS (Method 14): 1.55 min, 223.6 [M+H] +

[0833] Intermediate 1.158: 4-(5-chloropyrazin-2-yl)-3,5-dimethylisoxazole

[0834] The title compound (0.52 g) was prepared from 2-bromo-5-chloropyrazine (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 1.6. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 12 g silica column, eluted with 0-10% MeOH in DCM. LCMS (Method 19): 2.09 min, 210.2 [M+H] +

[0835] Intermediate 1.161: 2-chloro-5-(1-cyclopropyl-4-methyl-1H-1,2,3-triazol-5-yl)pyridine

[0836] From 1-cyclopropyl-4-methyltriazole (1.1g, 8.8mmol, CAS: 2370890-05-2), 5-bromo-2-chloropyridine (0.85g, 4.4mmol, 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) according to the procedure described for intermediate 1.125a. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 10 g silica column, eluting with 0-70% EtOAc in heptane, and by reversed-phase preparative HPLC (Method 2). LCMS (Method 14): 1.55 min, 223.6 [M+H] +

[0837] Intermediate 1.162: 5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridine-2-amine

[0838] 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 1.6. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25 g silica column, eluted with 0–2% MeOH in DCM. LCMS (Method 14): 1.26 min, 208.2 [M + H₂] +

[0839] Intermediate 1.165: 2-chloro-5-(1,4-dimethyl-1H-pyrazol-5-yl)pyrimidine

[0840] 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 1.125. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 12 g silica column, eluted with 0–2% MeOH in DCM. LCMS (Method 14): 1.51 min, 209.2 [M + H₂] +

[0841] Intermediate 1.173: 5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridine-2-amine Intermediate 1.173a: 1-Cyclopropyl-2,2-Diethoxy-ethyl ketone

[0842] 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 atmosphere. 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 a saturated aqueous solution of 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).

[0843] Intermediate 1.173b: 4-Cyclopropyl-1-methyl-1H-1,2,3-triazole

[0844] 4-Methylbenzenesulfonyl hydrazine (2.8 g, 15.1 mmol, CAS: 1576-35-8) was added to a stirred solution of intermediate 1.173a (2 g, 11.6 mmol) in MeOH (25 mL), and the mixture was stirred at room temperature for 1 h. Another portion of 4-methylbenzenesulfonyl hydrazine (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 and then heated 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 rapid column chromatography in Biotage Isolera One. TM Purification (40 g silica column, 2%-65% EtOAc in heptane) was performed to provide the title product (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).

[0845] Intermediate 1.173: 5-(4-cyclopropyl-1-methyl-1H-1,2,3-triazol-5-yl)pyridine-2-amine

[0846] 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 1.173b (0.3 g, 2.4 mmol) in toluene (6.1 mL), and 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) were 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 compounds were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then subjected to rapid column chromatography in Biotage Isolera One. TMPurification (12 g silica column, 2%-80% EtOAc in heptane) was performed 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).

[0847] Intermediate 1.174: 5-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyridin-2-amine

[0848] 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 PdG2 (0.25 g, 0.32 mmol), and tripotassium phosphate (0.5 M aqueous solution; 25 mL, 13 mmol) according to the procedure described for intermediate 1.3 and heated to 60 °C for 18 h. 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).

[0849] Intermediate 1.179: 6-(1,4-dimethyl-1H-pyrazol-5-yl)-5-fluoropyridine-3-amine

[0850] 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) according to the procedure described for intermediate 1.6 and heated at 120 °C for 1 h by microwave irradiation. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification (20g silica column, eluted with 20%-100% EtOAc in heptane). 1HNMR (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).

[0851] Intermediate 1.190: 2-(5-(6-chloropyridin-3-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-N,N-dimethyl Acetamide

[0852] Intermediate 1.190a: N,N-dimethyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)acetamide

[0853] 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 was stirred at room temperature for 20 h, then concentrated under vacuum. The residue was diluted with DCM and washed with a saturated aqueous solution of 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 analyzed by rapid column chromatography in Biotage Isolera One. TM Purification (40 g silica column, eluted with 0–10% MeOH in DCM) was performed to provide the title compound (0.7 g). LCMS (Method 14): 1.01 min, 169.2 [M + H₂] +

[0854] Intermediate 1.190: 2-(5-(6-chloropyridin-3-yl)-4-methyl-1H-1,2,3-triazol-1-yl)-N,N-dimethylacetamide

[0855] A solution of intermediate 1.190a (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 a saturated aqueous NH4Cl solution. 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 analyzed by rapid column chromatography in Biotage Isolera One. TMPurification (20 g silica column, 0-100% EtOAc in heptane, then 0-10% MeOH in DCM) was performed 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).

[0856] Intermediate 1.193: 5-(6-aminopyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxynitrile

[0857] 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) according to the procedure described for intermediate 1.6 and heated at 120 °C for 1 h by microwave irradiation. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 20 g silica column, eluted with 0-100% EtOAc in heptane, followed by 0-10% MeOH in DCM. LCMS (Method 14): 0.78 min, 200.2 [M + H₂] +

[0858] Intermediate 1.195: 5-(1,3,4-trimethyl-1H-pyrazol-5-yl)pyridine-2-amine

[0859] 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) by microwave irradiation at 110 °C for 6 min. 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 by microwave irradiation at 110 °C for 45 min. The 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] +

[0860] Intermediate 1.196: 5-(3,5-dimethylisothiazo-4-yl)pyridine-2-amine

[0861] The title compound (0.14 g) was prepared from 4-iodo-3,5-dimethylisothiazol (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 rapid column chromatography in Biotage Isolera One. TM Purification (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).

[0862] Intermediate 1.207: 6-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 4-yl)pyridine-3-amine

[0863] 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 organics were passed through a phase separator and concentrated under vacuum. The crude product was subjected to rapid column chromatography at Teledyne ISCO. Purification (12 g silica column, 0-100% elution in isohexane 3:1 EtOAc:EtOH) yielded the title compound (0.21 g) as a brown oil. LCMS (Method 28): 1.42 min, 319.5 [M+H] +

[0864] Intermediate 1.214: 6'-amino-1,2,4-trimethyl-[3,3'-bipyridine]-6(1H)-one

[0865] 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 1.207. The crude product was subjected to rapid column chromatography at Teledyne ISCO. Purification was performed using a 12 g silica column, eluted with 0-10% MeOH in DCM. LCMS (Method 29): 0.44 min, 230.2 [M+H] +

[0866] Intermediate 1.216: 5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridine-2-amine

[0867] 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 1.207. The crude product was subjected to rapid column chromatography at Teledyne ISCO. Purification was performed using a 12 g silica column, eluted with 0-10% MeOH in DCM. LCMS (Method 26): 0.53 min, 203.2 [M+H] +

[0868] Intermediate 1.219: 5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-amine

[0869] 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 rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 50 g silica 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 methanol-ammonia). LCMS (Method 14): 1.18 min, 243.2 [M+H] +

[0870] Intermediate 2.1: (S)-(1-((4-(2,3-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenyl tert-butyl propyl-2-yl)carbamate

[0871] At room temperature, triethylamine (0.16 mL, 1.2 mmol) was added to a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.20 g, 0.59 mmol, CAS: 138662-63-2) and intermediate 1.1 (0.12 g, 0.59 mmol) in EtOAc (5 mL). (50% w / w solution in EtOAc; 1.1 mL, 1.8 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted into EtOAc. The combined organic matter was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting in heptane with 75%–100% EtOAc) to provide the title compound (0.15 g). LCMS (Method 2): 1.02 min, 522.3 [M+H) +

[0872] Intermediate 1.219: 5-(1-methyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-amine

[0873] 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 rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 50 g silica 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 methanol-ammonia). LCMS (Method 14): 1.18 min, 243.2 [M+H] +

[0874] Intermediate 2.2: (S)-(1-((4-(3-chloropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylprop-2- tert-butyl carbamate

[0875] From intermediate 1,2 (0.18 g, 0.89 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.18 g, 0.89 mmol, CAS: 138662-63-2), The title compound (0.48 g) was prepared from a 50% w / w solution in EtOAc (1.7 mL, 2.7 mmol) and triethylamine (0.31 mL, 2.22 mmol) according to the procedure described for intermediate 2.1 and used without further purification. LCMS (Method 2): 1.02 min, 528.2 [M+H] +

[0876] Intermediate 2.3: (S)-(1-((4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenyl propyl-2-yl) tert-butyl carbamate

[0877] From intermediate 1.3 (0.25 g, 1.3 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.43 g, 1.25 mmol, CAS: 138662-63-2), The title compound (0.57 g) was prepared by the procedure described for intermediate 2.1 using 50% w / w solution in EtOAc (2.4 mL, 3.8 mmol) and triethylamine (0.35 mL, 2.5 mmol). The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 2): 0.98 min, 524.3 [M+H). +

[0878] Intermediate 2,4: (S)-(1-((4-(3-methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan- 2-yl)tert-butyl carbamate

[0879] From intermediate 1,4 (61 mg, 0.33 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.11 g, 0.82 mmol, CAS: 138662-63-2), The title compound (0.21 g) was prepared from a 50% w / w solution in EtOAc (0.21 mL, 0.33 mmol) and triethylamine (0.11 mL, 0.82 mmol) according to the procedure described for intermediate 2.1 and used without further purification. LCMS (Method 2): 1.00 min, 508.3 [M+H] +

[0880] Intermediate 2.5: (S)-(1-oxo-3,3-diphenyl-1-((4-(3-(trifluoromethyl)pyridin-4-yl)phenyl)amino 2-propyl-2-yl)tert-butyl carbamate

[0881] From intermediate 1.5 (75 mg, 0.31 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.11 g, 0.31 mmol, CAS: 138662-63-2), The title compound (0.16 g) was prepared from a 50% w / w solution in EtOAc (0.6 mL, 0.94 mmol) and triethylamine (0.09 mL, 0.63 mmol) according to the procedure described for intermediate 2.1 and used without further purification. LCMS (Method 2): 1.06 min, 562.3 [M+H] +

[0882] Intermediate 2.6: (S)-(1-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenyl tert-butyl propyl-2-yl)carbamate

[0883] From intermediate 1,6 (0.15 g, 0.76 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.26 g, 0.76 mmol, CAS: 138662-63-2), The title compound (0.27 g) was prepared by the procedure described for intermediate 2.1 using 50% w / w solution in EtOAc (1.4 mL, 2.3 mmol) and triethylamine (0.32 mL, 2.27 mmol). The crude product was purified by rapid column chromatography (eluting in heptane with 60%–70% EtOAc). LCMS (Method 3): 2.72 min, 522.3 [M+H). +

[0884] Intermediate 2.7: (S)-(1-((4-(3-(methylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-di tert-butyl phenylprop-2-yl)carbamate

[0885] From intermediate 1.7 (0.14 g, 0.35 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.12 g, 0.35 mmol, CAS: 138662-63-2), The title compound (0.16 g) was prepared by reacting triethylamine (0.15 mL, 1.05 mmol) with a 50% w / w solution in EtOAc (1.3 mL, 1.1 mmol) according to the procedure described for intermediate 2.1, wherein the reagents were added at 0 °C and the mixture was stirred at room temperature for 3 h. The crude product was analyzed by reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 30g C18 column, eluted with 30%-80% MeCN in 0.1M NH4HCO3 buffer at pH 10. LCMS (Method 2): 0.96 min, 523.3 [M+H2O] +

[0886] Intermediate 2.8: (S)-(1-((4-(3-(dimethylamino)pyridin-4-yl)phenyl)amino)-1-oxo-3,3- Diphenylpropyl-2-yl)tert-butyl carbamate

[0887] From intermediate 1,8 (75 mg, 0.35 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.13 g, 0.37 mmol, CAS: 138662-63-2), The title compound (0.14 g) was prepared by reacting triethylamine (0.17 mL, 1.23 mmol) with a 50% w / w solution in EtOAc (1.3 mL, 1.1 mmol) according to the procedure described for intermediate 2.1, wherein the reagents were added at 0 °C and the mixture was stirred at room temperature for 1.5 h. The crude product was analyzed by reversed-phase column chromatography in Biotage Isolera One.TM Purification was performed using a 30g C18 column, eluted with 30%-80% MeCN in 0.1M NH4HCO3 buffer at pH 10. LCMS (Method 2): 1.02 min, 537.3 [M+H2O] +

[0888] Intermediate 2.9: (S)-(1-((4-(3,5-dimethoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3-di tert-butyl phenylprop-2-yl)carbamate

[0889] From intermediate 1.9 (0.10 g, 0.44 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.15 g, 0.44 mmol, CAS: 138662-63-2), The title compound (0.16 g) was prepared by reacting triethylamine (0.21 mL, 1.54 mmol) with a 50% w / w solution in EtOAc (50% w / w solution; 0.84 mL, 1.3 mmol) according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 5% MeOH in DCM). LCMS (Method 2): 0.97 min, 554.3 [M+H] +

[0890] Intermediate 2.10: (S)-(1-((4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo-3,3- Diphenylpropyl-2-yl)tert-butyl carbamate

[0891] From intermediate 1.10 (90 mg, 0.41 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.14 g, 0.41 mmol, CAS: 138662-63-2), The title compound (98 mg) was prepared by reacting triethylamine (0.2 mL, 1.4 mmol) with a 50% w / w solution in EtOAc (50% w / w solution; 0.79 mL, 1.2 mmol) according to the procedure described for intermediate 2.1, wherein the reagents were added at 0 °C and the mixture was stirred at room temperature for 2 h. The crude product was purified by rapid column chromatography (eluting with 40% EtOAc in hexane). LCMS (Method 2): 1.00 min, 542.3 [M+H] +

[0892] Intermediate 2.11: (S)-(1-((4-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1- 3,3-diphenylprop-2-yl) tert-butyl carbamate

[0893] From intermediate 1.11 (0.12 g, 0.57 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.20 g, 0.57 mmol, CAS: 138662-63-2), The title compound (0.20 g) was prepared by the procedure described for intermediate 2.1 using 50% w / w solution in EtOAc (1.1 mL, 1.7 mmol) and triethylamine (0.28 mL, 2.0 mmol). The crude product was purified by rapid column chromatography (eluting with 1% MeOH in EtOAc). LCMS (Method 2): 0.86 min, 524.3 [M+H]. +

[0894] Intermediate 2.12: (S)-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino tert-butyl carbamate (1-(2 ...

[0895] From intermediate 1.12 (0.11 g, 0.53 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.18 g, 0.53 mmol, CAS: 138662-63-2), The title compound (0.28 g) was prepared from a 50% w / w solution in EtOAc (1.0 mL, 1.6 mmol) and triethylamine (0.18 mL, 1.32 mmol) according to the procedure described for intermediate 2.1 and used without further purification. LCMS (Method 4): 0.91 min, 538.3 [M+H] +

[0896] Intermediate 2.13: (S)-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino tert-butyl carbamate (1-(2 ...

[0897] From intermediate 1.13 (0.15 g, 0.70 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.24 g, 0.70 mmol, CAS: 138662-63-2), The title compound (0.29 g) was prepared by reacting triethylamine (0.24 mL, 1.75 mmol) with a 50% w / w solution in EtOAc (1.3 mL, 2.1 mmol) according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane, followed by elution with 5% MeOH in EtOAc. LCMS (Method 4): 0.94 min, 538.3 [M+H] +

[0898] Intermediate 2.14: (S)-(1-((4-(3,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3, 3-Diphenylprop-2-yl)tert-butyl carbamate

[0899] From intermediate 1.14 (0.10 g, 0.44 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.15 g, 0.44 mmol, CAS: 138662-63-2), The title compound (0.11 g) was prepared by reacting triethylamine (0.18 mL, 1.3 mmol) with a 50% w / w solution in EtOAc (50% w / w solution; 0.84 mL, 1.3 mmol) according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 10g silica column, eluting with 20%-80% EtOAc in heptane. LCMS (Method 4): 1.04 min, 540.3 [M+H] +

[0900] Intermediate 2.15: (S)-(1-((3-fluoro-4-(3-methylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-di tert-butyl phenylprop-2-yl)carbamate

[0901] From intermediate 1.15 (0.16 g, 0.79 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.27 g, 0.79 mmol, CAS: 138662-63-2), The title compound (0.20 g) was prepared by the procedure described for intermediate 2.1 using 50% w / w solution in EtOAc (1.5 mL, 2.4 mmol) and triethylamine (0.33 mL, 2.37 mmol). The crude product was purified by rapid column chromatography (eluting with 70% EtOAc in heptane). LCMS (Method 3): 2.71 min, 526.3 [M+H]. +

[0902] Intermediate 2.16: (S)-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl) tert-butyl amino-1-oxo-3,3-diphenylprop-2-yl)carbamate

[0903] From intermediate 1.16 (0.16 g, 0.69 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.24 g, 0.69 mmol, CAS: 138662-63-2), The title compound (0.12 g) was prepared by reacting triethylamine (0.29 mL, 2.07 mmol) with a 50% w / w solution in EtOAc (1.3 mL, 2.1 mmol) according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 1% MeOH in EtOAc). LCMS (Method 3): 2.49 min, 556.3 [M+H] +

[0904] Intermediate 2.17: (S)-(1-((4-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl) tert-butyl amino-1-oxo-3,3-diphenylprop-2-yl)carbamate

[0905] From intermediate 1.17 (0.19 g, 0.81 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.28 g, 0.81 mmol, CAS: 138662-63-2), The title compound (0.16 g) was prepared by reacting triethylamine (0.34 mL, 2.43 mmol) with a 50% w / w solution in EtOAc (1.6 mL, 2.4 mmol) according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 1% MeOH in EtOAc). LCMS (Method 4): 0.92 min, 556.3 [M+H] +

[0906] Intermediate 2.18: ((2S)-1-((3-fluoro-4-(3-fluoro-5-methoxypyridin-4-yl)phenyl)amino)-1-oxo tert-butyl carbamate (3,3-diphenylprop-2-yl)

[0907] From intermediate 1.18 (0.26 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.38 g, 1.1 mmol, CAS: 138662-63-2), The title compound (0.10 g) was prepared by the procedure described for intermediate 2.1 according to the method described in section 2.1: (50% w / w solution in EtOAc; 2.1 mL, 3.3 mmol) and triethylamine (0.46 mL, 3.3 mmol). The crude product was purified by rapid column chromatography (eluting with 40% EtOAc in heptane). LCMS (Method 3): 2.78 min, 560.3 [M+H). +

[0908] Intermediate 2.19: (S)-(1,1-bis(4-fluorophenyl)-3-((4-(3-methoxypyridin-4-yl)phenyl)amino)- 3-Oxopropyl-2-yl)tert-butyl carbamate

[0909] HATU (0.20 g, 0.52 mmol) was added to a stirred solution of intermediate 1,3 (0.10 g, 0.50 mmol) and (2S)-2-(tert-butoxycarbonylamino)-3,3-bis(4-fluorophenyl)propionic acid (0.19 g, 0.50 mmol, CAS: 481055-29-2) and triethylamine (0.14 mL, 1.0 mmol) in EtOAc (4 mL) at room temperature, and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution and extracted into EtOAc. The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 100% EtOAc) to provide the title compound (0.28 g). LCMS (Method 2): 0.98 min, 560.3 [M+H] +

[0910] Intermediate 2.29: (S)-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3,5-difluoro tert-butyl carbamate (phenylamino)-1-oxo-3,3-diphenylprop-2-yl)carbamate

[0911] At room temperature, a solution of intermediate 1.29 (0.10 g, 0.41 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenyl-propionic acid (0.15 g, 0.45 mmol, CAS: 138662-63-2), triethylamine (0.23 mL, 1.6 mmol), and DMAP (10 mg, 0.08 mmol) in MeCN (4 mL) was added. (50% w / w solution in EtOAc; 1.0 mL, 1.6 mmol) and the reaction mixture was stirred for 18 h. The mixture was diluted with saturated NaHCO3 aqueous solution and the crude product was extracted into EtOAc. The combined organic matter was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was analyzed by reversed-phase column chromatography in Biotage Isolera One. TM Purification (30 g C18 column, 20%–80% elution in 0.1% ammonia solution with MeCN) to provide the title compound (36 mg). LCMS (Method 3): 2.55 min, 574.2 [M + H) +

[0912] Intermediate 2.30: (S)-(1-((3,5-difluoro-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo- 3,3-Diphenylprop-2-yl)tert-butyl carbamate

[0913] From intermediate 1.30 (0.11 g, 0.47 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.17 g, 0.49 mmol, CAS: 138662-63-2) and (50% w / w solution in EtOAc; 0.42 mL, 0.70 mmol) The title compound (0.14 g) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid chromatography (eluting in heptane with 50%–100% EtOAc). LCMS (Method 4): 1.04 min, 560.3 [M+H) +

[0914] Intermediate 2.31: (S)-(1-((4-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo tert-butyl carbamate (3,3-diphenylprop-2-yl)

[0915] The title compound (0.14 g) was prepared from intermediate 1.31 (78 mg, 0.25 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (85 mg, 0.25 mmol, CAS: 138662-63-2), triethylamine (0.09 mL, 0.62 mmol), and HATU (0.11 g, 0.30 mmol) according to the procedure described for intermediate 2.19. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 10g ZIP silica column, eluted with 30%-100% EtOAc in heptane. LCMS (Method 4): 1.11 min, 60 1.4 [M+H] +

[0916] Intermediate 2.33: ((S)-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino tert-butyl carbamate (1r,4S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0917] From intermediate 1.13 (95 mg, 0.44 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (120 mg, 0.44 mmol, CAS: 1187224-06-1; prepared according to the method described in WO2020 / 011731) and (50% w / w solution in EtOAc; 0.73 mL, 1.2 mmol) The title compound (73 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 10% methanol in EtOAc). LCMS (Method 4): 0.98 min, 468.3 [M+H] +

[0918] Intermediate 2.34: (S)-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)amino)-1-oxo tert-butyl carbamate (3,3-diphenylprop-2-yl)

[0919] To a solution of intermediate 2.34 (0.13 g, 0.62 mmol), (2S)-2-(tert-butoxycarbonylamino)-3,3-diphenyl-propionic acid (0.47 g, 1.4 mmol, CAS: 138662-63-2), and DMAP (31 mg, 0.12 mmol) in DCM (3 mL) and MeCN (1.5 mL), EDCI (299 mg, 1.56 mmol) was added, and the reaction mixture was stirred at room temperature under argon for 21 h. Further addition of (2S)-2-(tert-butoxycarbonylamino)-3,3-diphenyl-propionic acid (0.23 g, 0.69 mmol) and EDCI (0.13 g, 0.69 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted into EtOAc. The organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid column chromatography (eluting with 50%–100% EtOAc in heptane) to provide the title compound (0.19 g). LCMS (Method 4): 0.89 min, 429.2 [M-Boc+H] +

[0920] Intermediate 2.35: (S)-(1-((3-fluoro-4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)amino)-1-oxo tert-butyl carbamate (3,3-diphenylprop-2-yl)

[0921] The title compound (0.19 g) was prepared from intermediate 1.35 (215 mg, 1.05 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.36 g, 1.1 mmol, CAS: 138662-63-2), triethylamine (0.16 mL, 1.2 mmol), and HATU (0.44 g, 1.2 mmol) according to the procedure described for intermediate 2.19 (except in a DMF / EtOAc (1:2) solvent mixture). The crude product was purified by rapid column chromatography (eluting with 5% MeOH in EtOAc). LCMS (Method 3): 2.30 min, 528.2 [M+H] +

[0922] Intermediate 2.36: (S)-(1-((4-(3-fluoropyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenylpropan- 2-yl)tert-butyl carbamate

[0923] From 4-(3-fluoropyridin-4-yl)aniline (0.35 g, 1.8 mmol, CAS: 928322-47-8), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.66 g, 1.8 mmol, CAS: 138662-63-2) and (50% w / w solution in EtOAc; 3.5 mL, 5.5 mmol) The title compound (0.45 g) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 1): 1.01 min, 512.3 [M+H) +

[0924] Intermediate 2.37: (S)-(1-((4-(2,5-dimethylpyrimidin-4-yl)phenyl)amino)-1-oxo-3,3-diphenyl tert-butyl propyl-2-yl)carbamate

[0925] From intermediate 1.37 (0.1 g, 0.5 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.17 g, 0.5 mmol, CAS: 138662-63-2) and (50% w / w solution in EtOAc; 0.91 mL, 1.5 mmol) The title compound (0.45 g) was prepared according to the procedure described for intermediate 2.1. The crude product was used directly without further purification. LCMS (Method 2): 0.97 min, 523.3 [M + H] +

[0926] Intermediate 2.38: (S)-(1-((4-(2,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenyl tert-butyl propyl-2-yl)carbamate

[0927] From 4-(2,5-dimethylpyridin-4-yl)aniline (52 mg, 0.26 mmol, CAS: 71153-40-7), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (90 mg, 0.26 mmol, CAS: 138662-63-2) and (50% w / w solution in EtOAc; 0.5 mL, 0.79 mmol) The title compound (46 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 8): 0.65 min, 521.9 [M+H) +

[0928] Intermediate 2.42: (S)-(1-((4-(3-(hydroxymethyl)pyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenyl tert-butyl propyl-2-yl)carbamate

[0929] The title compound (0.34 g) was prepared from intermediate 1.42 (0.28 g, 1.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.4 g, 1.2 mmol, CAS: 138662-63-2), triethylamine (0.4 mL, 2.9 mmol), and HATU (0.53 g, 1.4 mmol) according to the procedure described for intermediate 2.19. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 2): 0.88 min, 524.3 [M+H] +

[0930] Intermediate 2.43: (S)-(1-((4-(3-cyanopyridin-4-yl)phenyl)amino)-1-oxo-3,3-diphenyl propyl-2-yl) tert-butyl carbamate

[0931] From 4-(4-aminophenyl)nicotinamide (25 mg, 0.13 mmol, CAS: 2090576-40-0), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (44 mg, 0.13 mmol, CAS: 138662-63-2), triethylamine (0.04 mL, 0.32 mmol) and (50% w / w solution in EtOAc; 0.24 mL, 0.38 mmol) The title compound (66 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 2): 0.97 min, 419.2 [M-Boc+H] +

[0932] Intermediate 2.47: (S)-(1-((3-methoxy-4-(3-methoxypyridin-4-yl)phenyl)amino)-1-oxo- 3,3-Diphenylprop-2-yl)tert-butyl carbamate

[0933] From intermediate 1.47 (68 mg, 0.29 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (98 mg, 0.29 mmol, CAS: 138662-63-2), triethylamine (0.1 mL, 0.71 mmol) and (50% w / w solution in EtOAc; 0.55 mL, 0.86 mmol) The title compound (75 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was used directly without further purification. LCMS (Method 2): 0.96 min, 554.3 [M+H]+

[0934] Intermediate 2.48: (S)-(1-((3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)phenyl)amino tert-butyl carbamate (1-(2 ...

[0935] From intermediate 1.48 (0.15 g, 0.67 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.24 g, 0.70 mmol, CAS: 138662-63-2), triethylamine (0.28 mL, 2.0 mmol) and (50% w / w solution in EtOAc; 0.59 mL, 1.0 mmol) The title compound (0.21 g) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 4): 0.96 min, 543.2 [M+H) +

[0936] Intermediate 2.49: (S)-(1-oxo-1-((4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-3, 3-Diphenylprop-2-yl)tert-butyl carbamate

[0937] From 5-(4-aminophenyl)pyridin-2(1H)-one (87 mg, 0.47 mmol, CAS: 1159819-58-5), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.16 g, 0.47 mmol, CAS: 138662-63-2), triethylamine (0.04 mL, 0.32 mmol) and (50% w / w solution in EtOAc; 0.89 mL, 1.4 mmol) The title compound (52 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage IsoleraOne. TM Purification was performed using a 30g ZIP column with silica beads, in heptane with 40%–100% EtOAc, followed by elution with 5% MeOH in EtOAc. LCMS (Method 2): 0.84 min, 510.3 [M+H] +

[0938] Intermediate 2.50: (S)-(1-((4-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1- 3,3-diphenylprop-2-yl) tert-butyl carbamate

[0939] From 5-(4-aminophenyl)-4-methylpyridin-2(1H)-one (0.1 g, 0.51 mmol, CAS: 1258623-31-2), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.18 g, 0.51 mmol, CAS: 138662-63-2), triethylamine (0.18 mL, 1.3 mmol) and (50% w / w solution in EtOAc; 0.98 mL, 1.5 mmol) The title compound (35 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30 g ZIP column with silica beads, eluted with 60%–100% EtOAc in heptane, followed by elution with 7% MeOH in EtOAc. LCMS (Method 2): 0.86 min, 524.9 [M + H2]. +

[0940] Intermediate 2.51: (S)-(1-((4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)amino)-1- 3,3-diphenylprop-2-yl) tert-butyl carbamate

[0941] From intermediate 1.51 (0.18 g, 0.91 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.31 g, 0.91 mmol, CAS: 138662-63-2), triethylamine (0.32 mL, 2.3 mmol) and (50% w / w solution in EtOAc; 1.74 mL, 2.7 mmol) The title compound (0.46 g) was prepared according to the procedure described for intermediate 2.1. The crude product was used directly. LCMS (Method 2): 0.88 min, 524.3 [M+H] +

[0942] Intermediate 2.52: (S)-(1-oxo-1-((4-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4- 3,3-diphenylprop-2-yl)carbamate tert-butyl

[0943] The title compound (0.13 mg) was prepared from intermediate 1.52 (0.1 g, 0.44 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.18 mg, 0.53 mmol, CAS: 138662-63-2), triethylamine (0.21 mL, 1.5 mmol), and HATU (0.2 g, 0.53 mmol) according to the procedure described for intermediate 2.19 (except that DMF was used instead of EtOAc as the solvent). The crude product was purified by rapid column chromatography (eluting in 4% MeOH in EtOAc). LCMS (Method 3): 2.38 min, 549.3 [M+H] +

[0944] Intermediate 2.53: (S)-(1-((4-(3-(hydroxymethyl)pyridin-4-yl)-3-methoxyphenyl)amino)-1-oxo tert-butyl carbamate (3,3-diphenylprop-2-yl)

[0945] The title compound (38 mg) was prepared from intermediate 1.53 (51 mg, 0.17 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (68 mg, 0.20 mmol, CAS: 138662-63-2), DIPEA (0.12 mL, 0.67 mmol), and HATU (76 mg, 0.20 mmol) according to the procedure described for intermediate 2.19 (except in an EtOAc / MeCN (2:1) solvent mixture). The crude product was purified by rapid column chromatography (eluting with 10% MeOH in DCM). LCMS (Method 2): 0.88 min, 554.3 [M+H] +

[0946] Intermediate 2.54: (S)-(1-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(trifluoromethyl) tert-butyl carbamate (1-(2 ...

[0947] From intermediate 1.54 (0.1 g, 0.38 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.14 g, 0.39 mmol, CAS: 138662-63-2), triethylamine (0.28 mL, 2.0 mmol) and (50% w / w solution in EtOAc; 0.59 mL, 2.0 mmol) The title compound (56 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 100% EtOAc). LCMS (Method 4): 0.99 min, 606.3 [M+H] +

[0948] Intermediate 2.55: (S)-(1-((3-chloro-4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-1-oxo-3, 3-Diphenylprop-2-yl)tert-butyl carbamate

[0949] From intermediate 1.55 (0.11 g, 0.47 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.16 g, 0.47 mmol, CAS: 138662-63-2), triethylamine (0.2 mL, 1.4 mmol) and (50% w / w solution in EtOAc; 0.9 mL, 1.4 mmol) The title compound (65 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 0-50% EtOAc in heptane. LCMS (Method 4): 1.08 min, 556.3 [M+H] +

[0950] Intermediate 2.56: (S)-(1-((4-(2,5-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3, 3-Diphenylprop-2-yl)tert-butyl carbamate

[0951] From intermediate 1.56 (0.15 g, 0.69 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.24 g, 0.69 mmol, CAS: 138662-63-2), triethylamine (0.29 mL, 2.1 mmol) and (50% w / w solution in EtOAc; 1.3 mL, 2.1 mmol) The title compound (0.1 g) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 50% EtOAc in heptane). LCMS (Method 4): 1.06 min, 540.3 [M+H) +

[0952] Intermediate 2.57: (S)-(1-((4-(2,3-dimethylpyridin-4-yl)-3-fluorophenyl)amino)-1-oxo-3, 3-Diphenylprop-2-yl)tert-butyl carbamate

[0953] From intermediate 1.57 (0.11 g, 0.51 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.17 g, 0.51 mmol, CAS: 138662-63-2), triethylamine (0.21 mL, 1.5 mmol) and (50% w / w solution in EtOAc; 0.97 mL, 1.5 mmol) The title compound (0.12 g) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 70% EtOAc in heptane). LCMS (Method 3): 2.80 min, 540.3 [M+H) +

[0954] Intermediate 2.59: (S)-(1-((4-(1-benzyl-5-methyl-1H-pyrazol-4-yl)-3-fluorophenyl)amino)-1- 3,3-diphenylprop-2-yl) tert-butyl carbamate

[0955] From intermediate 1.59 (0.25 mg, 0.89 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.3 g, 0.88 mmol, CAS: 138662-63-2) and (50% w / w solution in EtOAc; 1.7 mL, 2.7 mmol) The title compound (0.28 g) was prepared as a mixture of positional isomers of (S)-(1-((4-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-3-fluorophenyl)amino)-1-oxo-3,3-diphenylprop-2-yl)carbamate tert-butyl ester according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TMPurification was performed using a 25g SiliCycle silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 1.12 min, 605.3 [M+H] +

[0956] Intermediate 2.60: (S)-(1-((4-(3,5-dimethylisoxazol-4-yl)-3-fluorophenyl)amino)-1-oxo- 3,3-Diphenylprop-2-yl)tert-butyl carbamate

[0957] From intermediate 1.60 (0.15 g, 0.75 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.27 g, 0.79 mmol, CAS: 138662-63-2), triethylamine (0.31 mL, 2.2 mmol) and (50% w / w solution in EtOAc; 1.3 mL, 2.2 mmol) The title compound (0.22 g) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 25% EtOAc in heptane). LCMS (Method 4): 1.08 min, 430.2 [M-Boc+H) +

[0958] Intermediate 2.62: (S)-(1-((4-(1-benzyl-1H-pyrazole-4-yl)-3-fluorophenyl)amino)-1-oxo-3, 3-Diphenylprop-2-yl)tert-butyl carbamate

[0959] From intermediate 1.62 (240 mg, 0.83 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (282 mg, 0.83 mmol, CAS: 138662-63-2), triethylamine (0.35 mL, 2.48 mmol) and (50% w / w solution in EtOAc; 1.58 mL, 2.48 mmol) The title compound (65 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 1.11 min, 591.3 [M+H] +

[0960] Intermediate 2.63: (S)-(1-((3-fluoro-4-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino tert-butyl carbamate (1-(2 ...

[0961] The title compound (64 mg) was prepared from intermediate 2.63 (95 mg, 0.43 mmol), (2S)-2-(tert-butoxycarbonylamino)-3,3-diphenyl-propionic acid (0.52 g, 1.5 mmol, CAS: 138662-63-2), DMAP (11 mg, 0.09 mmol), and EDCI (0.29 g, 1.5 mmol) according to the procedure described for intermediate 2.34. The crude product was subjected to reversed-phase chromatography in Biotage Isolera One. TM Purification was performed using a 60g C18 column, eluted with 15%–65% MeCN in 0.1% pH 10 0.1M NH4HCO3 buffer. LCMS (Method 3): 2.27 min, 543.2 [M + H2]. +

[0962] Intermediate 2.64: (S)-(1-((3-fluoro-4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl)amino)-1-oxo tert-butyl carbamate (3,3-diphenylprop-2-yl)

[0963] From intermediate 1.64 (0.26 g, 1.3 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.48 g, 1.4 mmol, CAS: 138662-63-2), triethylamine (0.53 mL, 3.8 mmol) and (50% w / w solution in EtOAc; 2.3 mL, 3.8 mmol) The title compound (0.14 g) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using an 80g ZIP column with silica beads, eluted with 0-10% MeOH in DCM. LCMS (Method 3): 1.72 min, 529.2 [M+H] +

[0964] Intermediate 2.66: (S)-(1-((3-fluoro-4-(5-oxo-5,6-dihydro-1,6-naphthid-8-yl)phenyl)amino)- 1-O-3,3-diphenylprop-2-yl)tert-butyl carbamate

[0965] From intermediate 1.66 (0.47 g, 1.9 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.66 g, 1.9 mmol, CAS: 138662-63-2), triethylamine (0.77 mL, 5.5 mmol) and (50% w / w solution in EtOAc; 3.3 mL, 5.5 mmol) The title compound (88 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TMPurification was performed using a 45g ZIP silica column, eluted with 50%-100% EtOAc in heptane. LCMS (Method 4): 0.93 min, 579.3 [M+H] +

[0966] Intermediate 2.67: (S)-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)amino)-1-oxo tert-butyl carbamate (3,3-diphenylprop-2-yl)

[0967] BTFFH (0.51 g, 1.6 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.48 g, 1.4 mmol, CAS: 138662-63-2) and DIPEA (0.83 mL, 4.8 mmol) in 1,2-dichloroethane (4.2 mL), and the reaction mixture was stirred at room temperature under argon for 1 h. Intermediate 1.67 (0.22 g, 1.1 mmol) was added, and the reaction mixture was heated at 80 °C for 6 h. 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 purified by rapid column chromatography (eluting with 100% EtOAc) and then by automated reversed-phase column chromatography in Biotage Isolera One. TM Purification (60 g C18 column, 0-80% 0.1% ammonia / MeCN / H2O elution in 0.1% ammonia at pH 11) yielded the title compound (0.23 g). LCMS (Method 4): 0.88 min, 529.2 [M+H2O] +

[0968] Intermediate 2.68: (S)-(1-((3-fluoro-4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl) tert-butyl amino-1-oxo-3,3-diphenylprop-2-yl)carbamate

[0969] From intermediate 1.68 (0.56 g, 2.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.74 g, 2.2 mmol, CAS: 138662-63-2), triethylamine (0.91 mL, 6.53 mmol) and (50% w / w solution in EtOAc; 4.2 mL, 6.5 mmol) The title compound (0.43 g) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 45% ethyl acetate in heptane). LCMS (Method 4): 1.03 min, 581.3 [M+H) +

[0970] Intermediate 2.69: (S)-(1-((3-fluoro-4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridine-7- tert-butyl carbamate (1-(2 ...

[0971] From intermediate 1.69 (0.24 g, 0.96 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.35 g, 1.0 mmol, CAS: 138662-63-2), triethylamine (0.4 mL, 2.9 mmol) and (50% w / w solution in EtOAc; 1.7 mL, 2.9 mmol) The title compound (0.14 g) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to automated reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 60g C18 column, eluted with 0-95% MeCN containing 0.1% formic acid in water containing 0.1% formic acid. LCMS (Method 13): 2.10 min, 568.2 [M+H] +

[0972] Intermediate 2.71: (S)-(1-((3-fluoro-4-(5-oxo-5,6-dihydro-1,6-naphthid-8-yl)phenyl)amino)- 1-O-3,3-diphenylprop-2-yl)tert-butyl carbamate

[0973] From intermediate 1.71 (0.19 g, 0.86 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.29 g, 0.86 mmol, CAS: 138662-63-2), triethylamine (0.36 mL, 2.6 mmol) and (50% w / w solution in EtOAc; 1.64 mL, 2.6 mmol) The title compound (98 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 0.94 min, 542.2 [M+H] +

[0974] Intermediate 2.72: (S)-(1-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6- tert-butyl carbamate (amino)-1-oxo-3,3-diphenylprop-2-yl)carbamate

[0975] The title compound (20 mg) was prepared from intermediate 1.72 (39 mg, 0.18 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (80 mg, 0.24 mmol, CAS: 138662-63-2), DIPEA (0.14 mL, 0.82 mmol), and BTFFH (86 mg, 0.27 mmol) according to the procedure described for intermediate 2.67. The crude product was subjected to automated reversed-phase column chromatography in Biotage Isolera One. TMPurification was performed using a 30g C18 column (MeCN / H2O in 0.1% ammonia at pH 11). LCMS (Method 4): 0.90 min, 539.2 [M+H2O] +

[0976] Intermediate 2.73: (S)-(1-((3',5'-dimethyl-[3,4'-bipyridin]-6-yl)amino)-1-oxo-3,3- Diphenylpropyl-2-yl)tert-butyl carbamate

[0977] The title compound (0.18 g) was prepared from intermediate 1.73 (0.23 g, 1.1 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.5 g, 1.5 mmol, CAS: 138662-63-2), DIPEA (0.89 mL, 5.1 mmol), and BTFFH (0.54 g, 1.7 mmol) according to the procedure described for intermediate 2.67. The crude product was subjected to automated reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 1.01 min, 523.2 [M+H] +

[0978] Intermediate 2.74: (S)-(1-((4-(1-benzyl-5-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-oxo- 3,3-Diphenylprop-2-yl)tert-butyl carbamate

[0979] From intermediate 1.74 (0.57 g, 2.2 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.74 g, 2.2 mmol, CAS: 138662-63-2), triethylamine (0.9 mL, 6.5 mmol) and (50% w / w solution in EtOAc; 4.1 mL, 6.5 mmol) The title compound (0.67 g) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 30g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 1.08 min, 587.3 [M+H] +

[0980] Intermediate 2.75: (S)-(1-((3-fluoro-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyrazol) 4-Pyridine-phenyl-amino-1-oxo-3,3-diphenylprop-2-yl)carbamate tert-butyl ester

[0981] The title compound (83 mg) was prepared from intermediate 1.75 (0.1 g, 0.39 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.14 g, 0.41 mmol, CAS: 138662-63-2), triethylamine (0.17 mL, 1.2 mmol), and HATU (0.22 g, 0.56 mmol) according to the procedure described for intermediate 2.19 (except for the use of DMF as solvent). The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g ZIP silica column, eluted with 50%-100% EtOAc in heptane. LCMS (Method 4): 0.92 min, 582.3 [M+H] +

[0982] Intermediate 2.76: (S)-(1-((4-(7-methoxy-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)amino)- 1-O-3,3-diphenylprop-2-yl)tert-butyl carbamate

[0983] From intermediate 1.76 (0.21 g, 0.84 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.29 g, 0.84 mmol, CAS: 138662-63-2), triethylamine (0.35 mL, 2.5 mmol) and (50% w / w solution in EtOAc; 1.6 mL, 2.5 mmol) The title compound (0.2 g) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g ZIP silica column, eluted with 40%-100% EtOAc in heptane. LCMS (Method 4): 1.01 min, 563.3 [M+H] +

[0984] Intermediate 2.77: (S)-(1-((4-(1-benzyl-6-oxo-1,6-dihydropyridin-2-yl)-3-fluorophenyl)amino tert-butyl carbamate (1-(2 ...

[0985] From intermediate 1.77 (0.18 g, 0.57 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.19 g, 0.57 mmol, CAS: 138662-63-2), triethylamine (0.24 mL, 1.7 mmol) and (50% w / w solution in EtOAc; 1.1 mL, 1.7 mmol) The title compound (86 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TMPurification was performed using a 30 g ZIP silica column, eluted with 30%–100% EtOAc in heptane. LCMS (Method 20): 1.01 min, 618.3 [M + H2]. +

[0986] Intermediate 2.78: (S)-(1-oxo-1-((4-(3-(2-oxo-2-(pyrrolidine-1-yl)ethyl)pyridine-4- 3,3-diphenylprop-2-yl)carbamate tert-butyl

[0987] From intermediate 1.78 (89 mg, 0.32 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.11 g, 0.33 mmol, CAS: 138662-63-2), triethylamine (0.13 mL, 0.95 mmol) and (50% w / w solution in EtOAc; 0.6 mL, 0.95 mmol) The title compound (61 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 12g ZIP silica column, eluted with 0-20% MeOH in EtOAc. LCMS (Method 4): 1.18 min, 605.4 [M+H] +

[0988] Intermediate 2.80: (S)-(1-((3-fluoro-4-(6-oxo-1,6-dihydropyrimidin-4-yl)phenyl)amino)-1-oxo tert-butyl carbamate (3,3-diphenylprop-2-yl)

[0989] The title compound (75 mg) was prepared from intermediate 1.80 (80 mg, 0.39 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.13 g, 0.39 mmol, CAS: 138662-63-2), DIPEA (0.15 g, 1.2 mmol), and BTFFH (0.19 g, 0.58 mmol) according to the procedure described for intermediate 2.67. The crude product was subjected to automated reversed-phase column chromatography in Biotage Isolera One. TM Purification (30g C18 column, elution with 10%-50% 0.1% ammonia / MeCN / H2O in 0.1% ammonia at pH 11). LCMS (Method 3): 1.65 min, 529.2 [M+H2O] +

[0990] Intermediate 2.81: (S)-(1-((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-oxo-3,3-di tert-butyl phenylprop-2-yl)carbamate

[0991] From 4-(3,6-dihydro-2H-pyran-4-yl)aniline (0.1 g, 0.57 mmol, CAS: 1039053-21-8), (S)-2-((tert-butoxycarbonyl)amino)-3,3-diphenylpropionic acid (0.2 g, 0.57 mmol, CAS: 138662-63-2), triethylamine (0.24 mL, 1.7 mmol) and (50% w / w solution in EtOAc; 1.1 mL, 1.7 mmol) The title compound (0.23 g) was prepared according to the procedure described for intermediate 2.1. The crude product was used directly without further purification. LCMS (Method 4): 1.04 min, 399.3 [M-Boc+H] +

[0992] Intermediate 2.83: ((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

[0993] From intermediate 1.16 (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 (50% w / w solution in EtOAc; 2.5 mL, 3.9 mmol) The title compound (71 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to automated reversed-phase column chromatography in Biotage Isolera One. TM Purification was performed using a 60g C18 column (MeCN / H2O in 0.1% ammonia at pH 11). LCMS (Method 4): 1.06 min, 486.2 [M+H] +

[0994] Intermediate 2.84: ((S)-2-((4-(1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl) tert-butyl amino(1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[0995] The title compound (0.6 g) was prepared from intermediate 1.84 (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 2.19 (except in an EtOAc / MeCN (2:1) solvent mixture). The crude product was subjected to rapid column chromatography in Biotage Isolera One. TMPurification was performed using a 20g ZIP silica column, eluted with 20%-100% EtOAc in heptane. LCMS (Method 16): 3.12 min, 561.2 [M+H] +

[0996] Intermediate 2.85: ((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

[0997] The title compound (0.12 g) was prepared from intermediate 1.52 (86 mg, 0.38 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.1 g, 0.38 mmol, CAS: 1187224-06-1), HATU (0.52 g, 1.4 mmol), and triethylamine (0.48 mL, 3.4 mmol) according to the procedure described for intermediate 2.19 (except in DMF as solvent). The crude product was purified by rapid column chromatography (eluting with 5% MeOH in DCM). LCMS (Method 3): 2.39 min, 479.3 [M+H] +

[0998] Intermediate 2.86: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(3-(2-oxo-2- (pyrrolidone-1-yl)ethyl)pyridin-4-yl)phenyl)amino)ethyl)tert-butyl carbamate

[0999] 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 (50% w / w solution in EtOAc; 0.53 mL, 0.89 mmol) The title compound (98 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was purified by rapid column chromatography (eluting with 10%–20% MeOH in EtOAc). LCMS (Method 4): 0.97 min, 535.3 [M+H) +

[1000] Intermediate 2.87: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(2-oxo-1,2-di) tert-butyl hydropyridine-4-yl)phenyl)amino)ethyl)carbamate

[1001] The title compound (49 mg) was prepared from intermediate 1.87 (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 2.19 (except in DMF as solvent). 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] +

[1002] Intermediate 2.88: ((S)-2-((4-(imidazo[1,2-a]pyridin-5-yl)phenyl)amino)-1-((1r,4S)- 4-Methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[1003] From intermediate 1.88 (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 (50% w / w solution in EtOAc; 0.53 mL, 0.89 mmol) The title compound (49 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g Silicycle silica column, eluted with 30%-100% EtOAc in heptane. LCMS (Method 4): 1.03 min, 463.3 [M+H] +

[1004] Intermediate 2.89: ((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

[1005] The title compound (18 mg) was prepared from intermediate 1.72 (78 mg, 0.36 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.13 g, 0.47 mmol, CAS: 1187224-06-1), DIPEA (0.28 mL, 1.6 mmol), and BTFFH (0.17 g, 0.54 mmol) according to the procedure described for intermediate 2.67. The crude product was subjected to automated reversed-phase column chromatography in Biotage Isolera One. TMPurification (30g C18 column, elution with 5%–85% MeCN in 0.1% ammonia / MeCN / H2O in 0.1% ammonia at pH 11). LCMS (Method 4): 0.95 min, 469.3 [M+H2O] +

[1006] Intermediate 2.90: ((S)-2-((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-((1r,4S)- 4-Methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[1007] The title compound (60 mg) was prepared from intermediate 1.73 (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 2.67. 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] +

[1008] Intermediate 2.93: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(tetrahydro-2H-pyran- 4-yl)phenyl)amino)ethyl)tert-butyl carbamate

[1009] 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) according to the procedure described for intermediate 2.19 (except in an EtOAc / MeCN (2:1) solvent mixture). The crude product was used directly. LCMS (Method 12): 2.83 min, 331.2 [M-Boc+H] +

[1010] Intermediate 2.94: ((S)-2-((4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)- 4-Methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[1011] 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 (50% w / w solution in EtOAc; 0.5 mL, 0.79 mmol) The title compound (93 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was used directly without further purification. LCMS (Method 4): 0.94 min, 347.0 [M-Boc+H] +

[1012] Intermediate 2.95: ((S)-2-((4-(3,6-dihydro-2H-pyran-4-yl)phenyl)amino)-1-((1r,4S)-4- tert-butyl methylcyclohexyl-2-oxoethyl)carbamate

[1013] From intermediate 1.81 (0.1 g, 0.57 mmol) 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 (50% w / w solution in EtOAc; 1.1 mL, 1.7 mmol) The title compound (65 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 25g Silicycle silica column, eluted with 10%-100% EtOAc in heptane. LCMS (Method 4): 1.10 min, 329.2 [M-Boc+H] +

[1014] Intermediate 2.96: ((S)-2-((4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-((1r,4S)-4- tert-butyl methylcyclohexyl-2-oxoethyl)carbamate

[1015] 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 (50% w / w solution in EtOAc; 0.5 mL, 0.84 mmol) The title compound (84 mg) was prepared according to the procedure described for intermediate 2.1. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification (4g silica column, eluted with 0-25% EtOAc in heptane). 1 H 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).

[1016] Intermediate 2.97: ((S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1r, 4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[1017] 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) under an argon atmosphere. 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 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] +

[1018] Intermediate 2.99: ((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

[1019] The title compound (39 mg) was prepared from intermediate 1.99 (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 2.97. Another portion of EEDQ (60 mg, 0.24 mmol) was added and the mixture was stirred for another 24 h, followed by post-processing. The crude product was purified by rapid column chromatography (4 g silica column, eluted with 0-25% EtOAc in heptane). LCMS (Method 14): 2.09 min, 562.2 [M+H] +

[1020] Intermediate 2.106: ((S)-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)-1- ((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[1021] The title compound (19 mg) was prepared from intermediate 1.106 (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 2.97. The crude product was purified by rapid column chromatography (5 g silica column, eluted with 20%–80% EtOAc in heptane). LCMS (Method 14): 1.99 min, 442.2 [M+H] +

[1022] Intermediate 2.108: (S)-(1-cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino tert-butyl 2-oxoethyl carbamate

[1023] The title compound (67 mg) was prepared from 5-(3,5-dimethylisoxazol-4-yl)pyridin-2-amine (0.11 g, 0.58 mmol, CAS: 1177269-12-3) and (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetic acid (0.15 g, 0.58 mmol, CAS: 109183-71-3) by heating at 90 °C for 16 h according to the procedure described for intermediate 2.97 (except for the use of IIDQ (0.35 g, 1.2 mmol) and DIPEA (0.41 mL, 2.3 mmol)). The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 12 g silica column, eluting with 0-100% EtOAc in heptane. LCMS (Method 14): 1.99 min, 429.2 [M+H] +

[1024] Intermediate 2.115: (S)-(1-cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino tert-butyl 2-oxoethyl carbamate

[1025] 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 2.97. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 40 g silica column, eluted with 0-3% MeOH in DCM. LCMS (Method 14): 2.00 min, 443.2 [M + H₂] +

[1026] Intermediate 2.119: (S)-(1-cyclohexyl-2-((4-(1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl) tert-butyl phenylamino)-2-oxoethyl)carbamate

[1027] The title compound (0.28 g) was prepared from intermediate 1.119 (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 2.19 (except in DMF as solvent). The crude product was used directly. LCMS: (Method 14) 1.75 min, 454.2 [M+H] +

[1028] Intermediate 2.125: ((S)-2-((5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino tert-butyl carbamate (1r,4S)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)carbamate

[1029] Under an argon atmosphere, intermediate 1.125 (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) were added with stirring and DIPEA (0.15 g, 1.1 mmol) and HATU (0.3 g, 0.79 mmol). The mixture was heated at 50 °C for 44 h. The reaction mixture was diluted with MeOH (1 mL) and then analyzed by reversed-phase column chromatography in Biotage Isolera One. TMPurification was performed using a 30g KP-C18_HS Biotage SNAP column, eluted with 5%–100% MeCN (containing 0.005M NH4OH) in aqueous buffer to provide the title compound (35 mg). LCMS: (Method 14) 1.83 min, 443.3 [M+H] + .

[1030] An alternative route to obtain intermediate 2.125: ((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 Intermediate 2.125a: ((S)-2-amino-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[1031] 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 ground in DCM to provide the title compound (0.85 g). 1 HNMR(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).

[1032] Intermediate 2.125: ((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

[1033] Xantphos (58 mg, 0.1 mmol) and Cs₂CO₃ (0.98 g, 3 mmol) were added to a suspension of intermediates 1.125a (0.3 g, 1.5 mmol) and 2.125a (0.27 g, 1.0 mmol) in degassed anhydrous 1,4-dioxane (14 mL). The mixture was degassed with argon for 5 min, then tris(dibenzylacetone)dipalladium(0) (46 mg, 0.05 mmol) was added and degassed for 5 min. The vial was sealed and the reaction mixture was heated to 100 °C for 18 h. The mixture was diluted with EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organics were dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification (20 g silica, 30%-100% EtOAc in heptane) was performed to give the title compound (0.12 g). 1 H 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).

[1034] Intermediate 2.132: (S)-(1-cycloheptyl-2-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)amino tert-butyl 2-oxoethyl carbamate

[1035] HATU (0.83 mg, 2.2 mmol) was added to a solution of intermediate 1.106 (0.62 g, 3.3 mmol), (2S)-2-(tert-butoxycarbonylamino)-2-cycloheptayl-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) under an argon atmosphere. The mixture was heated at 50 °C for 24 h. The mixture was partitioned between EtOAc and water, and the aqueous solution 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 rapid column chromatography in Biotage Isolera One. TM Purification (40 g silica column, eluted with 0-50% EtOAc in heptane) was performed to provide the title compound (0.28 g). LCMS: (Method 14): 1.85 min, 442.2 [M+H) +

[1036] Intermediate 2.135: ((S)-2-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)amino)-1-((1r, 4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[1037] The title compound (0.24 g) was prepared from 2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-amine (0.2 g, 1 mmol, CAS: 1094246-50-0), (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid (0.15 g, 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 2.132. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 10 g silica column, eluted with 30% EtOAc in heptane. LCMS (Method 14): 1.88 min, 444.2 [M+H] +

[1038] Intermediate 2.138: ((S)-2-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)amino)-1-((1r, 4S)-4-methylcyclohexyl)-2-oxoethyl)tert-butyl carbamate

[1039] The title compound (0.13 g) was prepared from intermediate 1.138 (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 2.132. The crude product was subjected to rapid column chromatography in Biotage Isolera One. TM Purification was performed using a 10 g silica column, eluted with 30% EtOAc in heptane. LCMS (Method 14): 1.93 min, 443.2 [M+H] +

[1040] Intermediate 2.140: ((S)-1-((1r,4S)-4-methylcyclohexyl)-2-((5-(5-methylpyrimidin-4-yl)pyridine) tert-butyl 2-(pyridyl)amino)2-oxoethyl)carbamate

[1041] The title compound (0.14 g) was prepared from intermediate 1.140 (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...

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 are CR 5 And the other one 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 1-3 Alkyl and C 1-2 Halogenated alkyl groups; R 1 and R 2 : (A) are all phenyl groups optionally substituted with one or more fluorine atoms; or (B) Together with the carbon atoms to which they are attached, they form groups selected from the following: , , and , Where * represents R 1 and R 2 The attached carbon atom, each R that appears 17 It is independently selected from fluorine, methyl, trifluoromethyl and methoxy, and m is 0, 1 or 2; R 3 It is hydrogen; R 4 Selected from one of the following groups: ， 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, then 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 1 and R 2 Together with the carbon atoms to which they are attached, they form groups selected from the following: ， Where * represents R 1 and R 2 The attached carbon atom, each R that appears 17 It is independently selected from fluorine and methyl, and m is 0, 1 or 2.

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: ， Where * represents R 1 and R 2 The attached carbon atoms, and each R 17 It is independently selected from hydrogen, fluorine, methyl, and trifluoromethyl.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from the following groups: ， 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, then each R 18 Substituents may be present on either ring of the bicyclic group.

7. The compound of claim 6 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 As defined in claim 1; each R 17 Independently selected from fluorine, methyl, and trifluoromethyl; R 20 and R 21 It is independently selected from hydrogen, fluorine, methyl and trifluoromethyl; and m is 0, 1 or 2.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 20 and R 21 It is independently selected from hydrogen, fluorine, methyl and trifluoromethyl; and m is 0.

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R 5 It is hydrogen.

11. A compound selected from: (S)-N-(1-((1',2'-dimethyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridine]-6-yl)amino)-1-oxo-3,3-diphenylprop-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-N-(1-((3',5'-dimethyl-[3,4'-bipyridine]-6-yl)amino)-1-oxo-3,3-diphenylprop-2-yl)-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-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-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamyl)-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]hept-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 (Non-4-yl)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide; Or its pharmaceutically acceptable salt.

12. A pharmaceutical composition comprising a compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

13. Use of the compound of claim 1 or 11 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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